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Biomedical subjects

I Findlay

Publications and source records attributed to I Findlay.

At least 19 recordsLinked to original sources
PubMed2004

The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure.

BACKGROUND: Heart failure is commonly associated with vascular disease and a high rate of athero-thrombotic events, but the risks and benefits of antithrombotic therapy are unknown. METHODS: The current study was an open-label, randomized, controlled trial comparing no antithrombotic therapy, aspirin (300 mg/day), and warfarin (target international normalized ratio 2.5) in patients with heart failure and left ventricular systolic dysfunction requiring diuretic therapy. The primary objective was to demonstrate the feasibility and inform the design of a larger outcome study. The primary clinical outcome was death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: Two hundred seventy-nine patients were randomized and 627 patient-years exposure were accumulated over a mean follow-up time of 27 +/- 1 months. Twenty-six (26%), 29 (32%), and 23 (26%) patients randomized to no antithrombotic treatment, aspirin, and warfarin, respectively, reached the primary outcome (ns). There were trends to a worse outcome among those randomized to aspirin for a number of secondary outcomes. Significantly (P =.044) more patients randomized to aspirin were hospitalized for cardiovascular reasons, especially worsening heart failure. CONCLUSIONS: The Warfarin/Aspirin Study in Heart failure (WASH) provides no evidence that aspirin is effective or safe in patients with heart failure. The benefits of warfarin for patients with heart failure in sinus rhythm have not been established. Antithrombotic therapy in patients with heart failure is not evidence based but commonly contributes to polypharmacy.

Aged↗
PubMed2004

Informed consent and the JHO in Scotland.

AIM: To define the views of junior house-officers (JHOs) concerning consent for general surgical conditions. METHODS: Questionnaire-based descriptive study on two cohorts of JHOs, separated by 3 years of major national and local directives. RESULTS: From the JHO perspective: (i) there has been a shift away from the JHO being the main signatory, (ii) many JHOs (58% in 2000; 47% in 2003) feel unsupported with respect to obtaining consent, (iii) knowledge concerning any consultant/unit's complication rates was poor (<30%), (iv) knowledge concerning complication rates for several paradigm procedures was also poor, though it improved from 2000 to 2003, (v) there is no formal training in consent. CONCLUSIONS: Despite the JHO group of 2003 outperforming that of 2000, there is major scope for improvement from patient, legal, educational and risk-management perspectives.

Attitude to Health↗
PubMed2003

Prenatal diagnosis of tetrasomy 18p using multiplex fluorescent PCR and comparison with a variety of techniques.

We report genetic characterization of isochromosome 18p using a combination of cytogenetic and molecular genetic methods, including multiplex fluorescent PCR. The patient was referred for chorionic villus sampling (CVS) due to advanced maternal age and maternal anxiety. The placental karyotype was 47,XX,+mar, with the marker having the appearance of a small supernumerary isochromosome. Because differentiating between isochromosomes and other structural rearrangements is normally very difficult, a variety of genetic tests including fluorescence in situ hybridization (FISH), PCR, and multiplex fluorescent PCR were undertaken to determine chromosomal origin and copy number and, thus, allow accurate diagnosis of the corresponding syndrome. FISH determined that the marker chromosome contained chromosome 18 material. PCR of a variety of short tandem repeats (STRs) confirmed that there was at least one extra copy of the maternal 18p material. However, neither FISH nor PCR could accurately determine copy number. Multiplex fluorescent PCR (MF-PCR) of STRs simultaneously determined that: (1) the marker included 18p material; (2) the marker was maternal in origin; (3) allele copy number indicated tetrasomy; and (4) contamination of the sample could be ruled out. Results were also rapid with accurate diagnosis of the syndrome tetrasomy 18p possible within 5 hours.

Adult↗
PubMed2001

Using MF-PCR to diagnose multiple defects from single cells: implications for PGD.

Single cell genetic analysis is generally performed using PCR and FISH. Until recently, FISH has been the method of choice. FISH however is expensive, has significant misdiagnosis rates, can result in interpretation difficulties and is labour intensive making it unsuitable for high throughput processing. Recently fluorescent PCR reliability has increased to levels at or surpassing FISH whilst maintaining low cost. However, PCR accuracy has been a concern due to allelic dropout. Multiplex PCR can now increase accuracy by using multiple markers for each chromosome to firstly provide diagnosis if markers fail and/or secondly confirm diagnosis. We compare a variety of diagnostic methods and demonstrate for the first time a multiplex PCR system providing simultaneous diagnosis and confirmation of the major aneuploidy chromosomes (21,18,13) and sex as well as DNA fingerprint in single cells. We also discuss the implications of using PCR for aneuploidy screening in preimplantation genetic diagnosis.

Aneuploidy↗
PubMed2001

Identifying the origin of single corneal cells by DNA fingerprinting: part I--implications for corneal limbal allografting.

PURPOSE: To demonstrate that the combination of impression cytology and single cell DNA fingerprinting represents a powerful tool that is suitable for detecting transplanted cells after corneal limbal allografting. METHODS: Fifty single cells were obtained by corneal impression cytology from 12 patients undergoing cataract surgery. Individual cells were isolated from samples by micromanipulation. Polymerase chain reaction and short tandem repeat profiling was used to obtain forensic standard "DNA fingerprints" from single cells. Blood samples taken at the time of impression cytology provided control "fingerprints." RESULTS: Informative DNA fingerprints were obtained from all corneal samples and 66% (33 of 50 cells) of isolated single cells. Of all fingerprints obtained, most (91%, 30 of 33 fingerprints) corneal fingerprints matched corresponding blood sample fingerprints. At least one corneal fingerprint matched the corresponding blood sample fingerprint in 83% (10 of 12 patients) of the patients in the study. CONCLUSIONS: This extremely specific single cell DNA fingerprinting system permits accurate identification of individual corneal epithelial cells, allowing very reliable determination of their origin, which will enable host and donor cells to be distinguished from each other after keratolimbal allografting procedures, even if the host and donor are the same sex or siblings. These DNA fingerprinting methods allow assessment of quality and quantity of donor cell survival, as well as survival time. The extreme sensitivity and accuracy of the technique means that should contamination occur, it would be identified, thus ensuring meaningful results.

Cell Transplantation↗
PubMed2001

Identifying the origin of single corneal cells by DNA fingerprinting: part II-- application to limbal allografting.

PURPOSE: Successful limbal allotransplantation allows regression of limbal stem cell deficiency features. Transplant survival is presumed if clinical improvement occurs. However, positive proof of surviving transplanted stem cells remains difficult. This follow-up study attempted to prove donor cell survival 5 years after limbal stem cell allograft in one woman with aniridia. METHODS: Impression cytology and single-cell DNA fingerprinting were used to investigate a previously studied patient. Corneal epithelial cells were harvested from five sites and isolated by micromanipulation. Polymerase chain reaction and short tandem repeat profiling were used to obtain forensic standard "DNA fingerprints" from single cells. (The technique is described in the preceding article, Part I.) Blood samples yielded host and donor DNA for comparison. Negative controls were performed for impression cytology and polymerase chain reaction. Simultaneous micro-scrape samples were also taken. RESULTS: Impression cytology samples permitted informative DNA fingerprints from all corneal sites and represented 76% (23/30) of tested cells. Fifty percent (15/30) of the fingerprints were "specific" but 83% (19/23) matched the host DNA fingerprint. The remaining 17% (4/23) represented contamination from various sources. Specific fingerprints were obtained in 55% (10/18) of the cells from micro-scrape samples. All samples giving sufficient information matched the host DNA fingerprint. All tested blood samples gave specific fingerprints. None of the sampled corneal cells gave a donor DNA fingerprint. CONCLUSIONS: In a single patient, no detectable long-term donor cell survival exists at 5 years. Positive identification would have provided unequivocal proof of donor cell survival. This technique gives useful information even if contamination occurs.

Aniridia↗
PubMed2000

Screening gamete donors for cystic fibrosis status.

Gamete donors are currently not tested for cystic fibrosis, even though carriers have a very high risk of producing children with the disease. We recommend that gamete donors be routinely tested for cystic fibrosis. Similar arguments exist for antenatal screening for cystic fibrosis.

Cystic Fibrosis↗
PubMed2000

Analysis of microbiological trends in peritoneal dialysis-related peritonitis from 1991 to 1998.

The microbial cause of peritoneal dialysis-related peritonitis is an important determinant of clinical outcome and the basis of widely used treatment guidelines. Five hundred forty-six cases of peritonitis in 374 patients from 1991 to 1998 were analyzed. The rate of peritonitis declined significantly from 1.37 episodes/patient-year in 1991 to 0.55 episode/patient-year in 1998 (P = 0.02). The rate of Gram-positive peritonitis decreased significantly from 0.75 to 0.28 episode/patient-year during the same period (P = 0.02). Conversely, the occurrence of Gram-negative peritonitis remained constant at approximately 0.16 episode/patient-year (P = 0.28). Staphylococcus epidermidis and Staphylococcus aureus were the most common causes of peritonitis, isolated in 27.8% and 19.3% of the culture-positive cases, respectively. A distinct decrease in peritonitis caused by S epidermidis was observed, with 0.40 episode/patient-year in 1991 compared with 0.11 to 0.20 episode/patient-year during subsequent years. The rate of infections caused by S aureus decreased significantly over time from a high of 0.21 episode/patient-year in 1992 to a low of 0.04 episode/patient-year in 1998 (P = 0.01). Pseudomonas aeruginosa, Escherichia coli, and KLEBSIELLA: species were the most common causes of Gram-negative peritonitis, identified in 7.1%, 6.8%, and 5.2% of culture-positive cases, respectively. The most dramatic increase in antibiotic resistance was seen among S epidermidis. From 1991 and 1992 to 1997 and 1998, resistance to ciprofloxacin increased from 5.4% to 47.8% (P = 0.003), and resistance to methicillin increased from 18.9% to 73.9% (P = 0.03). Our study showed significant trends in the causative pathogens of peritoneal dialysis-related peritonitis and dramatic increases in antibiotic resistance. These data support further study and warrant reevaluation of current treatment practices.

Case-Control Studies↗
PubMed2000

Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation: Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK)

AIMS: To determine characteristics, outcomes, prognostic indicators and management of patients with acute coronary syndromes without ST elevation. METHODS AND RESULTS: A prospective registry was carried out with follow-up for 6 months after index hospital admission. A history of acute cardiac chest pain was required plus ECG changes consistent with myocardial ischaemia and/or prior evidence of coronary heart disease. Patients with ST elevation or those receiving thrombolytic therapy were excluded. A total of 1046 patients were enrolled from 56 U.K. hospitals. The mean age was 66+/-12 years and 39% were female. The rate of death or non-fatal myocardial infarction at 6 months was 12.2% and of death, new myocardial infarction, refractory angina or re-admission for unstable angina at 6 months was 30%. In a multivariate analysis, patients >70 years had a threefold risk of death or new myocardial infarction compared with those <60 years (P<0.01) and those with ST depression or bundle branch block on the ECG had a five-fold greater risk than those with normal ECG (P<0.001). Aspirin was given to 87% and heparin to 72% of patients in hospital. At 6 months 56% received no lipid-lowering therapy at all. The 6-month rate of coronary angiography was 27% and any revascularization 15%. CONCLUSIONS: In this cohort there was a one in eight chance of death or myocardial infarction, and a one in three chance of death, new myocardial infarction, refractory angina or re-admission for unstable angina, over 6 months. Age and baseline ECG were useful markers of risk. Aspirin, heparin and statins were not given to about one-sixth, one-third and one-half respectively. Rates of angiography and revascularization appear low. A review of treatment strategies of unstable angina and myocardial infarction without ST elevation is warranted in the U.K. to ensure that patients are receiving optimum treatments to reduce mortality and morbidity.

Acute Disease↗
PubMed2000

Pre-implantation genetic diagnosis.

Genetic disorders are a major cause of miscarriage and fetal death. Pre-implantation genetic diagnosis (PGD) can be used to diagnose genetic defects before pregnancy has occurred by creating embryos by IVF, then removing single cells which are genetically analysed using FISH or PCR. Although successful, the techniques have many difficulties because they are highly specialised and at the extreme limit of sensitivity. Newer techniques, however, can rapidly diagnose multiple defects including chromosomal aneuploidy, sex and single gene defects. Embryonic cells can also be DNA fingerprinted to ensure that contamination has not occurred. As embryo screening can increase IVF success rates and decrease miscarriage rates, it will be increasing offered in routine IVF rather than just those patients at high genetic risk. These new, low cost techniques may ultimately allow PGD to be offered to all IVF patients regardless of risk.

Biopsy↗
PubMed2000

Inhibitory effects of vesnarinone on cloned cardiac delayed rectifier K(+) channels expressed in a mammalian cell line.

Vesnarinone, a phosphodiesterase inhibitor, prolongs cardiac action potential duration by inhibiting the delayed rectifier K(+) current, I(K). We examined the effect of this agent on human ether-a-go-go related gene (HERG) and KvLQT1/minK K(+) channels heterologously expressed in human embryonic kidney 293T cells with the whole-cell patch-clamp technique. HERG channel current was inhibited by vesnarinone in a concentration-dependent manner, whereas KvLQT1/minK current was hardly affected by the drug. The inhibition of HERG current by vesnarinone became more prominent and faster as the membrane potential was more depolarized. The properties of inhibition could be described by a first order reaction between the drug and the channel that was apparently independent of HERG channel gating. Although the unbinding rate constant of the drug was constant, the apparent binding rate constant increased as the membrane was more depolarized and the drug concentration was raised. This model also could explain the fast recovery from the drug's effect at hyperpolarized potentials and its rate-dependent inhibition of HERG. Therefore, the effect of vesnarinone on the HERG-K(+) current could be adequately described by a simple kinetic model of drug-channel interaction.

Action Potentials↗
PubMed1999

Extracellular links in Kir subunits control the unitary conductance of SUR/Kir6.0 ion channels.

Potassium (K+) channels are highly selective for K+ ions but their unitary conductances are quite divergent. Although Kir6.1 and Kir6.2 are highly homologous and both form functional K+ channels with sulfonylurea receptors, their unitary conductances measured with 150 mM extracellular K+ are approximately 35 and 80 pS, respectively. We found that a chain of three amino acid residues N123-V124-R125 of Kir6.1 and S113-I114-H115 of Kir6.2 in the M1-H5 extracellular link and single residues M148 of Kir6.1 and V138 of Kir6.2 in the H5-M2 link accounted for the difference. By using a 3D structure model of Kir6.2, we were able to recognize two independent plausible mechanisms involved in the determination of single channel conductance of the Kir6.0 subunits: (i) steric effects at Kir6.2V138 or Kir6.1M148 in the H5-M2 link influence directly the diffusion of K+ ions; and (ii) structural constraints between Kir6.2S113 or Kir6. 1N123 in the M1-H5 link and Kir6.2R136 or Kir6.1R146 near the H5 region control the conformation of the permeation pathway. These mechanisms represent a novel and possibly general aspect of the control of ion channel permeability.

Amino Acid Sequence↗
PubMed1999

Preimplantation genetic diagnosis using fluorescent polymerase chain reaction: results and future developments.

PURPOSE: Fluorescent polymerase chain reaction (PCR) is a multipurpose technique that can be used for diagnosing sex, single-gene defects, and trisomies as well as determining DNA fingerprints from single cells. However, its effectiveness must be assessed before clinical preimplantation genetic diagnosis (PGD) application. METHODS: Single and multiplex fluorescent PCR was applied to single cells and blastomeres. RESULTS: Fluorescent PCR can be used to diagnose sex from blastomeres and has been successfully applied in a clinical PGD sexing program resulting in a confirmed pregnancy. A further major advantage of fluorescent PCR is the ability to multiplex, providing multiple diagnoses and DNA fingerprints with a high reliability (approximately 75% for trisomy, 86% for DNA fingerprint) and good accuracy (70-80%). Allele dropout in multiplex PCR is approximately 20% per allele and does not appear to be associated with the fragment size. CONCLUSIONS: Fluorescent PCR is a powerful technique for PGD, and the effects of allele dropout must be considered, particularly in multiplex PCR.

Blastomeres↗
PubMed1998

Multiple genetic diagnoses from single cells using multiplex PCR: reliability and allele dropout.

We used a multiplex fluorescent PCR system containing seven primer sets on single cells from three different cell types (buccal, corneal and blastomere cells) and more than 3500 heterozygous alleles to investigate reliability and extent of allele dropout in multiplex PCRs at the single cell level. All three cell types gave similarly high reliability, accuracy and allele dropout rates, with similar reliability between singleplex and multiplex PCRs. Allele dropout was also consistent between the three cell types and did not significantly increase as allele size increased. These results indicate that multiplex fluorescent PCR is a reliable and accurate method of obtaining multiple diagnosis (eight chromosomes simultaneously) from single cells and maximizes the information available from single cell analysis.

Alleles↗
PubMed1998

Rapid trisomy diagnosis (21, 18, and 13) using fluorescent PCR and short tandem repeats: applications for prenatal diagnosis and preimplantation genetic diagnosis.

PURPOSE AND METHODS: Prenatal diagnosis of fetal trisomies is usually performed by cytogenetic analysis from amniotic fluid. This requires lengthy laboratory procedures and high costs and is unsuitable for large-scale screening of pregnant women. An alternative method, which is rapid and inexpensive and may potentially be suitable for diagnosing trisomies even from single fetal cells, is the fluorescent polymerase chain reaction (F-PCR) using polymorphic small tandem repeats (STRs). RESULTS: In this paper we present data demonstrating that fluorescent PCR amplification of STRs can be used for rapid diagnosis of trisomy 21, trisomy 18, and trisomy 13 and can be successfully applied to both prenatal diagnosis and diagnosis of single cells. This study also reports significant numbers of prenatal diagnoses using quantitative fluorescent PCR. CONCLUSIONS: We believe that further studies of greater numbers of samples will determine the absolute reliability of this technique. These results also provide a model for trisomy diagnosis from single cells using multiple STR markers for either preimplantation genetic diagnosis or, potentially, diagnosis from fetal cells isolated from maternal blood.

Chromosomes, Human↗