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Biomedical subjects

B Bakker

Publications and source records attributed to B Bakker.

At least 19 recordsLinked to original sources
PubMed2005

[First facioscapulohumeral muscular dystrophy prenatal diagnosis in a Bulgarian family].

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common myopathy. It is characterized by progressive descendent involvement of facial, shoulder girdle, truncal and lower extremities muscles. FSHD locus was mapped on the terminal part of the long arm of chromosome 4 (4q35). The disease is caused by a deletion of an integral number of tandem D4Z4 repeats and dimension of the pathological fragments < or = 38kb. Prenatal diagnosis of FSHD is possible but it is potentially difficult because of the big amount and high quality of DNA required. Hereby we describe the first prenatal tests performed for a Bulgarian family.

Adult↗
PubMed2004

Quality of life in adults following bone marrow transplantation during childhood.

SUMMARY: Quality of life (QOL) was assessed in 22 young adults, 14 years - on average- after having received bone marrow transplantation (BMT) during childhood at the Leiden University Medical Center. All were disease-free and >16 years when interviewed. The sickness impact profile and the Medical Outcome Study 36-item Short Form Health Survey were used as generic questionnaires in the assessment of QOL. The Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) was used as a disease-specific measure of QOL. Coping was assessed by means of the Utrecht coping list. BMT-related variables were obtained from medical files. Of the generic QOL measures, most results fell within the normal range of functioning, although some illness-related impairment was reported on subscales for general and work-related functioning. Compared to a reference sample of patients who had received BMT as adults, patients involved in this study scored significantly higher on the 'emotional well-being' subscale of the FACT-BMT, indicating significantly better emotional functioning. The age at BMT and total body irradiation (TBI) were not related to patients' QOL. We can conclude that at long term, having received BMT during childhood does not negatively affect the QOL of patients. Bone Marrow Transplantation (2004) 33, 329-336. doi:10.1038/sj.bmt.1704345 Published online 1 December 2003

Adolescent↗
PubMed2004

Disturbances of growth and endocrine function after busulphan-based conditioning for haematopoietic stem cell transplantation during infancy and childhood.

It is generally assumed that busulphan/cyclophoshamide (Bu/Cy)-based conditioning regimens for haematopoietic stem cell transplantation (SCT) do not affect growth. We evaluated growth and endocrine function after Bu/Cy-based conditioning in 64 children without a history of irradiation. Mean height standard deviation scores remained stable, but unexplained disturbances of growth after SCT were found in 17/48 (35%) of the children without growth-limiting disorders (10/23 in patients treated for haematological malignancies). In 10 patients, growth hormone (GH) secretion status was evaluated, and insufficient GH secretion was diagnosed in four patients. Thyroid function was evaluable in 52 patients. Two developed antibody-mediated thyroid disorders and 10 (19%) compensated primary hypothyroidism. Gonadal function was evaluable in 21 patients and was normal in all seven patients treated with low-dose Bu (8 mg/kg), whereas seven of the 14 children receiving high-dose Bu (16-20 mg/kg) developed gonadal failure; the majority of these patients had not been exposed to gonadotoxic therapy prior to Bu/Cy. Of the 49 evaluable patients, 16 developed subclinical hyperparathyroidism. We conclude that, besides gonadal and thyroid dysfunction, impaired growth and hyperparathyroidism often occur after Bu/Cy conditioning for SCT and that growth impairment may be the result of insufficient GH secretion.

Adolescent↗
PubMed2004

Genomic imbalances in mental retardation.

INTRODUCTION: It has been estimated that cytogenetically visible rearrangements are present in approximately 1% of newborns. These chromosomal changes can cause a wide range of deleterious developmental effects, including mental retardation (MR). It is assumed that many other cases exist where the cause is a submicroscopic deletion or duplication. To facilitate the detection of such cases, different techniques have been developed, which have differing efficiency as to the number of loci and patients that can be tested. METHODS: We implemented multiplex amplifiable probe hybridisation (MAPH) to test areas known to be rearranged in MR patients (for example, subtelomeric/pericentromeric regions and those affected in microdeletion syndromes) and to look for new regions that might be related to MR. RESULTS: In this study, over 30 000 screens for duplications and deletions were carried out; 162 different loci tested in each of 188 developmentally delayed patients. The analysis resulted in the detection of 19 rearrangements, of which approximately 65% would not have been detected by conventional cytogenetic analysis. A significant fraction (46%) of the rearrangements found were interstitial, despite the fact that only a limited number of these loci have so far been tested. DISCUSSION: Our results strengthen the arguments for whole genome screening within this population, as it can be assumed that many more interstitial rearrangements would be detected. The strengths of MAPH for this analysis are the simplicity, the high throughput potential, and the high resolution of analysis. This combination should help in the future identification of the specific genes that are responsible for MR.

Abnormalities, Multiple↗
PubMed2003

Effect of x-irradiation on growth and the expression of parathyroid hormone-related peptide and Indian hedgehog in the tibial growth plate of the rat.

AIM: To study the effect of irradiation on the longitudinal growth and the expression of parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (IHh) in tibial growth plates of rats. METHODS: At 3 weeks of age, 30 male rats received a single fraction of irradiation (8 Gy) to their right hind limb, and small groups of animals were sacrificed 1, 2, 3, 5, 7, 10, 15, and 26 weeks after irradiation. Weight and length of both irradiated and nonirradiated tibiae were measured, and sections of the tibiae were stained with HE. PTHrP and IHh were visualized using immunohistochemical techniques. RESULTS: Radiation resulted in persistent growth delay of the irradiated tibiae, with a difference in length of more than 10% between the irradiated and the nonirradiated tibiae 15 weeks or more after irradiation. The growth plate architecture was disturbed, and the expression of both PTHrP and IHh was decreased in the irradiated tibiae. CONCLUSION: As PTHrP and IHh are key regulators of both the pace and the synchronization of the differentiation of growth plate chondrocytes, the reduced expression of PTHrP and IHh may contribute to the changes found after irradiation.

Animals↗
PubMed2001

Roles of triosephosphate isomerase and aerobic metabolism in Trypanosoma brucei.

Kinetoplastid protozoa compartmentalize the first seven enzymes of glycolysis and two enzymes of glycerol metabolism in a microbody, the glycosome. While in its mammalian host, Trypanosoma brucei depends entirely on glucose for ATP generation. Under aerobic conditions, most of the glucose is metabolized to pyruvate. Aerobic metabolism depends on the activities of glycosomal triosephosphate isomerase and a mitochondrial glycerophosphate oxidase, and on glycerophosphate<-->dihydroxyacetone phosphate exchange across the glycosomal membrane. Using a combination of genetics and computer modelling, we show that triosephosphate isomerase is probably essential for bloodstream trypanosome survival, but not for the insect-dwelling procyclics, which preferentially use amino acids as an energy source. When the enzyme level decreased to about 15% of that of the wild-type, the growth rate was halved. Below this level, a lethal rise in dihydroxyacetone phosphate was predicted. Expression of cytosolic triosephosphate isomerase inhibited cell growth. Attempts to knockout the trypanosome alternative oxidase genes (which are needed for glycerophosphate oxidase activity) were unsuccessful, but when we lowered the level of the corresponding mRNA by expressing a homologous double-stranded RNA, oxygen consumption was reduced fourfold and the rate of trypanosome growth was halved.

Adenosine Triphosphate↗
PubMed2001

Maternal isodisomy for chromosome 2p causing severe congenital hypothyroidism.

Severe congenital hypothyroidism (CH) due to a total iodide organification defect (TIOD) is usually due to mutations in the thyroid peroxidase (TPO) gene located at chromosome 2p25. A homozygous deletion [DeltaT2512 (codon 808)] in exon 14 was identified in a patient with classical TIOD. The transmission pattern of the TPO gene in this family was anomalous; the mother was heterozygous for the deletion; and the mutation was absent in the father. Polymorphic short tandem repeat (STR) markers confirmed paternity and demonstrated on chromosome 2 that the propositus was homozygous for most markers on chromosome 2p and that these were identical to one of the maternal 2p homologs. A normal karyotype was found in the propositus, his parents and sister. We conclude that the homozygosity in the patient is due to partial maternal isodisomy of the short arm of chromosome 2, carrying a defective TPO gene. The patient, born small for gestational age, develops and grows well and appears healthy (while being treated with thyroxine) and has a normal phenotype except for a unilateral preauricular skin tag. This shows that partial maternal isodisomy for chromosome 2p (2pter - 2p12) is compatible with a minimal influence on normal development.

Base Sequence↗
PubMed2001

Combined pituitary hormone deficiency caused by compound heterozygosity for two novel mutations in the POU domain of the Pit1/POU1F1 gene.

The POU homeodomain containing transcriptional activator POU1F1, formerly called Pit1 or GHF-1, is required for the embryological determination and postnatal secretory function of the GH-, PRL-, and TSH-producing cells in the anterior pituitary. Several mutations in the gene encoding POU1F1 have been described, resulting in a syndrome of combined pituitary hormone deficiency involving these three hormones. Most of the patients with this phenotype have either a dominant negative mutation in codon 271 (R271W) or are homozygous for a recessive mutation in the POU1F1 gene; to date only one case has been reported with compound heterozygosity for two point mutations. Here, we describe a boy with severe deficiencies of GH, PRL, and TSH who had compound heterozygosity for two novel point mutations in the POU1F1 gene: a 1-bp deletion frameshift mutation (747delA), the first one described to date in this gene, which leads to a nonfunctional truncated protein lacking the entire DNA recognition helix of the POU homeodomain, and a missense mutation in the C-terminal end of the fourth alpha-helix of the POU-specific domain (W193R),which causes a 500-fold reduction in the ability to bind to DNA and activate transcription.

Cell Line↗
PubMed2000

Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer.

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype. Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant). The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.

Aged↗
PubMed2000

De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by deletion of most copies of the 3.3-kb subtelomeric D4Z4 repeat array on chromosome 4q. The molecular mechanisms behind the deletion and the high proportion of new mutations have remained elusive. We surveyed 35 de novo FSHD families and found somatic mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a nonmosaic de novo patient. A genotypic-severity score, composed of the residual repeat size and the degree of somatic mosaicism, yields a consistent relationship with severity and age at onset of disease. Mosaic females had a higher proportion of somatic mosaicism than did mosaic males. The repeat deletion is significantly enhanced by supernumerary homologous repeat arrays. In 10% of normal chromosomes, 4-type repeat arrays are present on chromosome 10. In mosaic individuals, 4-type repeats on chromosome 10 are almost five times more frequent. The reverse configuration, also 10% in normal chromosomes, was not found, indicating that mutations may arise from transchromosomal interaction, to which the increase in 4-type repeat clusters is a predisposing factor. The somatic mosaicism suggests a mainly mitotic origin; mitotic interchromosomal gene conversion or translocation between fully homologous 4-type repeat arrays may be a major mechanism for FSHD mutations.

Age of Onset↗
PubMed2000

Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update).

Presented is a cohort study to assess the nature and frequency of thyroid peroxidase (TPO) mutations in 45 patients (35 families) with congenital hypothyroidism due to a total iodide organification defect; incidence is 1:66,000 in The Netherlands. The presentation is consistently similar with a severe form of congenital hypothyroidism and also characterized by a complete and immediate release of accumulated radioiodide from the thyroid after sodium perchlorate administration. Sixteen different mutations were found, including eight novel mutations; the majority occurs in exons 8, 9, or 10. The GGCC insertion in exon 8 at nucleotide 1277, leading to an early termination signal in exon 9, is the most frequently occurring mutation. These mutations were detected in 29 families in both TPO alleles (13 homozygous and 16 compound heterozygous). In one family, partial maternal isodisomy of 2p was detected, in four families only one mutated TPO allele could be detected, and in one family no inactivating TPO mutation could be found. Because all patients clearly had the clinicopathologic features of a total iodide organification defect, we conclude that in these five families the mutations in the (other) alleles could be either located in the intronic sequences or in the promoter region. Mutations in the TPO gene result in total iodide organification defects.

Child↗
PubMed1999

Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT.

Few data are available on the long-term effect of bone marrow transplantation (BMT) on growth. This study examines those factors that play a role in the final height outcome of patients who underwent BMT during childhood. Data on 181 of 230 patients with aplastic anemia, leukemias, and lymphomas who had BMT before puberty (mean age, 9.8 +/- 2.6 years) and who had reached their final height were analyzed. An overall decrease in final height standard deviation score (SDS) value was found compared with the height at BMT (P < 10(7)) and with the genetic height (P < 10(7)). Girls did better than boys, and the younger in age the person was at time of BMT, the greater the loss in height. Previous cranial irradiation + single-dose total body irradiation (TBI) caused the greatest negative effect on final height achievement (P < 10(4)). Fractionation of TBI reduces this effect significantly and conditioning with busulfan and cyclophosphamide seems to eliminate it. The type of transplantation, graft-versus-host disease, growth hormone, or steroid treatment did not influence final height. Irradiation, male gender and young age at BMT were found to be major factors for long-term height loss. Nevertheless, the majority of patients (140/181) have reached adult height within the normal range of the general population.

Adolescent↗
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 negative iodine balance is found in healthy neonates compared with neonates with thyroid agenesis.

We studied the effects of the presence or absence of the thyroid gland on the iodine metabolism and excretion in term Dutch newborns by performing a retrospective study of the urinary iodine excretion in 193 term newborns with abnormal congenital hypothyroidism screening results. Thirty-six euthyroid newborns with decreased thyroxine-binding globulin levels were compared with 157 hypothyroid patients, 54 due to thyroid agenesis and 103 due to thyroid dysgenesis. A significant difference in the urinary iodine excretion was observed between the agenesis group (mean: 28 micrograms/24 h) and the euthyroid newborns (mean: 46 micrograms/24 h, P=0.001). In conclusion, healthy, euthyroid, term newborns excreted more iodine in their urine than newborns with thyroid agenesis. These results strongly indicated the existence of a temporarily negative iodine balance: the excretion of iodine prevailed over the intake and the newborn's thyroidal iodine, stored during pregnancy, could be used for thyroxine synthesis in the postnatal period. Since healthy term neonates were able to maintain adequate plasma free thyroxine concentrations under normal TSH stimulation, the prenatally acquired iodine stores could be considered sufficiently high to compensate for the transient postnatal losses.

Female↗
PubMed1997

Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer-susceptibility condition characterized by early onset colorectal cancer. Germ-line mutations in one of four DNA mismatch repair (MMR) genes, hMSH2, hMLH1, hPMS1, or hPMS2, are known to cause HNPCC. Although many mutations in these genes have been found in HNPCC kindreds complying with the so-called Amsterdam criteria, little is known about the involvement of these genes in families not satisfying these criteria but showing clear-cut familial clustering of colorectal cancer and other cancers. Here, we applied denaturing gradient-gel electrophoresis to screen for hMSH2 and hMLH1 mutations in two sets of HNPCC families, one set comprising families strictly complying with the Amsterdam criteria and another set in which at least one of the criteria was not satisfied. Interestingly, hMSH2 and hMLH1 mutations were found in 49% of the kindreds fully complying with the Amsterdam criteria, whereas a disease-causing mutation could be identified in only 8% of the families in which the criteria were not satisfied fully. In correspondence with these findings, 4 of 6 colorectal tumors from patients belonging to kindreds meeting the criteria showed microsatellite instability, whereas only 3 of 11 tumors from the other set of families demonstrated this instability. Although the number of tumors included in the study admittedly is small, the frequencies of mutations in the MMR genes show obvious differences between the two clinical sets of families. These results also emphasize the practical importance of the Amsterdam criteria, which provide a valid clinical subdivision between families, on the basis of their chance of carrying an hMSH2 or an hMLH1 mutation, and which bear important consequences for genetic testing and counseling and for the management of colorectal cancer families.

Adaptor Proteins, Signal Transducing↗