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Biomedical subjects

K Friend

Publications and source records attributed to K Friend.

15 recordsLinked to original sources
PubMed1996

Dynamic mutation loci: allele distributions in different populations.

To assess the relative contributions of trans-acting factors (replication and repair functions) and cis-acting elements (repeat and flanking DNA composition) to the mechanism of trinucleotide repeat sequence mutation we have analysed the distribution of copy number polymorphisms at 12 loci associated with dynamic mutations in 15 populations of different ethnic origins. Genome wide instability of repeats in a particular population would be evidence of trans-acting factor instigation of the mutation process, whereas instability at a particular locus (perhaps even in several populations) would be evidence that the composition of the particular locus was the most significant factor contributing to mutation. The FRA16A locus is highly polymorphic in only the European population. Some other loci exhibit distinct distributions of alleles between different populations. Therefore sequences in the vicinity of the repeat -- the cis component of a particular locus -- appear(s) to be more important in the mutation mechanism than sporadic genome-wide instability induced by trans-acting factors such as the DNA mismatch repair enzymes.

Alleles↗
PubMed1996

The orderliness of the growth hormone (GH) release process and the mean mass of GH secreted per burst are highly conserved in individual men on successive days.

Endocrine glands signal their remote target tissues via physiologically pulsatile release of regulatory molecules. A cardinal assumption of most pathophysiological experiments is that discrete attributes of pulsatile hormone secretion are stable over successive untreated observation intervals; i.e. repeated measurements show serial within-subject reproducibility. To test this hypothesis in the GH axis, we sampled blood every 10 min for 48 h in 14 healthy men (age range, 29-77 yr; body mass index, 21-51 kg/m2). The 2 consecutive 24-h serum profiles were subjected to ultrasensitive GH chemiluminescence assay (sensitivity, 0.002 micrograms/L) with a new dose-dependent variance model to estimate within-assay precision. We then applied deconvolution analysis to estimate the number, mass, amplitude, and duration of underlying GH secretory bursts as well as simultaneously calculate the apparent GH half-life and any concurrent basal hormone secretion. Test-retest consistency was assessed by the Pearson correlation coefficient, and differences were determined by paired nonparametric (Wilcoxon) testing. Comparing successive 24-h profiles, no significant differences existed in any of the foregoing secretion or half-life measures or in a novel estimate of the relative disorderliness of hormone release, namely approximate entropy. Correlation was minimal for secretory burst amplitude and half-duration. In contrast, the calculated mean mass of GH secreted per burst was highly conserved across sessions within subjects, with an r value of 0.932 (P < 10(-6). This correlation equaled or exceeded that of mean and integrated serum GH concentrations on consecutive days (r = 0.920; P = 0.00003). The calculated daily GH production rate was also strongly reproduced (r = 0.784; P = 0.0009). Moreover, the within-subject GH half-life and GH secretory burst frequency estimates were well correlated on successive days (P = 0.034-0.004; r = 0.568-0.711). Approximate entropy values were consistent at r = 0.837 (P = 0.0019). In addition, basal GH secretion rates correlated at r = 0.622 (P = 0.0176). We conclude that homeostatic control mechanisms within the GH-insulin-like growth factor I axis strongly preserve the day to day mean mass of GH secreted per burst and the serial orderliness of the GH release process in individual healthy men across a wide span of ages and body compositions.

Adult↗
PubMed1992

Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease.

It is now clear that mutations of at least two genetic loci can lead to autosomal dominant polycystic kidney disease (ADPKD). We have compared the clinical features of ADPKD caused by mutations at the PKD1 locus (linked to the alpha-globin complex on chromosome 16) with those of disease not linked to the locus (non-PKD1). We identified 18 families (285 affected members) with mutations at PKD1 and 5 families (49 affected individuals) in which involvement of this locus could be dismissed. Non-PKD1 patients lived longer than PKD1 patients (median survival 71.5 vs 56.0 years), had a lower risk of progressing to renal failure (odds ratio 0.35, 95% CI 0.13-0.92), were less likely to have hypertension (odds ratio adjusted for age and family of origin 0.29, 0.11-0.80), were diagnosed at an older age (median 69.1 vs 44.8 years), and had fewer renal cysts at the time of diagnosis. Although most of the PKD1 families were ascertained through clinics treating patients with renal impairment, no non-PKD1 family was identified through this source. Non-PKD1 ADPKD has a much milder phenotype than that linked to PKD1. Partly as a result of this difference in severity, the reported prevalence of this genotype is probably an underestimate.

Adolescent↗
PubMed1992

Evidence of founder chromosomes in fragile X syndrome.

The mutation responsible for fragile X syndrome and myotonic dystrophy involves the amplification of a simple trinucleotide repeat sequence, which increases in successive generations of affected pedigrees accounting for increasing penetrance of both disorders. This common molecular basis suggests that the two diseases may share other genetic features, but whereas myotonic dystrophy exhibits a significant founder chromosome effect, fragile X syndrome apparently has a very high mutation frequency. By haplotype analysis of microsatellite markers which flank the fragile X unstable element, we have uncovered evidence of founder chromosomes of the fragile X 'mutation'. Disorders caused by heritable unstable elements may therefore exhibit common genetic properties including anticipation and founder chromosomes.

Base Sequence↗
PubMed1991

Captopril renography in the diagnosis of renal artery stenosis: accuracy and limitations.

PURPOSE: The purpose of this study was to determine the sensitivity, specificity, and clinical usefulness of renography performed in combination with captopril administration ("captopril renography") in diagnosing renal artery stenosis. PATIENTS AND METHODS: Fifty-five patients with suspected renal artery stenosis underwent renography prior to performance of renal angiography. Renography was performed on two consecutive days using technetium-99m-diethylenetiamine pentaacetic acid (DTPA) as an index of glomerular filtration rate and iodine-131-orthoiodohippurate (OIH) as an index of renal blood flow. Captopril (25 mg orally, crushed) was administered 1 hour before the second study. Renal artery stenosis was defined as a stenosis exceeding 70%. Renographic criteria were then established, retrospectively, to differentiate renal artery stenosis from essential hypertension based on (1) asymmetry of function and (2) the presence of captopril-induced changes. RESULTS: Renal artery stenosis was detected in 35 of 55 patients (21 with unilateral and 14 with bilateral stenosis). Three criteria were established for diagnosing renal artery stenosis: (1) a percent uptake of DTPA by the affected kidney of less than 40% of the combined bilateral uptake, (2) a delayed time to peak uptake of DTPA, which was more than 5 minutes longer in the affected kidney than in the contralateral kidney, (3) a delayed excretion of DTPA, with retention at 15 minutes, as a fraction of peak activity, more than 20% greater than in the contralateral kidney. The presence of one or more of these criteria was diagnostic of renal artery stenosis, with a sensitivity and specificity of 71% and 75%, respectively before captopril administration, and 94% and 95% after captopril administration. Lesser degrees of asymmetry (i.e., uptake of 40% to 50%) had very poor diagnostic specificity. Among patients with bilateral stenoses, asymmetry identified the more severely affected kidney, but the presence or absence of stenosis in the contralateral kidney could not be reliably determined. When pre- and post-captopril studies were compared, the presence of captopril-induced scintigraphic changes was a highly specific finding for renal artery stenosis, but occurred in only 51% of the cases. OIH scintigraphy provided similar results, with slightly lower sensitivity and specificity. CONCLUSION: Asymmetry of DTPA uptake, time to peak uptake, or retention seen on a single post-captopril renogram is a highly sensitive and specific finding in detecting renal artery stenosis but does not distinguish unilateral from bilateral disease. If renograms are obtained both before and after captopril administration, the presence of captopril-induced change is a highly specific finding for the detection of renal artery stenosis, but the sensitivity of this finding is low.

Antihypertensive Agents↗
PubMed1991

Determination of Duchenne muscular dystrophy carrier status by single strand conformation polymorphism analysis of deleted regions of the dystrophin locus.

The molecular characterisation of the dystrophin gene, mutations in which are responsible for X linked Duchenne and Becker muscular dystrophies, has led to an array of strategies for the diagnosis of affected subjects and carriers. Initially these were based on blotting and hybridisation technologies but have recently been largely superseded by PCR based techniques which afford greater speed and sensitivity. We describe the use of single strand conformation polymorphism to detect heterozygosity in regions of the dystrophin locus which are deleted in affected males, to determine the carrier status of their female relatives.

Dystrophin↗
PubMed1990

Probe, VK5B, is located in the same interval as the autosomal dominant adult polycystic kidney disease locus, PKD1.

The polymorphic DNA probe VK5B (D16S94) was mapped by genetic linkage in families from the Centre d'Etude de Polymorphisme Humain (CEPH) as being in the same interval as the autosomal dominant adult polycystic kidney disease locus (PKD1). The maximum likelihood estimate of the genetic location of VK5B using multipoint linkage analysis was 9.6 cM proximal to 3'HVR (D16S85) and 5.4 cM distal to CRI-0327 (D16S63), in males. The VK5B probe may be useful in PKD1 families for prenatal and presymptomatic diagnosis of the disease. Additional typing of PKD1 families is required to determine whether the location of VK5B is distal or proximal to (PKD1).

Adult↗
PubMed1989

Assignment of anonymous DNA probes to specific intervals of human chromosomes 16 and X.

Anonymous DNA probes mapping to human chromosome 16 and the distal region of the human X chromosome were isolated from a genomic library constructed using lambda EMBL3 and DNA from a mouse/human hybrid. The hybrid cell contained a der(16)t(X;16)(q26;q24) as the only human chromosome. Fifty clones were isolated using total human DNA as a hybridisation probe. Forty six clones contained single copy DNA in addition to the repetitive DNA. Pre-reassociation with sonicated human DNA was used to map these clones by a combination of Southern blot analysis of a hybrid cell panel containing fragments of chromosomes 16 and X and in situ hybridisation. One clone mapped to 16pter----16p13.11, one clone to 16p13.3----16p13.11, four clones to 16p13.3----16p13.13, two clones to 16p13.13----16p13.11, one clone to 16p13.11, seven clones to 16p13.11----16q12 or 16q13, four clones to 16q12 or 16q13, three clones to 16q13----16q22.1, four clones to 16q22.105----16q24, and nineteen clones to Xq26----Xqter. Two clones mapping to 16p13 detected RFLPs. VK5 (D16S94) detected an MspI RFLP, PIC 0.37. VK20 (D16S96) detected a TaqI RFLP, PIC 0.37 and two MspI RFLPs, PIC 0.30 and 0.50. The adult polycystic kidney disease locus (PKD1) has also been assigned to 16p13. The RFLPs described will be of use for genetic counselling and in the isolation of the PKD1 gene. Similarly, the X clones may be used to isolate RFLPs for genetic counselling and the isolation of genes for the many diseases that map to Xq26----qter.

Animals↗
PubMed1976

In vitro sensitization to embryonic antigens.

Lymphoid cells from virgin, untreated BALB/c mice cultured 5 days on 12- or 13-day syngeneic mouse embryo fibroblasts (MEF) or on cells from a syngeneic 3-methylcholanthrene-induced mouse sarcoma (1315) were cytotoxic for 1315 tumor target cells when tested with a microcytotoxicity assay. They did not kill embryo or skin fibroblast target cells. Lymphoid cells cultured with 11-, 14- or 17-day MEF were not cytotoxic for cells from the 1315 tumor, from embryo or from adult skin. Lymphoid cells from multiparous BALB/c mice cultured on 11-, 12- or 13-day MEF, on line 1315 sarcoma cells or on skin fibroblasts were cytotoxic for tumor target cells. MEF were killed by multipara lymphoid cells that had been cultured on 11-, 12- or 13-day MEF or on the 1315 tumor line. Multipara lymphoid cells cultured on 1315 cells or 12-day MEF were cytotoxic for adult skin fibroblasts, while multipara lymphoid cells cultured on 14- or 15-day MEF were not cytotoxic for any of the target cells. The data thus indicate that lymphoid cells can mediate both primary and secondary immune reaction in vitro to antigens shared by neoplastic and normal embryonic cells, and that the primary reactions appear to be more specific to putatively embryonic tumor antigen(s) than the secondary ones.

Animals↗
PubMed1976

Efficient detection of soft agar grown colonies using a tetrazolium salt.

The use of 2-(p-iodophenyl)-3-(p-nitrophenul)-5-phenyl tetrazolium chloride at concentrations of from 0.25-1.0 mg/ml, when added to plates containing soft agar grown colonies, colors the cell clusters a deep brick red against a colorless background. This greatly facilitates the quantitation of such colonies since clusters of cells containing as few as 16-32 cells are visible macroscopically. Incubation for 20 h is optimal although coloration takes place as early as 6-8 h.

Agar↗