JM Wit | Leiden University (original) (raw)
Papers by JM Wit
Journal of Pediatric Endocrinology and Metabolism, 2009
Background: Premature thelarche is defined as breast development before 8 years of age. This is m... more Background: Premature thelarche is defined as breast development before 8 years of age. This is most often caused by central hormone disregulation and is accompanied by concurrent bone maturation. However, we present a case of premature thelarche with concurrent bone maturation without central hormone disregulation. Genes within the estrogen signaling pathway were examined for genetic changes which might be responsible for the clinical phenotype. Patient report: A girl presented with breast development from 18 months of age with undetectable serum estrogens, prepubertal serum gonadotropins, advanced growth and skeletal maturation, but no increase of uterine size, thus presenting a premature thelarche variant. Serum estrogens remained below detectable limits until she entered into an unremarkable puberty at 12.1 years of age. No abnormalities or SNPs were found in the genes tested. Conclusion: We describe a case of premature thelarche which cannot be attributed to a central cause of abnormal hormone levels or to alterations in genes suspected for this phenotype. We conclude that other yet to be identified factors are involved in this unique case of premature thelarche.
Nederlands tijdschrift voor geneeskunde, Jan 5, 1992
Bone, 2002
In this study, we investigate the expression of the androgen receptor (AR) in the tibial growth p... more In this study, we investigate the expression of the androgen receptor (AR) in the tibial growth plate and metaphyseal bone of male and female rats at the mRNA and protein level. Using in situ hybridization and immunohistochemistry, AR mRNA and protein were demonstrated in proliferating and early hypertrophic chondrocytes in the growth plate of 1-, 4-, and 7-week-old male and female rats. Immunostaining for AR was observed both in the nucleus and the cytoplasm. After sexual maturation at 12 and 16 weeks of age, AR expression decreased in both genders and was confined to a small rim of prehypertrophic chondrocytes. In female rats of 40 weeks of age, this expression pattern was still visible. In most age groups there was a tendency toward an increased AR mRNA expression in male vs. female rats except in the 7-week-old animals. At the protein level, sexually maturing 7-week-old male rats demonstrated a higher staining intensity compared to their female counterparts. At this stage, AR staining in the males was mainly confined to the nucleus, whereas in females staining was predominantly found in the cytoplasm. In the tibial metaphysis, AR mRNA was detected in lining cells, osteoblasts, osteocytes, and osteoclasts at all stages of development. At the protein level, a similar expression pattern was observed, except for an absence of immunostaining in the lining cells. The staining was both nuclear and cytoplasmic. In most age groups, mRNA and protein signals were higher in males compared with females. We have demonstrated the presence of AR mRNA and protein in the tibial growth plate and the underlying metaphyseal bone during development of the rat. In male rats, the presence of higher messenger and protein staining intensities, as well as preferential nuclear staining during sexual maturation, suggests that direct actions of androgens in chondrocytes and in bone forming cells may be involved in establishing the gender differences in the skeleton.
Hormone Research, 1989
Four out of 10 children in two unrelated families presented with a total pituitary growth hormone... more Four out of 10 children in two unrelated families presented with a total pituitary growth hormone (GH) and prolactin deficiency and a partial thyrotropin (TSH) deficiency. The GH gene was intact in family I. The pituitaries, visualized by magnetic resonance imaging, were normal. All children responded well to GH and L-thyroxine therapy. Baseline plasma somatostatin and its peak response to arginine infusion were elevated in family I and they had a milder TSH deficiency than family II. Plasma insulin showed a poor response to arginine infusion. This hereditary combination of pituitary deficiencies suggests a deficiency of a common positive transcription factor.
Nederlands tijdschrift voor geneeskunde, Jan 21, 1991
Nederlands tijdschrift voor geneeskunde, Jan 29, 1991
Journal of pediatric endocrinology & metabolism : JPEM, 2001
It is well established that estrogen is essential for statural growth during puberty, but until r... more 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 character...
Nederlands tijdschrift voor geneeskunde, Jan 3, 1998
Drugs research in children entails a number of problems: medical-ethical, pharmacological (owing ... more Drugs research in children entails a number of problems: medical-ethical, pharmacological (owing to the immaturity of the organs and the growth and development of the child) and financial (because children do not use many drugs). Consequently, children are exposed to insufficiently tested drugs and new therapeutic possibilities are withheld from them. Currently, little clinical drugs research in children is being carried out, but this is about to change. By now, European guidelines have been drawn up for the performance of clinical drugs trials according the 'good clinical practice' standards in children. In the Netherlands, a cooperative body has been set up (the Pediatric Pharmacology Network), which is to promote and coordinate paediatric pharmacological research in according with these guidelines.
Quality of Life Research, 2000
The 43-item TNO-AZL Preschool Children Quality of Life (TAPQOL) questionnaire was developed to me... more 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
Quality of Life Research, 1998
This study evaluates the agreement between child and parent reports on children's health-related ... more This study evaluates the agreement between child and parent reports on children's health-related quality of life (HRQoL) in a representative sample of 1,105 Dutch children (age 8-11 years old). Both children and their parents completed a 56 item questionnaire (TACQOL). The questionnaire contains seven eight-item scales: physical complaints, motor functioning, autonomy, cognitive functioning, social functioning, positive emotions and negative emotions. The Pearson correlations between the child and parent reports were between 0.44 and 0.61 (p < 0.001). The intraclass correlations were between 0.39 and 0.62. On average, the children reported a significantly lower HRQoL than their parents on the physical complaints, motor functioning, autonomy, cognitive functioning and positive emotions scales (paired t-test: p < 0.05). Agreement on all of the scales was related to the magnitude of the HRQoL scores and to some background variables (gender, age, temporary illness and visiting a physician). According to multitrait-multimethod analyses, both the child and parent reports proved to be valid.
Arthritis and Rheumatism, 2012
Objective: The development of osteoarthritis may be caused by activation of hypertrophic differen... more Objective: The development of osteoarthritis may be caused by activation of hypertrophic differentiation of articular chondrocytes. Healthy articular cartilage is highly resistant to hypertrophic differentiation, in contrast to other hyaline cartilage subtypes such as growth-plate cartilage. In this study, we set out to elucidate the molecular mechanism responsible for the difference in propensity to undergo hypertrophic differentiation between human articular and growth plate cartilage. Methods: Whole genome gene expression micro-array analysis of healthy human growth-plate and articular cartilage derived from the same adolescent donors was performed. Candidate genes, enriched in articular cartilage, were validated at the mRNA and protein level and examined for their potential to inhibit hypertrophic differentiation in two models. In addition, we studied a possible genetic association with osteoarthritis. Results: Pathway analysis demonstrated decreased Wnt-signaling in articular c...
Pediatrics, 2009
OBJECTIVE. This was a randomized, controlled trial to investigate the effect of Newborn Individua... more OBJECTIVE. This was a randomized, controlled trial to investigate the effect of Newborn Individualized Developmental Care and Assessment Program on growth, cognitive, psychomotor, and neuromotor development at 1 and 2 years in infants born at <32 weeks’ gestational age. METHODS. Infants were randomly assigned within 48 hours of birth to the newborn individualized developmental care and assessment program group (intervention) or basic developmental care group (control group [ie, incubator covers and nests]). At 1 and 2 years’ corrected age, growth was measured and standardized neurologic examinations were administered. Mental and psychomotor development was assessed by using the Dutch version of the Bayley Scales of Infant Development II. Neurologic outcome, Psychomotor Developmental Index, and Mental Developmental Index scores were combined a total outcome measure. RESULTS. One hundred sixty-eight infants were recruited (intervention: 84; control: 84). Four infants (newborn inter...
Nucleic Acids Research, 1992
We have recently identified a point mutation in the mitochondrially encoded tRNA L * u ge... more We have recently identified a point mutation in the mitochondrially encoded tRNA L * u gene which associates with a combination of type II diabetes mellitus and sensorineural hearing loss in a large pedigree. To extend this finding to other syndromes which exhibit a combination of diabetes mellitus and hearing loss we have sequenced all mitochondrial tRNA genes from two patients with the Wolfram syndrome, a rare congenital disease characterized by diabetes mellitus, deafness, diabetes insipidus and optic atrophy. In each patient, a single different mutation was identified. One Is an A to G transition mutation at np 12,308 in tRNA Leu < CUN) gene in a region which Is highly conserved between species during evolution. This mutation has been described by Lauber et al. (1) as associating with chronic progressive external ophthalmoplegia (CPEO). The other is a C to T transition mutation at np 15,904 In tRNA 17 * gene. Both mutations are also present In the general population (frequency tRNA Leu < CUN) mutation 0.16, tRNA Thr mutation 0.015). These findings suggest that evolutionarily conserved regions in mitochondrial tRNA genes can exhibit a significant polymorphism in humans, and that the mutation at np 12,308 in the tRNA Leu (CUN) gene is unlikely to be associated with CPEO and Wolfram syndrome. METHODS Patients Patients were diagnosed as having Wolfram syndrome if they exhibited the classical symptoms (22,23).
The Lancet, 1999
The success of the La Mascota twinning programme (Dec 12, p 1923) 1 in paediatric haemato-oncolog... more The success of the La Mascota twinning programme (Dec 12, p 1923) 1 in paediatric haemato-oncology between two developed (Switzerland and Italy) and one less developed country (Nicaragua) is a landmark achievement, which presents the twinning approach as ...
The Journal of Pediatrics, 1997
LETTERS the lower prevalence of AO in their population, it follows that the positive predictive v... more LETTERS the lower prevalence of AO in their population, it follows that the positive predictive values of our models applied to their patient population must be lower. The low specificity and positive predictive value that they report are thus not unexpected.
Journal of Medical Ethics, 2010
To evaluate whether the requirement of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more To evaluate whether the requirement of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;minimal risk and burden&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; for paediatric research without direct benefit to the subjects compromises the ability to obtain data necessary for improving paediatric care. To provide evidence-based reflections on the EU recommendation that allows for a higher level of risk. Systematic analysis of the approval/rejection decisions made by the Dutch Central Committee on Research involving Human Subjects (CCMO). The analysis included 165 proposals for paediatric research without direct benefit that were reviewed by the CCMO between January, 2000, and July, 2007. A separate, in-depth analysis of all drug studies included 18 early phase drug studies and nine other drug studies without direct benefit. 11 out of 165 studies were definitively rejected because the CCMO did not regard the risk and/or burden to be minimal. In three of these 11 cases (including two early phase drug studies) the requirement of minimal risk and burden was cited as the only reason for rejection. Four other early phase drug studies also involved risks and/or burdens that were not regarded to be minimal but were nevertheless approved. The requirement of minimal risk and burden, aiming to protect research subjects, occasionally leads to rejection of protocols. Early phase drug studies relatively often do not comply with the requirement. Committees may find ways to approve important studies that formally should be rejected, but that is not a desirable solution. The regulatory framework should be revised to make such occasional exceptions to the requirement legitimate and transparent.
The Journal of Clinical Endocrinology & Metabolism, 2001
GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10–20 pu... more 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 tot...
Hormone Research in Paediatrics, 2001
Objective: To evaluate the efficacy of oral dehydroepiandrosterone sulfate (DHEAS) treatment for ... more 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 ...
Hormone Research in Paediatrics, 2007
and close to target height. The dose should bring serum insulin-like growth factor I (IGF-I) leve... more and close to target height. The dose should bring serum insulin-like growth factor I (IGF-I) level and IGF-I/IGFbinding protein-3 ratio into, but not above, the normal range which would theoretically prevent long-term adverse events. Furthermore, we should strive for a regimen that would accomplish all this at the lowest cost (calculated over the whole period of treatment) [2]. Essentially, four therapeutic strategies have been used or advocated: The first was a fixed dosage, irrespective of body size, administered two or three times per week intramuscularly. This was prescribed between 1960 and 1980 in Europe, and somewhat longer in the USA, and led to a modest catch-up growth, resulting usually in a short stature in childhood and adolescence and a mean final height of about-2 SDS and-1.5 SDS, if puberty was induced (usually at an advanced age) [3]. The second strategy is to adapt the GH dose to the body size and to administer it daily subcutaneously (or six times a week, as in the Canadian study). Rachmiel et al. [1] call this strategy a 'fixed dose', but obviously this dose is only fixed in terms of milligrams per kilogram, not in absolute amounts. This strategy is commonly used at present. Within this strategy, there are still several options. For example, there are no scientific data indicating
Hormone Research, 1984
Acromegaly 142 Adrenal adenoma 224-cortex 185 Adrenalectomy 103 Amines 176 Y-Aminobutyric acid 33... more Acromegaly 142 Adrenal adenoma 224-cortex 185 Adrenalectomy 103 Amines 176 Y-Aminobutyric acid 33. 171 Androgenized females and males 108 Androstenedione 18 Angiotensin 11 176 Antral gastrin 127 Arginine vasopressin 91 Bcnzamides 153 Bicuculline 33 Brain 117 Breeding season 200 Bromocriptine 142 Cannabinoids 43 Catecholamine-synthesis inhibition 158 Circadian rhythms 103 Colonic thymidine kinase 127 Congenital adrenal hyperplasia 77 Continuous insulin infusion 65 Corticosterone 185 Corticotropin 185 Cortisol 86-metabolism 103-rhythms 103 Creatine kinase 232
Journal of Pediatric Endocrinology and Metabolism, 2009
Background: Premature thelarche is defined as breast development before 8 years of age. This is m... more Background: Premature thelarche is defined as breast development before 8 years of age. This is most often caused by central hormone disregulation and is accompanied by concurrent bone maturation. However, we present a case of premature thelarche with concurrent bone maturation without central hormone disregulation. Genes within the estrogen signaling pathway were examined for genetic changes which might be responsible for the clinical phenotype. Patient report: A girl presented with breast development from 18 months of age with undetectable serum estrogens, prepubertal serum gonadotropins, advanced growth and skeletal maturation, but no increase of uterine size, thus presenting a premature thelarche variant. Serum estrogens remained below detectable limits until she entered into an unremarkable puberty at 12.1 years of age. No abnormalities or SNPs were found in the genes tested. Conclusion: We describe a case of premature thelarche which cannot be attributed to a central cause of abnormal hormone levels or to alterations in genes suspected for this phenotype. We conclude that other yet to be identified factors are involved in this unique case of premature thelarche.
Nederlands tijdschrift voor geneeskunde, Jan 5, 1992
Bone, 2002
In this study, we investigate the expression of the androgen receptor (AR) in the tibial growth p... more In this study, we investigate the expression of the androgen receptor (AR) in the tibial growth plate and metaphyseal bone of male and female rats at the mRNA and protein level. Using in situ hybridization and immunohistochemistry, AR mRNA and protein were demonstrated in proliferating and early hypertrophic chondrocytes in the growth plate of 1-, 4-, and 7-week-old male and female rats. Immunostaining for AR was observed both in the nucleus and the cytoplasm. After sexual maturation at 12 and 16 weeks of age, AR expression decreased in both genders and was confined to a small rim of prehypertrophic chondrocytes. In female rats of 40 weeks of age, this expression pattern was still visible. In most age groups there was a tendency toward an increased AR mRNA expression in male vs. female rats except in the 7-week-old animals. At the protein level, sexually maturing 7-week-old male rats demonstrated a higher staining intensity compared to their female counterparts. At this stage, AR staining in the males was mainly confined to the nucleus, whereas in females staining was predominantly found in the cytoplasm. In the tibial metaphysis, AR mRNA was detected in lining cells, osteoblasts, osteocytes, and osteoclasts at all stages of development. At the protein level, a similar expression pattern was observed, except for an absence of immunostaining in the lining cells. The staining was both nuclear and cytoplasmic. In most age groups, mRNA and protein signals were higher in males compared with females. We have demonstrated the presence of AR mRNA and protein in the tibial growth plate and the underlying metaphyseal bone during development of the rat. In male rats, the presence of higher messenger and protein staining intensities, as well as preferential nuclear staining during sexual maturation, suggests that direct actions of androgens in chondrocytes and in bone forming cells may be involved in establishing the gender differences in the skeleton.
Hormone Research, 1989
Four out of 10 children in two unrelated families presented with a total pituitary growth hormone... more Four out of 10 children in two unrelated families presented with a total pituitary growth hormone (GH) and prolactin deficiency and a partial thyrotropin (TSH) deficiency. The GH gene was intact in family I. The pituitaries, visualized by magnetic resonance imaging, were normal. All children responded well to GH and L-thyroxine therapy. Baseline plasma somatostatin and its peak response to arginine infusion were elevated in family I and they had a milder TSH deficiency than family II. Plasma insulin showed a poor response to arginine infusion. This hereditary combination of pituitary deficiencies suggests a deficiency of a common positive transcription factor.
Nederlands tijdschrift voor geneeskunde, Jan 21, 1991
Nederlands tijdschrift voor geneeskunde, Jan 29, 1991
Journal of pediatric endocrinology & metabolism : JPEM, 2001
It is well established that estrogen is essential for statural growth during puberty, but until r... more 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 character...
Nederlands tijdschrift voor geneeskunde, Jan 3, 1998
Drugs research in children entails a number of problems: medical-ethical, pharmacological (owing ... more Drugs research in children entails a number of problems: medical-ethical, pharmacological (owing to the immaturity of the organs and the growth and development of the child) and financial (because children do not use many drugs). Consequently, children are exposed to insufficiently tested drugs and new therapeutic possibilities are withheld from them. Currently, little clinical drugs research in children is being carried out, but this is about to change. By now, European guidelines have been drawn up for the performance of clinical drugs trials according the 'good clinical practice' standards in children. In the Netherlands, a cooperative body has been set up (the Pediatric Pharmacology Network), which is to promote and coordinate paediatric pharmacological research in according with these guidelines.
Quality of Life Research, 2000
The 43-item TNO-AZL Preschool Children Quality of Life (TAPQOL) questionnaire was developed to me... more 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
Quality of Life Research, 1998
This study evaluates the agreement between child and parent reports on children's health-related ... more This study evaluates the agreement between child and parent reports on children's health-related quality of life (HRQoL) in a representative sample of 1,105 Dutch children (age 8-11 years old). Both children and their parents completed a 56 item questionnaire (TACQOL). The questionnaire contains seven eight-item scales: physical complaints, motor functioning, autonomy, cognitive functioning, social functioning, positive emotions and negative emotions. The Pearson correlations between the child and parent reports were between 0.44 and 0.61 (p < 0.001). The intraclass correlations were between 0.39 and 0.62. On average, the children reported a significantly lower HRQoL than their parents on the physical complaints, motor functioning, autonomy, cognitive functioning and positive emotions scales (paired t-test: p < 0.05). Agreement on all of the scales was related to the magnitude of the HRQoL scores and to some background variables (gender, age, temporary illness and visiting a physician). According to multitrait-multimethod analyses, both the child and parent reports proved to be valid.
Arthritis and Rheumatism, 2012
Objective: The development of osteoarthritis may be caused by activation of hypertrophic differen... more Objective: The development of osteoarthritis may be caused by activation of hypertrophic differentiation of articular chondrocytes. Healthy articular cartilage is highly resistant to hypertrophic differentiation, in contrast to other hyaline cartilage subtypes such as growth-plate cartilage. In this study, we set out to elucidate the molecular mechanism responsible for the difference in propensity to undergo hypertrophic differentiation between human articular and growth plate cartilage. Methods: Whole genome gene expression micro-array analysis of healthy human growth-plate and articular cartilage derived from the same adolescent donors was performed. Candidate genes, enriched in articular cartilage, were validated at the mRNA and protein level and examined for their potential to inhibit hypertrophic differentiation in two models. In addition, we studied a possible genetic association with osteoarthritis. Results: Pathway analysis demonstrated decreased Wnt-signaling in articular c...
Pediatrics, 2009
OBJECTIVE. This was a randomized, controlled trial to investigate the effect of Newborn Individua... more OBJECTIVE. This was a randomized, controlled trial to investigate the effect of Newborn Individualized Developmental Care and Assessment Program on growth, cognitive, psychomotor, and neuromotor development at 1 and 2 years in infants born at <32 weeks’ gestational age. METHODS. Infants were randomly assigned within 48 hours of birth to the newborn individualized developmental care and assessment program group (intervention) or basic developmental care group (control group [ie, incubator covers and nests]). At 1 and 2 years’ corrected age, growth was measured and standardized neurologic examinations were administered. Mental and psychomotor development was assessed by using the Dutch version of the Bayley Scales of Infant Development II. Neurologic outcome, Psychomotor Developmental Index, and Mental Developmental Index scores were combined a total outcome measure. RESULTS. One hundred sixty-eight infants were recruited (intervention: 84; control: 84). Four infants (newborn inter...
Nucleic Acids Research, 1992
We have recently identified a point mutation in the mitochondrially encoded tRNA L * u ge... more We have recently identified a point mutation in the mitochondrially encoded tRNA L * u gene which associates with a combination of type II diabetes mellitus and sensorineural hearing loss in a large pedigree. To extend this finding to other syndromes which exhibit a combination of diabetes mellitus and hearing loss we have sequenced all mitochondrial tRNA genes from two patients with the Wolfram syndrome, a rare congenital disease characterized by diabetes mellitus, deafness, diabetes insipidus and optic atrophy. In each patient, a single different mutation was identified. One Is an A to G transition mutation at np 12,308 in tRNA Leu < CUN) gene in a region which Is highly conserved between species during evolution. This mutation has been described by Lauber et al. (1) as associating with chronic progressive external ophthalmoplegia (CPEO). The other is a C to T transition mutation at np 15,904 In tRNA 17 * gene. Both mutations are also present In the general population (frequency tRNA Leu < CUN) mutation 0.16, tRNA Thr mutation 0.015). These findings suggest that evolutionarily conserved regions in mitochondrial tRNA genes can exhibit a significant polymorphism in humans, and that the mutation at np 12,308 in the tRNA Leu (CUN) gene is unlikely to be associated with CPEO and Wolfram syndrome. METHODS Patients Patients were diagnosed as having Wolfram syndrome if they exhibited the classical symptoms (22,23).
The Lancet, 1999
The success of the La Mascota twinning programme (Dec 12, p 1923) 1 in paediatric haemato-oncolog... more The success of the La Mascota twinning programme (Dec 12, p 1923) 1 in paediatric haemato-oncology between two developed (Switzerland and Italy) and one less developed country (Nicaragua) is a landmark achievement, which presents the twinning approach as ...
The Journal of Pediatrics, 1997
LETTERS the lower prevalence of AO in their population, it follows that the positive predictive v... more LETTERS the lower prevalence of AO in their population, it follows that the positive predictive values of our models applied to their patient population must be lower. The low specificity and positive predictive value that they report are thus not unexpected.
Journal of Medical Ethics, 2010
To evaluate whether the requirement of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more To evaluate whether the requirement of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;minimal risk and burden&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; for paediatric research without direct benefit to the subjects compromises the ability to obtain data necessary for improving paediatric care. To provide evidence-based reflections on the EU recommendation that allows for a higher level of risk. Systematic analysis of the approval/rejection decisions made by the Dutch Central Committee on Research involving Human Subjects (CCMO). The analysis included 165 proposals for paediatric research without direct benefit that were reviewed by the CCMO between January, 2000, and July, 2007. A separate, in-depth analysis of all drug studies included 18 early phase drug studies and nine other drug studies without direct benefit. 11 out of 165 studies were definitively rejected because the CCMO did not regard the risk and/or burden to be minimal. In three of these 11 cases (including two early phase drug studies) the requirement of minimal risk and burden was cited as the only reason for rejection. Four other early phase drug studies also involved risks and/or burdens that were not regarded to be minimal but were nevertheless approved. The requirement of minimal risk and burden, aiming to protect research subjects, occasionally leads to rejection of protocols. Early phase drug studies relatively often do not comply with the requirement. Committees may find ways to approve important studies that formally should be rejected, but that is not a desirable solution. The regulatory framework should be revised to make such occasional exceptions to the requirement legitimate and transparent.
The Journal of Clinical Endocrinology & Metabolism, 2001
GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10–20 pu... more 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 tot...
Hormone Research in Paediatrics, 2001
Objective: To evaluate the efficacy of oral dehydroepiandrosterone sulfate (DHEAS) treatment for ... more 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 ...
Hormone Research in Paediatrics, 2007
and close to target height. The dose should bring serum insulin-like growth factor I (IGF-I) leve... more and close to target height. The dose should bring serum insulin-like growth factor I (IGF-I) level and IGF-I/IGFbinding protein-3 ratio into, but not above, the normal range which would theoretically prevent long-term adverse events. Furthermore, we should strive for a regimen that would accomplish all this at the lowest cost (calculated over the whole period of treatment) [2]. Essentially, four therapeutic strategies have been used or advocated: The first was a fixed dosage, irrespective of body size, administered two or three times per week intramuscularly. This was prescribed between 1960 and 1980 in Europe, and somewhat longer in the USA, and led to a modest catch-up growth, resulting usually in a short stature in childhood and adolescence and a mean final height of about-2 SDS and-1.5 SDS, if puberty was induced (usually at an advanced age) [3]. The second strategy is to adapt the GH dose to the body size and to administer it daily subcutaneously (or six times a week, as in the Canadian study). Rachmiel et al. [1] call this strategy a 'fixed dose', but obviously this dose is only fixed in terms of milligrams per kilogram, not in absolute amounts. This strategy is commonly used at present. Within this strategy, there are still several options. For example, there are no scientific data indicating
Hormone Research, 1984
Acromegaly 142 Adrenal adenoma 224-cortex 185 Adrenalectomy 103 Amines 176 Y-Aminobutyric acid 33... more Acromegaly 142 Adrenal adenoma 224-cortex 185 Adrenalectomy 103 Amines 176 Y-Aminobutyric acid 33. 171 Androgenized females and males 108 Androstenedione 18 Angiotensin 11 176 Antral gastrin 127 Arginine vasopressin 91 Bcnzamides 153 Bicuculline 33 Brain 117 Breeding season 200 Bromocriptine 142 Cannabinoids 43 Catecholamine-synthesis inhibition 158 Circadian rhythms 103 Colonic thymidine kinase 127 Congenital adrenal hyperplasia 77 Continuous insulin infusion 65 Corticosterone 185 Corticotropin 185 Cortisol 86-metabolism 103-rhythms 103 Creatine kinase 232