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H Moldofsky

Publications and source records attributed to H Moldofsky.

At least 19 recordsLinked to original sources
PubMed2000

A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy.

Objective: To assess the continued efficacy of modafinil in the treatment of excessive daytime somnolence (EDS) of narcolepsy.Background: Modafinil has been shown to be a safe and effective treatment for the EDS presented by patients with narcolepsy. However, the duration of treatment has been relatively brief, particularly considering the chronic nature of the disease.Methods: Sixty-nine patients with narcolepsy, who completed a 6-week crossover study of modafinil continued on modafinil for 16 weeks of open-label treatment (300+/-100 mg). This was followed by 2 weeks during which patients were randomly and blindly allocated to continue modafinil (M) at the same dose (n=30), or placebo (P; n=33).Results: A mean dose of 330 mg of modafinil continued to produce a significant decrease in EDS as measured by the Maintenance of Wakefulness Test (9.7+/-7.9 for P; 16.4+/-13.7 for M; P=0.009), the Epworth Sleepiness Scale (15.4+/-5.8 for P; 13.2+/-5.7 for M; P=0.023), and the number of episodes of severe somnolence and sleep reported in patient diaries (8.2+/-7.2 for P; 4.2+/-5.2 for M; P=0.017). Modafinil had no significant effects on nocturnal sleep, blood pressure, heart rate, the electrocardiogram (ECG), weight, or mood.Conclusion: Modafinil continues to be an effective and well-tolerated drug after 16 weeks of treatment.

Journal Article↗
PubMed2000

Narcolepsy and the ability to resist sleep.

We describe five patients who presented with irresistible daytime sleepiness and who have the clinical and laboratory features of narcolepsy but differ from most patients with narcolepsy in their ability to resist falling asleep during the daytime. All of the patients described partial or complete remission of their symptoms. Using an HLA marker, the expected haplotypes for narcolepsy were found, but no specific genetic features were found associated with chromosome 6p that differentiated this group from patients with typical narcolepsy. Problems are discussed in the laboratory assessment of such patients using both the multiple sleep latency test and the maintenance of wakefulness test.

Journal Article↗
PubMed2000

The relationship of lymphocytes in blood and in lymph to sleep/wake states in sheep.

Based on evidence of a role for immune-associated cytokines in sleep induction, we investigated the possibility that lymphocyte distribution between blood and lymphatics could be altered as a function of sleep/wakefulness. Blood and lymph sample were obtained from 5 sheep during periods of slow-wave sleep and wake. Blood and lymph lymphocytes were phenotyped using monoclonal antibodies against CD4, CD8, gd T-cell receptors and a surface marker on ovine B cells. Lymph flow rates and efferent lymph cell output were measured. Lymph flow and prescapular efferent lymphocyte output were reduced during sleep compared to wakefulness (p<0.0005). There were no differences in lymphocyte subsets in the blood and in the lymph during sleep/wake brain states. These data indicate that migration of cells in the peripheral lymphatic system is altered during sleep compared to wakefulness.

Animals↗
PubMed2000

Brain-blood permeability: TNF-alpha promotes escape of protein tracer from CSF to blood.

The objective of this study was to determine the effect of tumor necrosis factor (TNF)-alpha on the efflux of protein from the central nervous system to blood based on assessing the clearance of radiolabeled albumin from the cerebrospinal fluid (CSF) to blood in rats. (125)I-labeled human serum albumin ((125)I-HSA) was injected into a lateral ventricle, and venous blood was sampled hourly to determine the basal CSF protein clearance into the blood. After this, rats were intraventricularly infused with 10 microliter TNF-alpha and 10 microliter (131)I-HSA (n = 6) or 10 microliter saline and 10 microliter (131)I-HSA (n = 6). Venous blood was sampled hourly for 3 h. (131)I-HSA tracer recovery increased threefold in the venous blood and was significantly higher in the spleen, muscles, and skin in animals treated with TNF-alpha. No significant changes were observed in control animals treated with saline. The data suggest that TNF-alpha promotes the clearance of protein macromolecules from the CSF to the venous blood.

Animals↗
PubMed1999

Adenosine: a mediator of interleukin-1beta-induced hippocampal synaptic inhibition.

Interleukin-1 (IL-1) is a pleotrophic cytokine implicated in a variety of central activities, including fever, sleep, ischemic injury, and neuromodulatory responses, such as neuroimmune, and neuroendocrine interactions. Although accumulating evidence is available regarding the expression pattern of this cytokine, its receptors in the CNS, and its mechanistic profile under pathological levels, it is unclear whether this substance modulates central neurons under physiological concentrations. Further, in light of the functional and spatial overlap between the adenosine and IL-1 systems, it is not known whether these two systems are coupled. We report here that, in rat brain slices, brief application of sub-femtomolar IL-1beta causes a profound decrease of glutamate transmission, but not GABAergic inhibition, in hippocampal CA1 pyramidal neurons. This decrease by IL-1beta is prevented by pharmacological blockade of adenosine A1 receptors. In addition, we show that IL-1beta failed to suppress glutamate transmission at room temperature. Because the production and release of adenosine in the CNS is thought to be metabolically dependent, this observation suggests that one of the functions of IL-1beta is to increase the endogenous production of adenosine. Together, these data suggest for the first time that sub-femtomolar levels of IL-1 can effectively modulate glutamate excitation in hippocampal neurons via an adenosine-dependent mechanism.

Adenosine↗
PubMed1999

Sleep problems in children with attention-deficit/hyperactivity disorder: impact of subtype, comorbidity, and stimulant medication.

OBJECTIVE: To determine the relationship of sleep problems to attention-deficit/hyperactivity disorder (ADHD), diagnostic subtype, comorbid disorders, and the effects of stimulant treatment. METHOD: On the basis of clinical diagnostic interviews, children aged 6 to 12 years were assigned to 4 groups: unmedicated ADHD (n = 79), medicated ADHD (n = 22), clinical comparison (n = 35), and healthy nonclinical comparison (n = 36). These groups were compared on 2 sleep questionnaires completed by the parents that assessed current sleep problems and factors associated with sleep difficulties (i.e., sleep routines, sleep practices, child and family sleep history). RESULTS: Factor analysis revealed 3 sleep problem categories: dyssomnias, parasomnias, and sleep-related involuntary movements. Linear regression analyses showed that (1) dyssomnias were related to confounding factors (i.e., comorbid oppositional defiant disorder and stimulant medication) rather than ADHD; (2) parasomnias were similar in clinical and nonclinical children; and (3) the DSM-IV combined subtype of ADHD was associated with sleep-related involuntary movements. However, sleep-related involuntary movements were more highly associated with separation anxiety. CONCLUSIONS: The results suggest that the relationship between sleep problems and ADHD is complex and depends on the type of sleep problem assessed as well as confounding factors such as comorbid clinical disorders and treatment with stimulant medication.

Attention Deficit Disorder with Hyperactivity↗
PubMed1999

Intracerebroventricular injection of TNF-alpha promotes sleep and is recovered in cervical lymph.

Recent studies have shown that the central nervous system (CNS) communicates with the periphery by the drainage of cerebrospinal fluid and brain interstitial fluid into blood and lymph. We hypothesized that tumor necrosis factor (TNF)-alpha would not only influence the CNS by promoting sleep but also would be directly transmitted into the peripheral immune system. Five hundred nanograms of 125I-labeled TNF-alpha were injected into the lateral ventricles of the brain of six sheep and sampled in venous blood and cervical and prescapular lymph every 30 min for 6 h. 125I-TNF-alpha was measured in lymph nodes and control fat, skin, and muscle tissues 6 h postinjection. 125I-TNF-alpha was detected in the cervical lymphatics within the first 30 min and peaked within 2-3 h. 125I-TNF-alpha counts were elevated in the nodes of the head and neck region. Polysomnographic recordings of four animals showed that TNF-alpha induced a significant increase in slow-wave sleep at postinjection hours 4 and 5. CNS TNF-alpha and its direct drainage into the lymphatic system may influence both the sleeping/waking brain and peripheral immune functions.

Animals↗
PubMed1998

Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder.

BACKGROUND: Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep. METHODS: This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone (n = 64) with fluoxetine (n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1-4, 6, and 8. RESULTS: Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine. CONCLUSIONS: Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

Adult↗
PubMed1998

Sleep disturbances in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the relationship between sleep disturbances and attention-deficit/hyperactivity disorder (ADHD). METHOD: Empirical research published since 1970 on sleep disturbances in children with ADHD was systematically reviewed. A "box-score" approach was used to examine consistency of findings across the studies, which used different outcome measures. RESULTS: Although subjective accounts of sleep disturbances in ADHD were prevalent, objective verification of these disturbances was less robust. The only consistent objective findings were that children with ADHD displayed more movements during sleep but did not differ from normal controls in total sleep time. An additional finding was that stimulant medication led to changes in the children's sleep (e.g., prolonged sleep latency, increased length of onset to first rapid eye movement cycle), but these changes were believed to be nonpathological. CONCLUSIONS: The exact nature of the sleep problems in children with ADHD remains to be determined. Many of the relevant issues have not been adequately addressed. Factors such as poorly defined diagnostic groups, small sample sizes, few studies, and methodological and procedural limitations make it difficult to determine the relationship between ADHD and sleep problems.

Attention Deficit Disorder with Hyperactivity↗
PubMed1998

Determinants of disability after a work related musculetal injury.

OBJECTIVE: Musculoskeletal soft tissue injuries consume considerable resources in personal suffering, medical care, work absenteeism, and compensation benefits. Our aim was to determine specific clinical and behavioral factors that prognostically influence return to work following musculoskeletal work related injuries. METHODS: A longitudinal cohort study was conducted on 148 randomly selected workers who had not returned to work in 3 months following musculoskeletal soft tissue injury. The cohort was identified from the files of the Workers' Compensation Board of Ontario, Canada. The workers were interviewed and assessed at 3, 9, 15, and 21 months after injury. The WHO Classification of Impairment, Disabilities and Handicap was used as the conceptual framework. The analysis employed a proportional hazards regression model with allowance for time dependent covariates. RESULTS: The rate of return to work for men was 1.5 times that for women, and 20% less for every 10 year increase in age. Controlling for sex and age, psychological distress and functional disability were associated with a slower rate of return to work. The rate of return to work for workers who were provided with modified jobs was 2 times higher than for those with no such accommodation in employment. CONCLUSION: The negative effect of psychological distress and functional disability on return to work rates must be considered in the design and delivery of rehabilitation programming for workers with musculoskeletal soft tissue injuries. The employer's provision of a "modified job" is important in the prevention of continued disability.

Adult↗
PubMed1997

Dopamine D2 receptors quantified in vivo in human narcolepsy.

Assays in brain tissues from humans suffering from narcolepsy, and from genetically narcoleptic dogs have suggested that dopamine function may be disturbed in this condition. We have used the specific D2 receptor ligand N-(3-[18F]fluoropropyl)-spiperone and positron tomography to study a group of 6 well-characterized medication-free, HLA-DR2 DRW15 DW6-positive narcoleptic patients and a group of age- and sex-matched control individuals during life. We found no difference in striatal D2 receptor binding between these two groups. These results suggest that narcolepsy is not associated with alterations in D2 receptor density and affinity.

Adolescent↗
PubMed1997

Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy.

Seventy-five patients meeting international diagnostic criteria for narcolepsy enrolled in a 6-week, three-period, randomized, crossover, placebo-controlled trial. Patients received placebo, modafinil 200 mg, or modafinil 400 mg in divided doses (morning and noon). Evaluations occurred at baseline and at the end of each 2-week period. Compared with placebo, modafinil 200 and 400 mg significantly increased the mean sleep latency on the Maintenance of Wakefulness Test by 40% and 54%, with no significant difference between the two doses. Modafinil, 200 and 400 mg, also reduced the combined number of daytime sleep episodes and periods of severe sleepiness noted in sleep logs. The likelihood of falling asleep as measured by the Epworth Sleepiness Scale was equally reduced by both modafinil dose levels. There were no effects on nocturnal sleep initiation, maintenance, or architecture, nor were there any effects on sleep apnea or periodic leg movements. Neither dose interfered with the patients' ability to nap voluntarily during the day nor with their quantity or quality of nocturnal sleep. Modafinil produced no changes in blood pressure or heart rate in either normotensive or hypertensive patients. The only significant adverse effects were seen at the 400-mg dose, which was associated with more nausea and more nervousness than either placebo or the 200-mg dose. As little as a 200-mg daily dose of modafinil is therefore an effective and well-tolerated treatment of excessive daytime somnolence in narcoleptic persons.

Adult↗
PubMed1997

Regional differences in technetium-99m-ECD clearance on brain SPECT in healthy subjects.

UNLABELLED: The aim of this study was to evaluate the in vivo stability of ECD brain SPECT. METHODS: Twenty normal volunteers (35.4 +/- 9.1 yr) each had six ECD scans at 30, 60, 120, 240, 360 and 480 min postinjection. Each scan was acquired for 24 min using a triple-head SPECT system. Average counts per pixel were measured from frontal, temporal, parietal, occipital, cerebellum, basal ganglia, thalamus and white matter regions. ECD clearance rates were calculated by fitting regional time activity data to a monoexponential equation. Regional gray-to-white matter (G/W) and gray-to-cerebellum (G/C) ratios were calculated for each scan. Analysis of variance was used to compare regional ECD clearance and ratio measurements. RESULTS: The average ECD clearance was 4.3%/hr. There was a significant regional variation in the ECD clearance, being higher for occipital (6.34%/hr) but lower for both white matter (2.39%/hr) and thalamus (2.45%/hr). Both G/W and G/C ratios showed a significant regional variation with time. The overall G/W ratio was 2.13 at 30 min and became progressively lower after 2 hr, reaching 1.78 at 8 hr. All regional G/W ratios declined with time except for thalamus where it remained constant at 2.15. The overall G/C ratio was 0.984 at 30 min but it declined after 4 hr, reaching 0.955 at 8 hr. All regional G/C ratios declined with time except for thalamus where it increased progressively from 0.955 to 1.120 at 8 hr. CONCLUSION: ECD clears from normal brain slowly and shows a significant regional variation. As a result, G/W contrast begins to decrease after 2 hr and the gray-matter activity pattern becomes significantly different after 4 hr. Therefore, the optimal imaging time may be between 30-120 min. However, images obtained up to 4 hr still maintain the initial gray-matter activity pattern.

Adult↗
PubMed1997

Sleep, daytime symptoms, and cognitive performance in patients with fibromyalgia.

OBJECTIVE: To assess sleep, daytime symptoms, and cognitive performance in patients with fibromyalgia (FM). METHODS: Ten female patients with FM (mean age 32 yrs) and a matched, noncomplaintive comparison group (n = 9; mean age 30 yrs) spent 2 nights in the sleep laboratory. After the 2nd night, subjects completed a computerized 20 min battery of self-assessment and performance tests at hourly intervals from 07:00 to 20:00 h. RESULTS: Patients with FM spent more time in stage 1 sleep; however, there were no group differences on any other sleep measures. They reported greater sleepiness, more fatigue, more pain, more negative mood, and lower accuracy on performance tasks across a 14 h day. The FM group was slower in speed, but not impaired in accuracy, on performance of complex tasks, i.e., grammatical reasoning, serial addition/subtraction, and a simulated multi-task office procedure. CONCLUSION: Patients with FM have diurnal impairment in speed of performance on complex cognitive tasks, which accompany light stage 1 electroencephalographic (EEG) sleep and their experience of diffuse pain and nonrestorative sleep symptoms of sleepiness, fatigue, and negative mood.

Adult↗
PubMed1996

The clinical course of musculoskeletal pain in empirically derived groupings of injured workers.

The purpose of this paper is to examine the clinical course of musculoskeletal, soft tissue, work-related injury. An analysis of empirically derived sub-groupings of workers based on prognostically important pain and disability variables assessed on enrollment into the study is described. Multidimensional time-dependent profiles are used to characterize stages in the development of pain, impairment, disability and handicap. The clinical course over the 18 months of study of the three subgroups is examined. The conceptual model, used to examine the workers' changing responses over time, is based on the World Health Organization Classification of Impairments, Disabilities and Handicaps (1980). Methodologically, the study employed a prospective longitudinal design. A randomly selected cohort of workers who had not returned to work by 3 months post-injury were identified from the files of the Workers' Compensation Board of Ontario. The workers were interviewed and examined on enrollment into the study at 3 months and subsequently at 9 months, 15 months and 21 months after injury. The outcomes were return to work or continued work disability. The results are based on those 104 workers who attended all four assessment periods. K means clustering was used to identify homogenous subgroups of workers. Repeated measures ANOVAs were used to characterize the stages of development of pain, impairment, disability and handicap. Duncan's multiple range test was used to compare pairs of means at each assessment period. Cluster groupings, based on three prognostically important clinical variables, number of pain sites, pain behavior and functional disability, obtained at the initial assessment were valid predictors of the number of days to return to work and total number of days on work disability. Prognostic stratification can enhance confidence in predictive decisions of clinical practice and improve clinical trials of therapy.

Adult↗
PubMed1996

Periodic K-alpha sleep EEG activity and periodic limb movements during sleep: comparisons of clinical features and sleep parameters.

The K-alpha sleep electroencephalographic (EEG) phenomenon is characterized by periodic (approximately 20-40 seconds) K-complexes, immediately followed by alpha-EEG activity (7.5-11 Hz) of 0.5- to 5.0-second duration. A group of 14 subjects with the periodic K-alpha anomaly was found to have a similar distribution pattern of interevent intervals as compared with previously published data for sleep-related periodic limb movements during sleep (PLMS). Sleep parameters and somatic symptoms of 30 patients with K-alpha were compared with 30 patients with PLMS. The periodic K-alpha group was predominantly female, younger, exhibiting more slow-wave sleep, gastrointestinal symptoms and muscular complaints and fewer movement arousals on overnight polysomnography. The K-alpha group presented uniformly with complaints of unrefreshing sleep, often associated with fibromyalgia and chronic fatigue syndrome. The PLMS group was predominantly male, showed greater sleep disruption and presented with a variety of sleep-related symptoms.

Adult↗
PubMed1996

The effects of bright light treatment on the symptoms of fibromyalgia.

OBJECTIVE: To investigate the effects of bright light treatment on the symptoms of pain, mood, and sleep in patients with fibromyalgia (FM) reporting seasonality of symptoms on the Seasonal Pattern Assessment Questionnaire (SPAQ). METHODS: A randomized 10 week crossover study compared the effects of 4 weeks of "visible electromagnetic fields" (EMF) (light condition; mean 4750 lux, SD 2337 lux) to 4 weeks of "nonvisible EMF" (no light condition) in 14 patients with FM having a minimum SPAQ score of 11. The light visor system (Bio-Brite) was fitted with an opaque filter for the "nonvisible EMF" control condition. RESULTS: No significant differences were found between treatment conditions on tenderness measured with dolorimetry, self-ratings of sleep, pain, mood, and global measures. Mood was not related to pain or sleep. There was significant reduction in depression scores and subjective pain, but increased tenderness and nocturnal awakenings related to time. CONCLUSION: The were no significant differences between the light and no light conditions on pain, mood, or sleep in patients with FM reporting seasonality of symptoms. No relationship was found between mood and the symptoms of FM (i.e., pain, sleep, and fatigue).

Adult↗