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Richard Knight

Publications and source records attributed to Richard Knight.

At least 19 recordsLinked to original sources
PubMed2006

Creutzfeldt-Jakob disease: a rare cause of dementia in elderly persons.

Creutzfeldt-Jakob disease (CJD) exists in inherited, acquired (variant and iatrogenic), and spontaneous (sporadic) forms. Although iatrogenic and variant forms of CJD usually affect relatively young persons, all forms may affect elderly persons, especially sporadic CJD. Sporadic CJD is a rare cause of dementia among middle-aged and elderly persons, and typical cases are clinically fairly distinct from more common forms of neurodegenerative dementias. However, clinical diagnosis can be a challenge for those who are not experienced with the disease. Fortunately, certain investigations can be very helpful. Although many cases of CJD (especially sporadic CJD) are not thought to be acquired illnesses, there is still a potential for onward transmission, and certain precautions are necessary to protect public health.

Adolescent↗
PubMed2006

Clinical implications of apoptosis in ischemic myocardium.

Apoptosis, a genetically programmed form of cell death, contributes to myocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury. The apoptotic program is complex, involving both pro- and anti-apoptotic proteins, and apoptosis occurs when the equilibrium between these opposing factors is perturbed. Some of these factors are intrinsic to the apoptotic pathway, such as the pro- and anti-apoptotic members of the Bcl2 family. Other, extrinsic, cellular factors can also modify the outcome of the response to an apoptotic stimulus. In this review, we have focused on some of these extrinsic factors, such as STAT-1 as a pro-apoptotic agent and the urocortins and Bag-1 as anti-apoptotic factors, since these may be potential therapeutic targets. In addition, we discuss the profound cytoprotective effects of the antibiotic, minocycline.

Animals↗
PubMed2006

Incidence of complementary therapy use in patients undergoing vestibular assessment.

OBJECTIVES: To determine the incidence of use of complementary therapies in patients with vestibular symptoms undergoing vestibular assessment. DESIGN: A prospective, questionnaire-based study. SETTING: A UK university hospital department of audiology with secondary and tertiary referrals. PARTICIPANTS: A consecutive series of 80 patients seen for vestibular assessment between November 2004 and May 2005. MAIN OUTCOME MEASURES: Use of complementary therapies; actual therapies used and patients' subjective opinion of efficacy. RESULTS: Thirteen patients (16 per cent) had tried some form of complementary therapy for their vestibular symptoms. Ginkgo biloba and acupuncture were the two most popular treatments. Seven patients made their decision as to which treatment to try on the basis of personal recommendation. Six of the 13 patients (46 per cent) reported that their choice of treatment(s) helped them. CONCLUSIONS: Sixteen per cent of patients seen for vestibular assessment had tried some form of complementary therapy for their vestibular symptoms. Clinicians should be aware of this and of the potential interactions between complementary therapies and conventional medicine.

Acupuncture Therapy↗
PubMed2006

Hemophilia therapy and blood-borne pathogen risk.

For a brief period, modern medical science was considered to have relegated infectious disease to that of a minor clinical challenge. However, several infectious diseases have emerged or re-emerged in recent years, raising epidemiological concerns, as well as issues over the availability of effective measures of control and treatment. Invariably, these infectious agents have been studied carefully in relation to the safety of blood products, often resulting in concern and action. Emerging diseases arise from many sources. Some are the result of viruses crossing the species barrier from animals to humans. In addition, combinations of these newly identified viruses may make each more difficult to treat, as in the case of human immunodeficiency virus and hepatitis C virus coinfection. Still others can arise from completely new biological mechanisms, such as the prion disease variant Creutzfeldt-Jacob disease, which has spread from infected cattle to humans, particularly in the United Kingdom. The emergence of new viruses and new disease sources has had a significant impact on coagulation factor therapies and blood donation policies. We must deal with these multiple threats and their potential to compromise the safety of our blood supply.

Animals↗
PubMed2005

Genetic prion disease: the EUROCJD experience.

A total of 10-15% of human transmissible spongiform encephalopathies (TSEs) or prion diseases are characterised by disease-specific mutations in the prion protein gene (PRNP). We examined the phenotype, distribution, and frequency of genetic TSEs (gTSEs) in different countries/geographical regions. We collected standardised data on gTSEs between 1993 and 2002 in the framework of the EUROCJD collaborative surveillance project. Our results show that clinicopathological phenotypes include genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker disease (GSS). Genetic TSE patients with insert mutation in the PRNP represent a separate group. Point and insertional mutations in the PRNP gene varies significantly in frequency between countries. The commonest mutation is E200K. Absence of a positive family history is noted in a significant proportion of cases in all mutation types (12-88%). FFI and GSS patients develop disease earlier than gCJD. Base pair insertions associated with the Creutzfeldt-Jakob disease (CJD) phenotype, GSS, and FFI cases have a longer duration of illness compared to cases with point mutations and gCJD. Cerebrospinal fluid 14-3-3 immunoassay, EEG, and MRI brain scan are useful in the diagnosis of CJD with point mutations, but are less sensitive in the other forms. Given the low prevalence of family history, the term "gTSE" is preferable to "familial TSE". Application of genetic screening in clinical practice has the advantage of early diagnosis and may lead to the identification of a risk of a TSE.

Adult↗
PubMed2005

Intradialytic serum protein concentrations differ between nightly nocturnal and conventional haemodialysis.

AIM: Nocturnal haemodialysis (NHD) is a new haemodialysis (HD) modality that has been shown to have many benefits when compared with conventional haemodialysis (CHD). Previous results from our NHD programme have demonstrated a 7% fall in the postdialysis serum albumin concentration when compared with the pre-HD levels. A similar, physiological, 9% haemodilution of albumin is seen in normal individuals on assuming a supine posture. METHOD: In this observational study, the intradialytic change in the concentration of 11 serum proteins (total protein, albumin, alkaline phosphatase, gamma glutamyl transferase, alanine transaminase, amylase, transferrin, complement factors 3 and 4, free thyroxine and C-reactive protein (CRP)) was measured in 10 patients on NHD and in 10 age- and sex-matched controls on CHD. The ultrafiltration rate (UFR) was also recorded. RESULTS: We demonstrated an intradialytic fall in the total protein (0.63%), albumin (2.40%), alkaline phosphatase (1.84%), amylase (8.82%), complement factor 3 (2.73%) and CRP (8.19%) in patients on NHD. This was of a lesser magnitude than that occurring in the pilot study but still approximated the physiological fall in serum proteins occurring with overnight recumbency in normal individuals. In contrast, all serum proteins measured rose during CHD, reflecting intravascular volume contraction and haemoconcentration. The UFR was significantly lower in NHD than CHD (234.52+/-20.90 mL/h vs 435.38+/-38.44 mL/h, P<0.001). CONCLUSION: We concluded that NHD is a modality that facilitates the use of a low UFR and hence the slow removal of volume which, in turn, results in a minimal perturbation of the normal recumbent volume distribution mechanism and the partial preservation of the normal physiological response to recumbency of the serum protein concentration.

Adult↗
PubMed2005

'Flexible' or 'lifestyle' dialysis: is this the way forward?

BACKGROUND: Despite the advent of two new dialysis options, nocturnal home haemodialysis and short daily haemodialysis, many units are yet to build them into the modalities on offer to end-stage renal failure patients. The reasons behind this inertia are complex but primarily include anxieties about workload, budgetary implications and outcome data. METHOD: The Geelong dialysis programme, where both nocturnal home haemodialysis and short daily haemodialysis are offered, is compared with Australian and New Zealand national profiles. RESULTS: Significant profile differences emerge when comparing sessions/week and h/week between the three groups. Most Australian (92.93%) and New Zealand (95.07%) haemodialysis patients dialyse for three sessions/week. This contrasts to Geelong where only 73.6% dialyse for three sessions/week. 18.8% of Geelong haemodialysis patients versus 1.8% (Australia) and 0.9% (New Zealand) dialyse for five or more sessions/week. Australia and New Zealand follow similar h/session patterns although more Australians (44.2%) dialyse for 4 h and fewer (24.2%) for 5 h than their New Zealand counterparts (39.6% and 29.8%, respectively), and few dialyse outside the 3.5-5 h window. In contrast, 6.7% of Geelong patients dialyse for 2-2.5 h/session versus Australia (0.9%) and New Zealand (0.2%). This represents the Geelong short daily dialysis programme. More Geelong patients (>15%) dialyse >/=8 h/week and represent the Geelong nocturnal home haemodialysis programme. CONCLUSION: The flexible Geelong programme has been supported without exceeding the budget applied to a conventional dialysis programme with the same patient numbers.

Appointments and Schedules↗
PubMed2004

Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO.

OBJECTIVES: This study is aimed at investigating the novel use of minocycline for cardiac protection during ischemia/reperfusion (I/R) injury, as well as its mechanism of action. BACKGROUND: Minocycline is a tetracycline with anti-inflammatory properties, which is used clinically for the treatment of diseases such as urethritis and rheumatoid arthritis. Experimentally, minocycline has also been shown to be neuroprotective in animal models of cerebral ischemia and to delay progression and improve survival in mouse models of neurodegenerative diseases. METHODS: We studied 62 rat intact hearts exposed to I/R and cell cultures of neonatal and adult rat ventricular myocytes. RESULTS: Minocycline significantly reduced necrotic and apoptotic cell death, both in neonatal and adult myocytes, not only when given prior to hypoxia (p < 0.001), but also at reoxygenation (p < 0.05). Moreover, in the intact heart exposed to I/R, in vivo treatment with minocycline promoted hemodynamic recovery (p < 0.001) and cell survival, with reduction of infarct size (p < 0.001), cardiac release of creatine phosphokinase (p < 0.001), and apoptotic cell death (p < 0.001). In regard to its antiapoptotic mechanism of action, minocycline significantly reduced the expression level of initiator caspases, increased the ratio of XIAP to Smac/DIABLO at both the messenger RNA and protein level, and prevented mitochondrial release of cytochrome c and Smac/DIABLO (all, p < 0.05). These synergistic actions dramatically prevent the post-ischemic induction of caspase activity associated with cardiac I/R injury. CONCLUSIONS: Because of its safety record and multiple novel mechanisms of action, minocycline may be a valuable cardioprotective agent to ameliorate cardiac dysfunction and cell loss associated with I/R injury.

Animals↗
PubMed2004

Prion protein heterogeneity in sporadic but not variant Creutzfeldt-Jakob disease: UK cases 1991-2002.

Human prion diseases can occur as an idiopathic disorder (sporadic Creutzfeldt-Jakob disease) or can be acquired, as is the case for variant Creutzfeldt-Jakob disease. These disorders are characterized by the accumulation of a protease-resistant form of the host-encoded prion protein termed PrP(Sc) in the brains of affected individuals. PrP(Sc) has been proposed to be the principal, if not sole, component of the infectious agent, with its accumulation in the central nervous system the primary event leading to neurodegeneration. A major question remains as to whether self-propagating structural differences in PrP(Sc) might account for the clinicopathological diversity evident in Creutzfeldt-Jakob disease and whether different prion protein types underlie the existence of different strains of causative agent. Here, we describe the results of a large-scale biochemical study of PrP(Sc) from autopsy-proved cases of variant Creutzfeldt-Jakob disease (n = 59) and compare these with cases of sporadic Creutzfeldt-Jakob disease (n = 170) in the United Kingdom over the period 1991 to 2002. The results show PrP(Sc) in variant Creutzfeldt-Jakob disease to be remarkably stereotyped. In contrast, considerable heterogeneity in PrP(Sc) exists both between and within cases of sporadic Creutzfeldt-Jakob disease.

Adolescent↗
PubMed2004

The tubulin-binding agent combretastatin A-4-phosphate arrests endothelial cells in mitosis and induces mitotic cell death.

The tubulin-binding agent combretastatin A-4-phosphate (CA-4-P), rapidly disrupts the vascular network of tumors leading to secondary tumor cell death. In vitro, CA-4-P destabilizes microtubules and causes endothelial cell death. In this study we analyze the mechanisms by which CA-4-P induces the death of proliferating endothelial cells. We demonstrate that at >/=7.5 nmol/L, CA-4-P damages mitotic spindles, arrests cells at metaphase, and leads to the death of mitotic cells with characteristic G(2)/M DNA content. Mitotic arrest was associated with elevated levels of cyclin B1 protein and p34(cdc2) activity. Inhibition of p34(cdc2) activity by purvalanol A caused mitotic-arrested cells to rapidly exit mitosis, suggesting that sustained p34(cdc2) activity was responsible for metaphase arrest. Pharmacological prevention of entry into mitosis protected cells from undergoing cell death, further establishing the link between mitosis and cell death induction by CA-4-P. CA-4-P-mediated cell death shared characteristics of apoptosis but was independent of caspase activation suggesting the involvement of a non-caspase pathway(s). These data suggest that induction of apoptosis in endothelial cells by CA-4-P is associated with prolonged mitotic arrest. Therefore, by activating cell death pathways, CA-4-P, in addition to being an effective anti-vascular agent, may also interfere with regrowth of blood vessels in the tumor.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Urocortins: take them to heart.

The urocortins, together with corticotropin releasing hormone (CRH), have a long evolutionary pedigree. In the brain, CRH largely mediates anxiogenic effects associated with the stress response, while the urocortins are concerned with adaptive and coping behaviour. The urocortins, in particular, are also expressed in peripheral sites, including the heart. Here, they may play an autocrine/paracrine role, since CRH-R2 receptor subtypes, which preferentially bind the urocortins, are also expressed in the heart. Endogenous cardiac urocortin expression is enhanced by ischaemia/reperfusion injury in vitro, and addition of exogenous urocortins reduces cell death caused by ischaemia/reperfusion in vitro, ex vivo and in vivo. In the isolated perfused heart, urocortin improves haemodynamic recovery, and partially prevents the reduction in high energy phosphates following ischaemia/reperfusion. Urocortin-mediated cardioprotection involves several mechanisms, including increased expression of Kir6.1 K(ATP) channels and HSP90, although other as yet poorly understood mechanisms have also been implicated. Moreover, there is early data suggesting that urocortin has beneficial haemodynamic effects in an ovine model of heart failure, and further studies of the value of both endogenous and exogenous urocortins in the compromised heart are clearly needed. In man, there is suggestive, though indirect, data, that urocortin may also provide an endogenous myocyte salvage mechanism against iatrogenic ischaemia/reperfusion injury associated with bypass surgery. These experimental studies suggest that assessment of the clinical use of urocortins as direct and/or cardioplegic therapies in ischaemia/reperfusion, and maybe heart failure, should be actively pursued.

Animals↗
PubMed2003

Variant CJD: the present position and future possibilities.

Variant Creutzfeldt-Jakob disease (CJD) is one of the transmissible spongiform encephalopathies (TSEs), or prion diseases, and is thought to be due to transmission of BSE from cattle to man via diet. These are characterized by the tissue deposition of an abnormal isoform of the normal cellular prion protein, a progressive, fatal neurological course and having the potential for infectivity. Infectivity is difficult to inactivate, and instances of iatrogenic CJD have been reported. The involvement of the tonsil, appendix and other lymphoid tissue in variant CJD has increased concerns about possible human-to-human spread.

Animals↗
PubMed2003

Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases.

BACKGROUND AND PURPOSE: Variant Creutzfeldt-Jakob disease (vCJD) is a rare but important cause of dementia and death in young patients and is causally linked to bovine spongiform encephalopathy. Symmetrical hyperintensity in the pulvinar (posterior) nuclei of the thalamus (pulvinar sign) on brain MR images was described as a specific, noninvasive, diagnostic sign of vCJD in a previous small series. This purpose of this larger study was to evaluate this sign prospectively and further define the MR imaging characteristics of vCJD. METHODS: As part of the ongoing surveillance program in the United Kingdom, MR images of suspected cases of vCJD were collected during a 6-year period. All available images were assessed prospectively by one observer for the presence of the pulvinar sign. Images of neuropathologically confirmed cases were then assessed independently by two neuroradiologists for the degree of hyperintensity of the pulvinar on images of different MR sequences, and for the presence of abnormal hyperintensity in other areas of the brain. Discrepancies were reviewed jointly and a consensus opinion formed. RESULTS: Prospective analysis identified the pulvinar sign in 74 of 82 cases of vCJD. In the retrospective study, the pulvinar sign, as defined by hyperintensity of the pulvinar relative to the anterior putamen, was present on seven (9%) of 75 T1-weighted, 77 (71%) of 108 T2-weighted, 47 (81%) of 58 proton density-weighted, and 30 (100%) of 30 fluid-attenuated inversion-recovery (FLAIR) images. Diffusion-weighted images were available in two cases and were positive for the pulvinar sign in one. Other features were hyperintensity of the dorsomedial thalamic nuclei (93%), caudate head (40%), and periaqueductal gray matter (83%) on FLAIR images. CONCLUSION: In the appropriate clinical context, demonstration of the pulvinar sign on MR images is a highly accurate diagnostic sign for vCJD. FLAIR sequence is more sensitive than other sequences. Positive MR images may obviate more invasive diagnostic tests in most cases.

Brain↗
PubMed2002

Urocortin promotes hemodynamic and bioenergetic recovery and improves cell survival in the isolated rat heart exposed to ischemia/reperfusion.

OBJECTIVES: This study evaluates the hemodynamic, bioenergetic and cytoprotective effects of urocortin (Ucn) in the isolated rat heart exposed to ischemia (I)/reperfusion (R). BACKGROUND: We have previously demonstrated that administration of exogenous Ucn reduces infarct size in ischemic-reperfused rat hearts. METHODS: Urocortin 10(-8)M was added to the perfusate before I, before I and during R, and during R alone in the isolated pulsed rat heart exposed to 35 min I followed by 60 min R. RESULTS: Partial to complete recovery of diastolic pressure and developed pressure was seen irrespective of when Ucn was perfused. In particular, beneficial effects are observed when Ucn is only given during R. Urocortin given only before I, and before I and over R, although not during R alone, also produces significant recovery of high-energy phosphate pools. In each group, improvement in ventricular function is associated with reduction both in myocardial damage, assessed by creatine phosphokinase release, and in endothelial cell and cardiomyocyte apoptosis, assessed by caspase 3 activity and fluorescent-based terminal deoxynucleotidyl transferase mediated nick end labelling enhanced with counterstains. These improvements in ventricular performance, bioenergetics and cell survival are not secondary to any inotropic effects of Ucn. CONCLUSIONS: This is the first report to show enhanced cardiac function induced by Ucn during I/R. Because the cytoprotective and functional benefits are still produced when Ucn is given only at R, these data suggest that Ucn may be useful clinically in the management of myocardial infarction.

Adenosine Triphosphate↗
PubMed2002

Activation of protein kinase B/Akt by urocortin is essential for its ability to protect cardiac cells against hypoxia/reoxygenation-induced cell death.

Urocortin (Ucn), is a peptide related to hypothalamic corticotrophin-releasing factor (CRF) and binds with a high affinity to the CRF-R2 beta receptor which is expressed in the heart. Ucn promotes cardiac myocyte survival against hypoxia reoxygenation (HR) injury and this involves activation of the mitogen activated protein kinase pathway (MEK1/2 p42/44 MAPK). In this study we report that Ucn stimulates the phosphorylation of protein kinase B (PKB/Akt) via phosphatidylinositol (PI) 3-OH kinase (PI-3 kinase). To investigate the signalling pathways that mediate the anti-apoptotic and cell survival effect of Ucn in hypoxia reoxygenation (HR), gene based inhibitors of MEK1/2, PI-3 kinase and Akt were over-expressed in rat neonatal cardiac myocytes and cell survival effects against HR were assessed. The dominant negative mutants of the MEK1/2, PI-3 kinase and Akt inhibited Ucn mediated cardioprotection in HR and active PI-3 kinase was itself cardioprotective. In addition, chemical inhibitors of the PI-3 kinase pathway, wortmannin and LY294002 inhibit Ucn mediated cardioprotection in HR in both neonatal and adult cardiac myocytes. Hence the PI-3 kinase/Akt pathway is required in addition to MEK1/2 to mediate Ucn cardioprotection in HR. To our knowledge this is the first report of the activation of the PI-3 kinase/Akt pathway by a member of the CRF family of peptides.

Androstadienes↗
PubMed2002

Neuropathology of variant Creutzfeldt-Jakob disease.

The clinical, neuropathological genetic and biochemical features of variant Creutzfeldt-Jakob disease (vCJD) are compared to the 926 other cases of suspected CJD referred to the National CJD Surveillance Unit laboratory from 1990-2001. Histological studies of the central nervous system, lymphoid tissues and other organs were accompanied by immunocytochemistry for prion protein (PrP); Western blot analysis of PrPRES was performed on frozen brain tissue. The pathology of vCJD showed relatively uniform morphological and immunocytochemical characteristics, with PrP accumulation in lymphoid tissues, but not in other non-neural tissues. PrPRES accumulation in vCJD showed a uniform glycotype pattern distinct from sporadic CJD. All cases of vCJD were methionine homozygotes at codon 129 of the PrP gene. In view of the spread of bovine spongiform encephalopathy in Europe and Japan, continuing surveillance is required for all forms of CJD, with histological and biochemical analysis of suspected cases to allow an accurate laboratory diagnosis.

Animals↗