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Biomedical subjects

K Farrell

Publications and source records attributed to K Farrell.

At least 19 recordsLinked to original sources
PubMed2006

Electroclinical features of absence seizures in childhood absence epilepsy.

OBJECTIVE: To accurately define the electroclinical features of absence seizures in children with newly diagnosed, untreated childhood absence epilepsy (CAE). METHODS: The authors searched an EEG database for absence seizures in normal children with new onset untreated absence epilepsy. Seventy consecutive children were classified into IGE syndromes. The clinical and EEG features of the seizures in the children with CAE were analyzed using video-EEG recordings. RESULTS: The authors analyzed 339 absence seizures in 47 children with CAE. The average seizure duration was 9.4 seconds and clinical features consisted of arrest of activity, loss of awareness, staring, and 3-Hz eyelid movements, but there was individual variation. Ictal EEG predominantly showed regular 3-Hz generalized spike and wave (GSW) with one or two spikes per wave; however, disorganization of discharges was common and three or more spikes per wave occurred rarely. Postictal slowing was frequent. Interictal abnormalities included fragments of GSW, posterior bilateral delta activity, and focal discharges. Although all 47 children met the current criteria for CAE, only 5 fulfilled the recently proposed criteria for CAE. CONCLUSION: The heterogeneous nature of each clinical and EEG feature of untreated absence seizures is of critical importance when determining criteria for childhood absence epilepsy.

Canada↗
PubMed2006

Selecting doctors for postgraduate training in paediatrics using a competency based assessment centre.

The design and implementation of an assessment centre in the South Yorkshire and South Humberside deanery for selecting doctors into postgraduate training in paediatric medicine is described. Eleven competency domains were identified in the job analysis. An assessment centre comprising of four exercises was implemented to assess candidates. There were modest relationships between candidates' performance on the various assessment centre exercises. Outcomes based on interview performance were related to, but not the same as, outcomes based on the combined results of the three other assessment centre exercises. Candidates perceived the assessment centre to be a fair selection method. It is concluded that an assessment centre approach to SHO recruitment is feasible and provides a greater breadth and depth of information about candidates than does a structured interview.

Chi-Square Distribution↗
PubMed2005

Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.

Adult↗
PubMed2004

Paroxysmal eyelid movements: a confusing feature of generalized photosensitive epilepsy.

BACKGROUND: Persistent, frequent, nonepileptic paroxysmal eyelid movements were observed in 19 children and adults with well-controlled generalized epilepsy. METHODS: Patients were identified from five epilepsy centers. RESULTS: Seventeen patients were female and two male. All had generalized photosensitive epilepsy requiring antiepileptic drugs (AEDs). In two children, paroxysmal eyelid movements began 2 to 4 years before their epilepsy was noted; in the remainder, it was noted when epilepsy was first diagnosed. Age at last follow-up was 8 to 38 years (average 21 years) with average follow-up of 9 years. All patients showed photosensitive generalized spike-wave discharges on EEG. Paroxysmal eyelid movements were a source of diagnostic confusion, but direct examination and video during EEG recording distinguished the attacks from absence seizures. In all cases, the epilepsy is completely or nearly completely controlled with AEDs, but the paroxysmal eyelid movements have not resolved with age. In 12 cases, there was a family history of the eyelid disorder without epilepsy. Videos of patients and an affected parent are available on the Neurology Web site. CONCLUSION: There is an association between paroxysmal eyelid movements and photosensitive generalized epilepsy, creating diagnostic confusion.

Adolescent↗
PubMed2004

Spasms in children with definite and probable mitochondrial disease.

The diagnosis of mitochondrial encephalomyopathies is complex and a system for classification of the diagnosis as definite, probable, and possible has been proposed. The objective of this study was to explore the spectrum of epileptic disorders associated with probable and definite mitochondrial disease in children using this classification system. The patient population with mitochondrial disease and epilepsy was selected from a tertiary care children's hospital. Interictal electroencephalograms and video-EEG recordings were used to characterize seizure types. Ten children fulfilled the criteria for probable or definite mitochondrial disease and had epilepsy. Four had siblings with a similar clinical phenotype. Spasms were the most common seizure type and were the initial seizure type in seven patients and two siblings. Four patients had only partial seizures, with or without generalization, and one patient had seizures that were difficult to classify. Blood lactate concentrations were elevated consistently in patients with partial seizures alone but were occasionally normal in children with spasms. Spasms were the most common presenting seizure type in children with probable and definite mitochondrial disease.

Child↗
PubMed2004

Trustworthiness of information about blood donation and transfusion in relation to knowledge and perceptions of risk: an analysis of UK stakeholder groups.

There is evidence that the public perceive blood transfusion as risky, and there is a growing literature exploring factors associated with perceived transfusion risk. One contributory factor might be the types of information different key stakeholders (e.g. general practitioners, anaesthetists, health/life style journalists and blood donors) rely on for information. This article addresses four unanswered questions about transfusion/donation risk, namely (1) do different stakeholder groups perceive different sources of information as more or less trustworthy, (2) to what extent is the perceived trustworthiness related to levels of knowledge and perceived risk, (3) is optimistic bias observed across the stakeholder groups, and (4) is knowledge related to levels of perceived risk across the stakeholder groups? A questionnaire survey was used to assess the trustworthiness of sources of information, perceived risk and knowledge. Four stakeholder groups were examined, namely (1) blood donors (n = 250), (2) general practitioners (n = 88), (3) anaesthetists (n = 143) and (4) medical journalists (n = 20). The results showed that (1) judgements of trustworthiness vary as a function of stakeholder groups, and (2) it is what people think they know rather than what they actually know that is related to judgements of trustworthiness and perceptions of risk. Judgements of trustworthiness are generally unrelated to perceptions of risk, and all stakeholder groups show optimistic bias. The implications of these findings for risk communication, specifically relating to transfusion medicine, are discussed.

Attitude to Health↗
PubMed2003

Amino acid conjugates: metabolites of 2-propylpentanoic acid (valproic acid) in epileptic patients.

In this study, spectroscopic and chromatographic evidence is presented for the identification and characterization of the metabolites, valproyl glutamate (2-propylpentanoyl glutamate, VPA-GLU) and valproyl glutamine (2-propylpentanoyl glutamine, VPA-GLN) in the urine, serum, and cerebrospinal fluid (CSF) of patients on valproic acid (VPA) therapy. Moreover, the identification of valproyl glycine (2-propylpentanoyl glycine, VPA-GLY) in the serum and urine of patients on VPA, albeit in trace concentrations, is also reported here. The three amino acid conjugates excreted in urine accounted for about 1% of the VPA dose in four patients who were on VPA therapy chronically and had reached steady state. VPA-GLU was quantitatively the most prominent metabolite (0.66-13.1 microg/mg creatinine) compared with VPA-GLN (0.78-9.93 microg/mg creatinine) and VPA-GLY (trace-1.0 microg/mg creatinine) in overnight urine samples of all patients studied (n = 29). The relatively low serum concentrations of the three amino acid conjugates of VPA in six patients suggest that the metabolites are readily excreted once formed. In contrast, whereas VPA GLY was absent in the CSF of one patient on VPA, the concentrations of VPA-GLU and VPA-GLN in this CSF sample were 9 and 5 times, respectively, their corresponding serum concentrations.

Adolescent↗
PubMed2001

Confidence in the safety of blood for transfusion: the effect of message framing.

BACKGROUND: Blood transfusion is a universally used, life-saving medical intervention. However, there are increasing concerns among patients about blood safety. This study investigates the effect of message framing, a means of presenting information, on confidence in blood transfusion safety. STUDY DESIGN AND METHODS: The same factual information regarding the safety of blood for transfusion was presented to a sample of 254 adult students (donors and nondonors) as either a gain frame (lives saved), a loss frame (lives lost), or a combined frame (a loss frame expressed in a positive context). This provided a basic two-way, between-subjects design with 1) blood donation history (donors vs. nondonors) and 2) message frame (gain, loss, and combined) functioning as the between-groups factors. It was hypothesized that participants would consider blood safer if information was presented as a gain frame. The role of stress appraisals as potential mediators of the framing effect was also explored. RESULTS: As predicted, participants receiving the gain-frame information were significantly more confident of the safety of blood for transfusion than those receiving loss-frame information or both. This was unaffected by donation history or appraisals of stress associated with transfusion. The extent to which blood was considered safe was negatively associated, independently of framing effects, with perceptions that transfusion was threatening. CONCLUSION: Information about transfusion should be conveyed to patients in a form focusing on the positive, rather than the negative, known facts about the safety of blood.

Adult↗
PubMed2001

Current perceived risks of transfusion in the UK and relevance to the future acceptance of blood substitutes.

Data has been gathered on the perception of risk associated with blood donation and transfusion (including the use of so-called blood substitutes) by UK general practitioners (GPs), anaesthetists, healthcare journalists and blood donors of both genders. A questionnaire survey was conducted from March-July 2000 involving (i) GPs (n = 88), (ii) anaesthetists (n = 143), (iii)journalists (n = 20), and (iv) blood donors (n = 250). Respondents rated (scale of 1-7) the general risk of blood transfusion and the risk of infection associated with blood transfusion and donation. Respondents were asked through free response questions to identify the risks they most associated with blood transfusion and the infections associated with blood transfusion and donation. They were also asked to indicate their preference for their own blood, compared to donor blood or a blood substitute and to make a choice between donated blood or a blood substitute. The percentage of respondents who preferred to receive their own blood, compared to donor blood or a suitable substitute, was 73-94%. When required to choose between donor blood or a blood substitute, there were significant (P < 0.05) differences between sample groups: anaesthetists and GPs preferred to receive a blood substitute (52-59%), whereas blood donors and journalists preferred donated blood (74-93%). These findings have clear implications for the future development and implementation of modern transfusion options, including the use and acceptability of blood substitutes as alternatives to donor blood.

Blood Donors↗
PubMed2000

Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter.

We tested the hypothesis that astrocytic glycogen sustains axon function during and enhances axon survival after 60 min of glucose deprivation. Axon function in the rat optic nerve (RON), a CNS white matter tract, was monitored by measuring the area of the stimulus-evoked compound action potential (CAP). Switching to glucose-free artificial CSF (aCSF) had no effect on the CAP area for approximately 30 min, after which the CAP rapidly failed. Exposure to glucose-free aCSF for 60 min caused irreversible injury, which was measured as incomplete recovery of the CAP. Glycogen content of the RON fell to a low stable level 30 min after glucose withdrawal, compatible with rapid use in the absence of glucose. An increase of glycogen content induced by high-glucose pretreatment increased the latency to CAP failure and improved CAP recovery. Conversely, a decrease of glycogen content induced by norepinephrine pretreatment decreased the latency to CAP failure and reduced CAP recovery. To determine whether lactate represented the fuel derived from glycogen and shuttled to axons, we used the lactate transport blockers quercetin, alpha-cyano-4-hydroxycinnamic acid (4-CIN), and p-chloromercuribenzene sulfonic acid (pCMBS). All transport blockers, when applied during glucose withdrawal, decreased latency to CAP failure and decreased CAP recovery. The inhibitors 4-CIN and pCMBS, but not quercetin, blocked lactate uptake by axons. These results indicated that, in the absence of glucose, astrocytic glycogen was broken down to lactate, which was transferred to axons for fuel.

4-Chloromercuribenzenesulfonate↗
PubMed2000

Gas chromatography/negative ion chemical ionization mass spectrometry and liquid chromatography/electrospray ionization tandem mass spectrometry quantitative profiling of N-acetylcysteine conjugates of valproic acid in urine: application in drug metabolism studies in humans.

We report a GC/NICI-MS assay and a LC/ESI-MS/MS assay for the analysis of N-acetylcysteine (NAC) conjugates of (E)-2,4-diene VPA (NAC I and NAC II) identified in humans. The assay also includes the analysis of the NAC conjugate of 4,5-epoxy VPA (NAC III), an identified metabolite in rats treated with 4-ene VPA for its use in metabolic studies in animals. The highly sensitive GC/MS assay was designed to monitor selectively the diagnostic and most abundant [M - 181](-) fragment anion of the di-PFB derivatives of NAC I, NAC II, and NAC IV, the internal standard (IS) and the PFB derivative of NAC III. The higher selectivity of LC/MS/MS methodology was the basis for an assay which could identify and quantitate the underivatized conjugates simultaneously using MRM of the diagnostic ions m/z 130 and 123 arising from the CID of their protonated molecular ions [MH](+). The GC/MS assay employed liquid-liquid extraction whereas the LC/MS/MS assay used a solid-phase extraction procedure. Linearity ranges of the calibration curves were 0.10-5.0microg ml(-1) by GC/MS and 0.10-1.0microg ml(-1) by LC/MS/MS for NAC I, NAC II and NAC III (r(2) = 0.999 or better). Both assays were validated for NAC I and NAC II and provided good inter- and intra-assay precision and accuracy for NAC I and NAC II. The LOQ by LC/MS/MS was 0.1microg ml(-1), representing 1 ng of NAC I and NAC II. The same LOQ (0.1microg ml(-1)) was observed by GC/MS and was equivalent to 100 pg of each metabolite. NAC III was detected at concentrations as low as 0.01 microg ml(-1) by both methods. The total urinary excretion of the NAC conjugates in four patients on VPA therapy was determined to be 0.004-0.088% of a VPA dose by GC/MS and 0.004-0. 109% of a VPA dose by LC/MS/MS.

Acetylcysteine↗
PubMed2000

Factors associated with behavioral and cognitive abnormalities in children receiving topiramate.

The objective of this study was to examine the factors associated with the occurrence of behavioral and cognitive abnormalities in children treated with topiramate. A retrospective chart review of patients up to 18 years of age who had been treated with topiramate at a tertiary epilepsy center was performed. Behavioral or cognitive abnormalities were observed in 11 (14.6%) of 75 children between 2 weeks and 4 months after initiation of therapy. The mean dosage (4.6 mg/kg daily) at which these abnormalities were observed was similar to the mean final dose (5.8 mg/kg daily) in children without abnormalities. The mean rate of dosage increase was 0.72 mg/kg weekly and 0.7 mg/kg weekly in those with and without abnormalities, respectively. Five of the 11 children with behavioral or cognitive abnormalities had a previous history of behavioral or cognitive abnormalities, but only nine of the 64 children without abnormalities had a previous history of behavioral or cognitive abnormalities (P = 0.03). Lamotrigine was used concurrently in four of the 11 children with behavioral or cognitive abnormalities but in only seven of the 64 children without abnormalities (P = 0.05). Behavioral and cognitive abnormalities in children treated with topiramate do not appear to be related to the rate of dosage increase. A previous history of behavioral problems and the concurrent use of lamotrigine may be predisposing factors.

Adolescent↗
PubMed2000

A competency model for general practice: implications for selection, training, and development.

BACKGROUND: The role of the general practitioner (GP) has changed significantly over the past decade. This problem is compounded by growing concern over postgraduate attrition rates from medicine, with current estimates as high as 19%. AIM: To define a comprehensive model of the competencies required for the job role of GP. METHOD: Three independent studies were conducted to define GP competencies including (1) critical incidents focus groups with GPs, (2) behavioural coding of GP-patient consultations, and (3) critical incidents interviews with patients. Study 1 was conducted with GPs (n = 35) from the Trent region. Study 2 involved observation of GP-patient consultations (n = 33 consultations), and Study 3 was conducted with patients (n = 21), all from a Midlands-based medical practice. RESULTS: The data collected from the three studies provided strong evidence for a competency model comprising 11 categories with a summary of the associated behavioural descriptions. Example competencies included empathy and sensitivity, communication skills, clinical knowledge and expertise, conceptual thinking, and coping with pressure. CONCLUSIONS: Triangulation of results was achieved from three independent studies. The competencies derived imply that a greater account of personal attributes needs to be considered in recruitment and training, rather than focusing on academic and clinical competency alone. The model could be employed for future research in design of selection techniques for the role of GP.

Clinical Competence↗
PubMed2000

Identification and characterization of N-acetylcysteine conjugates of valproic acid in humans and animals.

Reactive and hepatotoxic metabolites formed from the biotransformation of valproic acid (VPA) are normally detoxified by conjugating with GSH and followed by mercapturic acid metabolism to produce their respective N-acetylcysteine (NAC) conjugates. Hence, the levels of NAC conjugates of VPA in human urine are an indirect measure of exposure of the liver toward reactive metabolites of the anticonvulsant drug. We report here the synthesis, identification, and characterization of a second NAC conjugate of (E)-2-propyl-2, 4-pentadienoic acid in the urine samples (n = 39) of humans on VPA therapy, namely, (E)-5-(N-acetylcystein-S-yl)-2-ene VPA by gas chromatography/mass spectrometry and liquid chromatography with tandem mass spectrometry. In this study, we were able to separate the diastereomers of (E)-5-(N-acetylcystein-S-yl)-3-ene VPA by HPLC. The NAC conjugate of 4,5-epoxy VPA, namely, 5-NAC-4-OH-VPA gamma-lactone, previously identified in rats treated with 2-propyl-4-pentenoic acid (4-ene VPA), was not detected in any of the human urine samples studied. This suggests that in humans, the P-450 metabolism of 4-ene VPA to the reactive epoxide is not a significant pathway. The excretion of the NAC conjugate of (E)-2, 4-diene VPA glucuronide in the urine of seven patients on VPA was also examined and was not detected. The limit of detection of 5-NAC-3-keto VPA and its decarboxylated product, 1-NAC-3-heptanone, was estimated at 25 ng (signal to noise ratio > 3). Neither 5-NAC-3-keto VPA nor 1-NAC-3-heptanone was detected in the urine of patients on VPA therapy or 4-ene VPA-treated guinea pigs, but 1-NAC-3-heptanone was detected in the urine of 4-ene VPA-treated rats.

Acetylcysteine↗
PubMed1999

K(+)-induced reversal of astrocyte glutamate uptake is limited by compensatory changes in intracellular Na+.

Glutamate uptake is coupled to counter-transport of K+, and high external K+ concentrations can induce reversal of glutamate uptake in whole-cell patch-clamp and isolated membrane preparations. However, high external K+ causes little or no reversal of glutamate uptake in intact astrocytes, suggesting a regulatory mechanism not evident in membrane preparations. One mechanism by which intact cells could limit the effects of altered extracellular ion concentrations on glutamate transport is by compensatory changes in intracellular Na+ concentrations. This possibility was examined using astrocyte cultures treated in two ways to reduce the driving force for glutamate uptake: incubation in high K+ (with reciprocal reduction in Na+), and incubation with metabolic inhibitors to induce ATP depletion. ATP depletion produced a rise in intracellular Na+, a collapse of the membrane sodium gradient and a massive reversal of glutamate uptake. By contrast, incubation in high K+/low Na+ medium did not significantly alter the sodium gradient and did not induce glutamate uptake reversal. The sodium gradient was shown to be maintained under these conditions by compensatory reductions in intracellular Na+ that approximately matched the reductions in extracellular Na+. These findings suggest a mechanism by which astrocytes may limit reversal of glutamate uptake under high K+/low Na+ conditions, and further suggest a general mechanism by which Na(+)-dependent transport processes could be shielded from fluctuating extracellular ion concentrations.

Adenosine Triphosphate↗
PubMed1999

Retrospective study of late febrile seizures.

This retrospective study documents the clinical features, electroencephalographic data, and outcome of 50 children with a history of seizures with fever that occurred after 5 years of age. Children with afebrile seizures before the onset of febrile seizures were excluded. Outcome was based on a cross-sectional survey and the follow-up period was 1-13 years. Of the 50 children, 40 had two or fewer febrile seizures after 5 years of age, and febrile seizures did not occur after 10 years of age. Twenty had complex febrile seizures, and 16 had a first-degree relative with febrile seizures. Five developed afebrile seizures, and 18 had educational difficulties. Epileptiform electroencephalographic abnormalities were observed in 22 but were not predictive of later afebrile seizures. Febrile seizures that occur after 5 years of age recur infrequently and cease by 10 years of age. The risk of developing afebrile seizures in this group is small.

Adolescent↗