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Biomedical subjects

B Bakker

Publications and source records attributed to B Bakker.

33 records · Page 2Linked to original sources
PubMed1996

An Xp22.1-p22.2 YAC contig encompassing the disease loci for RS, KFSD, CLS, HYP and RP15: refined localization of RS.

To facilitate the positional cloning of the genes involved in retinoschisis (RS), keratosis follicularis spinulosa decalvans (KFSD), Coffin-Lowry syndrome (CLS), X-linked hypophosphatemic rickets (XLH, locus name HYP) and X-linked dominant cone-rod degeneration (locus name RP15), we have extended the molecular map of the Xp22 region. Screening of several YAC libraries allowed us to identify 156 YACs, 52 of which localize between markers DXS414 (P90) and DXS451 (kQST80H1). Analysis of their marker content facilitated the construction of a YAC contig from the region spanning (in this order): DXS414 - DXS987 - DXS207 - DXS1053 - DXS197 - DXS 43 - DXS1195 - DXS418 - DXS999 - PDHA1 - DXS7161 - DXS443 - DXS 7592 - DXS1229 - DXS365 - DXS7101 - DXS7593 - DXS1052 - DXS274 - DXS989 - DXS451. The region between DXS414 and DXS451 covers about 4.5-5 Mb. Two additional markers (DXS7593 and DXS7592) were placed in the region, thereby increasing the genetic resolution. Using the deduced marker order, the analysis of key recombinants in families segregating RS allowed us to refine the critical region for RS to 0.6 Mb, between DXS418 and DXS7161.

Abnormalities, Multiple↗
PubMed1995

Rapid detection of BRCA1 mutations by the protein truncation test.

More than 75% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA1, result in truncated proteins. We have used the protein truncation test (PTT) to screen for mutations in exon 11, which encodes 61% of BRCA1. In 45 patients from breast and/or ovarian cancer families we found six novel mutations: two single nucleotide insertions, three small deletions (1-5 bp) and a nonsense mutation identified two unrelated families. Furthermore, we were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with PTT, we detected aberrantly spliced products affecting exons 5 and 6 in one of two BRCA1-linked families examined. The protein truncation test promises to become a valuable technique in detecting BRCA1 mutations.

BRCA1 Protein↗
PubMed1995

Long-term consequences of high-dose total-body irradiation on hepatic and renal function in primates.

Radiation effects in non-human primates were studied in order to define the long-term risk of total-body irradiation (TBI) for bone marrow transplantation patients. The long-term effects of TBI could be investigated by keeping 84 monkeys of different ages, from an experiment on acute effects, under continuous observation for a period up to 25 years. The control group consisted of non-irradiated monkeys with a comparable age distribution and identical housing conditions. Since radiation was the common toxic agent, the different age groups provided the possibility to investigate the occurrence of deterministic effects after TBI. In the present study emphasis was placed on the assessment of hepatic and renal function and the associated histopathology. The values of the liver function parameters, such as alkaline phosphatase and gamma glutamyl transferase in the irradiated group were significantly increased after TBI (p < 0.05). Also the parameters of kidney dysfunction, e.g. haematocrit and blood urea nitrogen showed a significant change in the irradiated old-aged (post-irradiated interval > 15 years) cohort (p < 0.005). The impairment of the liver and renal functions, did not lead to clinical symptoms and were only associated with mild morphologic changes in the irradiated group of monkeys. In the population of bone marrow transplant patients treated with TBI, alterations in hepatic and renal function parameters after a post-irradiated interval of > 10 years can be anticipated. This could have consequences for the tolerance and toxicity of a broad range of drugs to be administered as additional medications.

Animals↗
PubMed1992

Cardiovascular evaluation in Turner syndrome: utility of MR imaging.

Forty patients with karyotypically proven Turner syndrome were prospectively studied using magnetic resonance imaging (MRI) and echocardiography in order to determine the frequency of cardiovascular anomalies and to assess the utility of both imaging modalities as methods for cardiovascular evaluation in Turner syndrome. Cardiovascular anomalies were found in 45% of patients. A high absolute prevalence of bicuspid aortic valve (17.5%) and aortic coarctation (12.5%) were observed relative to comparable series. Of clinically significant abnormalities, three of five aortic coarctations and four of five ascending aortic dilatations were solely MRI detected and not evident at echocardiographic examination. MRI is thus seen as a valuable adjunct to echocardiography in the cardiovascular evaluation of Turner syndrome patients. The usefulness of MRI primarily relates to its ability to provide excellent visualisation of the entire thoracic aorta where a large proportion of clinically significant anomalies occur in Turner syndrome.

Adolescent↗
PubMed1991

Mapping of dystrophin brain promoter: a deletion of this region is compatible with normal intellect.

Using a mouse genomic fragment containing the brain-specific promoter region of the dystrophin gene, we have located the brain promoter 75-300 kb proximal of the muscle promoter. Within our DMD-families we detected a patient who lacks both the brain-specific and muscle-specific promoter sequences. The normal intellectual capabilities of the patient argue against an indispensable role of the brain-specific first exon in mental functioning. The possibility exists that a NH2-terminally truncated dystrophin has taken over the function of the normal dystrophins in brain and/or muscle.

Adult↗
PubMed1990

Somatic origin of inherited haemophilia A.

We found a partial deletion of the clotting factor VIII gene of about 2000 bp, spanning exon 5 and part of intervening sequence 4 and 5 in an isolated patient with severe haemophilia A. The mother of the patient, who appeared to be a non-carrier on the basis of coagulation assays and restriction fragment length polymorphism analysis in the family, turned out to be a mosaic for the deletion, not only in her germ cells, but also in various somatic cells. These findings suggest that the mutation is the result of an event in early embryogenesis. If mosaicism for a mutation, either gonadal or somatic, proves to be a common phenomenon in human genetics, it is imperative to reconsider genetic risks for (future) sibs of any apparently new mutant of a hereditary disease.

Chromosome Deletion↗
PubMed1990

Insulin-like growth factor binding proteins in human breast cancer cells: relationship to hIGFBP-2 and hIGFBP-3.

Human breast cancer cells (HBCC) secrete at least four different forms of IGFBPs. We have previously demonstrated that hIGFBP-1 is a minor component of IGFBPs secreted by Hs578T cells and is absent in CM from MCF-7 cells. In our present report, we describe the immunological and structural relationship of HBCC IGFBPs to hIGFBP-2 and hIGFBP-3. Analysis of conditioned media (CM) from Hs578T by Western ligand blotting revealed three IGFBPs of apparent Mr = 38K, 28K, and 24K; CM from MCF-7 revealed only two IGFBPs, of apparent Mr = 31K and 24K. Immunoprecipitation studies with polyclonal antibodies raised against hIGFBP-2 and hIGFBP-3 demonstrated that the 38K IGFBP in Hs578T CM is immunologically related to hIGFBP-3, while the 31K IGFBP in MCF-7 cells is related to the hIGFBP-2. Analysis by Northern blot demonstrated that MCF-7 cells contained mRNA for hIGFBP-2, while Hs578T cells contained the mRNA characteristic of the hIGFBP-3. The identity of the 24K IGFBP remains unknown, and may represent a distinct IGFBP. Of note, assay of CM following removal of BPs by acid chromatography demonstrated no detectable IGF-I or -II. The role of these IGFBPs in HBCC is of interest in view of the potential modulation of IGF actions by these proteins.

Blotting, Western↗
PubMed1989

Characterization of insulin-like growth factor binding proteins from human breast cancer cells.

The insulin-like growth factor binding proteins (IGF-BPs) are structurally and immunologically distinct from the IGF type 1 or type 2 receptors and are characterized by two major forms: a large, GH-dependent BP found in human plasma (Mr = 150 k) and a small GH-independent BP (Mr = 28-42 k) present in human plasma, amniotic fluid, and HEP G2 cells. Using affinity cross-linking techniques, we have identified several binding proteins secreted by human breast cancer cell lines (Hs578T, MDA-231, T-47D, and MCF-7). Under nonreducing conditions these proteins migrated at an apparent Mr = 35, 28, 27, and 24 k, while reducing conditions revealed bands of apparent Mr = 35, 32, 27, and 24 k. Competitive binding studies in T-47D-conditioned media demonstrated that these BPs bound more IGF-II than IGF-I, and that IGF-II potently inhibited binding of either IGF-I or -II. Immunological studies using a polyclonal antibody against the HEP G2 small BP revealed no immunoreactive BP in conditioned media from MCF-7 and T-47D and only slight immunoreactivity in conditioned media from Hs578T and MDA 231. Analysis by Northern blot, using a probe from the cDNA sequence of the HEP G2 BP, demonstrated that Hs578T and MDA-231 cell lines contained small amounts of the 1.65 kilobase mRNA characteristic of the HEP G2 BP, while MCF-7 and T-47D tested negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗
PubMed1988

Demonstration of insulin-like growth factor (IGF-I and -II) receptors and binding protein in human breast cancer cell lines.

The insulin like growth factors (IGFs), potent mitogens for a variety of normal and transformed cells, have been reported to be secreted by several human breast cancer cell lines (BC). We have investigated the binding characteristics of IGF-I and -II in four human BC: MCF-7, T-47D, MDA 231 and Hs578T. Binding studies in microsomal membrane preparations detected high specific binding for both IGF in all four BC studied. Cross-linking with 125I-IGF-I, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) under reduced conditions, revealed the presence of an alpha subunit of apparent Mr = 130,000 in MCF-7, T-47D and MDA 213 cells. When 125I-IGF-II was cross-linked, a major band of apparent Mr = 260,000 was seen in all BC. This band was inhibited by IGF-II, but not by insulin. Cross-linking of 125I-IGF-I to conditioned media from BC demonstrated the presence of three binding proteins of apparent Mr = 45,000, 36,000 and 29,000 in all BC but T-47D, in which the 36,000 band was not seen. These data demonstrate that BC possess classical receptors for both IGF-I and -II and, furthermore, that BC produce specific binding proteins for these growth factors.

Breast Neoplasms↗
PubMedDate not supplied

Pubertal development and growth after total-body irradiation and bone marrow transplantation for haematological malignancies.

UNLABELLED: Pubertal development after total-body irradiation (TBI) was investigated in 40 children (21 boys) treated with allogeneic bone marrow transplantation (BMT) for haematological malignancies at a mean age of 11.3 years. The mean age at the last visit was 19.0 years. Twenty-five patients (15 boys) were prepubertal at BMT. Data on secondary sexual characteristics, the pituitary-gonadal axis and longitudinal growth were retrospectively collected from the medical records. In boys not receiving additional testicular irradiation (n = 19), penile growth and pubic hair development was normal and all had serum testosterone levels within the adult range. The majority of them, however, had incidental elevations of LH, suggesting minor Leydig cell damage. Testicular volume at last measurement was small (mean: 10.5 ml) and serum FSH levels were elevated in all boys, with normalisation in only one, suggesting severe impairment of reproductive gonadal function. Of the ten girls who received BMT before puberty, six had a spontaneous onset of puberty and menarche; the four other girls needed hormonal substitution therapy. Recovery of gonadal function after cessation of substitution was seen in one girl, who became pregnant but had a spontaneous abortion. Decrease in height SDS was seen in the majority of patients and was positively correlated with male gender and lower age at the time of BMT. CONCLUSION: Careful monitoring of both gonadal function and growth after bone marrow transplantation and total body irradiation is warranted in order to detect disturbances early and ensure normal pubertal development in children treated for haematological malignancies.

Adolescent↗
PubMedDate not supplied

A European pilot quality assessment scheme for molecular diagnosis of Huntington's disease.

This paper reports a European pilot External Quality Assessment (EQA) scheme for the molecular diagnosis of Huntington's disease (HD). The European Molecular Genetics Quality Network (EMQN) chose HD as a relatively simple assay that allows a range of difficulty in terms of technical competence and interpretation. Fourteen centres from 12 different countries participated. The scheme organiser provided five cases together with mock clinical information. The participating laboratories were asked to complete the analyses and return the reports in English to their normal laboratory format within a fixed period. The scheme demonstrates a level of potential misdiagnosis in molecular analysis of HD as well as a wide variety in way of reporting laboratory results. Overall 9/146 (6.2%) of alleles fell outside the set limits, and the rate of misdiagnosis was 1/78 (1.3%). A closer estimate of diagnostic accuracy will require expansion of the scheme.

Adult↗