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Biomedical subjects

J Yardley

Publications and source records attributed to J Yardley.

At least 19 recordsLinked to original sources
PubMed2004

The effect of aging and caloric restriction on mitochondrial protein density and oxygen consumption.

It has been proposed that part of the anti-aging mechanism of caloric restriction (CR) involves changes in mitochondrial function. To investigate this hypothesis, mitochondria from various tissues of male Brown Norway rats (fully fed and CR) were isolated and respiration rates determined. In mitochondria from liver, heart, brain and kidney, there were no significant effects of CR on state 4 mitochondrial respiration rate. Further experiments using liver mitochondria under a variety of incubation conditions confirmed that CR does not alter mitochondrial respiration rate in this tissue. However, the respiration rate of mitochondria from brown adipose tissue (BAT) of CR animals was approximately three-fold higher compared to mitochondria from fully fed controls. Mitochondrial protein density was significantly higher in liver tissue of CR animals; it was significantly lower in heart and unchanged in BAT. It is concluded that whilst CR results in tissue-specific changes in mitochondrial respiration rate, these effects do not explain the CR-induced changes in free radical production reported previously for these organelles.

Aging↗
PubMed2001

Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy.

Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial dystrophies, leading to corneal opacification. This group of conditions includes Fuchs' endothelial dystrophy of the cornea (FECD), one of the commonest indications for corneal transplantation performed in developed countries, posterior polymorphous dystrophy (PPCD) and the congenital hereditary endothelial dystrophies (CHED). A genome-wide search of a three-generation family with early-onset FECD demonstrated significant linkage with D1S2830 (Z(max) = 3.72, theta = 0.0). Refinement of the critical region defined a 6-7 cM interval of chromosome 1p34.3-p32 within which lies the COL8A2 gene. This encodes the 703 amino acid alpha2 chain of type VIII collagen, a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD. This is the first description of the molecular basis of any of the corneal endothelial dystrophies or of mutations in type VIII collagen in association with human disease. This suggests that the underlying pathogenesis of FECD and PPCD may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest derived corneal endothelial cell.

Amino Acid Sequence↗
PubMed2000

Crossover breakpoint mapping identifies a subtelomeric hotspot for male meiotic recombination.

Segregation analysis of CEPH and other pedigrees yielded six paternal crossover breakpoints in the approximately 85 kb interval between the minisatellite loci D16S309 (MS205) and D16S83 (EKMDA2) in 16p13.3. Three crossovers were mapped to within the same small (<3 kb) interval, which does not co-localize with any tandem repeat array or expressed sequence. Haplotyping of loci harbouring single nucleotide polymorphism (SNP) markers in this interval confirmed the exchange of flanking markers in the three recombinant individuals. Sequence analysis revealed the presence of recombination-associated motifs and binding sites for the protein translin. Haplotyping of 108 individuals from three European populations at four loci harbouring SNPs showed substantial linkage equilibrium across this interval. Hence molecular and population genetic data are consistent with the presence of an intense male-specific recombination hotspot at this locus.

Chromosome Mapping↗
PubMed1999

Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and antidepressant agents.

Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.

Animals↗
PubMed1999

Colon stricture and volvulus in a patients with scleroderma.

Gastrointestinal involvement in scleroderma is almost universal. We describe a patient with a benign stricture and volvulus of transverse colon, a life threatening but treatable complication of scleroderma bowel disease. We review the literature on colon volvulus in scleroderma and discuss the importance of recognizing this rare complication.

Adult↗
PubMed1998

Influences of array size and homogeneity on minisatellite mutation.

Unstable minisatellites display high frequencies of spontaneous gain and loss of repeats in the human germline. Most length changes arise through complex recombination events including intra-allelic duplications/deletions and inter-allelic transfers of repeats. Definition of the factors modulating instability requires both measurement of mutation rate and detailed analysis of mutant structures at the level of individual alleles. We have measured mutation rates in sperm for a wide range of alleles of the highly unstable human minisatellite CEB1. Instability varies by three orders of magnitude between alleles and increases steadily with the size of the tandem array. Structural analysis of mutant molecules derived from six alleles revealed that it is the rate of intra-allelic rearrangements which increases with array size and that intra-allelic duplication events tend to cluster within homogeneous segments of alleles; both phenomena resemble features of trinucleotide repeat instability. In contrast, inter-allelic transfers occur at a fairly constant rate, irrespective of array length, and show a mild polarity towards one end of the minisatellite, suggesting the possible influence of flanking DNA on these conversion-like events.

Alleles↗
PubMed1994

A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer.

From 1988 to 1991, 284 patients with prostatic cancer and painful bone metastases were treated with either radiotherapy or strontium-89 (200 MBq). Patients were first stratified according to suitability for local or hemibody radiotherapy, then randomly allocated that form of treatment or strontium-89 (i.v. injection). After 4, 8 and 12 weeks pain sites were mapped, toxicity monitored, and all additional palliative treatments recorded. There was no significant difference in median survival (after > 80% had died); 33 weeks following strontium-89 and 28 weeks following radiotherapy (p = 0.1). All treatments provided effective pain relief; improvement was sustained to 3 months in 63.6% after hemibody radiotherapy compared with 66.1% after strontium-89, and in 61% after local radiotherapy compared with 65.9% in the comparable strontium-89 group. Fewer patients reported new pain sites after strontium-89 than after local or hemibody radiotherapy (p < 0.05). Radiotherapy to a new site was required by 12 patients in the local radiotherapy group compared with 2 after strontium-89 (p < 0.01), although there was no significant difference between hemibody radiotherapy (6 patients) and strontium-89 (9 patients) in this respect. Platelets and leukocytes fell by an average 30-40% after strontium-89 but sequelae were uncommon, and other symptoms rare.

Aged↗
PubMed1993

Radionuclide-targeted therapy for the management of metastatic bone pain.

Strontium-89 is preferentially taken up at sites of increased bone mineral turnover, its uptake adjacent to malignant metastases being up to five times greater than for normal bone. Strontium-89 is also selectively retained in bone adjacent to metastatic sites. The initial therapeutic ratio is therefore good and increases with time. The pharmacokinetics of strontium-89 thus favor the objective of achieving a clinically effective beta radiation dose to tumor deposits while minimizing radiation exposure to healthy tissue. Clinical studies show that 150 MBq [corrected] strontium-89 can relieve bone pain in up to 80% of patients with prostatic metastases. Greater activities do not appear to increase this level of response. Once a response has been achieved, strontium-89 therapy can be repeated when pain recurs. Although hematologic toxicity at this dosage is low, strontium-89 should not be given to patients with evidence of significant bone marrow depression. With this precaution, no serious toxicity has been encountered when the agent is administered at the recommended doses.

Bone Neoplasms↗
PubMed1991

Diagnosis of Campylobacter pylori gastritis.

Campylobacter pylori is a bacterium that inhabits gastric mucosa. It causes chronic active gastritis and is highly associated with duodenal ulcer. Campylobacter pylori has a urease enzyme (not present in man), which allows diagnosis by a [14C]urea breath test. We compared two noninvasive tests, the breath test and serum ELISA, to biopsy and histologic diagnosis. Twenty-two patients who underwent gastroduodenoscopy for evaluation of possible peptic ulcer disease entered the study. The breath test detected the organism in eight of eight patients biopsy-positive for the organism (sensitivity 100%). The breath test was negative in 12 of the 14 patients who were biopsy-negative (specificity 86%). The ELISA was performed in 14 patients. It was positive in 5 of 5 patients biopsy-positive for the organism (sensitivity 100%) and negative in 7 of 9 patients who were biopsy-negative (specificity 78%). We conclude that both the ELISA and the [14C]urea breath test are excellent noninvasive methods to detect Campylobacter pylori. However, only the breath test is suitable for following the response to treatment, as it detects the presence of the organism rather than an immune response to it.

Breath Tests↗
PubMed1989

Collagenous colitis, enteropathic arthritis, and autoimmune diseases: results of a patient survey.

We surveyed all patients with collagenous colitis seen at Johns Hopkins over a 4-year period, using a standardized, previously validated telephone questionnaire. Of 29 patients, 2(7%), including the index case, had monoarticular reactive arthritis. Five additional patients (17%) had a coexisting autoimmune illness. Collagenous colitis should be added to the list of causes of enteropathic arthritis. In addition, collagenous colitis should be considered in the differential diagnosis of diarrhea occurring in patients with known autoimmune diseases.

Aged↗
PubMed1987

Total parenteral nutrition and intestinal development: a neonatal model.

Total parenteral nutrition (TPN) is widely used in premature and/or surgical neonates, but there is little information available about its effects on intestinal growth and development. Adult TPN models have demonstrated mucosal atrophy, and a young piglet model showed similar but increased intestinal hypotrophy. We have investigated these effects in the neonatal piglet model. Five three-day old piglets received a glucose (40 g/kg/d), amino acid (8 g/kg/d), and fat (4 g/kg/d) solution intravenously for 3 weeks. Matched littermates were fed an artificial sow-milk formula enterally at an equivalent caloric rate (215 kcal/kg/d). A third littermate was sow breast fed for the same study period. No differences were seen in the TPN or formula-fed piglets in weight gain (31 to 34 g/kg/d), hematocrit (25% to 27%), BUN (12 to 13 mg/dL), total serum protein (4.1 to 4.4 g/dL), or total bilirubin (0.4 to 0.6 mg/dL); however, the TPN animals were mildly hyperglycemic (167 mg/dL). The sow-fed control group had greater weight gain (51 g/kg/d) but were without caloric restriction. There were significant decreases in weight and length of the gastrointestinal tract, particularly in the proximal small bowel of the TPN piglets. Compared with formula piglets or sow-fed controls, the TPN proximal small bowel weight was reduced by 67% and 72%, respectively. Similar but less marked differences were seen in the TPN distal small bowel. There were no significant differences in the proximal or distal small bowel measurements between the formula and sow-fed piglets, despite their differences in overall weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Increase of cardiac output by afterload reduction in patients with severe congestive heart failure using nitroglycerin discs. A double-blind placebo-controlled haemodynamic study.

In a double-blind crossover study, the haemodynamic effects of nitroglycerin discs were compared with placebo in 9 patients with severe chronic congestive heart failure. Hourly measurements were made throughout 24 hours for the placebo and the active treatment; the first 6 hours were used as a dose titration phase to achieve at least a 5 mmHg decrease in pulmonary arterial diastolic pressure. Active treatment, requiring 30 mg of nitroglycerin in most patients, produced a significant improvement in the cardiac index compared with placebo, as assessed from the end of the dose titration period to the 24th hour. Values determined as baseline, as the average from hour 7 to 24, and at the 24th hour for active discs were 2.3, 2.5 and 2.6 litres/min/m2, whereas for the placebo they were 2.3, 2.2. and 2.2 l/min/m2, respectively. Heart rate remained unchanged during the study, though mean systemic arterial blood pressure and vascular resistance were lower during active treatment. Right atrial and pulmonary arterial pressures did not change. In conclusion, nitroglycerin discs decrease afterload and improve cardiac performance over 24 hours in patients with heart failure.

Administration, Topical↗