Biomedical subjects
Publications and source records attributed to R Harris.
We devised a specimen to test EM autoradiographic resolution for calcium-45 (and phosphorous-33). A dry emulsion film was used for soluble compounds. We obtained a resolution (HD) value of 2300 +/- 500 A. This value is no larger than that previously obtained for Carbon -14, whose emission is about 1.6-fold lower. This result is as expected on theoretical grounds.
An intensive regimen of combined etoposide (VP-16) and 5-azacitidine (5-Az) was used to treat 96 children and adolescents with refractory or relapsed acute nonlymphocytic leukemia (ANLL). Patients were given two sequential five-day courses of VP-16, 250 mg/m2 for three days, followed by 5-Az, 300 mg/m2 for two days. An additional five-day course was administered if marrow aplasia was not evident by day 13. A complete remission rate of 45% was achieved with a median of two courses of VP-16 and 5-Az. The outcome of induction therapy was not influenced by prior treatment, blast cell morphology, or disease status on study entry (refractory or relapsed). Twenty-seven patients have relapsed after remission periods of 35 to 920 days (median, 110 days); seven others are free of leukemia for up to 519 days. The effectiveness of VP-16/5-Az combination therapy in patients refractory to anthracyclines and cytarabine indicates a potential role for these compounds in first-line treatment of patients with ANLL.
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We explored the potential role of microbial synergy in an experimental rat osteomyelitis model. Osteomyelitis was assessed by gross pathologic conditions and quantitative cultivation of rat tibiae for the implanted organisms 21 days after challenge. When Staphylococcus aureus was used alone, the 50% infective dose (ID50) and the 100% infective dose (ID100) were 400 and 25,000 colony-forming units (CFU), respectively. When Bacteroides fragilis was inoculated alone, the ID50 was 150,000 organisms, and the ID100 was not confidently determined. Subinfectious numbers of B. fragilis added to the staphylococcal inocula yielded an ID100 as low as 20 staphylococci. Mixed inocula with 20 or 200 staphylococci and increasing numbers of B. fragilis yielded a dose-dependent increase in the number of staphylococci isolated from osteomyelitic tibiae. Multiple linear regression analysis confirmed the two inocula and their interaction to be significantly predictive of the 21-day quantitative assessment of staphylococci (r = 0.80). Synergy was most striking at low bacterial inocula. When even large numbers of S. aureus were added to B. fragilis, the B. fragilis inoculum required to initiate B. fragilis osteomyelitis was essentially unchanged. We conclude that small numbers of B. fragilis allow remarkably low numbers of S. aureus (20 or 200 CFU) to establish osteomyelitis in the rat.
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The finding of a genetically linked polymorphic DNA marker has made possible a predictive test for Huntington's chorea. This DNA probe has so far been used only for research and has technical limitations, but some workers now wish to apply it to clinical predictions. Those identified by the probe as being probable carriers of the Huntington's chorea gene would be exposed to uncertain psychological risks and social pressures. Ethical guidelines should be established, but these require greater knowledge of the potential benefits and hazards of this powerful new procedure. Controlled clinical trials are urgently needed.
The structure of reverse (R)-banded and telomeric (T)-banded chromosomes was studied by examination of the same chromosomes first in the light microscope (LM) followed by the scanning electron microscope (SEM). This procedure demonstrated a structural basis to both the R- and T-banding techniques. A direct correlation was shown between the LM staining patterns and the structural patterns observed in the SEM. In the R-banded chromosomes the positively stained R-bands, viewed by LM, corresponded to highly fibrous three-dimensional regions in the SEM. The negatively stained R-interbands corresponded to flatter regions from which material appeared to have been extracted. These structural observations strongly support the suggestion that chromosomal material is preferentially lost from the R-interbands with aggregation of fibres in the R-bands. T-banded chromosomes showed a similar structure to the R-banded chromosomes. The positively stained T-bands located at the telomeres corresponded to regions of highly aggregated fibres. The remainder of the chromosome, corresponding to the negatively stained area, had a flattened and extracted appearance. These similarities in morphology between the T- and R-banded chromosomes support the view that T-bands result from a progressive breakdown of the R-banded chromosome structure.
Analysis of available nucleotide sequence data for class I HLA genes has established that the seventh intron is one of the gene regions which expresses the highest degree of locus specificity (the percentage sequence divergence between nonallelic genes minus the percentage sequence divergence between allelic genes). We have subcloned short DNA sequences including this region from the HLA-Cw3 gene. Two clones, pC250 and pC800, were tested by hybridizing them at high stringency to a panel of clones containing class I HLA genes. Under conditions permitting a strong hybridization signal with a C-locus gene, pC800 also expressed a weak but significant hybridization to other class I genes, while pC250 appeared to hybridize exclusively to the C-locus gene. Hybridization of the pC250 probe at high stringency to Hind III-digested genomic DNA from a panel of unrelated individuals and homozygous typing cell lines revealed a single band in all cases. However, equivalent hybridization against Eco RI-digested DNA revealed two hybridization bands, one at 7.9 kb which correlated with the serologically defined Cw5 and Cw8 alleles, and one at 7.6 kb which correlated with the Cw1, Cw2, Cw3, Cw4, Cw6, and Cw7 alleles.
Eleven families with X-linked dominant hypophosphataemic rickets (HPDR) have been typed for a series of X chromosome markers. Linkage with probe 99.6 (DXS41) was demonstrated with a peak lod score of 4.82 at 10% recombination. Multilocus linkage analysis showed that HPDR maps distal to 99.6; this probe has previously been located at Xp22.31-p21.3 by in situ hybridisation. In the mouse hypophosphataemia (Hyp) maps to the distal part of the X chromosome; our location in man is consistent with a scheme which relates the mouse and human X chromosomes by two rearrangements. No marker has yet been found which shows no recombination with HPDR.
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Data from our trial of periconceptional vitamin supplementation for the prevention of neural tube defects have been analysed to assess the influence of various factors on recurrence rates of neural tube defect. Our data suggest that the risk of recurrence of neural tube defect is influenced by the number of previous neural tube defects, area of residence, immediately prior miscarriage, and interpregnancy interval. None of these factors, however, contributed any significant differential risk between supplemented and unsupplemented mothers. Hence we conclude that the highly significant difference in recurrence rates of neural tube defect between supplemented and unsupplemented mothers was due to vitamin supplementation.
HLA haplotype sharing was studied in 35 sibships in which there were two or more members with rheumatoid arthritis (RA). Haplotype sharing RA siblings was random in 15 sibships which included members with clinical or immunological features of autoimmune thyroid disease. In the remaining 20 'non-thyroid' sibships the frequencies of RA siblings sharing 0, 1, or 2 haplotypes were 0.04, 0.48, and 0.48 respectively (p = 0.006). 67% of RA probands in the 'thyroid' families and 90% in the other families were HLA-DR4 positive. It is suggested that there is genetic heterogeneity in the pathogenesis of RA with at least two independent genes within the major histocompatibility complex (MHC) predisposing to RA. One gene is in linkage disequilibrium with HLA-DR4, while results of comparison of DR antigen frequencies in DR4 negative RA and control groups suggest that the other is in linkage disequilibrium with HLA-DR1 and 3. In the thyroid disease families both genes are frequently present and as either may predispose to arthritis, HLA haplotype sharing is random. The frequencies of HLA haplotype sharing in the 'non-thyroid' families suggest that there is a dominant susceptibility gene in linkage disequilibrium with HLA-DR4, whose frequency is 5% and penetrance about 20%.
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A total of 102 families with Duchenne muscular dystrophy has been studied with linked DNA polymorphisms as an aid to estimating carrier risks for female relatives. Early work using probes RC8, L1.28, and pXUT23 gave very little clinically useful information because of the high recombination rates between these probes and Duchenne muscular dystrophy and the low proportion of women who were heterozygous. Clinically useful results were obtained using probes 99-6, 754, and particularly pERT87. Examples are given of deductions which can be made using these probes. The importance of a genetic register is stressed as a tool for long term contact with the families and other professionals.
Affinity chromatography of serum on lentil lectin bound to Sepharose 4B has been used to identify different forms of alpha-fetoprotein in serum of patients with liver disease. We studied eight patients with non-malignant liver disease, finding that 7-15% of the serum alpha-fetoprotein bound to the lectin. In contrast, for 15 patients with malignant liver disease, 25-83% of the serum alpha-fetoprotein bound to the lectin. Evidently, this simple technique can be used effectively to differentiate these two conditions.