Improving uptake of immunisation. Mobile children miss out.
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Diphtheria-Tetanus-Pertussis Vaccine↗
Biomedical subjects
G Barrett
Publications and source records attributed to G Barrett.
Substitution of l-leucovorin for d,l-leucovorin in the rescue from high-dose methotrexate treatment in patients with osteosarcoma.
Studies in which high-dose methotrexate (HDMTX) is used for the treatment of osteosarcoma have utilized commercial formulations of d,l-leucovorin (leucovorin calcium) for rescue from potential methotrexate (MTX) toxicity. These formulations are racemic mixtures containing equal amounts of d and l isomers of leucovorin. All of the available data indicate that the l isomer is the pharmacologically active diastereomer. A clinical study was conducted to determine if l-leucovorin was as safe and efficacious as d,l-leucovorin in the rescue of patients with osteosarcoma who were treated with HDMTX (12.5 g/m2 over 6 h). Because d,l-leucovorin consists of equal proportions of d and l isomers, l-leucovorin was administered at half the usual dose of d,l-leucovorin. In patients with delayed methotrexate excretion, l-leucovorin doses were escalated from 7.5 to 50 mg every 3 h until the MTX level was 0.3 mumol/l or less. Due to the low incidence of osteosarcoma, a control group of patients previously treated with d,l-leucovorin was utilized for comparison. Efficacy of l-leucovorin was determined by its ability to prevent HDMTX-associated toxicity. Demographic and clinical toxicity data from three patients who received 22 courses of MTX rescued with l-leucovorin were compared with data from six patients who had received 42 MTX courses rescued with d,l-leucovorin. Some liver function abnormalities and leukocyte elevations were found in both groups and were attributed to MTX administration. No clinical toxicity attributable to l-leucovorin was observed. l-Leucovorin in half the d,l-leucovorin dose was (equally) effective as a rescue treatment.
Adolescent↗
Identification of a negative regulatory element involved in tissue-specific expression of mouse renin genes.
The 5' flanking region of the mouse renin genes (Ren-1d and Ren-2d) contains two motifs that are homologous to known negative regulatory elements (NREs). Ren-2d has a 150-base-pair (bp) insertion 5' to the upstream putative NRE (NRE-1), which is lacking in Ren-1d. We tested the functionality of these sequences by using site-directed mutagenesis to delete individually each putative NRE from Ren-1d and to delete the 150-bp insertion from Ren-2d. We examined the effect of these mutations on the expression of the reporter gene chloramphenicol acetyltransferase, which was expressed from a truncated thymidine kinase promoter fused to the renin regulatory region. This plasmid was transfected into human choriocarcinoma JEG-3 cells. Only the upstream NRE (positions -619 to -597) was found to be functional in Ren-1d. The deletion of a 150-bp insertion from Ren-2d resulted in the suppression of chloramphenicol acetyltransferase activity to the level of Ren-1d expression. These data suggest that the upstream NRE that is functional in Ren-1d, but not in Ren-2d, may be partly responsible for differential expression of the renin genes in various tissues. The molecular mechanism of the NRE was examined by studying its interaction with nuclear proteins in submandibular gland and JEG-3 cells by gel-mobility-shift assays. Specific nuclear protein binding was observed only to the upstream NRE and the molecular mass of this protein was approximately 72 kDa as determined by Southwestern blot analysis. Thus our results suggest that both Ren-1d and Ren-2d conserve a cis-acting NRE in the 5' flanking region. In Ren-1d, this NRE could bind a specific nuclear protein resulting in the inhibition of Ren-1d expression in these tissues. On the other hand, the NRE in Ren-2d is nonfunctional due to interference by an adjacent 150-bp insertion.
Animals↗
Transgenic animal models of cardiovascular disease.
Transgenic experimentation has become a crucial part of hypertension and atherosclerosis research, and is growing more important in several other areas of cardiovascular disease. It has recently made a particular contribution to understanding the role of the renin-angiotensin system in controlling hypertension. The study of blood pressure regulation, cardiac hypertrophy, atherogenesis and thrombosis are also benefiting from the transgenic approach.
Animals↗
Jerk-locked averaging: technique and application.
Jerk-locked averaging (JLA) is used to record the timing and distribution of brain activity preceding brisk involuntary movements such as those observed in patients with myoclonus. JLA is capable of revealing a premyoclonus spike in the absence of paroxysmal activity in the routine EEG. The technique of JLA is described together with a consideration of the way in which the presence or absence of premyoclonus activity and the somatosensory evoked potential (SEP) can help to classify patients with involuntary movement disorders. The relationship between the premyoclonus spike and the N25-P33 complex of the SEP is discussed. Although the most common finding in patients with myoclonus of cortical origin is a large, well-defined positive-negative spike with the positive peak occurring about 20 ms before electromyographic onset, a wide variety of time relationships and topographies has been observed in other disorders of involuntary movement and some of these are described. The lack of correlation between the apparent origin of the premyoclonus spike in motor cortex and pathology in patients with myoclonus is discussed.
Brain↗
Molecular mechanism of tissue-specific regulation of mouse renin gene expression by cAMP. Identification of an inhibitory protein that binds nuclear transcriptional factor.
Renin gene expression in the mouse kidney and submandibular gland (SMG) are differentially regulated by cAMP. In this study, we examined the potential molecular mechanism responsible for this tissue-specific regulation. 32P end-labeled synthetic oligonucleotide containing mouse renin cAMP-responsive element (CRE) was incubated with kidney nuclear extracts from either control or cAMP-treated mice and analyzed by gel mobility shift assay. Our results demonstrated that cAMP induced a nuclear protein which complexed with the CRE oligonucleotide in a specific manner. This nuclear protein-DNA binding was competed effectively by the oligonucleotide containing human chorionic gonadotropin alpha-subunit CRE but not by the mouse renin DNA fragment from which the CRE was deleted by site-directed mutagenesis. In contrast, no DNA-protein complex formation could be detected when this [32P]CRE oligonucleotide was incubated with the SMG nuclear extract from control or cAMP-treated mice. However, CRE-binding protein complex formation was demonstrated in the SMG nuclear extract when the incubation was performed in the presence of 0.8% sodium deoxycholate and 1.2% Nonidet P-40, detergents that dissociate protein-protein complexes. Furthermore, in the absence of deoxycholate, we observed that SMG nuclear extract attenuated the binding of the kidney CRE-binding protein to mouse renin CRE in a dose-dependent manner and this inhibitory effect of SMG nuclear extract disappeared in the presence of sodium deoxycholate. This inhibitory nuclear protein in SMG is specific for CRE-binding protein since it does not affect nuclear protein binding to synthetic DNA oligonucleotides of human collagenase AP-1 and human metallothionein AP-2. Our data further suggest that inhibitory nuclear protein is present in lower quantities in other extrarenal tissues, i.e. testes, liver, brain, heart, but is not detectable in the kidney. Taken together, these results suggest that the SMG and certain extrarenal tissues contain nuclear trans-acting factor(s) that interact with CRE-binding protein, thereby interfering with its binding to mouse renin CRE. The presence of this inhibitory protein in the mouse SMG nucleus may contribute to the tissue-specific regulation of the renin gene expression by cAMP.
8-Bromo Cyclic Adenosine Monophosphate↗
Human secreted carbonic anhydrase: cDNA cloning, nucleotide sequence, and hybridization histochemistry.
Complementary DNA clones coding for the human secreted carbonic anhydrase isozyme (CA VI) have been isolated and their nucleotide sequences determined. These clones identify a 1.45-kb mRNA that is present in high levels in parotid submandibular salivary glands but absent in other tissues such as the sublingual gland, kidney, liver, and prostate gland. Hybridization histochemistry of human salivary glands shows mRNA for CA VI located in the acinar cells of these glands. The cDNA clones encode a protein of 308 amino acids that includes a 17 amino acid leader sequence typical of secreted proteins. The mature protein has 291 amino acids compared to 259 or 260 for the cytoplasmic isozymes, with most of the extra amino acids present as a carboxyl terminal extension. In comparison, sheep CA VI has a 45 amino acid extension [Fernley, R. T., Wright, R. D., & Coghlan, J. P. (1988b) Biochemistry 27, 2815]. Overall the human CA VI protein has a sequence identity of 35% with human CA II, while residues involved in the active site of the enzymes have been conserved. The human sheep secreted carbonic anhydrases have a sequence identity of 72%. This includes the two cysteine residues that are known to be involved in an intramolecular disulfide bond in the sheep CA VI. The enzyme is known to be glycosylated and three potential N-glycosylation sites (Asn-X-Thr/Ser) have been identified. Two of these are known to be glycosylated in sheep CA VI. Southern analysis of human DNA indicates that there is only one gene coding for CA VI.
Amino Acid Sequence↗
Physiology of short-term verbal memory.
These studies document a series of brain events accompanying short-term memory functions. For auditory verbal material the sequence involves at least two different sites within auditory cortex subserving sensory and cognitive processes of memorization. During the scanning of the short-term store structures within the medial temporal lobes, presumably the hippocampus, are active. There is an inconsistency between these results and the clinical observations of the need for an intact dominant parietal lobe for auditory short-term memory to function normally. Magnetic recordings showed no focal dipolar source of activity in the parietal lobe during any aspect of auditory short-term memory. The discrepancy could be accounted for by considering the parietal lobe lesion as "disconnecting" the lateral temporal cortex from the deep medial hippocampal structures thereby impeding auditory short-term functions (Geschwind, 1965). These studies show that the physiological analysis of brain events in the msec range can provide information about relatively complex cognitive processes underlying short-term memory. The magnetic and electrical recording methods provide a noninvasive way to study human brain functions involved in cognition that can then be correlated with behavioral measures of specific cognitive activities.
Brain↗
Myoclonic epilepsy in an HIV positive patient: neurophysiological findings.
An HIV-positive patient is described who presented with action myoclonus. Unusually, focal sinusoidal EEG burst complexes with a frequency of 40 and 55 Hz could be recorded over the sensorimotor cortex. Activity having a similar frequency was evoked in this area by posterior tibial nerve stimulation in the affected leg, and jerk-locked averaging showed that myoclonic jerks were preceded by similar cortical sinusoidal waves.
Acquired Immunodeficiency Syndrome↗
The pathophysiology of acute optic neuritis. An association of gadolinium leakage with clinical and electrophysiological deficits.
Eighteen patients with acute optic neuritis underwent optic nerve magnetic resonance imaging (MRI) before and after injection of gadolinium-diethylene triamine pentacetic acid (Gd-DTPA). Ten were re-examined 4 weeks later. Leakage of Gd-DTPA across the blood-optic nerve barrier was a consistent finding in the acute lesion, and its presence was associated with abnormal visual acuity and colour vision, retro-ocular pain on eye movement, and afferent pupillary defect, and a reduced amplitude of the P100 component of the visual evoked potential. Gd-DTPA leakage had ceased in 9/11 nerves when restudied 4 wks later, and this evolution was associated with improved visual acuity and an increased P100 amplitude. Leakage is likely to reflect inflammation, and we conclude that the latter plays an important part in the production of conduction block and clinical deficit, and that its resolution is an important step in clinical remission from acute episodes of demyelination.
Adolescent↗
The role of the macula densa in renin synthesis.
1. The role of the macula densa in renin synthesis was studied using mice with one hydronephrotic kidney. 2. Renin synthesis was assessed by measurement of renal renin, renal mRNA for renin and plasma renin. 3. Sodium depletion stimulated mRNA and renal renin to a similar extent in the hydronephrotic and contralateral kidney. 4. Enalapril stimulated mRNA concentration in both kidneys but renal renin did not rise in the hydronephrotic kidney. 5. Propranolol did not alter the response to sodium depletion in either kidney. 6. The macula densa is not crucial for the stimulation of renin synthesis following sodium depletion. However, it may regulate renin production after mRNA synthesis, possibly by controlling the conversion of prorenin to renin.
Animals↗
Exaggerated startle reflexes in an elderly woman.
A 76-year-old woman with a 5-year history of excessive startle is reported. Electrophysiological recordings were made of muscle activation after acoustic and proprioceptive stimulation. The findings are discussed in relation to current knowledge of the startle reflex and classification of startle syndromes. It is concluded that this patient is best regarded as having a pathological exaggeration of the normal startle reflex rather than other causes of stimulus-sensitive muscle jerks.
Aged↗
Brain potentials in a memory-scanning task. I. Modality and task effects on potentials to the probes.
Event-related potentials were measured in normal young subjects during a memory-scanning paradigm modified from one proposed by Sternberg. The stimuli used were verbal (digits) and non-verbal (musical notes) with the verbal stimuli and notes presented acoustically and the verbal stimuli also presented visually. In this paradigm each set of stimuli was presented for memorization, and then, after a 2 sec interval, a probe item appeared and was identified by the subject as belonging or not belonging to the memorized set. Memorized set sizes of 1, 3 and 5 items were studied. The potentials are described in terms of scalp distribution, latency and amplitude, and are compared with behavioral descriptors of performance (accuracy and reaction time). These potentials are also compared with those evoked by an auditory target-detection task ('odd-ball' paradigm) in the same subject at the same session. The potentials evoked by the probe stimuli consisted of a positive (P50-90), negative (N100-150), positive (P185-225) sequence in the first 250 msec, followed by a later, long-lasting (approximately 700 msec) positive component (labeled P3). This positivity consisted of an earlier component (latency of approximately 350-400 msec) with a frontal distribution, followed by a larger and later parietal component. The amplitude of the frontal component and the latency of the parietal component varied with the number of items in the memorized set differently from behavioral reaction times. Stimulus modality also affected both the amplitude and latency of the sustained parietal positive potential. Memory processes associated with the P3 complex in the 'odd-ball' task and the long-lasting positivity in the memory-scanning task are discussed.
Adult↗
Cognitive event-related potentials in multiple sclerosis.
Twenty-three patients with multiple sclerosis (MS) and 1 patient with isolated optic neuritis (mean age 37.5 yrs, average duration of disease 10 yrs) were tested with auditory and visual cognitive event-related potentials (ERPs) using an oddball paradigm. The results were compared with data from 19 age-matched healthy controls. All patients had magnetic resonance imaging (MRI) head scans and 19 had comprehensive neuropsychological testing. The stimulus-related components of the ERPs were normal for nearly all patients, but 10 showed abnormalities of the later cognitive-related components and another 3 had waveforms in which the cognitive components could not be identified. These abnormalities were found mainly for the auditory test. Of these 13 patients, 11 had significantly prolonged reaction times (RT) or reduced target recognition performance. Five of 8 MS patients with normal IQ and memory function tests had abnormal ERPs with the reverse being true for 4 of 10 patients. Patients with abnormal ERPs showed a higher MRI cerebral lesion score and had a longer duration of illness and greater physical disability than patients with normal ERPs. It is concluded that the generation of ERPs is in part dependent on the integrity of cerebral white matter and that ERPs may indicate subtle degrees of cognitive dysfunction not always detected by standard tests of intellect.
Adult↗
Effect of mineralocorticoids and salt loading on renin release, renal renin content and renal renin mRNA in mice.
1. DOCA and 9 alpha-fludrocortisone were given to mice on a high-sodium diet for periods of up to 20 weeks, resulting in decreases in plasma renin concentration, renal renin concentration and renal renin mRNA with both treatments. 2. Plasma renin concentration was suppressed prior to suppression of renin mRNA and renal renin levels, indicating that suppression of synthesis and secretion of renin occur separately. 3. The decrease in renal renin concentration that occurred with DOCA was greater and more rapid than the decrease that occurred with 9 alpha-fludrocortisone, suggesting that DOCA caused intra-renal breakdown of renin. 4. When DOCA was given to mice on a low-sodium diet, plasma renin concentration and renal renin concentration increased, indicating that the effects of DOCA on renin levels were dependent on dietary sodium. 5. Renin secretion and synthesis appeared to be controlled by different mechanisms and sodium balance has an important effect on both processes.
Animals↗
Auditory long latency event-related potentials in Alzheimer's disease and multi-infarct dementia.
An auditory discrimination paradigm was employed to elicit event-related brain potentials in 13 patients with Alzheimer's disease and 14 patients with multi-infarct dementia. The P300 latency was significantly prolonged in 12 patients with dementia compared with age-matched controls and showed a significant negative correlation with the score of Wechsler Adult Intelligence Scale (WAIS), especially with that of Digit Span subtest. There was no disease specificity. After physostigmine treatment, P300 latency decreased and WAIS score increased in 6 among 10 cases.
Aged↗
Spontaneous passage of a colon 'cast' in a patient with ischaemic colitis.
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Colitis↗
Human auditory and somatosensory event-related potentials: effects of response condition and age.
In order to develop an experimental paradigm for clinical application of cognitive event-related potentials we have recorded these potentials in a group of 27 healthy Japanese, aged 20-78 years, using all 4 stimulus/response combinations of auditory or somatosensory stimuli requiring a counting or button-press response. In an oddball paradigm we recorded N1 and P2 components to frequent auditory stimuli and P100, N150 and P200 components to frequent somatosensory stimuli. These components were also observed in the target responses for their respective modalities together with N2, P270, P3 and slow-wave components. P3 latency increased linearly with age for all 4 experimental conditions, although this increase was not statistically significant for the somatosensory stimulus/button-press response combination. The latency of P270 also increased significantly with age for the auditory stimulus/button-press response combination but did not do so in either of the counting response conditions. The principal difference between the latencies of ERPs to auditory compared with somatosensory stimuli was that P3 was significantly longer for somatosensory stimulation, although differences in task difficulty may have influenced this finding. With regard to amplitude, N2, P3 and slow-wave were all significantly more positive for somatosensory compared with auditory stimulation. The topography of P3 evoked by somatosensory stimuli was most predominant at central electrodes, whereas the auditory P3 was larger parietally. The button-press response was associated with potentials which were smaller in amplitude and shorter in latency than those associated with the count response. The button-press response had a marked effect on the amplitude of P3 recorded at the vertex and the central electrode contralateral to the moving finger.
Adult↗