Digital signal processing actigraphy.
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Humans↗
Biomedical subjects
D Redmond
Publications and source records attributed to D Redmond.
Oculomotor impairment during chronic partial sleep deprivation.
OBJECTIVE: The effects of chronic partial sleep (sleep deprivation) and extended sleep (sleep augmentation) followed by recovery sleep on oculomotor function were evaluated in normal subjects to explore the usefulness of oculomotor assessment for alertness monitoring in fitness-for-duty testing. METHODS: Sixty-six commercial drivers (24-62 years, 50m/16f) participated in a 15 day study composed of 3 training days with 8h time in bed per night, 7 experimental days with subjects randomly assigned to either 3, 5, 7, or 9h time in bed, and 3 recovery nights with 8h time in bed. Data from 57 subjects were used. Saccadic velocity (SV), initial pupil diameter (IPD), latency to pupil constriction (CL), and amplitude of pupil constriction (CA) were assessed and correlated with the sleep latency test (SLT), the Stanford sleepiness scale (SSS), and simulated driving performance. RESULTS: Regression analyses showed that SV slowed significantly in the 3 and 5h groups, IPD decreased significantly in the 9h group, and CL increased significantly in the 3h group. SLT and SSS significantly correlated with SV, IPD, CL, and driving accidents for the 3h group, and with CL for the 5h group. Analyses also showed a significant negative correlation between decreasing SV and increasing driving accidents in the 3h group and a significant negative correlation between IPD and driving accidents for the 7h group. CONCLUSIONS: The results demonstrate a sensitivity primarily of SV to sleepiness, and a correlation of SV and IPD to impaired simulated driving performance, providing evidence for the potential utility of oculomotor indicators in the detection of excessive sleepiness and deterioration of complex motor performance with chronic partial sleep restriction. SIGNIFICANCE: This paper shows a relationship between sleep deprivation and oculomotor measures, and suggests a potential utility for oculometrics in assessing operational performance readiness under sleep restricted conditions.
Accidents, Traffic↗
Nationwide study of haemolytic uraemic syndrome: clinical, microbiological, and epidemiological features.
AIMS: To establish the incidence and aetiology of haemolytic uraemic syndrome (HUS) in Australia and compare clinical and microbial characteristics of sporadic and outbreak cases. METHODS: National active surveillance through the Australian Paediatric Surveillance Unit with monthly case notification from paediatricians, July 1994 to June 1998. Children under 15 years presenting with microangiopathic haemolytic anaemia, thrombocytopenia, and acute renal impairment were identified. RESULTS: Ninety eight cases were identified (incidence 0.64 per 10(5) children <15 years/annum and 1.35 per 10(5) children <5 years/annum). Eighty four were associated with diarrhoea (64 sporadic, 20 constituting an outbreak) and 14 were atypical. Shiga toxin producing Escherichia coli (STEC) O111:H- was the most common isolate in sporadic HUS and caused the outbreak. However O111:H- isolates from outbreak and sporadic cases differed in phage type and subtyping by DNA electrophoresis. STEC isolates from sporadic cases included O26:H-, O113:H21, O130:H11, OR:H9, O157:H-, ONT:H7, and ONT:H-. STEC O157:H7 was not isolated from any case. Only O111:H- isolates produced both Shiga toxins 1 and 2 and possessed genes encoding E coli attaching and effacing gene (intimin) and enterohemolysin. Outbreak cases had worse gastrointestinal and renal disease at presentation and more extrarenal complications. CONCLUSIONS: Linking national surveillance with a specialised laboratory service allowed estimation of HUS incidence and provided information on its aetiology. In contrast to North America, Japan, and the British Isles, STEC O157:H7 is rare in Australia; however, non-O157:H7 STEC cause severe disease including outbreaks. Disease severity in outbreak cases may relate to yet unidentified virulence factors of the O111:H- strain isolated.
Adolescent↗
Impaired verbal memory is associated with impaired motor performance in schizophrenia: relationship to brain structure.
Deficient ability to take advantage of predictable elements in the performance of cognitive tasks has been proposed as an underlying factor for a number of deviances in schizophrenia. In a schizophrenic sample (n=39), we propose and test the view that certain memory and motor anomalies arise because of a compromise in the capacity to take advantage of the redundant (predictable) features of cognitive tasks. Results demonstrate a relationship between reduced capacity to take advantage of predictable features of two different cognitive processing tasks, one verbal memory, and the other motor. Poorer verbal recall on high-redundancy word lists was associated with a reduced ability to produce synchronous finger tapping in response to a high redundancy auditory stimulus, and inversely correlated with formal thought disorder ratings. These relationships, we suggest, reflect a specific and common schizophrenic deficit in the use of redundancies, not attributable to a generalized deficiency in performance. Structural imaging evidence from a subsample of these subjects (n=16) implicates frontal areas as the locus of this cognitive impairment.
Adult↗
Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity.
The negative effects of sleep deprivation on alertness and cognitive performance suggest decreases in brain activity and function, primarily in the thalamus, a subcortical structure involved in alertness and attention, and in the prefrontal cortex, a region subserving alertness, attention, and higher-order cognitive processes. To test this hypothesis, 17 normal subjects were scanned for quantifiable brain activity changes during 85 h of sleep deprivation using positron emission tomography (PET) and (18)Fluorine-2-deoxyglucose ((18)FDG), a marker for regional cerebral metabolic rate for glucose (CMRglu) and neuronal synaptic activity. Subjects were scanned prior to and at 24-h intervals during the sleep deprivation period, for a total of four scans per subject. During each 30 min (18)FDG uptake, subjects performed a sleep deprivation-sensitive Serial Addition/Subtraction task. Polysomnographic monitoring confirmed that subjects were awake. Twenty-four hours of sleep deprivation, reported here, resulted in a significant decrease in global CMRglu, and significant decreases in absolute regional CMRglu in several cortical and subcortical structures. No areas of the brain evidenced a significant increase in absolute regional CMRglu. Significant decreases in relative regional CMRglu, reflecting regional brain reductions greater than the global decrease, occurred predominantly in the thalamus and prefrontal and posterior parietal cortices. Alertness and cognitive performance declined in association with these brain deactivations. This study provides evidence that short-term sleep deprivation produces global decreases in brain activity, with larger reductions in activity in the distributed cortico-thalamic network mediating attention and higher-order cognitive processes, and is complementary to studies demonstrating deactivation of these cortical regions during NREM and REM sleep.
Adult↗
Mouse Wnt8B is expressed in the developing forebrain and maps to chromosome 19.
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Amino Acid Sequence↗
Length of illness and the gradient from positive to negative semantic priming in schizophrenic patients.
Schizophrenic patients, especially those with positive thought disorder, have been shown to show greater facilitation in a semantic priming task than normal controls and depressed patients. While some investigators have replicated these effects, others have not been able to do so. Differences in method and in the chronicity of the patients make it difficult to interpret the discrepancy between findings. The present study was conducted to examine the effect of length of illness (LOI) on semantic priming, a factor that might explain differences in replication success. Thirty schizophrenic patients performed a lexical decision task in a semantic priming paradigm. The LOI of this group ranged from 5 to 31 years. Facilitation in the priming task was positive for patients with short LOIs and declined to negative values in patients with long LOIs. The gradient of decline was significant. Analysis of the separate components of facilitation indicates that the decline was primarily due to a steady reduction of the speed with which patients responded to the associated word pairs; speed of response to non-associated pairs was unaffected. As this was a cross-sectional study it is not possible to determine whether the decline can be attributed to a cumulative effect of length of illness, or to prior initial differences in pathology that affect the probability of chronicity.
Adult↗
Expression of SPARC during development of the chicken chorioallantoic membrane: evidence for regulated proteolysis in vivo.
SPARC is a secreted glycoprotein that has been shown to disrupt focal adhesions and to regulate the proliferation of endothelial cells in vitro. Moreover, peptides resulting from the proteolysis of SPARC exhibit angiogenic activity. Here we describe the temporal synthesis, turnover, and angiogenic potential of SPARC in the chicken chorioallantoic membrane. Confocal immunofluorescence microscopy revealed specific expression of SPARC protein in endothelial cells, and significantly higher levels of SPARC were observed in smaller newly formed blood vessels in comparison to larger, developmentally older vessels. SPARC mRNA was detected at the earliest stages of chorioallantoic membrane morphogenesis and reached maximal levels at day 13 of embryonic development. Interestingly, steady-state levels of SPARC mRNA did not correlate directly with protein accumulation; moreover, the protein appeared to undergo limited degradation during days 10-15. Incubation of [125I]-SPARC with chorioallantoic membranes of different developmental ages confirmed that extracellular proteolysis occurred during days 9-15, but not at later stages (e.g., days 17-21). Comparison of peptides produced by incubation with chorioallantoic membranes with those generated by plasmin showed an identical pattern of proteolysis. Plasmin activity was present throughout development, and in situ zymography identified sites of plasminogen activator activity that corresponded to areas exhibiting high levels of SPARC expression. Synthetic peptides from a plasmin-sensitive region of SPARC, between amino acids 113-130, stimulated angiogenesis in the chorioallantoic membrane in a dose-dependent manner; in contrast, intact SPARC was inactive in similar assays. We have shown that SPARC is expressed in endothelial cells of newly formed blood vessels in a manner that is both temporally and spatially restricted. Between days 9 and 15 of chorioallantoic membrane development, the protein undergoes proteolytic cleavage that is mediated, in part, by plasmin. SPARC peptides released specifically by plasmin induce angiogenesis in vivo. We therefore propose that SPARC acts as an intrinsic regulator of angiogenesis in vivo.
Allantois↗
Clozapine-induced seizures and EEG changes.
Clozapine, an atypical antipsychotic drug, is widely used in refractory schizophrenia. At New Hampshire Hospital, 7 of the first 35 patients treated (20%) had convulsions. Patterns were tonic-clonic (5), complex partial (2), and myoclonic (3). Seizures were dose-related and may be anticholinergic in etiology. EEG changes are frequent with clozapine, particularly as dosage is increased. Twenty-six of 35 patients (74%) had EEG abnormalities at some time during clozapine treatment. EEG is a sensitive means of detecting clinical toxicity. When EEG abnormalities (slowing, dysrhythmia, or paroxysmal discharges) are detected, immediately lowering the dose by at least 25-50 mg per day and adjusting weekly until EEG returns to baseline can reduce the incidence of seizures.
Adult↗
Human autopsy-tissue distribution of menogaril and its metabolites.
Autopsy-tissues were obtained from eight patients who had last received menogaril (total cumulative dose, 175-1080 mg/m2) intravenously (one patient) or orally (seven patients) from 1 to 285 days prior to death. Tissue samples were assayed for menogaril and its metabolities by high-pressure liquid chromatography. Unchanged menogaril was found only in a single lung-tissue sample from a patient who had died < 24 h after receiving his last treatment. N-Demethylmenogaril was found in two lung-tissue samples and in single samples of the thyroid, lymph node, pancreas, cerebellum, and tumor. The major menogaril metabolite found in human autopsy-tissues was 7-deoxynogarol. The highest 7-deoxynogarol concentrations were found in the large bowel (median, 201 ng/g), liver (median, 183 ng/g), and lung (median, 177 ng/g). The heart ranked as the 9th of 18 organs in median 7-deoxynogarol concentration, after the large bowel, liver, lung, tumor, thyroid, skeletal muscle, adrenal gland, and kidney. The lowest concentrations were detected in brain tissue. Our results suggest that the low degree of cardiac toxicity and the possible pulmonary toxicity of menogaril may be related to relative tissue concentrations of menogaril metabolites. Tumor 7-deoxynogarol concentrations were comparable with those in normal tissues, except that concentrations in intracerebral tumors were higher than those in the normal brain. Tissue 7-deoxynogarol concentrations appeared to be directly related to the cumulative dose and inversely related to the time from the last treatment to death; the value obtained by dividing dose by time correlated (P < 0.05) with tissue 7-deoxynogarol concentrations.
Chromatography, High Pressure Liquid↗
Tolerability of prophylactic Lariam regimens.
Three hundred and fifty-nine US Marines participated in a randomized double-blind clinical trial to assess tolerance of two prophylactic mefloquine regimens [250 mg salt weekly (n = 157) or 250 mg daily for 3 days followed by 250 mg weekly (n = 46)] compared with 300 mg weekly chloroquine (n = 156) over a 12-week period. The study participants were seen daily for four days, then weekly for 11 weeks. On each visit, the subject answered two computerized questionnaires (a review of body systems and an evaluation of mood states), participated in a physician interview, and was administered medications under supervision. A random sample of each group was assigned to either pharmacokinetic sampling or two wear a wrist watch size computerized sleep monitor (actigraph). The frequencies of intercurrent illness and other concomitant medications were tabulated. End study mefloquine plasma levels were obtained on all study participants. The results obtained showed no compromise in function due to dizziness or incoordination in the mefloquine groups. Overall, both weekly mefloquine and loading dose mefloquine were well tolerated. Sleep disturbance and increased dream activity were detected in the mefloquine groups. Depressive feelings were noted in two to three times more individuals in the mefloquine groups than in the chloroquine group early in the course of the study, and resolved in the majority of subjects as tolerance developed. Steady state mefloquine plasma levels were attained rapidly with the loading dose regimen in four days versus seven weeks with weekly mefloquine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effect of flunarizine on electroencephalogram recovery and brain temperature in gerbils after brain ischemia.
BACKGROUND AND PURPOSE: This study was designed to determine whether flunarizine enhances the rate of brain recovery as measured by electroencephalography after cerebral ischemia and whether these effects are attributable to changes in brain temperature. METHODS: Male gerbils (n = 81) were treated with either 10 mg/kg flunarizine or its vehicle, beta-cyclodextrin, intraperitoneally, 60 minutes before bilateral carotid occlusion of either 4 or 6 minutes' duration. The electroencephalogram was continuously recorded in the preischemic, ischemic, and postischemic stages of the experiment and rated for the time necessary for the return of 4-6, 7-10, and 11-15 Hz activity. In a second set of experiments, intracerebral temperature was monitored for 60 minutes before ischemia, during 10 minutes of carotid occlusion, and for 60 minutes after ischemia. RESULTS: Flunarizine pretreatment resulted in significantly more rapid return of electroencephalographic activity in each of the three frequency categories monitored when compared with those animals pretreated with vehicle alone (p less than 0.001). Flunarizine had no effect on brain temperature before, during, or up to 60 minutes after termination of ischemia. CONCLUSIONS: Flunarizine, which has been of efficacy in reducing neuronal death, mortality, and functional impairment when administered after ischemic insults, may have prophylactic value in accelerating brain recovery from ischemia, but does not have this effect as a result of altered brain temperature.
Animals↗
Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity.
PURPOSE: To identify the major sites of platinum accumulation within neural tissues after treatment with cisplatin and to determine the relationship between cumulative dosage, time, and the development of histopathological and clinical neurotoxicity. PATIENTS AND METHODS: Twenty-one patients treated antemortem with cisplatin had neural tissue harvested at autopsy. Neural tissues were assayed for platinum and examined for histopathologic evidence of neurotoxicity. The relationship between histopathologic neurotoxicity and various pharmacologic parameters was analyzed. RESULTS: Tissue platinum levels were found to be highest in the dorsal root ganglia and lowest in tissue protected by the blood-brain barrier. For peripheral nerve, dorsal root, and dorsal root ganglia, a linear relationship was observed between platinum levels and cumulative dose. Platinum levels in neural tissue were not observed to decrease with time. Histopathologic toxicity closely matched an index of exposure to platinum (cumulative dose and log of time). Clinical and histopathologic neurotoxicity was found to occur with higher accumulations of platinum, with the highest levels found in patients with clinical evidence of neurotoxicity. CONCLUSIONS: The dorsal root ganglia was the most vulnerable neural structure. This is consistent with the clinical presentation of sensory neuropathy in cisplatin neurotoxicity. Central structures of the spinal cord and brain were protected from platinum accumulation. The increasing histopathologic toxicity, with an index of exposure to platinum, suggests that it is retained indefinitely in an actively neurotoxic form. The pharmacologic parameters examined correlate with the development of and are consistent with the clinical and laboratory features of cisplatin neurotoxicity.
Adult↗
Bioavailability and pharmacology of oral idarubicin.
A total of 9 patients entered in a phase I trial who received oral idarubicin daily for 3 days took part in pharmacokinetic studies, and bioavailability studies were performed on 13 additional patients receiving single doses of oral idarubicin alternating with i.v. treatment. The data were best fit by a two-compartment model (distribution and elimination compartments for i.v. drug and absorption and single-phase elimination for oral drug). For different idarubicin doses in the phase I and bioavailability studies, the median values for the terminal half-life of idarubicin varied from 5.6 to 11.6 h. High concentrations of the active metabolite idarubicinol were formed. Idarubicinol was eliminated more slowly than was the parent compound, with median half-lives for different dose levels varying from 8 to 32.7 h. Although most pharmacokinetic parameters were similar in plasma and whole blood, peak concentrations and AUCs in whole blood were about 3-4 times those calculated in plasma for idarubicin and about 1.5-2 times those determined in plasma for idarubicinol, indicating fairly extensive uptake into erythrocytes. Oral bioavailability was determined by comparing oral idarubicin to i.v. drug with respect to the combined idarubicin and idarubicinol plasma AUCs, and it varied from 12%-49% (median, 29%). Bioavailability was essentially the same (30%) when whole-blood values were used. Urinary excretion of the drug was less than 5% of the delivered dose by 96 h. Granulocytopenia correlated with plasma idarubicinol "estimated" clearance and steady-state volume of distribution, with whole-blood idarubicinol AUC, area under the moment curve (AuMC), and "estimated" clearance and volume of distribution, and with whole-blood combined idarubicin and idarubicinol AUCs. This suggests that drug contained in erythrocytes plays a major role in toxicity and that idarubicinol may play a larger role in toxicity than does the parent compound.
Administration, Oral↗
Depolarization-induced presynaptic calcium accumulation may occur by an N-type channel that is blocked by flunarizine.
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Animals↗
Phase I and pharmacology study of intravesical mitoxantrone for recurrent superficial bladder tumors.
A phase 1 study of intravesical mitoxantrone was done in patients with superficial bladder tumors recurrent after previous intravesical therapy. Mitoxantrone (5 to 10.5 mg.) was instilled in the bladder via catheter and was left in situ for 2 hours. Each patient received 6 treatments at 1-week intervals. Pharmacology studies were conducted in a subset of consenting patients. Dysuria, urinary frequency and hematuria were dose-limiting at 10 to 10.5 mg., the dose recommended for our phase 2 studies. One patient treated with 7.5 mg. mitoxantrone had bladder contracture after severe bladder injury caused by the drug. The interval free of recurrence increased in 5 of 8 patients treated with 10 to 10.5 mg. mitoxantrone and in 6 of 19 treated at lower dose levels. One patient who had residual evaluable tumor in the bladder at treatment experienced a complete remission for 16 months. Only 1 of 18 patients who underwent pharmacology studies had any mitoxantrone detectable in the blood after intravesical administration. This patient had severe irritative symptoms at treatment. No systemic toxicity was noted in any patient. Of the mitoxantrone instilled into the bladder 33 to 100% (mean 75%) was recovered in the specimen voided at the end of treatment. In summary, intravesical mitoxantrone is reasonably well tolerated and should be studied further at a dose of 10 mg. per week for 6 weeks. Caution should be exercised, since bladder contracture was seen in 1 patient. Systemic absorption and toxicity are negligible.
Administration, Intravesical↗
Circadian rhythm in human activity objectively quantified by actigraphy.
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Adult↗
Toxicity and evidence for metabolic alterations in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated guinea pigs fed by total parenteral nutrition.
The effect of total parenteral nutrition (TPN) on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in male, Hartley-strain guinea pigs was determined. At a single dose of 2 micrograms TCDD/kg, TPN-fed guinea pigs maintained body weight at a level which was slightly, but consistently, below that of the TPN-fed control animals. However, despite the sustenance of body weight, TCDD-treated animals died or were sacrificed due to morbidity between Days 8 and 24 following treatment. Approximately 50% of this group demonstrated a profound loss of body weight within a few days prior to death or sacrifice. With the exception of the pattern of weight loss, the signs of toxicity in the TPN-fed, TCDD-treated animals were strikingly similar to those observed in TCDD-treated guinea pigs fed ad libitum. Although livers from TCDD-treated, TPN-fed animals demonstrated increased content of lipid and cytochrome P-450, this tissue appeared to be morphologically and functionally comparable to that from TPN-fed controls. Of the blood chemistry examined, only the serum concentrations of 3,5,3'-triiodothyronine were significantly decreased in the treated animals fed by TPN. Results were also compared to TCDD-treated guinea pigs fed ad libitum and respective pair-fed controls. Many of the physiological and biochemical responses observed in animals fed ad libitum following TCDD treatment could be explained by a decrease in food consumption. This study demonstrated that although food consumption clearly accounts for the major effect of TCDD on body weight loss in guinea pigs fed ad libitum, additional physiological and/or biochemical alterations occurred which also contribute to body weight loss, other signs of toxicity, and subsequent lethality.
Animals↗