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Biomedical subjects

J McKay

Publications and source records attributed to J McKay.

At least 19 recordsLinked to original sources
PubMed1991

Ototoxicity due to cis-diamminedichloroplatinum in the treatment of ovarian cancer: influence of dosage and schedule of administration.

Ototoxicity associated with administration of cisplatin was assessed in four groups of patients suffering from advanced ovarian carcinoma. The purpose was to determine the influence of dosage, schedule of administration, and long-term treatment on pure-tone thresholds and other auditory parameters. One hundred and forty-five serial audiograms were obtained in 60 patients and compared with baseline audiograms. The treatment protocol consisted of two different dosages (low--50 mg/m2 and high--100 mg/m2) and three different schedules of administration (short--6 months, extended--12 months, and treatment in blocks--intervening months in which cisplatin was withheld). Using a conservative definition of auditory toxicity and statistical analyses of pure-tone threshold differences between groups, the results indicated that the low dose-short treatment regimens with either monthly administration of cisplatin, or administration in blocks, were the least ototoxic. Ototoxicity was found to increase with increasing cumulative dosages. Hearing loss was primarily in the high frequencies. The most severe ototoxic effects, which include tinnitus and hearing loss in the speech frequency range, were associated with the administration of high dosages over a short period of time. Individual variability in susceptibility to ototoxicity necessitates systematic audiometric monitoring throughout therapy.

Adult↗
PubMed1990

Azimuthal sensitivity of neurons in primary auditory cortex of cats. I. Types of sensitivity and the effects of variations in stimulus parameters.

1. Preliminary to studying the organization of azimuthal sensitivity of neurons along frequency-band strips in the primary auditory cortex (AI) of cat (see companion paper), this study examined the sensitivity of 251 units in cat AI to variations in the azimuthal location of sound sources in the frontal hemifield. Most units (231) were tested with tones at the characteristic frequency (CF; frequency to which the unit had the lowest threshold). Unit CFs ranged from 5 to 36 kHz. A large number of units (91) were tested with broadband noise stimuli, and a few units were also tested at other frequencies within the cell's tuning response area. 2. When tested at stimulus intensities 20-30 dB above CF or noise threshold, the different forms of azimuthal sensitivity exhibited by AI neurons could be divided into (1) contra-field azimuth functions; (2) ipsi-field functions; (3) central-field functions; (4) omnidirectional functions, and (5) multipeaked functions. Contra-field azimuth functions were the most prevalent, with 45.9% of units tested with CF tones and 42.9% of units tested with noise exhibiting this type of azimuthal sensitivity. Ipsi-field azimuthal sensitivity was found in 16.9% of units tested with CF tones and 19.8% of units tested with noise. Central-field azimuthal sensitivity was seen in 10.8% of units tested with CF tones and 17.6% of units tested with noise. Omnidirectional azimuthal sensitivity was seen in 19.9% of units tested with CF tones and 17.6% of units tested with noise, whereas multipeaked azimuthal sensitivity was found in 6.5% of units tested with CF tones and 5.5% of units tested with noise. 3. The effects of increasing stimulus intensity on azimuthal sensitivity were examined in 185 units tested with CF tones and 67 units tested with noise. For four major classes of azimuthal sensitivity (contra-field, ipsi-field, central-field and omnidirectional), the most common effect (approximately 60% of each class) was for the azimuth function to remain constant in form by the defining criteria for these classes. The next most common effect for all classes except omnidirectional azimuth functions was for an expansion of the azimuthal range eliciting responses. (The definition of omnidirectionality precluded any expansion of the response range in this class of azimuth function). A smaller number of units in some classes showed a compression of the azimuth function to a smaller response range, and others showed more complex expansive and compressive effects with increasing stimulus intensity.(ABSTRACT TRUNCATED AT 400 WORDS)

Acoustic Stimulation↗
PubMed1989

Reduced bone mass in daughters of women with osteoporosis.

To determine whether premenopausal daughters of women with postmenopausal osteoporosis have lower bone mass than other women of the same age, we measured the bone mineral content of the lumbar spine and femoral neck and midshaft, using dual-photon absorptiometry, in 25 postmenopausal women with osteoporotic compression fractures and in 32 of their premenopausal daughters; we then compared the results with those in normal controls. As compared with normal postmenopausal women, women with osteoporosis had lower bone mineral content in the lumbar spine, femoral neck, and femoral midshaft by 33, 24, and 15 percent, respectively (P less than 0.001 for each comparison by the one-tailed t-test). As compared with normal premenopausal women, the daughters of women with osteoporosis had lower bone mineral content at these sites by 7, 5, and 3 percent, respectively (P = 0.03, 0.07, and 0.15, respectively, by the one-tailed t-test). In terms of a standardized score, we calculated that the mean (+/- SEM) relative deficits in bone mineral content in the daughters of women with osteoporosis were 58 +/- 18 percent (lumbar spine) and 34 +/- 16 percent (femoral neck) of the relative deficits in their mothers. We conclude that daughters of women with osteoporosis have reduced bone mass in the lumbar spine and perhaps in the femoral neck; this reduction in bone mass may put them at increased risk for fractures. We also conclude that postmenopausal osteoporosis may result partly from a relatively low peak bone mass rather than from excessive loss of bone.

Bone and Bones↗
PubMed1989

Allograft incorporation: a biomechanical evaluation in a rat model.

Allogeneic bone from Sprague-Dawley rat femurs was subjected to levels of freezing and/or irradiation that are known to have produced changes in the associated immune responses to these grafts. This bone was transplanted into an experimentally created gap in the femur of Lewis rats. The subsequent healing of the transplants in the Lewis rats was studied at 2, 4, 8, and 16 weeks after transplantation using torsion testing to failure. There was no clear advantageous biologic response in the union of the grafted material accompanying the alterations in immunologic response as measured by biomechanical testing of the proximal osteosynthesis site in torsion. The torsional strength of all of these groups remained lower than that of intact bone. Furthermore, none of the frozen and/or irradiated allografts exceeded the strength of the fresh allograft at a statistically significant level.

Animals↗
PubMed1988

A highly conserved, 5' untranslated, inverted repeat sequence is ineffective in translational control of the alpha 1(I) collagen gene.

An inverted repeat sequence, extending from the 5' untranslated region of the first exon through the translation initiation codon, is highly conserved in the alpha 1(I), alpha 2(I) and alpha 1(III) collagen genes of mammals and birds. It has been suggested that this sequence functions in translational control of collagen gene expression. When the upstream axis of the dyad of symmetry was deleted, the efficiency of translation of transcripts from a human alpha 1(I) collagen-bovine growth hormone fusion gene was unchanged in either transiently or stably transfected cells. Furthermore, mRNA levels were not affected when the same deletion was transferred to a collagen-human growth hormone fusion gene in which the collagen sequence retained the first intron. Examination of human alpha 1(I) DNA, extending from the start of transcription to the start of translation, by the DNAse I protection procedure revealed evidence for protein binding to a sequence just upstream of the inverted repeat sequence but not to the inverted repeat itself. Our studies therefore indicate that this highly conserved DNA sequence does not function generally in translational or transcriptional control of type I procollagen synthesis.

Animals↗
PubMed1988

Antithrombin Oslo: type Ib classification of the first reported antithrombin-deficient family, with a review of hereditary antithrombin variants.

Patients with classical antithrombin deficiency (Type I) from seven unrelated kindreds were studied by crossed immunoelectrophoresis of plasma in the presence and absence of heparin. The only abnormal pattern was found in the kindred first reported by Egeberg in 1965. An abnormal cathodal peak of antithrombin antigen was found in the presence, but not the absence, of heparin in the first dimension gel. We have named this variant antithrombin Oslo. Such evidence of an abnormal protein, despite equivalent low levels of antithrombin antigen and activity, has been denoted previously by Sas as Type Ib deficiency. In the context of this new report, we review the literature to date on 33 other variants of the Types Ib, II and III subclassifications with a discussion of the value of the classification scheme.

Antithrombins↗
PubMed1988

The first intron of the alpha 1(I) collagen gene contains several transcriptional regulatory elements.

The first intron of the human alpha 1(I) collagen gene contains a negatively acting element that inhibits transcription of the chloramphenicol acetyltransferase gene driven by either a collagen or an SV40 basal promoter (Bornstein, P., McKay, J., Morishima, J., Devarayalu, S., and Gelinas, R. E. (1987) Proc. Natl. Acad. Sci. U. S. A. 84, in press). We now find that this element is flanked by sequences that both neutralize the inhibitory effect and impart a net positive effect on transcription. A collagen-human growth hormone minigene was constructed in which varying lengths of the collagen intron were retained. Plasmids were transfected into chick tendon fibroblasts, and transcriptional activity was measured by solution hybridization with an antisense RNA probe. The presence of the intact intronic sequence stimulated transcription by a factor of 2-3-fold in comparison with intron-deleted plasmids. However, the isolated negatively acting element inhibited transcription by a factor of 15-20-fold. Surprisingly, this effect was markedly orientation-dependent. Intronic segments flanking the negatively acting element stimulated transcription both when cloned 5' to the collagen promoter in chloramphenicol acetyltransferase-based plasmids and 3' in collagen-human growth hormone constructions. We conclude that expression of the alpha 1(I) collagen gene is controlled by several intronic elements that function coordinately with 5'-flanking and promoter elements.

Acetyltransferases↗
PubMed1988

Effect of early menopause on bone mass in normal women and patients with osteoporosis.

PURPOSE: Early menopause is widely regarded as a risk factor for osteoporosis. The aim of this study was to determine whether this risk is conferred by a lower bone mass. PATIENTS AND METHODS: Two hundred thirteen normal postmenopausal women and 55 women with postmenopausal osteoporosis (vertebral fractures) underwent bone mass measurements at the lumbar spine, femoral neck, and midshaft using dual-photon absorptiometry. To examine the effect of early menopause, postmenopausal normal women were stratified according to whether menopause occurred before or after the age of 50 years. Patients with osteoporosis were stratified in the same way. RESULTS: Patients with osteoporosis had menopause at an earlier age than control subjects, but the difference in bone mass between the patients with osteoporosis and the control subjects could not be attributed to this earlier age at menopause. Furthermore, within the osteoporotic patient group, those with early menopause did not have lower bone mass than those with normal age at menopause. Similarly, within the normal subject group, those with early menopause did not have lower bone mass than those with normal age at menopause. CONCLUSION: Patients with osteoporosis have lower bone mass, which is independent of the age at menopause. Although a small effect (less than or equal to 5 percent) of early menopause on bone mass cannot be entirely excluded, these data suggest that the amount of bone lost following menopause is the same irrespective of the age at which menopause occurs. If early menopause is a risk factor for osteoporosis, the risk is not conferred by a bone mass substantially lower than predicted had menopause occurred later, but may be related to the duration of exposure to minimal trauma at low bone mass.

Age Factors↗
PubMed1988

Interactions between the promoter and first intron are involved in transcriptional control of alpha 1(I) collagen gene expression.

The first intron of the human collagen alpha 1(I) gene contains several positively and negatively acting elements. We have studied the transcription of collagen-human growth hormone fusion genes, containing deletions and rearrangements of collagen intronic sequences, by transient transfection of chick tendon fibroblasts and NIH 3T3 cells. In chick tendon fibroblasts, but not in 3T3 cells, inversion of intronic sequences containing a previously studied 274-base-pair segment, A274, resulted in markedly reduced human growth hormone mRNA levels as determined by an RNase protection assay. This inhibitory effect was largely alleviated when deletions were introduced in the collagen promoter of plasmids containing negatively oriented intronic sequences. Evidence for interaction of the promoter with the intronic segment, A274, was obtained by gel mobility shift assays. We suggest that promoter-intron interactions, mediated by DNA-binding proteins, regulate collagen gene transcription. Inversion of intronic segments containing critical interactive elements might then lead to an altered geometry and reduced activity of a transcriptional complex in those cells with sufficiently high levels of appropriate transcription factors. We further suggest that the deleted promoter segment plays a key role in directing DNA interactions involved in transcriptional control.

Chromosome Deletion↗
PubMed1987

Regulatory elements in the first intron contribute to transcriptional control of the human alpha 1(I) collagen gene.

Several lines of evidence have suggested that the regulation of type I collagen gene transcription is complex and that important regulatory elements reside 5' to, and within, the first intron of the alpha 1(I) gene. We therefore sequenced a 2.3-kilobase HindIII fragment that encompasses 804 base pairs of 5' flanking sequence, the first exon, and most of the first intron of the alpha 1(I) human collagen gene. A 274-base-pair intronic sequence, flanked by Ava I sites (A274), contained a sequence identical to a high-affinity decanucleotide binding site for transcription factor Sp1 and a viral core enhancer sequence. DNase I protection experiments indicated zones of protection that corresponded to these motifs. When A274 was cloned 5' to the chloramphenicol acetyltransferase (CAT) gene, driven by an alpha 1(I) collagen promoter sequence, and expression was assessed by transfection, significant orientation-specific inhibition of CAT activity was observed. This effect was most apparent in chicken tendon fibroblasts, which modulate their level of collagen synthesis in culture. We propose that normal regulation of alpha 1(I) collagen gene transcription results from an interplay of positive and negative elements present in the promoter region and within the first intron.

Amino Acid Sequence↗
PubMed1987

Hydrotherapy pools.

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Costs and Cost Analysis↗