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Biomedical subjects

T Cook

Publications and source records attributed to T Cook.

At least 19 recordsLinked to original sources
PubMed2006

Ultrasound-guided injection and occlusion of the trachea in fetal sheep.

OBJECTIVES: To access the fetal sheep trachea by ultrasound-guided transthoracic injection in order to deliver gene therapy vectors or occlude the trachea with a detachable balloon. METHODS: Fetal sheep were operated on at a mean gestational age of 102 (range, 81-116) days (term = 145 days). Under ultrasound guidance, either a 20-G spinal (for vector delivery) or a 16-G Kellett (for placement of an occlusive balloon) needle was inserted via the fetal thorax into the fetal trachea. RESULTS: Using the 20-G spinal needle the trachea was accessed successfully in 33/36 fetuses, with 97% survival. Failure to inject was related to fetal position and gestational age. Blood vessel damage causing significant morbidity occurred in two fetuses (6%). Tracheal occlusion was achieved by puncturing the trachea with the 16-G needle and advancing an endoluminal balloon in three out of five attempts in a mean time of 17 (range, 16-19) min, with 100% survival. In one case, the balloon became sited within the accessory lobe bronchus and was not inflated. At postmortem examination 21 days later, all balloons remained inflated and occluded the trachea, and the lung-to-body weight ratio and airways morphometric indices were consistent with relative pulmonary hyperplasia in the obstructed lungs. CONCLUSIONS: Ultrasound-guided transthoracic tracheal puncture is a reliable technique in fetal sheep, with low morbidity and mortality. Using this technique, a detachable endotracheal balloon can be placed to provoke pulmonary growth. Advances in needle design and balloon size may improve the success rate.

Animals↗
PubMed2006

Variations with age in the mechanical properties of human skin in vivo.

To quantitatively assess the viscoelastic properties of human skin, an in vivo testing method has been developed and previously reported. In this method, a strain-gauged pretension device is first used to determine the natural skin tension and then to apply a predetermined tension. A suction cup device with a rectangular cross-section and semi-circular ends is then applied to the pretensioned area and the skin deflection versus negative pressure characteristic is recorded. With the basic characteristics of the skin stress field determined by the geometry of the cup as a homogeneous stress state, the stress-strain response curve is computed from the recorded data. Using a constant pressurisation rate testing mode, the back and forearm of 116 healthy male and female subjects ranging in age from two to 67 years were tested. Variations in the shape and average slope (approximate modulus) of the stress-strain curves have been investigated with changes in age and sex. It has been found that the average slope decreases through maturation, reaches a minimum between the ages of 15 and 25, and then appears to increase with advancing age. The data points begin to diverge after approximately 30 years of age. It is hypothesised that this diverging phenomenon may be a result of the cumulative effect of ultraviolet radiation on the collagen and elastin networks. An examination of the shape of the curves appears to indicate that stiffness of collagen in the dermis increases with increasing age. However, it appears that the lower portions of the curves, possibly associated with the elastin and ground substance components, undergo changes not common to every individual. It is also hypothesised that 'scatter' in the data obtained from females and the sudden change noted in the shape of the curves at puberty may be due to hormonal changes.

Adolescent↗
PubMed2006

Clinically applicable procedure for gene delivery to fetal gut by ultrasound-guided gastric injection: toward prenatal prevention of early-onset intestinal diseases.

Targeting gene therapy vectors to the fetal intestinal tract could provide a novel means toward prevention of the early postnatal intestinal pathology of cystic fibrosis and other conditions, such as congenital enteropathy, that cause intestinal failure. Among these conditions, cystic fibrosis is by far the most common lethal genetic disease. It is caused by a functional absence or deficiency of the cystic fibrosis transmembrane conductance regulator and manifests in the gut as meconium ileus. Prenatal treatment of genetic disease may avoid early-onset tissue damage and immune sensitization, and may target cells that are less accessible in the adult. We investigated gene transfer to the fetal gut, using a minimally invasive injection technique. First-generation replication-deficient adenoviral vectors encoding the beta-galactosidase gene and transduction-enhancing agents were injected into the stomach of early-gestation fetal sheep (n = 8, 60 days of gestation; term, 145 days) under ultrasound guidance. Reporter gene expression was observed 2 days after injection in the villi of the gastrointestinal epithelia after 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining and beta-galactosidase immunohistochemistry of fetal tissues. Expression of beta-galactosidase, as measured by enzyme-linked immunosorbent assay, was enhanced after pretreatment of the fetal gut with sodium caprate, which opens tight junctions, and after adenovirus complexation with DEAE-dextran, which confers a positive charge to the virus. Instillation of the fluorocarbon perflubron after virus delivery resulted in tissue transduction from the fetal stomach to the colon. Using a clinically relevant technique, we have demonstrated widespread gene transfer to the fetal gastrointestinal epithelia.

Adenoviridae↗
PubMed2004

Widespread and efficient marker gene expression in the airway epithelia of fetal sheep after minimally invasive tracheal application of recombinant adenovirus in utero.

Cystic fibrosis is a common lethal genetic disease caused by functional absence of the cystic fibrosis transmembrane conductance regulator (CFTR). Although a candidate disease for in utero gene therapy, demonstration of potentially therapeutic levels of transgene expression in the fetal airways after minimally invasive gene delivery is a mandatory prerequisite before application of this approach in humans can be considered. We report here on the delivery of a beta-galactosidase expressing adenovirus directly to the airways of fetal sheep in utero using ultrasound-guided percutaneous injection of the trachea in the fetal chest. Injection of adenoviral particles to the fetal airways was not associated with mortality and resulted in low-level expression in the peripheral airways. However, complexation of the virus with DEAE dextran, which confers a positive charge to the virus, and pretreatment of the airways with Na-caprate, which opens tight junctions, increased transgene expression, and a combination of these two enhancers resulted in widespread and efficient gene transfer of the fetal trachea and bronchial tree. Using a percutaneous ultrasound-guided injection technique, we have clearly demonstrated proof of principle for substantial transgene delivery to the fetal airways providing levels of gene expression that could be relevant for a therapeutic application of CFTR expressing vectors.

Adenoviridae↗
PubMed2004

Reduced toxicity of F-deficient Sendai virus vector in the mouse fetus.

Current concerns over insertional mutagenesis by retroviral vectors mitigate investigations into alternative, potentially persistent gene therapy vector systems not dependent on genomic integration, such as Sendai virus vectors (SeVV). Prenatal gene therapy requires efficient gene delivery to several tissues, which may not be achievable by somatic gene transfer to the adult. Initially, to test the potential and tropism of the SeVV for gene delivery to fetal tissues, first-generation (replication- and propagation-competent) recombinant SeVV, expressing beta-galactosidase was introduced into late gestation immunocompetent mice via the amniotic and peritoneal cavities and the yolk sac vessels. At 2 days, this resulted in very high levels of expression particularly in the airway epithelium, mesothelium and vascular endothelium, respectively. However, as expected, substantial vector toxicity was observed. The efficiency of gene transfer and the level of gene expression were then examined using a second-generation SeVV. The second generation was developed to be still capable of cytoplasmic RNA replication and therefore high-level gene expression, but incapable of vector spread due to lack of the gene for viral F-protein. Vector was introduced into the fetal amniotic and peritoneal cavities, intravascularly, intramuscularly and intraspinally; at 2 days, expression was observed in the airway epithelia, peritoneal mesothelia, unidentified cells in the gut wall, locally at the site of muscle injection and in the dorsal root ganglia, respectively. Mortality was dramatically diminished compared with the first-generation vector.

Adenoviridae↗
PubMed2003

The hopes and fears of in utero gene therapy for genetic disease--a review.

Somatic gene delivery in utero is a novel approach to gene therapy for genetic disease. It is based on the concept that application of gene therapy vectors to the fetus in utero may prevent the development of early disease related tissue damage, may allow targeting of otherwise inaccessible organs, tissues and still expanding stem cell populations and may also provide postnatal tolerance against the therapeutic transgenic protein. This review outlines the hypothesis and scientific background of in utero gene therapy and addresses some of the frequently expressed concerns raised by this still experimental, potentially preventive gene therapy approach. We describe and discuss the choice of vectors, of animal models and routes of administration to the fetus. We address potential risk factors of prenatal gene therapy such as vector toxicity, inadvertent germ line modification, developmental aberration and oncogenesis as well as specific risks of this procedure for the fetus and mother and discuss their ethical implications.

Adult↗
PubMed2003

Use of the laryngeal tube in 100 patients.

BACKGROUND: The laryngeal tube has a potential role during anaesthesia, but there have been only a few studies assessing its efficacy during the entire course of anaesthesia, and all previous studies used prototypes. We studied 100 patients to assess the efficacy of a new laryngeal tube during the entire course of anaesthesia. METHODS: After induction of anaesthesia, the laryngeal tube was inserted (up to two times) and adequacy of ventilation was assessed. The airway pressure at which gas leaked around the device was measured. The device was used during anaesthesia, while ventilation was controlled. The device was removed after the patient had opened the mouth to verbal command. Any complications during and after anaesthesia were recorded. RESULTS: Ventilation was possible at the first attempt in 90 patients, at the second attempt in another seven patients, and adequate ventilation failed after two attempts in three patients. Median (interquartile range) leak pressure was 28 (22-30) cmH2O. In all 97 patients, the laryngeal tube was used until the end of surgery. However, in two of the 97 patients the airway was partially obstructed during anaesthesia and it was necessary to reposition the device. The laryngeal tube was tolerated well during emergence from anaesthesia. No hypoxia, regurgitation, vomiting or laryngospasm occurred in any patient. On removal of the laryngeal tube, no blood was detected on the device and no apparent ischaemic changes to the tongue were observed in any patient. Post-operatively, six patients complained of a mild sore throat, and no patient complained of difficulty in swallowing or numbness of the oropharynx. CONCLUSION: The laryngeal tube can be useful for maintaining a patent airway during anaesthesia.

Adolescent↗
PubMed2002

Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia.

OBJECTIVES: To evaluate the effects of finasteride, a specific type II 5-alpha-reductase inhibitor, on symptoms of benign prostatic hyperplasia, prostate volume, and urinary flow during a 7 to 8-year period. METHODS: A total of 190 men with symptomatic benign prostatic hyperplasia and enlarged prostates entered one of two Phase II double-blind 3 to 6-month studies. Of these, 156 patients continued taking open-label finasteride, and more than 70 patients completed 7 to 8 years of treatment. The symptoms were scored using a patient self-administered modified Boyarsky symptom questionnaire. Prostate volume was measured by magnetic resonance imaging or ultrasonography, and the maximal urinary flow rate was assessed noninvasively. RESULTS: Treatment with finasteride for 7 to 8 years led to sustained improvement in symptoms, reduction in prostate volume (28% from baseline), and increased urinary flow (median 2.5 mL/s from baseline). Decreases in dihydrotestosterone (86%) and prostate-specific antigen (54%) levels were also maintained. Long-term finasteride treatment was safe and generally well tolerated. CONCLUSIONS: Long-term treatment with finasteride was well tolerated and resulted in durable symptom relief and improvement in prostate volume and urinary flow.

Adult↗
PubMed2001

Urothelial malignant disease and Chinese herbal nephropathy.

We have previously reported occurrence of a specific type of nephropathy due to ingestion of Chinese herbs (Chinese herbal nephropathy [CHN]) in two patients in the UK. These cases highlighted the role of aristolochic acid in causing this nephropathy, which was first described in a Belgian cohort. We now report development of invasive transitional cell carcinoma of the urinary tract associated with the presence of aristolochic acid-DNA adducts in one of these patients. This work clearly shows the carcinogenic potential of aristolochic acid in this new type of nephropathy.

Aristolochic Acids↗
PubMed2001

Posttransplantation lymphoproliferative disorder initially seen as iris mass and uveitis.

Primary ocular posttransplantation lymphoproliferative disorder is rare. Epstein-Barr virus is implicated as the cause as a result of systemic immunosuppression after transplant surgery. We studied a patient who developed ocular posttransplantation lymphoproliferative disorder after orthotopic liver transplantation. Slitlamp and light microscopic photographs confirmed the diagnosis.

Female↗
PubMed2001

Bone marrow contributes to renal parenchymal turnover and regeneration.

In order to establish whether extra-renal cells contribute to the turnover and repair of renal tissues, this study examined kidneys of female mice that had received a male bone marrow transplant and kidney biopsies from male patients who had received kidney transplants from female donors. By using in situ hybridization to detect Y-chromosomes it could be demonstrated that circulating stem cells frequently engraft into the kidney and differentiate into renal parenchymal cells. In the human renal grafts it was confirmed that some of the recipient-derived cells within the kidney exhibited a tubular epithelial phenotype, by combining in situ hybridization with immunostaining for the epithelial markers CAM 5.2 and the lectin Ulex europaeus. Female mouse recipients of male bone marrow grafts showed co-localization of Y-chromosomes and tubular epithelial markers Ricinus communis and Lens culinaris, and a specific cytochrome P450 enzyme (CYP1A2) indicating an appropriate functional capability of clustered newly formed marrow-derived tubular epithelial cells. Y-chromosome-containing cells were observed within glomeruli, with morphology and location appropriate for podocytes. Within the murine kidney, these Y-chromosome-positive cells were negative for the mouse macrophage marker F4/80 antigen and leukocyte common antigen, but were vimentin-positive. The presence of bone marrow-derived cells was noted in both histologically normal mouse kidneys and in human transplanted kidneys suffering damage from a variety of causes. These data indicate that bone marrow cells contribute to both normal turnover of renal epithelia and regeneration after damage, and it is suggested that this could be exploited therapeutically.

Animals↗