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Hospital Communication Systems↗
Biomedical subjects
K Farrell
Publications and source records attributed to K Farrell.
Radiation inactivation studies of the dopamine reuptake transporter protein.
Using radiation inactivation, we have estimated the target size for the neuronal dopamine transporter protein. The specific binding of several radioligands previously shown to label the dopamine transporter was determined in an irradiated striatal membrane preparation. The apparent target size of the 1-[1-(2-[3H]benzo[b]thienyl)cyclohexyl]piperidine site was approximately 98 kDa. However, the apparent target size of the "cocaine binding site," as measured with the cocaine analogue 2 beta-[3H]carbomethoxy-3 beta-(4-fluorophenyl)tropane in the same assays, was approximately 140 kDa. Radiation inactivation of the binding of other ligands (GBR-12935 and mazindol) led to target size estimates in the same range (94 kDa and 133 kDa, respectively). All of these target sizes are significantly larger than the estimate of 70 kDa derived from the deduced amino acid sequence for the cloned dopamine reuptake transporter cDNA. Larger target sizes than expected have also been reported for ligand binding to the sodium-dependent serotonin transporter and glucose transporter. The estimated sizes for the ligand binding site(s) associated with the dopamine transporter protein are difficult to reconcile with a single transporter protein of 70 kDa. We conclude that the dopamine transporter protein is a homo- or hetero-oligomer when occupied in situ by uptake-blocking drugs like cocaine.
Animals↗
Unverricht-Lundborg disease: absence of nonallelic genetic heterogeneity.
Unverricht-Lundborg disease is a clinically recognizable form of progressive myoclonus epilepsy. Recently, in several families of both Finnish and Mediterranean extraction segregating Unverricht-Lundborg disease, the gene for this disease was linked to the same region of the long arm of chromosome 21. We performed linkage analysis in eight families, including four of neither Baltic nor Mediterranean origin, using a polymorphic (CA)n repeat marker for the human liver-type 6 phosphofructokinase (PFKL) gene, previously mapped to 21q22.3. No recombinations were observed between the disease phenotype and the PFKL marker and a maximum lod score of 5.63 was obtained. These findings confirm tight linkage between PFKL and the gene for Unverricht-Lundborg disease and strongly suggest a lack of nonallelic genetic heterogeneity of the disease.
Adolescent↗
Intravenous immunoglobulin induces interferon-gamma and interleukin-6 in vivo.
Immunoglobulin is known to be an immunomodulator. It can induce protein mediators from mononuclear cells, particularly monocytes in vitro. Intravenous immunoglobulin (IVIg) has been used as a therapy in several clinical situations. In this study, the influence of IVIg infusion on the plasma levels of two protein mediators, interferon-gamma (IFN-gamma) and interleukin-6 (IL-6), was assessed in patients with secondary generalized epilepsy. Compared to preinfusion levels, plasma interferon-gamma was increased in 18 of 18 patients 20 min after the 6- to 8-hr infusion of IVIg. Plasma interferon-gamma levels reached their peak at various times from 20 min to 3 days post IVIg infusion, dependent upon the individual patient. Plasma IL-6 levels also increased after IVIg infusion. Generally, IL-6 reached its peak level after IFN-gamma. No activated T cells or B cells were observed as determined by the expression of surface CD25, CD23, and HLA-DR 20 min following the infusion when the IFN-gamma and IL-6 levels were assessed. The expression of the high-affinity receptor for IgG, CD64, on monocytes was significantly enhanced after IVIg infusion, while the low-affinity receptor for IgG, CD32, was only slightly increased. Cytoplasmic staining of PBMC indicates that both CD16-positive and CD16-negative cells may contribute to the increase seen in plasma IFN-gamma. These data raise the possibility that the therapeutic effects of intravenous immunoglobulin may be related, at least in part, to the immunomodulatory activity as demonstrated by the changes in plasma levels of IFN-gamma and IL-6.
Adolescent↗
Failure to recognize status epilepticus in a paralysed patient.
Paralysis induced by neuromuscular blocking agents facilitates ventilation of seriously ill patients but may preclude clinical recognition of seizures. We describe the occurrence of severe cognitive impairment in a 14-year-old girl in whom status epilepticus was recognized only when pancuronium was withdrawn after 14 hours of paralysis. This patient emphasizes a potential danger of paralysis from drugs in patients with acute cerebral dysfunction.
Adolescent↗
Characterization of a naturally occurring ecotropic receptor that does not facilitate entry of all ecotropic murine retroviruses.
A fibroblast cell line (MDTF) derived from the feral mouse Mus dunni is resistant to infection by Moloney murine leukemia virus (Mo-MuLV), an ecotropic murine leukemia virus (E-MuLV) (M. R. Lander and S. K. Chattopadadhyay, J. Virol. 52:695-698, 1984). MDTF cells can be infected by other E-MuLVs such as Friend MuLV and Rauscher MuLV, which have been demonstrated to use the same receptor as Mo-MuLV in NIH 3T3 cells (A. Rein and A. Schultz, Virology 136:144-152, 1984). We have now shown that the block to Mo-MuLV infection of MDTF cells occurs at the level of the envelope-receptor interaction. We have cloned the ecotropic receptor cDNA from MDTF cells (dRec) and compared its sequence with that of the NIH 3T3 cell receptor (mRec). Although the deduced dRec and mRec proteins differ at only four amino acid residues, we demonstrate that these changes account for the resistance of MDTF cells to Mo-MuLV infection. Our findings suggest that retroviruses in the same receptor class can exhibit different host ranges due to single amino acid differences in their cellular receptor.
3T3 Cells↗
Classifying epileptic syndromes: problems and a neurobiologic solution.
Because the effectiveness of an antiepileptic drug in controlling a particular seizure type and the prognosis for remission may differ between epileptic syndromes, accurate syndrome classification is crucial. However, a lack of universally accepted diagnostic criteria for some syndromes makes precise classification impossible in many patients. When syndromic classification is not possible, it is often more useful to consider genetic, clinical, electroencephalographic, neuropsychologic, radiologic, and other laboratory factors in characterizing the epileptic condition and selecting the optimal treatment.
Child, Preschool↗
Acute encephalomyelitis: extending the neurological manifestations of acute rheumatic fever?
The clinical course of a five-year-old boy who developed meningeal irritation, encephalomyelitis, and optic neuritis four weeks after Streptococcus pyogenes pharyngitis is detailed. The patient responded to therapy with corticosteroids and recovered fully. Review of the literature reveals that a wide range of neurological disorders have been described in association with rheumatic fever. We suggest that disseminated encephalomyelitis in this child most probably was related to the streptococcal infection and that the spectrum of post-infectious neurological disorders associated with Streptococcus pyogenes may be broader than is currently appreciated.
Acute Disease↗
Magnetic resonance imaging in pseudotumor cerebri.
The pathophysiology of pseudotumor cerebri is unclear, but may relate to an abnormality in water transport in the brain. The authors performed MR imaging in seven children with pseudotumor cerebri; the signal intensity in the white matter was normal in all patients. These data suggest that periventricular brain water content is not increased markedly in children with pseudotumor cerebri. The authors speculate that this may relate to the establishment of an equilibrium between increased resistance to cerebrospinal fluid outflow and increased brain stiffness, occurring as a consequence of increased cerebral blood-volume and/or interstitial pressure.
Adolescent↗
Continuous intrathecal baclofen treatment of severe spasms in two children with spinal-cord injury.
This study reports the use of intrathecal baclofen in two ventilator-dependent children with severe spasms secondary to spinal-cord injury. Baclofen was delivered via a subcutaneously implanted, programmable pump. The children were followed for 12 and 24 months. Baclofen dramatically reduced spasms, resulting in more stable ventilation, improved ease of care, reduced distress and better integration into the community. Although effective, intrathecal baclofen represents a significant intervention; careful consideration must be given to potential complications and the need for long-term management. Full effectiveness was dependent on free CSF flow.
Adolescent↗
Line defects in gel phase lipid monolayers.
We investigate various models of the hydrolysis of gel-phase phosphatidylcholine monolayers by phospholipase A2 (Grainger et al. (1989) FEBS Lett. 252, 73-82). We assume that the probability of hydrolysis of a given lipid depends only upon how many of its nearest neighbour lipids have already been hydrolysed. We find that the experimental data are consistent with a model in which line defects exist in the gel phase and that lipids on such defects are more easily hydrolysed than the other gel-phase lipids. Based on this model, we calculate the course of hydrolysis of a gel-phase region possessing line defects, and we suggest how such a structure might be made and the model tested. An experiment, similar to that proposed by us, has been carried out by Grainger et al. (1990) Biochim. Biophys. Acta 1023, 365-379). We also calculate the fractal dimension, df, of the interface created by the hydrolytic process and show that a measurement of df might identify how this process proceeds.
Computer Simulation↗
'Pure' and 'complicated' forms of hereditary spastic paraplegia presenting in childhood.
Of 23 children with hereditary spastic paraplegia (HSP), spasticity was the only neurological abnormality in eight patients (pure form). Additional neurological abnormalities in the 15 with complicated HSP included cognitive impairment, pseudo-bulbar palsy, cerebellar dysfunction and polyneuropathy. 19 children presented with abnormal gait, recognised at a mean age of three years in the pure form and five years in the complicated form. These forms were distinguished at a mean age of 11 years. Early non-motor developmental delay or rapidly ascending paraparesis, with spread of spasticity to the arms and with involvement of bulbar structures, predicted development of the complicated form. The pure form was inherited in an autosomal dominant manner in five patients. The autosomal recessive form was commonly associated with additional neurological abnormalities and a more rapid rate of progression.
Activities of Daily Living↗
Metabolic profiling of valproic acid in patients using negative-ion chemical ionization gas chromatography-mass spectrometry.
A negative-ion chemical ionization gas chromatographic-mass spectrometric method for the determination of valproic acid (VPA) and fourteen of its metabolites in a single chromatographic run is reported. The assay features the use of four internal standards and is applicable to the analysis of small serum and urine volumes. A combination of pentafluorobenzyl and trimethylsilyl derivatization resulted in the [M - 181]- ion as the base peak for all the metabolites measured. When these ions were monitored sensitivities in the low picogram levels were achieved. The VPA metabolite profile was determined in pediatric patients on VPA monotherapy and on combined VPA therapy with either carbamazepine or clobazam. The recently characterized diene metabolite, (E,E)-2,3'-diene-VPA, was found to be a major serum metabolite of VPA. In the patient groups taking VPA in combination with carbamazepine, the induction of omega and omega-1 pathways of VPA metabolism was apparent, while the levels of the beta-oxidation products were significantly decreased.
Adolescent↗
Electrophysiologic studies, computed tomography, and neurologic outcome in acute bacterial meningitis.
To determine the value of computed tomography and electrophysiologic studies in predicting neurologic outcome, we prospectively studied 41 children with acute bacterial meningitis, using clinical examination, computed tomography of the head, electroencephalography, brain-stem auditory evoked response, and visual evoked potential mapping during the acute illness. Two children died; 32 of the remaining 39 children were reviewed clinically, electrophysiologically, and with computed tomography between 5 and 38 months after the illness. The electrophysiologic data obtained during the illness were not found to alter the acute-stage management. Focal or generalized suppression, demonstrated on the electroencephalogram, was associated with a poor outcome. Cerebral infarction and edema, demonstrated by computed tomography of the head, were predictive of a poor outcome, but enlarged ventricular and subarachnoid spaces and increased subdural effusions were of no predictive value. Neither computed tomographic scans nor electrophysiologic data were better indicators of neurologic prognosis than the clinical examination.
Acute Disease↗
The high incidence of valproate hepatotoxicity in infants may relate to familial metabolic defects.
The incidence of fatal hepatic failure associated with valproic acid (VPA) therapy is highest in children under the age of three years, particularly in those with developmental delay. The pathogenesis of VPA hepatotoxicity is unclear but may relate to the accumulation of a toxic metabolite of VPA which impairs fatty-acid oxidation. We describe two unrelated infants with developmental delay who developed hepatic failure while receiving VPA. Siblings of both children subsequently developed hepatic steatosis and intractable seizures without being exposed to VPA. This suggests that the two children who developed liver failure when receiving VPA may have had a familial metabolic disorder. Familial metabolic disorders may account partly for the higher incidence of fatal hepatotoxicity described in infants receiving VPA.
Chemical and Drug Induced Liver Injury↗
Decline in head growth and cognitive impairment in survivors of acute lymphoblastic leukaemia.
Twenty five children in remission, who were asymptomatic and who had last been treated at least two years before for acute lymphoblastic leukaemia, were examined neurologically and neuropsychologically. Their treatment included early cranial irradiation (24 Gy or 18 Gy), intrathecal methotrexate, and systemic chemotherapy. One half of the children demonstrated a decline in head circumference centile, which occurred in all patients treated with 24 Gy and in those patients treated with 18 Gy under the age of 3 years. In those children whose head growth was reduced, performance was significantly impaired in neuropsychological tests designed to assess concentration and short term memory. These children also developed clinically important learning difficulties in the classroom. Minor neurological dysfunction was present in almost half of the entire group. These data suggest that the treatment employed to prevent central nervous system leukaemia (primarily cranial irradiation) has a deleterious effect on head and brain growth and intellectual function.
Adolescent↗
Routine screening of blood and urine for severe reactions to anticonvulsant drugs in asymptomatic patients is of doubtful value.
Severe or fatal reactions to anticonvulsant agents are fortunately rare. We examined the value of routine screening of blood and urine to detect early signs of such reactions in asymptomatic patients. The basic assumptions of this type of screening program have been faulty or unproven, and the results of studies, although not definitive, have not supported the value of such programs. Our recommendations, approved by the Canadian Association for Child Neurology, suggest that asymptomatic patients not undergo routine screening of blood and urine but, rather, be informed of the early symptoms of severe toxic reactions and be asked to report them immediately to a physician.
Adult↗
The effect of carbamazepine on valproic acid disposition in adult volunteers.
1. Pharmacokinetic parameters for valproic acid (VPA) were determined before and following 2 weeks of carbamazepine (CBZ) administration in five healthy male volunteers. Mean VPA dosage was 16.4 mg kg-1 day-1. CBZ dosage was started at 100 mg twice daily and increased after 1 week to a total daily dose of 300 mg. 2. After CBZ administration, mean VPA plasma clearance increased from 0.90 +/- 0.18 s.d. to 1.26 +/- 0.24 l h-1 (P less than 0.05) as did clearance of free VPA (20.8 +/- 7.6 to 37.0 +/- 13.6 l h-1). Mean VPA elimination rate constant increased from 0.051 +/- 0.011 to 0.067 +/- 0.011 h-1 (P less than 0.05) after CBZ administration. 3. Mean area under the serum concentration vs time curve decreased from 675.0 +/- 130.5 to 475.7 +/- 75.7 mg l-1 h (P less than 0.05) after CBZ administration. Mean serum VPA half-life decreased from 14.0 +/- 2.4 to 10.6 +/- 1.4 h (P less than 0.05). Mean serum VPA trough concentrations decreased from 44.0 +/- 16.7 to 27.0 +/- 10.4 micrograms ml-1 (P less than 0.05). 4. A significant change was not observed in the mean VPA volume of distribution after CBZ coadministration suggesting that enzyme induction rather than a competition for plasma protein binding sites was involved in this interaction. 5. Despite the increased clearance of VPA, the urinary recovery of VPA or conjugate did not increase after CBZ administration.
Adult↗