Characterizing sleep disorders in an autism-specific collection of electronic health records.

OBJECTIVE/BACKGROUND: Sleep problems are common in people on the autism spectrum. This study reviews one detailed approach to querying the electronic health record (EHR) in a large tertiary care center. PATIENTS/METHODS: We developed methods for identifying people on the autism spectrum and defined their sleep problems using the key words, "sleep" or "melatonin", or International Classification of Diseases (ICD) codes. We examined treatment responses of these individuals to melatonin supplementation. RESULTS: Sleep problems were documented in 86% of patients with ages ranging from 6 to 30 years old. Our specific keyword search yielded more patients with sleep diagnoses than ICD codes alone. About two-thirds of patients who received melatonin supplementation reported benefit from its use. CONCLUSIONS: Our study provides a framework for using deidentified medical records to characterize sleep, a common co-occurring condition, in people on the autism spectrum. Using specific keywords could be helpful in future work that queries the EHR.

Is anaesthesia of the deep branch of the lateral plantar nerve specific for the diagnosis of proximal metatarsal pain in the horse?

OBJECTIVES: To investigate the specificity of anaesthesia of the deep branch of the lateral plantar nerve (DB-LPN). METHODS: Twenty horses had DB-LPN anaesthesia performed by a single injection technique as part of a lameness investigation. The mechanical nociceptive threshold (NT) was measured using a handheld force meter at six points on the lateral aspect of the limb: before diagnostic anaesthesia (T0), and at 15 (T15) and 30 (T30) minutes post anaesthesia. Paired t-tests were performed and significance was set at p <0.05. In addition, ten cadaveric limbs were injected with 2.5 ml new methylene blue solution using a single injection technique to evaluate the extent of dye diffusion within the proximal metatarsal region. RESULTS: Compared with T0, there was a significant decrease in NT for all points combined at T15 (p = 0.008) and also at T30 (p = 0.007). There was a significant decrease in NT at T15 on the lateral third metatarsal bone (p = 0.012). At T30 there was a significant decrease in NT at the lateral sesamoid (p = 0.007), lateral third metatarsal bone (p = 0.031), and mid metatarsus (p = 0.033). Four out of 20 horses had a NT greater than 10 N at the lateral heel bulb at T30. In the cadaveric limbs, the total diffusion distance for all limbs (mean ± SD) was 70.4 ± 20.5 mm. Dye surrounded the DB-LPN in all limbs and the lateral plantar nerve (LPN) in nine out of 10 limbs. CLINICAL SIGNIFICANCE: Concurrent anaesthesia of the LPN is likely to occur when DB-LPN anaesthesia is performed using a single injection technique.

Predictors of CNS injury as measured by proton magnetic resonance spectroscopy in the setting of chronic HIV infection and CART.

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS). Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr, and Glx/Cr) were measured in the basal ganglia, the frontal white matter, and gray matter, and the best predictive models were selected using a bootstrap-enhanced Akaike information criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr, whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease.

Invertebrate responses to the management of genetically modified herbicide-tolerant and conventional spring crops. I. Soil-surface-active invertebrates.

The effects of herbicide management of genetically modified herbicide-tolerant (GMHT) beet, maize and spring oilseed rape on the abundance and diversity of soil-surface-active invertebrates were assessed. Most effects did not differ between years, environmental zones or initial seedbanks or between sugar and fodder beet. This suggests that the results may be treated as generally applicable to agricultural situations throughout the UK for these crops. The direction of the effects was evenly balanced between increases and decreases in counts in the GMHT compared with the conventional treatment. Most effects involving a greater capture in the GMHT treatments occurred in maize, whereas most effects involving a smaller capture were in beet and spring oilseed rape. Differences between GMHT and conventional crop herbicide management had a significant effect on the capture of most surface-active invertebrate species and higher taxa tested in at least one crop, and these differences reflected the phenology and ecology of the invertebrates. Counts of carabids that feed on weed seeds were smaller in GMHT beet and spring oilseed rape but larger in GMHT maize. In contrast, collembolan detritivore counts were significantly larger under GMHT crop management.

The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease.

The National NeuroAIDS Tissue Consortium (NNTC) was founded in 1998, in response to the scientific need for well-characterized central nervous system (CNS) and peripheral nervous system (PNS) tissues and fluids from HIV-infected individuals. In addition to performing the routine functions of non-transplant anatomic tissue banks, the Consortium offers a unique model for the integration of independent research entities in order to provide well-characterized tissues and fluids for the international research community. Herein, we describe the structure of the Consortium, pointing out the inherent strengths of linking together multiple independent sites for the purpose of banking HIV-infected nervous system tissues. We describe the neuropathology protocol that was adopted and successfully implemented at the four participating banks of the Consortium.

Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex.

OBJECTIVE: To investigate the relation between biochemical alterations and disease severity in HIV-cognitive motor complex (HIV-CMC). BACKGROUND: HIV-CMC encompasses both the milder form (HIV-minor cognitive motor disorder [HIV-MCMD]) and the more severe form (HIV-dementia). There is no validated marker to monitor disease severity noninvasively. METHODS: A total of 54 patients with HIV-CMC (20 with HIV-MCMD, 34 with HIV-dementia) and 29 seronegative healthy volunteers were evaluated for cerebral metabolite abnormalities using proton (1H) MRS in the frontal cortex, frontal white matter, and basal ganglia. RESULTS: The three subject groups showed different concentrations of myoinositol (MI; p = 0.0005) and choline-containing compounds (CHO; p = 0.004) in the frontal white matter. HIV-dementia patients had metabolite changes in all three brain regions whereas HIV-MCMD patients had abnormalities in the frontal white matter only. HIV-CMC patients had elevated MI (p < 0.0001) and CHO (p = 0.004) levels with increasing AIDS dementia complex stage, and N-acetyl compounds (NA) were decreased only in moderate to severe stages of dementia. Furthermore, CD4 count and CSF viral load, but not plasma viral load, showed significant effects on cerebral metabolite concentrations, which in turn showed significant effects on the HIV-dementia scale. CONCLUSIONS: In early stages of HIV-CMC, frontal white matter showed evidence of glial proliferation (with elevated MI and CHO levels) and cell membrane injury (with increased CHO levels), but no significant neuronal injury (with normal NA concentrations). HIV-MCMD and HIV-dementia patients have different neurochemical abnormalities. Because these biochemical alterations are related to clinical disease severity, they may be useful surrogate markers for noninvasive quantitative assessment of brain injury in patients with HIV-CMC.

A phase I/II trial of nimodipine for HIV-related neurologic complications.

BACKGROUND: Few effective treatments are available for AIDS dementia complex (ADC) and HIV-associated neuropathy. However, recent in vitro studies indicate that nimodipine, a voltage-dependent calcium channel antagonist, can prevent HIV-related neuronal injury and may provide a novel form of treatment for these disorders. METHODS: To determine the safety and possible efficacy of this agent, 41 patients with mild to severe ADC, including 19 patients with neuropathy, were entered into the AIDS Clinical Trial Group multicenter, phase-I and phase-II study. Nimodipine at 60 mg p.o., five times daily; 30 mg p.o., three times daily; or placebo was administered for 16 weeks as adjuvant treatment to antiretroviral therapy. RESULTS: Neuropsychological performance at baseline, measured by the composite neuropsychological Z score (NPZ-8), correlated significantly with the ADC stage and with CSF levels of neopterin, a marker of immune activation. No significant differences in toxicity were observed among the three arms. Intent-to-treat analysis showed no significant change in the NPZ-8, although improvement was suggested in the high-dose arm. In addition, a trend toward stabilization in peripheral neuropathy was observed in both nimodipine arms compared with placebo. CONCLUSIONS: Nimodipine and other similar nonantiretroviral agents may provide a safe and promising avenue of treatment for neurologic disorders associated with HIV infection. The results of this study indicate that further clinical trials are warranted.

Electrically induced release of endogenous noradrenaline and dopamine from brain slices: pseudo-one-pulse stimulation utilized to study presynaptic autoinhibition.

Slices of rat hypothalamus (noradrenaline experiments) or rabbit caudate nucleus (dopamine experiments) were prepared, superfused, and field-stimulated using series of monophasic rectangular pulses. Noradrenaline, dopamine and the main dopamine metabolite, dihydroxyphenylacetic acetic acid (DOPAC), were determined using HPLC with electrochemical detection. Electrical stimulation was performed using the following protocols: 1) 4 pulses delivered at 100 Hz; this type of stimulation is referred to as pseudo-one-pulse stimulation (POP); its short duration of only 32 ms does not allow the development of autoinhibition; 2) 2 bursts of 4 pulses at 100 Hz, delivered 1 s apart (2-POP-stimulation); 3) 8 pulses at 1 Hz (dopamine experiments only); 4) 36 pulses at 3 Hz. Noradrenaline experiments. The alpha 2-adrenoceptor antagonist yohimbine (1 mumol/l) did not enhance noradrenaline overflow following POP stimulation, but enhanced the overflow following 2-POP-stimulation by about 50% and that following 36-pulse-stimulation by almost 100%. Dopamine experiments. The D2-dopamine receptor antagonist sulpiride (3 mumol/l) facilitated the overflow of dopamine elicited with 2-POP-stimulation (66%), 8 pulses/1 Hz (92%), and 36 pulses/3 Hz (140%). It did not significantly facilitate the overflow of dopamine following POP-stimulation (19%). The overflow of DOPAC was not, or only slightly, increased by electrical stimulation, and its spontaneous outflow was more than three times higher than that of dopamine. Furthermore, the electrically induced overflow of dopamine did not exceed the outflow of DOPAC at any of the stimulation conditions employed. The results of the present study bear out important claims of the autoreceptor theory and confirm the data obtained in previous experiments using labelled transmitters.

Serotonin uptake blockers influence serotonin autoreceptors by increasing the biophase concentration of serotonin and not through a "molecular link".

The mechanism of the attenuation, by serotonin uptake blockers, of the release-inhibiting effect of exogenous serotonin autoreceptor agonists was studied in rabbit brain cortex and rat hypothalamus slices. The slices were preincubated with 3H-serotonin and then superfused and stimulated electrically. In rabbit brain slices stimulated by trains of 4 pulses at 100 Hz, 5-carboxamidotryptamine and 5-methoxytryptamine reduced the evoked overflow of tritium, and their concentration-response curves were not changed by any of three serotonin uptake inhibitors, namely citalopram, fluvoxamine and 6-nitroquipazine. In contrast, when the slices were stimulated by trains of 10 pulses at 0.033 Hz, fluvoxamine shifted the concentration-response curve of 5-methoxytryptamine to the right. Experiments with the autoreceptor antagonist metitepine indicated that little, if any, endogenous autoinhibitory tone developed in the course of trains of 4 pulses/100 Hz, irrespective of the absence or presence of uptake inhibitors, as well as during trains of 10 pulses/0.033 Hz in the absence of uptake inhibitors, whereas marked autoinhibition developed when 10 pulses/0.033 Hz were applied in the presence of fluvoxamine. In rat hypothalamic slices stimulated by trains of 4 pulses at 100 Hz, citalopram also failed to change the concentration-response curve of 5-methoxytryptamine. These results indicate that serotonin uptake blockers attenuate the effect of exogenous autoreceptor agonists by an increase in the biophase concentration of released serotonin and, hence, in endogenous autoinhibitory tone, and not by some direct "molecular link" unrelated to the biophase concentration of released serotonin.

Developmental toxicity of Clarified Slurry Oil applied dermally to rats.

Clarified Slurry Oil (CSO), the heavy residual fraction from the fluidized catalytic cracker, was applied to the shaven backs of groups of 10 pregnant rats at doses of 0, 4, 8, 30, 125, and 250 mg/kg/day. All groups received the test material on gestation days 0-19. CSO was applied undiluted and left uncovered on the skin; collars were placed on the rats to minimize ingestion of the test material. Signs of maternal toxicity, some of which were seen at dose levels as low as 8 mg/kg/day, included vaginal bleeding, decreased body weight gain, reduced food consumption, death, increased relative liver weights, atrophy of the thymus, and aberrant serum chemistry. The number of fetal resorptions/deaths was markedly increased and the number of viable offspring decreased by CSO at dosages of 30 mg/kg/day and above. The group receiving 250 mg/kg/day carried no viable offspring. Fetuses from pregnant females exposed to CSO at dose levels in excess of 8 mg/kg/day were smaller than those from control and 4 mg/kg/day groups, and their skeletons showed decreased ossification. Abnormal external development and visceral development were observed in living and dead fetuses exposed in utero to CSO at dose levels as low as 8 mg/kg/day. Based on these data, 4 mg/kg/day represents the No-Observed-Adverse-Effect-Level for both maternal and developmental toxicity.

Systemic toxicity from subchronic dermal exposure, chemical characterization, and dermal penetration of catalytically cracked clarified slurry oil.

Clarified slurry oil (CSO), the heavy residual fraction from the fluidized catalytic cracker, was applied to the shaven backs of groups of 10 male and 10 female Sprague-Dawley rats 5 days/week for 13 weeks at doses of 8, 30, 125, or 500 mg/kg/day, and to another group for 2 weeks at doses of 2000 mg/kg/day. The rats were fitted with cardboard Elizabethan collars to minimize the ingestion of the test material, which was applied undiluted and remained uncovered on the skin. A similar group of rats served as controls; they were treated in the same manner except that no CSO was applied to their skin. There was a dose-related mortality and depression of body weight gain in the rats treated with CSO at doses of 30 mg/kg/day or greater; none of the rats dosed at 2000 mg/kg/day survived more than 2 weeks. The primary target organs of CSO toxicity were the liver, thymus, and bone marrow. The effects on the liver included increased weight (250% at 500 mg/kg/day), cholangiolitis, diffuse liver cell degeneration and hypertrophy, necrosis, fibrosis, decreased serum glucose, increased levels of alkaline phosphatase, aspartate aminotransferase, alanine amino transferase, bilirubin, and triglycerides. The thymus was found to be small and upon microscopic examination to be atrophic or hypoplastic. Erythroid hypoplasia was found in the bone marrow of some of the rats dosed at 30 mg/kg/day and increased in severity with increasing dose. The erythroid hypoplasia was accompanied by a dose-related anemia. Even in the rats dosed at 8 mg/kg/day, very slight abnormalities in the bile ducts were observed upon microscopic examination of the liver. Chromatographic separation and analyses demonstrated that CSO contains about 58% 3- to 5-ring polycyclic aromatic hydrocarbons (PAHs) and approximately 8-10% carbazole derivatives. In vitro and in vivo skin penetration studies demonstrated that the carbazole materials penetrate through the skin to a considerable extent (about 44%); less penetration was observed with 2- or 3-ring (8-13%) or 5-ring PAHs (3%).

A composite model for multiple assays of skin irritation.

A model for skin irritation was developed for simultaneous evaluation of the influence on irritation of abrasion, occlusion, and duration of treatment and for fulfillment of requirements for labeling considerations under DOT, CPSC-FHSA, OSHA, and EEC. This model greatly reduces the number of animals required to address submissions under multiple agencies compared to performing each test separately. In this model, which we have called a Composite Skin Irritation test, a test material is placed on three pairs of intact and abraded sites on each rabbit; one pair of sites is occluded for 4 hours, one for 24 hours, and the other left unoccluded for 24 hours. Results are presented from 88 composite tests with 80 petroleum-related materials. For the materials tested, abrasion of the skin had no effect on the irritation response. Occlusion of the test site generally did not result in dramatic increases in response, except for petroleum refinery streams with a boiling range below 500 degrees F. Exposure for 4 hours rather than 24 hours generally resulted in less irritation; however, for individual compounds, the irritation from the 4-hour exposure could not be predicted from the response to the 24-hour exposure. Of the 80 materials tested, 12 would be labeled as skin irritants under CPSC guidelines, three under OSHA, and 20 under EEC. Of the 20 that would be labeled under EEC criteria, only seven would be labeled under CPSC criteria. At least for petroleum-related materials, results from skin irritation studies performed under one set of conditions cannot be used to predict the degree of irritation that would be produced under a different set of exposure conditions.

[Interaction of the neuropeptides substance P and neurotensin with central monoamine transmitter systems]. / Zur Wechselwirkung der Neuropeptide Substanz P und Neurotensin mit zentralen Monoamintransmittersystemen.

In the present paper, findings on two neuropeptides, substance P (SP) and neurotensin (NT), are presented and discussed with respect to a neuromodulatory role of these peptides on brain monoamine transmitter systems. Substance P: In view of the close morphological relationship of serotonin-(5-HT-) and SP-neurons in the brainstem of the rat the effect of SP was studied in vitro on the field stimulated release of 3H-5-HT from slices of medulla oblongata. Substance P enhanced the electrically induced release of 3H-5-HT without affecting the basal release. Furthermore, the immunohistochemical evidence for the coexistence of SP and 5-HT in neurons of this area was corroborated by employing neurochemical lesioning techniques. Neurotensin: Binding sites for NT in the substantia nigra and the ventral tegmentum of the rat were decreased after stereotaxic injection of the neurotoxin 6-hydroxydopamine, which specifically destroys catecholamine-containing neurons. The results indicate a localization of NT-receptors on dopaminergic neurons in these regions. In the striatum and the nucleus accumbens, the field stimulated release of 3H-dopamine in vitro was markedly and dose-dependently increased in the presence of NT, demonstrating a direct effect of the peptide on dopamine-containing nerve terminals. In the medial preoptic nucleus, a high density of NT-binding sites was measured and stereotaxically microinjected NT caused a rise in plasma levels of luteinizing hormone (LH). Concomitantly, noradrenaline levels in the injected region were significantly reduced. The results favour an interaction of NT and noradrenergic neurons in the hypothalamic control of LH secretion.

Reduction of [3H]muscimol binding sites in rat dorsal spinal cord after neonatal capsaicin treatment.

Two-day-old rats were pretreated with 50 mg/kg of capsaicin. After 3--4 months, specific binding of [3H]muscimol and [3H]strychnine was measured in membrane preparations from dorsal spinal cord. A 20-30% decrease of the number of [3H]muscimol binding sites was observed after capsaicin treatment. In contrast, [3H]strychnine binding was unchanged. The results provide indirect evidence for a presynaptic location of GABA receptors on capsaicin-sensitive primary afferent neurons.

Mepiprazole, a new psychotropic drug: effects on uptake and retention of monoamines in rat brain synaptosomes.

The influence of mepiprazole (EMD 16,923), a new pyrazol-ylalkyl-piperazine derivative, on the uptake of 3H-norepinephrine (NE), 3H-dopamine (DA), and 3H-serotonin (5-HT) into rat brain synaptosomes from cerebral cortex, corpus striatum, and hypothalamus was investigated in comparison with several psychotropic drugs, including oxypertine, d-amphetamine, imipramine, desipramine, chlorimipramine, amitriptyline, and chlorpromazine in vitro. Mepiprazole was a relatively weak inhibitor of monoamine uptake and exhibited its strongest action on the hypothalamic 5-HT uptake, being almost equipotent with desipramine (IC50 = 0.9 MUM). Furthermore, the influence of the drugs on the retention of 3H-amines previously taken up by whole rat brain synaptosomes was studied. Unlike the tricyclic antidepressants, mepiprazole as well as oxypertine and d-amphetamine markedly increased the efflux of radioactivity during a 20-min incubation at 37 degrees C at low concentrations (10(-6) to 10(-5) M), whereas at 10(-4) M all drugs greatly enhanced the efflux. The ability of mepiprazole to increase 5-HT concentration at the receptor level by a combination of neuronal uptake inhibition and release is discussed in relationship to the central actions of the drug.