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Biomedical subjects

G de Jong

Publications and source records attributed to G de Jong.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cancer dose-response modeling of epidemiological data on worker exposures to aldrin and dieldrin.

The paper applies classical statistical principles to yield new tools for risk assessment and makes new use of epidemiological data for human risk assessment. An extensive clinical and epidemiological study of workers engaged in the manufacturing and formulation of aldrin and dieldrin provides occupational hygiene and biological monitoring data on individual exposures over the years of employment and provides unusually accurate measures of individual lifetime average daily doses. In the cancer dose-response modeling, each worker is treated as a separate experimental unit with his own unique dose. Maximum likelihood estimates of added cancer risk are calculated for multistage, multistage-Weibull, and proportional hazards models. Distributional characterizations of added cancer risk are based on bootstrap and relative likelihood techniques. The cancer mortality data on these male workers suggest that low-dose exposures to aldrin and dieldrin do not significantly increase human cancer risk and may even decrease the human hazard rate for all types of cancer combined at low doses (e.g., 1 microgram/kg/day). The apparent hormetic effect in the best fitting dose-response models for this data set is statistically significant. The decrease in cancer risk at low doses of aldrin and dieldrin is in sharp contrast to the U.S. Environmental Protection Agency's upper bound on cancer potency based on mouse liver tumors. The EPA's upper bound implies that lifetime average daily doses of 0.0000625 and 0.00625 microgram/kg body weight/day would correspond to increased cancer risks of 0.000001 and 0.0001, respectively. However, the best estimate from the Pernis epidemiological data is that there is no increase in cancer risk in these workers at these doses or even at doses as large as 2 micrograms/kg/day.

Aldrin↗
PubMed1999

Immunohistochemical localization of somatostatin receptor sst2A in sarcoid granulomas.

BACKGROUND: In a previous study, we demonstrated the presence of receptors for somatostatin, a neuropeptide with immunoregulatory properties, in the inflammatory lesions of patients suffering from sarcoidosis and other granulomatous diseases by in vivo somatostatin receptor scintigraphy and in vitro autoradiography. However, it was not possible to identify exactly which cell types expressed the somatostatin receptors and which subtype was expressed. In this study we used a polyclonal antiserum directed against the sst2A receptor to identify more accurately the sst2A-expressing cells in sarcoidosis and other granulomatous diseases. DESIGN: Tissue biopsies from 12 patients with sarcoidosis, one patient with giant cell arteritis and one patient with Wegener's granulomatosis were studied by immunohistochemistry with the sst2A-specific antiserum. Two of the sarcoidosis patients were treated with the somatostatin analogue octreotide (100 microg t.i.d.). RESULTS: Epithelioid cells, multinucleated giant cells and a subset of CD68+ macrophages stained positive for sst2A in 9 out of 12 of the sarcoid biopsies and in both non-sarcoid granuloma biopsies. Treatment with octreotide resulted in clinical improvement in one out of two treated patients. CONCLUSION: The identification of somatostatin receptors on granuloma macrophages, epithelioid cells and giant cells, and the successful treatment of one patient with sarcoidosis with a somatostatin analogue, may offer new possibilities for treatment of granulomatous diseases.

Adult↗
PubMed1999

High prevalence of the Cys282Tyr HFE mutation facilitates an improved diagnostic service for hereditary haemochromatosis in South Africa.

OBJECTIVE: The aim of the study was to investigate the molecular basis of hereditary haemochromatosis (HH) in South Africa in order to establish a reliable, cost-effective molecular diagnostic service for this potentially lethal disorder. DESIGN: DNA samples of patient and control groups were screened for two common haemochromatosis (HFE) gene mutations. The local frequencies of mutations C282Y and H63D were determined and the DNA results correlated with biochemical parameters. SETTING: Patients were referred from private practitioners, health workers and pathologists for a molecular diagnosis of HH at the University of Stellenbosch Medical School. Twenty-two of the 244 referrals were clinically diagnosed with HH, while the remaining patients were family members of the probands or unrelated subjects referred solely on the basis of an abnormal iron profile. RESULTS: Seventeen of the 22 patient referrals (77%) diagnosed with HH were homozygous for the C282Y mutation, 3 (14%) were compound heterozygotes for mutations C282Y and H63D, and 2 patients (9%) did not exhibit either mutation. Screening of 458 control individuals from the general South African population demonstrated a carrier frequency of approximately 17% for the C282Y mutation among whites, implying that up to 1 out of every 115 South Africans of European descent may be homozygous for this founder-type mutation. Among 64 healthy blood donors of mixed ancestry, we detected 2 individuals heterozygous and 1 homozygous for the C282Y mutation. CONCLUSIONS: The detection of mutations C282Y and H63D at a high frequency in the majority of affected South African patients facilitates accurate pre-clinical and confirmatory diagnosis of HH in South Africa. Early detection by DNA screening and subsequent treatment by repeated phlebotomy can prevent disease onset in affected individuals. DNA diagnosis is particularly applicable to a common genetic disease such as HH, which is underdiagnosed and potentially lethal, but treatable.

Adult↗
PubMed1998

Attenuation of HLA-DR expression by mononuclear phagocytes infected with Mycobacterium tuberculosis is related to intracellular sequestration of immature class II heterodimers.

MHC class II expression was examined in macrophages infected with Mycobacterium tuberculosis. IFN-gamma increased the surface expression of class II molecules in THP-1 cells and this was markedly reduced in cells infected with M. tuberculosis. Despite this effect, steady state levels of HLA-DRalpha, HLA-DRbeta, and invariant (Ii) chains were equivalent in control and infected cells. Metabolic labeling combined with pulse-chase experiments and biochemical analysis showed that the majority of class II molecules in infected cells became resistant to endoglycosidase H, consistent with normal Golgi processing. However, results of intracellular staining and dual color confocal microscopy revealed a significant defect in transport of newly synthesized class II molecules through the endocytic compartment. Thus, compared with findings in control cells, class II molecules in infected cells colocalized to a minimal extent with a lysosomal-associated membrane protein-1+ endosomal compartment. In addition, in contrast to control cells, class II molecules in infected cells failed to colocalize with endocytosed BSA under conditions where this marker is known to label late endosomes, lysosomes, and the MHC class II compartment. Consistent with defective transport along the endocytic pathway, the maturation of SDS-stable class II alphabeta dimers--dependent upon removal of Ii chain and peptide loading of class II dimers in the MHC class II compartment--was markedly impaired in M. tuberculosis-infected cells. These findings indicate that defective transport and processing of class II molecules through the endosomal/lysosomal system is responsible for diminished cell surface expression of MHC class II molecules in cells infected with M. tuberculosis.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1998

Flow cytometry of mitotic cells.

We have developed a procedure using flow cytometric measurement of a mitosis-specific antigen that may be used to count mitotic cells and sort them from non-mitotic cells. The procedure may also be used in conjunction with measurement of cellular DNA content and of bromodeoxyuridine incorporation into cellular DNA to assign cells to the G1/G0, S, G2, or M phase of the cell cycle.

Antibodies, Monoclonal↗
PubMed1998

RSH (Smith-Lemli-Opitz) syndrome: "severe" phenotype with ectrodactyly.

We describe the antenatal ultrasound findings of growth retardation, oligohydramnios, mesomelic limb shortness, and cardiac, renal, and hand defects in a fetus who was postnatally diagnosed as having RSH ("Smith-Lemli-Opitz") syndrome. An unusual finding was ectrodactyly of both hands.

Brain↗
PubMed1998

Familial hypercholesterolemia: potential diagnostic value of mutation screening in a pediatric population of South Africa.

Three founder-related low-density lipoprotein receptor (LDLR) gene mutations, D154N, D206E and V408M, cause familial hypercholesterolemia (FH) in approximately 90% of South African Afrikaners. Two hundred and twenty-one South African children, from 85 affected families, were screened for the specific mutation identified previously in the index case. Sixty boys and 56 girls were heterozygous for mutation D154N (FH3), D206E (FH1) or V408M (FH2). Total and LDL cholesterol (LDLC) levels were similar among the children heterozygous for the three founder mutations, and mean values were significantly higher compared to those without a known mutation (p < 0.0001). Plasma cholesterol levels overlapped considerably between the different groups, suggesting that modifiable lifestyle factors remain important in children with FH. This study demonstrates the potential diagnostic value of mutation screening in a pediatric population with an enrichment of particular gene mutations.

Adolescent↗
PubMed1998

Prolactin-regulated apoptosis of Nb2 lymphoma cells: pim-1, bcl-2, and bax expression.

Lactogen-dependent Nb2 lymphoma cells, widely employed for studying prolactin (PRL) mitogenic mechanisms, are also useful for investigations of apoptosis in T-lineage lymphocytes. Utilizing PRL-dependent Nb2-11 cultures, apoptosis-regulatory genes were evaluated for participation in dexamethasone- (DEX) provoked cell death or its inhibition by PRL. Treatment of lactogen-starved, G1-arrested Nb2-11 cells with DEX (100 nM) activated apoptosis within 12 h evaluated by flow cytometric analysis of fragmented DNA. This effect was not associated with altered expression of bcl-2, bax, or pim-1. PRL (10 ng/mL), coincubated with DEX-treated cells, completely blocked DEX-induced apoptosis. This inhibition was associated with increased expression of bcl-2 and pim-1 mRNAs, genes reported to suppress apoptosis, within 2-6 h after addition of the hormone. Moreover, the increased transcription of bcl-2 and pim-1 was coupled to increases in their protein levels. The results suggest that bcl-2, bax, and pim-1 do not play a critical role in DEX-induced apoptosis in Nb2 cells. However, expression of bcl-2, together with pim-1, may have a role in mediating the antiapoptotic actions of PRL.

Animals↗
PubMed1997

Butyrate-induced reversal of dexamethasone resistance in autonomous rat Nb2 lymphoma cells.

The parental rat Nb2 lymphoma is a prolactin (PRL)-dependent T cell line. Exposure of a PRL-independent subline, Nb2-SFJCD1, to sodium butyrate (NaBT) causes transient reversal of their growth factor-independent proliferation in association with constitutive expression of protooncogenes pim-1 and c-myc. In the present study, we investigated the effect of NaBT treatment on the sensitivity of Nb2-SFJCD1 cells to dexamethasone (DEX)-induced apoptosis. Pretreatment with NaBT (2 mM, 72 h) partially reversed resistance to apoptosis in Nb2-SFJCD1 cells exposed to DEX (100 nM) for 12 h, assessed by flow cytometric analyses of DNA fragmentation. However, the cytolytic effect of DEX was abrogated by PRL in a time- and concentration-dependent manner. Evaluation of apoptosis-associated gene expression in NaBT-pre-treated cultures incubated with DEX or DEX+PRL indicated that the apoptosis resistance did not stem from altered bcl-2 or bax expression. However, there was a strong correlation between the resistance to DEX-activated apoptosis and their enhanced expression of pim-1 mRNA and protein. The results show that it is possible to reverse DEX-induced apoptosis of Nb2 pre-T cells and suggest the pim-1 gene product has an important role as a suppressor of this process, perhaps functioning as a mediator of PRL action.

Journal Article↗
PubMed1997

Effects of three parameters on speaking fundamental frequency.

Speaking fundamental frequency levels and usage (SFF, F0) are of interest to many investigators who study human speech and voice. Substantial research in the area has been carried out; common foci include SFF as related to infant cry, age, gender, adolescent voice change, language, race, voice pathology, and so on. Yet there still are a number of relationships which are not well understood and three of them will be addressed in this project. They involve the long-held notions that (1) a secular trend exists with SFF being lowered over time, (2) the use of university students in research of this type will create bias because they are physically different from average individuals, and (3) SFF can vary systematically for different types of speech (especially for oral reading and extemporaneous speaking). Experiments assessing these questions were carried out, but only certain of the postulates were supported. That is, while some evidence of a secular trend was found, it appeared inconsequential during the past quarter of this century; second, although university students were found to be slightly larger than a cohort approaching the average population, only minor vocal differences were found. Finally, it was observed that, in general, oral reading resulted in higher mean SFF's than those for spontaneous speech. However, this difference was not robust and, due to reversals, the resulting metric did not appear to be of good predictive value for individual speakers.

Adolescent↗
PubMed1997

Mortality of workers exposed to dieldrin and aldrin: a retrospective cohort study.

OBJECTIVE: To investigate the occurrence of long term health effects in humans exposed to aldrin and dieldrin, with an update of an earlier retrospective cohort mortality study. METHODS: A group of 570 workers employed between 1 January 1954 and 1 January 1970 either in a production or formulation plant were followed up for mortality until 1 January 1993. There were extensive industrial hygiene data available and biological monitoring data of aldrin and dieldrin for most of the workers. From these data individual estimates were made of the total intake of dieldrin. A total number of 2539.37 person-years at risk was added to the original study. RESULTS: 118 deaths were observed compared with 156 expected. No increase in mortality from liver cancer was found. However, there was an excess in mortality from rectal cancer. This excess was inversely related to the dose gradient. An analysis by job title did not show any excess cancer in any particular job. CONCLUSION: The study does not support a carcinogenic effect of dieldrin and aldrin in humans.

Adult↗
PubMed1996

Isolation, renaturation and partial characterization of recombinant human transferrin and its half molecules from Escherichia coli.

Recombinant human transferrin as well as N- and C-terminal half-transferrins, produced in Escherichia coli, are deposited in inclusion bodies by the bacteria. The isolation and purification of the recombinant proteins from these inclusion bodies are described here. The amino acid compositions and N-terminal sequences of the proteins were determined, and found to be in agreement with the known protein structure of human serum transferrin. Renaturation of the recombinant proteins is described, resulting in water-soluble iron-binding molecules. Iron binding was confirmed by 59Fe labelling, absorption spectrophotometry and EPR spectrometry.

Amino Acid Sequence↗
PubMed1996

A novel deletion at codon 441 of the APC gene associated with ophthalmic lesions (CHRPE) in a South African family.

A novel mutation at codon 441 in exon 10 of the adenomatous polyposis coli (APC) gene was identified in a South African family of mixed ancestry, using a convenient, non-radioactive, heteroduplex-SSCP screening assay. This single thymidine deletion after nucleotide position 1322 creates a frameshift resulting in a downstream stop codon at amino acid residue 453 of the APC gene. Genotypes of nine family members were subsequently correlated with the presence or absence of congenital hypertrophy of the retinal pigment epithelium (CHRPE), since expression of this common extracolonic manifestation of FAP is largely determined by the length of the truncated protein. CHRPE was absent in the five unaffected family members analysed, while four mutation positive subjects showed these ophthalmic lesions. Correlation between the molecular analysis and ophthalmic examinations, performed without knowledge of clinical and genetic status respectively, provided additional evidence in favour of the view that the range of phenotypic expression in FAP may result from different allelic manifestations of APC mutations.

Adenomatous Polyposis Coli↗
PubMed1996

Alterations in pim-1 and c-myc expression associated with sodium butyrate-induced growth factor dependency in autonomous rat Nb2 lymphoma cells.

Whereas Nb2-11 lymphoma cells critically require prolactin (PRL) for growth, Nb2-SFJCD1 subline cells are growth factor independent. Treatment with the differentiating agent, sodium butyrate (NaBT), has been demonstrated previously to lead to growth arrest of Nb2-SFJCD1 cells and a transient reversion to PRL growth requirement following removal of NaBT. In the present study, the relation of NaBT-induced growth arrest to the cell cycle was examined using flow cytometry, and the effect of PRL on expression of the immediate-early proto-oncogenes, pim-1 and c-myc, in NaBT-pretreated cultures was evaluated. Treatment of Nb2-SFJCD1 cells with 2 mM NaBT for 72 h caused growth arrest in the majority of the cells in the G1 phase of the cell cycle, an effect similar to that produced by lactogen deprivation in PRL-dependent Nb2 cultures. The addition of PRL stimulated a concentration-dependent re-entry into the cell cycle. In other experiments, NaBT treatment significantly reduced the steady-state levels of pim-1 and c-myc mRNA. Stimulation with PRL induced a rapid and concentration-dependent biphasic accumulation of each mRNA with similar kinetics. Maximal expression of both proto-oncogenes occurred within 2-4 h and after 12 h. Results from mRNA stability studies suggest that the observed increases in expression of pim-1 and c-myc most likely do not reflect increased stability of the transcripts. The results indicate that NaBT-induced differentiation in autonomous Nb2-SFJCD1 causes growth arrest of the cells in the G1 phase of the cell cycle and reduces the basal levels of pim-1 and c-myc mRNAs. Mitogenic stimulation with PRL reinitiates cell cycle progression characterized by biphasic expression of each proto-oncogene. It is suggested that NaBT is a useful tool for investigation of the malignant progression from growth factor dependency to autonomy in the Nb2 lymphoma paradigm.

Animals↗
PubMed1995

Perinatal death in two sibs with infantile cortical hyperostosis (Caffey disease).

We describe 2 sibs with lethal, prenatal-onset cortical hyperostosis. Antenatal sonographic diagnosis of the first sib was that of short limb dwarfism and thoracic dysplasia (nonspecific), possibly osteogenesis imperfecta. The second sib had a similar appearance on ultrasonography. The thickened, irregularly echodense diaphyses were an aid to diagnosis. Although sporadic cases and autosomal dominant inheritance have been described, an autosomal recessive cause for the lethal prenatal onset cases cannot be excluded.

Adult↗
PubMed1995

An in vitro study on the binding of Al(III) to human serum transferrin with the isoelectric focusing technique.

Transferrin saturated with Al3+ subjected to isoelectric focusing (IEF) in a pH gradient can be separated into four fractions, representing the apotransferrin, transferrin with aluminum at the metal binding site in the C- or N-terminal lobe, or both. The electrophoretic mobilities of these four fractions are identical to those of the iron-transferrin counterparts. Simultaneous binding of aluminum and iron to transferrin can also be demonstrated. The decreased saturation after IEF indicates that the affinity of transferrin for aluminum is low compared with its affinity for iron. This effect is particularly evident when bicarbonate is used as the synergistic anion in the loading procedure. In contrast, loading of transferrin with aluminum in the presence of oxalate produces a di-aluminum-transferrin complex that is stable during IEF.

Aluminum↗
PubMed1995

A two-step targeting approach for delivery of doxorubicin-loaded liposomes to tumour cells in vivo.

A two-step targeting approach was used to deliver doxorubicin-loaded liposomes to a murine tumour cell (P388 leukaemia) grown in culture and, more importantly, in vivo. Targeting was mediated through the use of an antibody specific for the Thy 1.2 antigen that is highly expressed on P388 cells. Briefly, the approach consists of prelabeling target cells with biotinylated anti-Thy 1.2 antibody prior to administration of drug-loaded liposomes that have streptavidin covalently attached to their surface. Results from in vitro studies demonstrate that a 30-fold increase in cell-associated lipid and a 20-fold increase in cell-associated doxorubicin can be achieved over control liposomes using this two-step procedure. Flow-cytometry and fluorescent-microscopy data were used to confirm that P388 cells can be stably labeled with the biotinylated anti-Thy 1.2 antibody in vivo. Subsequently, liposome-targeting studies were initiated in vivo, where target cell binding was assessed following i.p. or i.v. injection of doxorubicin-loaded liposomes into animals bearing P388 tumours prelabeled with biotinylated antibody. A streptavidin-mediated 3.7-fold increase in cell-associated lipid and drug was achieved when the liposomes were given i.p. When doxorubicin-loaded streptavidin liposomes were injected i.v., P388 cells located in the peritoneal cavity were specifically labeled, although the efficiency of this targeting reaction was low. Less than a 2-fold increase in cell-associated lipid was achieved through the use of target-specific (streptavidin-coated) liposomes. These studies demonstrate that the presence of a well-labeled target cell population within the peritoneal cavity will not promote accumulation of an i.v. injected, targeted liposomal drug. Furthermore, the importance of separating target-cell-specific binding from non-specific uptake by tumour-associated macrophages is discussed.

Animals↗