Richard Wyse - Academia.edu (original) (raw)

Papers by Richard Wyse

SUMMARY Thedominance ofMustard's operation fortransposition ofthegreatarteries hasbeen challe... more SUMMARY Thedominance ofMustard's operation fortransposition ofthegreatarteries hasbeen challenged bytherecentrevival ofSenning's repair because itpromises better long-term results interms ofvenousobstruction andatrial haemodynamics. Thesehypotheses were tested byrecording jugular venousflow waveforms transcutaneously in24postoperative patients withsimple complete transposition using abidirectional Doppler blood velocimeter. Eight patients hadundergone Mustard's operation and 16theSenning alternative; all hadpreviously hadapostoperative cardiac catheterisation. Bothgroupsofpatients hadsimilar left ventricular, pulmonary arterial, andsystemic venous atrial pressures.Nochild showed any evidence atcatheterisation ofeither mitral regurgitation or of superior venacaval pathway obstruction. These twofindings were endorsed bythetranscutaneous Doppler recordings. Jugular venousflow innormal children exhibits twomaxima, one ofatrial filling during ventricular systole, theother ofv...

From the Myocardial Metabolism Research Laboratories, The Rayne Institute, St. Thomas’ Hospital, ... more From the Myocardial Metabolism Research Laboratories, The Rayne Institute, St. Thomas’ Hospital, and *Department of Pediatric Cardiology, The lnstkute of Chikl Health, Oreat Crmond Street Hospital, London, England. This work was supported by grants from the Medical Research Council, the British Heart Foundation and St. Thomas’ Hospital Research Endowments Fund, London, England. Manuscript received September 24, 1980; revised manuscript received January 5, 1981, accepted January 8, 1981. Address for reprints: Derek M. Yellon, FhD, The Rayne Institute, St. Thomas’ Hospital, London SE 1, England. A new nonrotating multiple biopsy device has been developed to allow Interface Between Normal and Heart During

The roles of posterior bulging of the interventricular septum (septal bulge) and of systolic sept... more The roles of posterior bulging of the interventricular septum (septal bulge) and of systolic septal mitral apposition in patients with simple transposition of the great arteries are not known. Cross sectional echocardiograms of 40 such patients were reviewed (after exclusion of those with fixed left ventricular outflow tract obstruction) and haemodynamic findings were compared with long and short axis measurements within the left ventricle. There was no significant correlation between the degree of septal bulge and systolic gradient across the left ventricular outflow tract, but septal bulge correlated weakly with systolic right ventricular pressure and inversely with pulmonary arteriolar resistance index. Systolic left ventricular outflow gradient was inversely related to the minimum systolic distance between the anterior mitral leaflet and interventricular septum. No patients without complete systolic apposition of the anterior mitral leaflet and interventricular septum had a left ventricular outflow gradient >20 mm Hg. Conversely, even when cross sectional echocardiography showed apparently total obstruction of the left ventricular outflow tract at some time in systole there was often no significant gradient detected during haemodynamic study. In the short axis cuts closeness of the papillary muscles to the interventricular septum or to each other was unrelated to systolic gradient. This study shows that (a) cross sectional echocardiography can identify fixed obstruction of the left ventricular outflow tract in simple transposition of the great arteries; (b) the degree of septal bulge, unless complicated by fibrous thickening of the anterior mitral leaflet and interventricular septum, is unrelated to the gradient across the left ventricular outflow tract; (c) the absence of systolic septallmitral apposition excludes a significant gradient at that site across the left ventricular outflow tract; and (d) papillary muscle geometry is unrelated to dynamic gradients across the left ventricular outflow tract in this condition.

It has long been envisaged that gene disruption or gene correction in affected target cells can b... more It has long been envisaged that gene disruption or gene correction in affected target cells can be efficiently conducted in vitro and in vivo and over the recent years several tools for achieving this goal were developed. Designer nucleases such as zinc finger nucleases (ZFNs) were extensively explored and more recently transcription activator-like effector nucleases (TALENs) were introduced for sequence-specific genome engineering in the mammalian genome. ZFNs and TALENs are fusion proteins containing a customized DNA-binding motif for sequence-specific DNA binding linked to a nuclease for introduction of double-stranded DNA breaks. Both systems were explored in mammalian cells using non-viral and viral delivery methods. Herein, we will provide a state-ofthe-art overview of available virus-based delivery systems for sufficient expression of functional TALENs. We will cover the molecular design of recombinant viruses containing TALEN expression cassettes and we will mention advantages and disadvantages of the respective systems. Although the relevance of these viral vector systems for novel developments in molecular medicine and genome engineering need to be further evaluated, we believe that with further improvements these viral vectors for TALEN delivery will play an emerging role in bioengineering and for establishing novel therapeutic concepts.

Cochrane Database of Systematic Reviews, 2018

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evalua... more This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the effectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. We will differentiate, as far as possible between neuroprotective and symptomatic effects.

Science, 2018

New insights identify a possible target for slowing neurodegeneration

Goodpasture syndrome, a rare human autoimmune disorder, is characterized by the presence of patho... more Goodpasture syndrome, a rare human autoimmune disorder, is characterized by the presence of pathogenic autoantibodies that react with the components of the glomerular basement membrane. The clinical condition of the Goodpasture syndrome is characterized by an acute necrotizing glomerulonephritis, often with accompanying pulmonary hemorrhage. Notably, the Goodpasture antigen has been localized to the noncollagenous domain of the α3 chain of type IV collagen. Additionally, human leukocyte antigen-DR2, and to a lesser extent human leukocyte antigen-DR4, have been identified as important restriction elements. The role of T cells in Goodpasture syndrome is indicated by the highly restricted specificity of the antibody response and the strong major histocompatibility complex class II association. In this review article, we briefly describe the latest views on the molecular and cellular themes of Goodpasture syndrome.

Parkinsonism & Related Disorders, 2021

OBJECTIVE Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite o... more OBJECTIVE Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions. METHODS The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. RESULTS Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. CONCLUSIONS We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.

Movement Disorders, 2020

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic ne... more Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra, and accumulation of iron and alpha-synuclein; it follows a characteristic pattern throughout the nervous system. Despite, decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials. Considering this dilemma, we have reviewed and organized solutions of varying importance that can be exclusive or additive and outline approaches to help generate successful development of neuroprotective drugs for PD: 1) select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement; 2) combine treatments that target multiple pathways; 3) establish earliest interventions and develop better prodromal biomarkers; 4) adopt rigorous methodology and specific disease-relevant designs for disease-modifying clinical trials; 5) customize drug with better brain biodistribution; 6) prioritize repurposed drugs as a first line approach; 7) adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value.

Journal of Ayub Medical College

Wheat allergy has been suggested to represent an important allergic disease. This study collates ... more Wheat allergy has been suggested to represent an important allergic disease. This study collates clinical and laboratory aspects in patients with wheat allergy in Al-Kharj city, Saudi Arabia. Total and specific IgE were measured in 15 suspected cases of wheat allergy. Protein allergenicity was assessed with Western blotting. Significant elevation of total and specific IgE was found in 4 cases. Basophlia was also demonstrated on blood film. Western blotting results showed 2 bands (83 and 40 kDa). Wheat allergy must also be considered when planning treatment of asthma and eczema of adult patients.

The Yale Journal of Biology and Medicine, 2009

Self renewal and apoptosis of haemopoietic stem cells (HSC) represent major factors that determin... more Self renewal and apoptosis of haemopoietic stem cells (HSC) represent major factors that determine the size of the haemopoietic cell mass. Changes in self renewal above or below the steady state value of 0.5 will result in either bone marrow expansion or aplasia, respectively. Despite the growing body of research that describes the potential role of HSC, there is still very little information on the mechanisms that govern HSC self renewal and apoptosis. Considerable insight into the role of HSC in many diseases has been gained in recent years. In light of their crucial importance, this article reviews recent developments in the understanding of the molecular, biological, and physiological characteristics of haemopoietic stem cells.

Cardiovascular Research, 1983

Seven hundred and twenty three biopsies were obtained from 20 dogs after coronary artery ligation... more Seven hundred and twenty three biopsies were obtained from 20 dogs after coronary artery ligation for 5, 30, 45, 60 or 120 min (n = 4 dogs for each group). Paired values for blood flow (radioactive microspheres) and tissue ATP content were obtained for each biopsy and related to the duration of ischaemia. Three states of ischaemic injury could be recognised. In the first, designated as "tolerable" ischaemia, coronary flow was reduced by up to 50%. In this flow band, ATP depletion was relatively small and time-independent. If flow was reduced by 60 to 80%, a state of "critical" ischaemia was identified where ATP depletion was both flow- and time-dependent and, in this relatively narrow range, small changes in flow or duration could result in major changes in ATP depletion. With severe flow reductions of greater than 80%, designated as "lethal" ischaemia, a complex pattern emerged such that with up to 30 min of ischaemia, ATP fell progressively with increasing time and flow deprivation. Between 30 and 45 min ATP depletion accelerated and beyond 45 min the time-dependency disappeared with tissue ATP content remaining relatively constant at a severely depressed level for several hours. All of these results are discussed in the light of earlier proposals (disputed) that tissue injury as expressed by ATP depletion can be predicted by the product of ischaemic duration and flow deprivation.

Cardiovascular Research, 1978

Following pulmonary arterial constriction, 22 pigs developed right ventricular failure and 10 rig... more Following pulmonary arterial constriction, 22 pigs developed right ventricular failure and 10 right ventricular hypertrophy. Comparing results with those obtained in 21 normal pigs (no pulmonary artery constriction), it was found the right ventricular peak systolic and end-diastolic pressures, cardiac output, and right ventricular weight distinguished hypertrophied and failing hearts from normal ones. Cardiac output was lower in failing hearts than in hypertrophied hearts and was the only variable which significantly differentiated between these two groups. Left ventricular pressures and left ventricular and right ventricular dP/dtmax, and maximum [(dP/dt)/P] did not distinguish failing from hypertrophied hearts. Left ventricular pressure, maximum [(dP/dt)/P] and left ventricular and right ventricular dP/dtmax were not significantly different in the three groups.

The Annals of Thoracic Surgery, 1989

Quantitative assessment of high-energy phosphate levels, including degradation or utilization dur... more Quantitative assessment of high-energy phosphate levels, including degradation or utilization during ischemia, has not previously been performed in infants and children. Animal experiments suggest that high-energy phosphate metabolism varies with maturation. To help answer these questions, 24 patients aged 2 months to 8 years underwent myocardial biopsy immediately after the institution of cardiopulmonary bypass (16 to 20°C). Additional samples were obtained at 16 and 45 minutes after aortic cross-clamping and administration of cardioplegia (St. Thomas's solution) (in vivo ischemia). Seven patients also underwent major myocardial resection. Resected specimens were placed in a 37°C bath and divided into equal-sized samples that were removed at ten-minute intervals (in vitro ischemia). All samples were immersed in liquid nitrogen and analyzed for adenine nucleotide pool metabolites using highperformance liquid chromatography. Levels of adenosine triphosphate were high before cross-clamping but uring the past decade, major advances have been D made that extend fundamental observations in myocardial metabolism in such a way as to bring new knowledge into direct clinical application [ 11. Controlled circumstances in a bloodless field with unimpaired visualization directly affect the technical performance of cardiac surgical procedures, which must be reflected in results. This is especially true in congenital cardiac procedures, where the size of the field is small, technical demands considerable, and time limited. The price one pays for a bloodless, immobile operative field is myocardial ischemia. Despite extraordinary advances in cardiac surgery for infants and children with congenital heart defects, operative morbidity and mortality remain high for repair of many defects. Diminished ventricular function is a principal determinant of outcome in these patients [2, 31. An important correlate of myocardial function after ischemia is the level of adenosine triphosphate (ATP). The