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Disasters often set the stage for scientific inquiry within the field of occupational safety and health. This is especially true when the long-term consequences of exposures associated with a particular disaster are unclear. However, a responder research study can be costly and difficult to design, and researchers must consider whether the proposed study will produce useful, reliable results and is a prudent public health investment.The decision process can be segregated into various components, including scientific rationale that should be formally recognized as critical to efficiently and effectively determine whether a research study is warranted. The scientific rationale includes certain controlling or “gatekeeper” factors that should be present to proceed with research.

The pharmacokinetics and pharmacodynamics of adinazolam mesylate (10 mg), N-desmethyl adinazolam mesylate (NDMAD, 10 mg), and alprazolam (1 mg) were investigated in 9 healthy male subjects in a randomized, blinded, single-dose, 4-way crossover study. All drugs were intravenously infused over 30 minutes. Plasma adinazolam, NDMAD, and alprazolam concentrations, electroencephalographic (EEG) activity in the beta (12-30 Hz) range, performance on the Digit Symbol Substitution Test (DSST), and subjective measures of mood and sedation were monitored for 12 to 24 hours. Mean pharmacokinetic parameters for adinazolam, NDMAD, and alprazolam, respectively, were as follows: volume of distribution (L), 106, 100, and 77; elimination half-life (hours), 2.9, 2.8, and 14.6; and clearance (mL/min), 444, 321, and 84. More than 80% of the total infused adinazolam dose was converted to systemically appearing NDMAD. All 3 benzodiazepine agonists significantly increased beta EEG activity, with alprazolam showing the strongest agonist activity and adinazolam showing the weakest activity. Alprazolam and NDMAD significantly decreased DSST performance, whereas adinazolam had no effect relative to placebo. Adinazolam, NDMAD, and alprazolam all produced significant observer-rated sedation. Plots of EEG effect versus plasma alprazolam concentration demonstrated counterclockwise hysteresis, consistent with an effect site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model, yielding an effect site equilibration half-life of 4.8 minutes. The exponential effect model described NDMAD pharmacokinetics and EEG pharmacodynamics. The relation of both alprazolam and NDMAD plasma concentrations to DSST performance could be described by a modified exponential model. Pharmacokinetic-dynamic modeling was not possible for adinazolam, as the data did not conform to any known concentration-effect model. Collectively, these results indicate that the benzodiazepine-like effects occurring after adinazolam administration are mediated by mainly NDMAD.

Objectives. The goals of this study were two-fold: ( 1) to assess the relationship between blood lead levels and neurobehavioral test performance in a nationally representative sample of adults from the third National Health and Nutrition Evaluation Survey and ( 2) to analyze the results from previously published studies of occupational lead exposure that used the same neurobehavioral tests as those included in the survey. Methods. Regression models were used to test and estimate the relationships between measurements of blood lead and performance on a simple reaction time, a symbol-digit substitution, and a serial digit learning test in adults aged 20–59 years who participated the survey. Mixed models were used to analyze the data from the occupational studies. Results. The blood lead levels of those participating in the survey ranged from 0.7 to 41.8 μg/dl. The estimated geometric mean was 2.51 μg/dl, and the estimated arithmetic mean was 3.30 μg/dl. In the survey, no statistically significant relationships were found between blood lead concentration and performance on the three neurobehavioral tests when adjusted for covariates. In the occupational studies, the groups exposed to lead consistently performed worse than control groups on the simple reaction time and digit-symbol substitution tests. Conclusions. The results from the survey and the occupational studies do not provide evidence for impairment of neurobehavioral test performance at levels below 25 μg/dl, the concentration that the Centers for Disease Control and Prevention define as elevated in adults. The average blood lead level of the exposed groups in the occupational studies was 41.07 μg/dl, less than 50 μg/dl, the minimum concentration that the Occupational Safety and Health Administration requires for medical removal from the workplace. Given the evidence of impaired neurobehavioral performance in these groups, the 50 μg/dl limit should be reevaluated.

We aimed to compare the efficacy of valproic acid (VPA) on paresthesias and sleep in RLS to that of levodopa (LD). Twenty patients with idiopathic restless legs syndrome (RLS) were treated with 600 mg slow-release VPA and 200 mg slow-release LD+50mg benserazid in a randomized, placebo-controlled, cross-over, double-blind setting with polysomography (PSG) at the end of each 3-week treatment periods. There was no major difference between the efficacy of valproic acid or LD. Periodic leg movements in sleep (PLMS) and PLM arousal index (PLMAI) significantly decreased with LD (p < or= 0.005). However, LD, but not VPA, significantly increased arousals not associated with PLMS (p = 0.002). Decrease of intensity and duration of RLS symptoms were more pronounced with VPA (p < or= 0.022) than with LD (NS). We conclude that slow-release VPA provides a treatment alternative for RLS.

Reductions in right prefrontal cerebral blood flow have been correlated with symptomatic improvement in depressed individuals receiving electroconvulsive therapy (ECT). Non-invasive near infrared spectroscopy has previously been shown to reliably measure changes in cerebral hemoglobin concentrations and oxygen saturation. In this study, we measured the concentration and oxygen saturation of hemoglobin on the right and left frontal brain regions of nine patients during right unilateral ECT. In all patients, we have found that the electrically induced seizure causes a stronger cerebral deoxygenation on the side ipsilateral to the electrical current (-21+/-5%) with respect to the contralateral side (-6+/-4%). On the brain side ipsilateral to the ECT electrical discharge, we have consistently observed a discharge-induced decrease in the total hemoglobin concentration, i.e. in the cerebral blood volume, by -7+/-3 microM, as opposed to an average increase by 6+/-3 microM on the contralateral side. The ipsilateral decrease in blood volume is assigned to a vascular constriction associated with the electrical discharge, as indicated by the observed decrease in cerebral oxy-hemoglobin concentration and minimal change in deoxy-hemoglobin concentration during the electrical discharge on the side of the discharge. These findings provide indications about the cerebral hemodynamic/metabolic mechanisms associated with ECT, and may lead to useful parameters to predict the individual clinical outcome of ECT.

The third National Health and Nutrition Examination Survey (NHANES III) contained three computerized neurobehavioral tests from the Neurobehavioral Evaluation System (NES): simple reaction time, symbol-digit substitution and serial digit learning. The neurobehavioral data that were collected came from a nationally representative sample of adults 20-59 years old. Performance on the tests was related to sex, age, education level, family income and race-ethnicity. Performance decreased as age increased, and increased as education level and family income increased. Differences in performance between sexes, levels of education and racial-ethnic groups tended to decrease as family income increased. The relationship between age and performance on the symbol-digit substitution test varied by education level and by racial-ethnic group. The relationship between age and performance on the serial digit learning test varied by racial-ethnic group. Questionnaire variables that were related to performance on one or more of the tests included the reported amount of last night's sleep, energy level, computer or video game familiarity, alcoholic beverages within the last 3 h and effort. Persons who took the tests in English or Spanish performed differently on the symbol-digit substitution and serial digit learning tests. Performance on all the tests decreased as test room temperature increased.

In this study, open-label valproate (VPA) was administered to patients as a treatment for periodic limb movement disorder (PLMD). Six patients aged 28 to 62 years with complaints of sleep disturbance and at least five periodic limb movements (PLMs) per hour of sleep underwent polysomnograms (PSGs) with and without low-dose VPA treatment (125-600 mg at bedtime). After a baseline PSG, patients received VPA therapy from 2 weeks to 14 months, until the time of the follow-up PSG on VPA (median, 5 months; mean, 6 months). All six patients experienced subjective improvement in daytime alertness. Sleep efficiency was improved from 76% to 88% (p = 0.003), stage 1 (light) sleep decreased from 26% to 13% (p = 0.04), stage 3 and 4 (deep) sleep increased from 19% to 30% (p = 0.01), and rapid eye movement sleep was unchanged. There was a trend toward a reduction in the number of PLMs per hour of sleep and in the percentage of arousals associated with PLMs. All of the patients continued taking VPA after the PSGs were completed. One patient discontinued VPA 1 month after completion of the last PSG because of short-term side effects, and one patient stopped VPA 22 months after the last PSG because of weight gain. Thus, these data indicate that VPA has a long-term beneficial effect on sleep consolidation in patients with PLMD.

Restless legs syndrome (RLS) can occur with an autosomal-dominant mode of inheritance. To determine if there are distinguishing features of RLS pedigrees which might clarify molecular mechanisms of pathogenesis, five pedigrees with 81 affected members were analyzed for age of onset, sex ratio, and transmission pattern. One-factor analysis of variance of ages of onset between generations was carried out, and segregation ratios were calculated for each generation. These kindreds showed an autosomal-dominant mode of inheritance and a male:female ratio of 1:1.4 (p = 0.15). One of the five analyzed pedigrees shows some evidence of reduced penetrance. In two of the five analyzed pedigrees, there is statistical support for anticipation (p

We have studied the effects of two cholesterol-lowering medications, lovastatin and pravastatin, on different sleep parameters in hypercholesterolemic subjects. These medications are 3-hydroxy-methylglutaryl coenzyme A inhibitors. Only subjects who had complained of sleep disturbance while on previous treatment with lovastatin were enrolled. Sixteen subjects (11 men and 5 women) underwent a randomized, double-blind, three-way crossover treatment with lovastatin, pravastatin, and placebo. Each phase of the study lasted 4 weeks. A placebo wash-out period of 4 weeks separated each treatment phase. At the end of each treatment phase, subjects were admitted to the sleep laboratory for 2 consecutive nights. No statistical differences were detected during treatment with lovastatin, pravastatin, and placebo for sleep parameters such as total sleep time, total awake time, wake time after sleep onset, efficiency of sleep, and percent of different phases of sleep. Our study suggests that lovastatin and pravastatin do not have a significant effect on sleep parameters in hypercholesterolemic subjects that could explain their complaints of insomnia. Nevertheless, the subjects did have moderate sleep disturbances that could account for insomnia and most likely predate the use of HMG-CoA reductase inhibitors.

We examined the role of personality and self-esteem in university students' (N = 200) use of communication technologies. More disagreeable individuals spent increased time on calls, whereas extraverted and neurotic individuals reported increased time spent text messaging. More disagreeable individuals and those with lower self-esteem spent increased time using instant messaging (IM). For addictive tendencies related to communication technologies, more neurotic individuals reported stronger mobile phone addictive tendencies, while more disagreeable individuals and those with lower self-esteem reported stronger IM addictive tendencies.

The objective was to assess the potential benefits of the routine use of the MOS SF-36 Health Survey (SF-36) in the care of ambulatory patients. The design was a longitudinal, prospective, randomized, controlled study set in the outpatient neurology clinic at the New England Medical Center. There were 163 consecutive patients with epilepsy who had 210 follow-up visits with one of two epileptologists. The patients completed the SF-36 before the patient-physician encounter and the forms were optically scanned. The SF-36 results of the intervention group patients were given to the physicians before the encounter and withheld for control group patients. For intervention group patients, the physicians completed a questionnaire assessing the impact of the SF-36 on the process of care. After the visit, all patients completed a satisfaction questionnaire. The main outcome measures were the physicians' responses to standardized questions about the usefulness of the SF-36 for communication with and management of epilepsy patients and the patients' responses to standardized questions about their satisfaction with care. The physicians indicated that the SF-36 provided new information in 63% of the intervention group encounters. A change in therapy was prompted in 13%. The physicians rated the SF-36 as at least moderately useful for communication in 14% of the encounters and to management in 8%. The lower (indicating worse health status) the patients' SF-36 scale scores, the more useful the SF-36 results were rated by the physicians for communication and management. It was concluded that the routine use of health status measures may enhance patients' care.

Skin conductance orienting response (OR) to a whistle was measured during selective cerebral deactivation associated with posterior cerebral (PCA) and intracarotid (ICA) amobarbital procedures in a seizure disorder patient. Complete suppression of the OR occurred following both right and left ICA procedures, whereas no reduction in the OR occurred following either PCA injection. Memory performance was independent of OR suppression, as adequate memory was evident in the Intact right hemisphere and poor memory in the seizure focus hemisphere with both the ICA and PCA tests. Anosognosia occurred after the right ICA, but not the PCA procedures or the left ICA procedure. Selective unllateral deactivation of the hippocampus, mesial temporal and calcarine cortex, and lateral thalamus does not impair OR elicitation or awareness of deficit, whereas unilateral deactivation of ICA vascularized regions abolishes the OR. Conversely, anosognosia occurs following right ICA, but not with selective suppression of...

A large International Restless Legs Syndrome (RLS) Study Group has been formed. As its first task, the group has taken upon itself the role of definig the clinical features of the RLS. As minimal criteria for diagnosis, the group proposes the following four features: (a) desire to move the extremities, often associated with paresthesias/dysesthesias; (b) motor restlessness; (c) worsening of symptoms at rest with at least temporary relief by activity, and (d) worsening of symptoms in the evening or night. Other features commonly seen in RLS include sleep disturbance, periodic limb movements in sleep and similar involuntary movements while awake, a normal neurological examination in the idiopathic from, a tendency for the symptoms to be worse in middle to older age, and, in some cases, a family history suggestive of an autosomal dominant mode of inheritance.

Alkylation of DNA gives rise to adducts, not only at the bases, but also at the phosphate groups giving phosphotriesters1–3. 2-Hydroxy-alkylation of phosphodiester functions in DNA causes considerable strand breakage already in neutral solution4. This effect has been suggested to be involved in the higher genotoxicity of 2-hydroxyalkylating agents as compared to, for instance, the corresponding methoxy compounds5.

We have investigated the amplitude and phase of spontaneous low-frequency oscillations (LFOs) of the cerebral deoxy- and oxy-hemoglobin concentrations ([Hb] and [HbO]) in a human sleep study using near-infrared spectroscopy (NIRS). Amplitude and phase analysis was based on the analytic signal method, and phasor algebra was used to decompose measured [Hb] and [HbO] oscillations into cerebral blood volume (CBV) and flow velocity (CBFV) oscillations. We have found a greater phase lead of [Hb] vs. [HbO] LFOs during non-REM sleep with respect to the awake and REM sleep states (maximum increase in [Hb] phase lead: ~ π/2). Furthermore, during non-REM sleep, the amplitudes of [Hb] and [HbO] LFOs are suppressed with respect to the awake and REM sleep states (maximum amplitude decrease: 87%). The associated cerebral blood volume and flow velocity oscillations are found to maintain their relative phase difference during sleep, whereas their amplitudes are attenuated during non-REM sleep. These results show the potential of phase-amplitude analysis of [Hb] and [HbO] oscillations measured by NIRS in the investigation of hemodynamics associated with cerebral physiology, activation, and pathological conditions.

Restless legs syndrome (RLS) is believed to be a condition primarily of middle to older age. However, it can have its onset in childhood. Five illustrative case histories with an autosomal dominant mode of inheritance are described. A mother and her 3 children (age: 612, 4, and 112 years) as well as a 16-year-old patient from a second family have typical RLS signs of leg discomfort (paresthesias) and motor restlessness prevalent at night and at rest, with temporary relief by activity. Polysomnography or videotaping revealed periodic limb movements in sleep (PLMS) and, in some cases, involuntary jerking of the legs was present during wakefulness as well. Clinicians should be aware that RLS can occur in childhood and adolescence and may be more common than heretofore recognized. "Growing pains" and attention deficit hyperactivity disorder (ADHD) are in the differential diagnosis of RLS in childhood.

A method for treating migraine in non-epileptic subjects which involves administering to subjects an effective amount of a pharmaceutical composition comprising a sulfamate of the following formula

Urban air pollution, originating in western countries mainly from automotive engine exhausts, contains thousands of components, many of which are genotoxic, i.e. are putative cancer initiators. Other pollution components, such as NO2 and certain particles, may have cocarcinogenic/promotive effects, at least at higher exposure levels. Cancer risk assessment of this complex mixture has to combine data from the exposure history, from epidemiological studies as well as from animal carcinogenicity tests, and from in vitro studies of fractions and individual components. Data for metabolism and pharmaco-kinetics have also to be considered. A multiplicative linear model is assumed to be valid for cancer initiation at low levels. Attempts are being made to determine the target dose from ultimate carcinogens (reactive metabolites) via macromolecule adduct levels, and to base the risk assessment on the radiation-dose equivalent to the chemical dose. So far this has been possible only for simple alkenes, which are metabolized to epoxides, and indirectly, via benzo(a)pyrene (BaP), for particle-bound polycyclic aromatic hydrocarbons (PAH). The lifetime risk of cancer (all sites) from ethene is estimated accordingly to 1.4 x 10(-4) per microgram m-3, and from PAH to 12 x 10(-4) per ng m-3 BaP. For other components indicated to give risk contribution (NOx, volatile PAH, benzene, aldehydes, butadiene) essential data are lacking and only very rough estimates can be given at this time.

Cancer initiators (mutagens) present, due to the absence of definable no effect threshold, a special problem in toxicology, requiring a high sensitivity of detection methods. Disease epidemiology aiming at identification of carcinogens and quantification of associated risks has a low resolving power, the detectable incidence or mortality increments being often orders of magnitude larger than those which are of public concern. Other drawbacks of disease epidemiology is the long latency times and the influence of confounders. The use of genetic endpoints as biomarkers suffers from low cause specificity, although this drawback seems to be overcome, partly at least, by emerging methods for determination of mutation spectra at the DNA level. Proximal cancer initiators/mutagens are electrophilic compounds or metabolites that can react with nucleophilic atoms in nucleic acids and proteins. These reactions lead to ‘adducts’ that can be identified and quantified e.g. in lymphocytes and erythrocytes in blood samples. The shift from biological observations to chemical analysis permits sufficient sensitivity, and measurement can be done shortly after onset of exposure. The well-defined life span of the adducts to hemoglobin (Hb) offer possibilities of dose calculation and risk estimation. For these reasons the measurement of adducts to Hb and DNA constitutes a powerful epidemiological tool, applications of which has been initiated in work environments and the general environment and also in the search for a priori unknown carcinogens.

This report outlines recommendations for postexposure interventions to prevent infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, and tetanus in persons wounded during bombings or other events resulting in mass casualties. Persons wounded during such events or in conjunction with the resulting emergency response might be exposed to blood, body fluids, or tissue from other injured persons and thus be at risk for bloodborne infections. This report adapts existing general recommendations on the use of immunization and postexposure prophylaxis for tetanus and for occupational and nonoccupational exposures to bloodborne pathogens to the specific situation of a mass-casualty event. Decisions regarding the implementation of prophylaxis are complex, and drawing parallels from existing guidelines is difficult. For any prophylactic intervention to be implemented effectively, guidance must be simple, straightforward, and logistically undemanding. Critical review during development of this guidance was provided by representatives of the National Association of County and City Health Officials, the Council of State and Territorial Epidemiologists, and representatives of the acute injury care, trauma and emergency response medical communities participating in CDC's Terrorism Injuries: Information, Dissemination and Exchange (TIIDE) project. The recommendations contained in this report represent the consensus of U.S. federal public health officials and reflect the experience and input of public health officials at all levels of government and the acute injury response community.

We present concurrent NIRS-fMRI measurements on a human subject during a finger tapping test. The optical data were collected with a frequency domain experimental apparatus (ISS, Inc., Champaign IL) comprising sixteen laser sources at 690 nm, sixteen laser sources at 830 nm and four photomultiplier tube detectors. The lasers were coupled to optical fibers that led the light onto the subject's head. A special optical helmet (fMRI-compatible) with a retractable and resilient set of optical fibers was devised to improve the coupling between the fibers and the scalp. The fMRI data were collected with a 3 Tesla Siemens Trio magnetic resonance scanner and a quadrature birdcage radiofrequency coil. The spatial and temporal comparison of the fMRI and NIRS signals associated with brain activation showed a very good agreement, confirming the role of NIRS as a reliable brain monitor for functional studies.

Near-infrared spectroscopy (NIRS) has been used for functional brain imaging by employing properly designed source-detector matrices. We demonstrate that by embedding a NIRS source-detector matrix within an electroencephalography (EEG) standard multi-channel cap, we can perform functional brain mapping of hemodynamic response and neuronal response simultaneously. In this study, the P300 endogenous evoked response was generated in human subjects using an auditory odd-ball paradigm while concurrently monitoring the hemodynamic response both spatially and temporally with NIRS. The electrical measurements showed the localization of evoked potential P300, which appeared around 320 ms after the odd-ball stimulus. The NIRS measurements demonstrate a hemodynamic change in the fronto-temporal cortex a few seconds after the appearance of P300.

Restless legs syndrome (RLS) is a common disorder with a prevalence of 5% to 15%. Primary care physicians must become familiar with management of this disorder. This algorithm for the management of RLS was written by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion. Restless legs syndrome is divided into intermittent, daily, and refractory types. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and addressing the possibility of iron deficiency, are discussed. The role of carbidopa/levodopa, dopamine agonists, opioids, benzodiazepines, and anticonvulsants for the different types of the disorder is delineated.

Autonomous detection systems (ADSs) are under development to detect agents of biologic and chemical terror in the environment. These systems will eventually be able to detect biologic and chemical hazards reliably and provide approximate real-time alerts that an agent is present. One type of ADS that tests specifically for Bacillus anthracis is being deployed in hundreds of postal distribution centers across the United States. Identification of aerosolized B. anthracis spores in an air sample can facilitate prompt on-site decontamination of workers and subsequent administration of postexposure prophylaxis to prevent inhalational anthrax. Every employer who deploys an ADS should develop detailed plans for responding to a positive signal. Responding to ADS detection of B. anthracis involves coordinating responses with community partners and should include drills and exercises with these partners. This report provides guidelines in the following six areas: 1) response and consequence management planning, including the minimum components of a facility response plan; 2) immediate response and evacuation; 3) decontamination of potentially exposed workers to remove spores from clothing and skin and prevent introduction of B. anthracis into the worker's home and conveyances; 4) laboratory confirmation of an ADS signal; 5) steps for evaluating potentially contaminated environments; and 6) postexposure prophylaxis and follow-up.

The objective of this study was to evaluate the kinetics and dynamics of midazolam when administered by three different infusion schemes, using electroencephalography to measure pharmacodynamic effects. In a three-way crossover study, 8 volunteers received midazolam (0.1 mg/kg) by constant-rate intravenous infusion. The durations of midazolam infusions for the three trials were 1 minute, 1 hour, and 3 hours. Plasma midazolam concentrations and electroencephalographic (EEG) activity in the 13- to 30-Hz range were monitored for 24 hours. Based on separate analysis of each subject-trial, mean values for volume of distribution and distribution or elimination half-life did not significantly vary. Central compartment volume and clearance differed among the three midazolam infusion trials; however, the magnitude of change was small. EEG activity in the 13- to 30-Hz range significantly increased for all three midazolam infusion trials. Plots of midazolam plasma concentration versus pharmacodynamic EEG effect for the 1-hour and 3-hour infusion trials did not reveal evidence of either counterclockwise or clockwise hysteresis. Plots from the 1-minute infusion trial demonstrated counterclockwise hysteresis, consistent with an equilibration effect-site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model. Analysis of all three infusion trials together yielded the following mean estimates: maximum EEG effect, 16.3% over baseline; 50% maximum effective concentration, 31 ng/mL; and an apparent rate constant for drug disappearance from the effect compartment which approached infinity. Despite the delay in effect onset during the 1-minute midazolam infusion, midazolam infusions in duration of up to 3 hours produce CNS sedation without evidence of tolerance.

Objective : Periodic limb movements in sleep (PLMS) may or may not be associated with restless legs syndrome (RLS). The number of PLMS is commonly used to assess the clinical severity and sleep quality of patients with RLS. It is still unclear whether the sleep disorder of periodic limb movement disorder (PLMD) is different from the sleep disorder in RLS. Methods : We compared the polysomnograms (PSGs) of 27 prospectively recruited RLS patients and 26 retrospectively recruited age- and sex-matched PLMD patients without RLS symptoms. Results : The PLM index and the index of arousal-associated PLMS (PLMAI) were significantly higher in PLMD, whereas the index of EEG arousals not associated with any sleep-related event was significantly higher in RLS. In PLMD patients, the PLMI correlated negatively with the percentage of PLMS associated with an arousal, whereas this correlation was positive in RLS patients. Further, RLS patients spent significantly more time in wake-after-sleep onset, had more rapid eye movement sleep (REM) and less sleep stage I. Conclusions : We conclude that the sleep disorder in RLS differs from that in PLMD. Spontaneous, not PLM associated EEG arousals should be included in the assessment of the sleep structure of patients with RLS, particularly in studies concerned with drug-efficacy.

We have performed cerebral near-infrared spectroscopy (NIRS) and polysomnography (electro-encephalography, electro-oculography, electro-myography, pulse oximetry, and respiratory monitoring) during all-night sleep in five human subjects. Polysomnography data were used for sleep staging, while NIRS data were used to measure the concentration and the oxygen saturation of hemoglobin in the frontal brain region. Immediately after sleep onset we observed a decrease in the cerebral concentration of oxy-hemoglobin ([HbO2]) and an increase in the concentration of deoxy-hemoglobin ([Hb]), consistent with a decrease in the cerebral blood flow velocity or an increase in cerebral metabolic rate of oxygen. An opposite trend (increase in [HbO2] and decrease in [Hb]) was usually observed after transition to deep sleep (stages III and IV). During rapid eye movement (REM) sleep, we observed an increase in [HbO2] and decrease in [Hb], consistent with an increase in the cerebral blood flow that overcompensates the increase in the metabolic rate of oxygen associated with REM sleep.© (2003) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

We have performed near-infrared spectroscopy on the forehead of human subjects during all-night sleep. The evolution of the sleep stages during the night has been identified by electroencephalography.

The relative contribution of cytochrome P450 3A (CYP3A) to the oral clearance of amitriptyline in humans has been assessed using a combination of in vitro approaches together with a clinical pharmacokinetic interaction study using the CYP3A-selective inhibitor ketoconazole. Lymphoblast-expressed CYPs were used to study amitriptyline N-demethylation and E-10 hydroxylation in vitro. The relative activity factor (RAF) approach was used to predict the relative contribution of each CYP isoform to the net hepatic intrinsic clearance (sum of N-demethylation and E-10 hydroxylation). Assuming no extrahepatic metabolism, the model-predicted contribution of CYP3A to net intrinsic clearance should equal the fractional decrement in apparent oral clearance of amitriptyline upon complete inhibition of the enzyme. This hypothesis was tested in a clinical study of amitriptyline (50 mg, p.o.) with ketoconazole (three 200 mg doses spaced 12 hours apart) in 8 healthy volunteers. The RAF approach predicted CYP2C19 to be the dominant contributor (34%), with a mean 21% contribution of CYP3A (range: 8%-42% in a panel of 12 human livers). The mean apparent oral clearance of amitriptyline in 8 human volunteers was decreased from 2791 ml/min in the control condition to 2069 ml/min with ketoconazole. The average 21% decrement (range: 2%-40%) was identical to the mean value predicted in vitro using the RAF approach. The central nervous system (CNS) sedative effects of amitriptyline were slightly greater when ketoconazole was coadministered, but the differences were not statistically significant. In conclusion, CYP3A plays a relatively minor role in amitriptyline clearance in vivo, which is consistent with in vitro predictions using the RAF approach.

To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point.Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs.The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins.Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.

Restless legs syndrome (RLS) can occur with an autosomal-dominant mode of inheritance. To determine if there are distinguishing features of RLS pedigrees which might clarify molecular mechanisms of pathogenesis, five pedigrees with 81 affected members were analyzed for age of onset, sex ratio, and transmission pattern. One-factor analysis of variance of ages of onset between generations was carried out, and segregation ratios were calculated for each generation. These kindreds showed an autosomal-dominant mode of inheritance and a male:female ratio of 1:1.4 (p = 0.15). One of the five analyzed pedigrees shows some evidence of reduced penetrance. In two of the five analyzed pedigrees, there is statistical support for anticipation (p0.05). These variations in penetrance and anticipation suggest possible genetic heterogeneity.

Unilateral suppression of beta activity, unilateral suppression of sleep spindles, and unilateral delta slowing on EEG have not been previously compared regarding accompanying neuroradiological (NR) and clinical neurological (CN) findings in children. We studied EEGs in children under age 10 years with unilateral beta suppression (n = 80), spindle suppression (n = 51) or unilateral delta slowing (n = 49). There were no significant differences between the three groups of abnormal EEGs in their relationships with NR and CN. Unilateral suppression of sleep spindles and beta activity are at least as accurate as focal slowing in lateralizing NR and CN findings.

Background Kinetic and dynamic consequences of metabolic inhibition were evaluated in a study of the interaction of ketoconazole, a P4503A inhibitor, with alprazolam and triazolam, two 3A substrate drugs with different kinetic profiles. Methods In a double-blind, 5-way crossover study, healthy volunteers received (A) ketoconazole placebo plus 1.0 mg alprazolam orally, (B) 200 mg ketoconazole twice a day plus 1.0 mg alprazolam, (C)ketoconazole placebo plus 0.25 mg triazolam orally, (D) 200 mg ketoconazole twice a day plus 0.25 mg triazolam, and (E) 200 mg ketoconazole twice a day plus benzodiazepine placebo. Plasma concentrations and pharmacodynamic parameters were measured after each dose. Results For trial B versus trial A, alprazolam clearance was reduced (27 versus 86 mL/min; P < .002) and apparent elimination half-life (t½ prolonged (59 versus 15 hours; P < .03), whereas peak plasma concentration (Cmax) was only slightly increased (16.1 versus 14.7 ng/mL). The 8-hour pharmacodynamic effect areas for electroencephalographic (EEG) beta activity were increased by a factor of 1.35, and those for digit-symbol substitution test (DSST) decrement were increased by 2.29 for trial B versus trial A. For trial D versus trial C, triazolam clearance was reduced (40 versus 444 mL/min; P < .002), t½ was prolonged (18.3 versus 3.0 hours; P < .01), and Cmax was increased (2.6 versus 5.4 ng/mL; P < .001). The 8-hour effect area for EEG was increased by a factor of 2.51, and that for DSST decrement was increased by 4.33. Observed in vivo clearance decrements due to ketoconazole were consistent with those anticipated on the basis of an in vitro model, together with in vivo plasma concentrations of ketoconazole. Conclusion For triazolam, an intermediate-extraction compound, impaired clearance by ketoconazole has more profound clinical consequences than those for alprazolam, a low extraction compound. Clinical Pharmacology & Therapeutics (1998) 64, 237–247; doi

Objective: There is an increased risk of patients with obstructive sleep apnea syndrome (OSAS) to have stroke or cardiac infarcts. Besides hypertension, epinephrine-induced platelet activation could be a further reason for the increased cardiovascular morbidity and mortality in OSAS. Methods: During a 4-month period (August 1994 to December 1994) we recruited prospectively 76 patients referred for polysomnograms because of a suspected sleep disorder such as OSAS. Results: Fifty patients had no respiratory events during sleep (non-OSAS), 19 patients had more than five but less than 50 obstructive apneas or hypopneas per hour of total sleep time (mild-to-moderate OSAS group), and seven patients had an apnea hypopnea index of more than 50 per hour of total sleep time (severe OSAS group). Blood pressure, plasma epinephrine levels, and P-selectin expression (as a marker for platelet activation) were measured in every patient at 9 PM and 6 AM (before and after the polysomnogram). There was a significant correlation of the apnea hypopnea index with 9 PM and 6 AM systolic and diastolic blood pressure, with 9 PM platelet activation, and with 6 AM epinephrine levels mainly due to high values in the severe OSAS group. Conclusions: Our results suggest that platelet activation, epinephrine, and high blood pressure play a role in the high prevalence of cerebrovascular and cardiovascular events in patients with OSAS.

The pharmacokinetics and pharmacodynamics of the benzodiazepine anxiolytic alprazolam (1 mg orally) were compared between young and elderly healthy volunteers. Eight young subjects (mean age 29.8 years) and eight elderly volunteers (mean age 68.4 years) received oral placebo and alprazolam (1.0 mg) in a randomized, double-blind, single-dose crossover study. In the elderly subjects, plasma concentrations were higher, although not significantly so, than in young volunteers 0.25, 0.5, and 0.75 hours after dosage. Apparent elimination half-life, time of maximum concentration, maximum concentration, volume of distribution, and apparent clearance were similar for the two groups. In both groups, alprazolam treatment (versus placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and fatigue, reduced excitement, increased feelings of spaciness, and perception of thinking slowed. For some measures, the alprazolam-placebo difference was greater in young than in elderly subjects. In both groups, alprazolam significantly impaired performance on the digit-symbol substitution test (DSST). EEG studies indicated significant increases in relative beta amplitude (13-30 Hz range) after alprazolam compared to placebo. Percent DSST decrement and percent EEG change were highly correlated with plasma alprazolam concentrations for both groups. There were modest increases in alprazolam plasma concentration in the elderly compared to the younger group shortly after drug administration, but there was no evidence of increased sensitivity to the pharmacodynamic effects of alprazolam in the elderly.

Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and 500 mg of caffeine in a randomized, double-blind, single-dose crossover study. Caffeine kinetics were nonlinear, with clearance significantly reduced and elimination half-life prolonged at the 500-mg compared to the 250-mg dose. The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500-mg dose exceeded those of the 250-mg dose. The lower dose of caffeine enhanced performance on the digit symbol substitution test and a tapping speed test compared to placebo; high-dose caffeine produced less performance enhancement than the lower dose. The plasma concentration versus response relationship revealed concentration-dependent increases in anxiety and improvements in cognitive and motor performance at low to intermediate concentrations. Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8-11 Hz) and beta (12-30 Hz) ranges; however, effects were not dose-dependent. While favorable subjective and performance-enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption, from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.

The objective was to assess the potential benefits of the routine use of the MOS SF-36 Health Survey (SF-36) in the care of ambulatory patients. The design was a longitudinal, prospective, randomized, controlled study set in the outpatient neurology clinic at the New England Medical Center. There were 163 consecutive patients with epilepsy who had 210 follow-up visits with one of two epileptologists. The patients completed the SF-36 before the patient-physician encounter and the forms were optically scanned. The SF-36 results of the intervention group patients were given to the physicians before the encounter and withheld for control group patients. For intervention group patients, the physicians completed a questionnaire assessing the impact of the SF-36 on the process of care. After the visit, all patients completed a satisfaction questionnaire. The main outcome measures were the physicians' responses to standardized questions about the usefulness of the SF-36 for communication with and management of epilepsy patients and the patients' responses to standardized questions about their satisfaction with care. The physicians indicated that the SF-36 provided new information in 63% of the intervention group encounters. A change in therapy was prompted in 13%. The physicians rated the SF-36 as at least moderately useful for communication in 14% of the encounters and to management in 8%. The lower (indicating worse health status) the patients' SF-36 scale scores, the more useful the SF-36 results were rated by the physicians for communication and management. It was concluded that the routine use of health status measures may enhance patients' care.

To examine the feasibility of administering and the psychometric properties of a general health status questionnaire in adults with epilepsy, and to assess the health status of these patients.Prospective, cross-sectional, observational study.Neurology clinic of a tertiary care medical center.One hundred forty-eight ambulatory adults with epilepsy.Patients completed the SF-36, a general health status questionnaire. Respondent burden and data quality as well as psychometric characteristics were evaluated. Patients' SF-36 scale scores, adjusted for comorbidities, were compared with those of 641 people without chronic conditions with the same sociodemographic characteristics.Administering the SF-36 to adult outpatients with epilepsy is feasible and results are psychometrically sound. Compared with those who were not ill, patients had significantly (p0.001) lower (0 = worst, 100 = best) scores in six of the eight SF-36 domains: general health perceptions (57.7 vs 82.1), mental health (61.3 vs 79.6), vitality (53.5 vs 67.8), role limitations owing to physical (69.6 vs 95.0) and emotional problems (67.2 vs 88.4), and social functioning (75.2 vs 89.9).Lower SF-36 scores may reflect patients' assessments of the balance among epilepsy, seizures, and antiepileptic drug therapy-related effects. Incorporating health status information into therapeutic decision making may help to attain the ultimate goal of improving patients' health.

Although an association between migraine and epilepsy has long been discussed, it has rarely been studied systematically. According to the evidence from the large epidemiologic study reviewed in this article, individuals with epilepsy are 2.4 times more likely to develop migraine than their relatives without epilepsy. Risk of migraine is elevated in patients with partial-onset and generalized-onset seizures. The comorbidity of migraine and epilepsy may be explained by a state of neuronal hyperexcitability that increases the risk of both disorders. Clinical and EEG features useful in the differential diagnosis of migraine and epilepsy as well as in the diagnosis of both conditions when they occur concurrently are reviewed. When migraine and epilepsy occur together, therapy with agents effective for both conditions should be considered.