Identifying subtypes of Hypersomnolence Disorder: a clustering analysis.

BACKGROUND: Patient heterogeneity is problematic for the accurate assessment and effective treatment of Hypersomnolence Disorder. Clustering analysis is a preferred approach for establishing homogenous subclassifications. Thus, this investigation aimed to identify more homogeneous subclassifications of Hypersomnolence Disorder through clustering analysis. METHODS: Patients undergoing polysomnography (PSG) and multiple sleep latency test (MSLT) assessment for hypersomnolence were recruited as part of a larger investigation. A sample of patients with Hypersomnolence Disorder was determined based on a post hoc chart review protocol. After removing persons with missing data, 62 participants were included in the analyses. Self-report total sleep time, Epworth Sleepiness Scale (ESS) score, and Sleep Inertia Questionnaire (SIQ) score were chosen as clustering variables to mirror Hypersomnolence Disorder diagnostic traits. A statistically-driven clustering process produced two clusters using Ward's D hierarchical approach. Clusters were compared across characteristics, self-report measures, PSG/MSLT results, and additional objective measures. RESULTS: The resulting clusters differed across a variety of hypersomnolence-related subjective metrics and objective measurements. A more severe hypersomnolence phenotype was identified in a cluster that also had elevated depressive symptoms. This cluster endorsed significantly greater daytime sleepiness, sleep inertia, and functional impairment, while displaying longer sleep duration and worse vigilance. CONCLUSIONS: These results provide growing support for a nosological reformulation of hypersomnolence associated with psychiatric disorders. Future research is necessary to solidify the conceptualization and characterization of unexplained hypersomnolence presenting with-and-without psychiatric illness.

Effects of oral temazepam on slow waves during non-rapid eye movement sleep in healthy young adults: A high-density EEG investigation.

Slow waves are characteristic waveforms that occur during non-rapid eye movement (NREM) sleep that play an integral role in sleep quality and brain plasticity. Benzodiazepines are commonly used medications that alter slow waves, however, their effects may depend on the time of night and measure used to characterize slow waves. Prior investigations have utilized minimal scalp derivations to evaluate the effects of benzodiazepines on slow waves, and thus the topography of changes to slow waves induced by benzodiazepines has yet to be fully elucidated. This study used high-density electroencephalography (hdEEG) to evaluate the effects of oral temazepam on slow wave activity, incidence, and morphology during NREM sleep in 18 healthy adults relative to placebo. Temazepam was associated with significant decreases in slow wave activity and incidence, which were most prominent in the latter portions of the sleep period. However, temazepam was also associated with a decrease in the magnitude of high-amplitude slow waves and their slopes in the first NREM sleep episode, which was most prominent in frontal derivations. These findings suggest that benzodiazepines produce changes in slow waves throughout the night that vary depending on cortical topography and measures used to characterize slow waves. Further research that explores the relationships between benzodiazepine-induced changes to slow waves and the functional effects of these waveforms is indicated.

Effects of oral temazepam on sleep spindles during non-rapid eye movement sleep: A high-density EEG investigation.

Benzodiazepines are commonly used medications that alter sleep spindles during non-rapid eye movement (NREM) sleep, however the topographic changes to these functionally significant waveforms have yet to be fully elucidated. This study utilized high-density electroencephalography (hdEEG) to investigate topographic changes in sleep spindles and spindle-range activity caused by temazepam during NREM sleep in 18 healthy adults. After an accommodation night, sleep for all participants was recorded on two separate nights after taking either placebo or oral temazepam 15 mg. Sleep was monitored using 256-channel hdEEG. Spectral analysis and spindle waveform detection of sleep EEG data were performed for each participant night. Global and topographic data were subsequently compared between temazepam and placebo conditions. Temazepam was associated with significant increases in spectral power from 10.33 to 13.83 Hz. Within this frequency band, temazepam broadly increased sleep spindle duration, and topographically increased spindle amplitude and density in frontal and central-posterior regions, respectively. Higher frequency sleep spindles demonstrated increased spindle amplitude and a paradoxical decrease in spindle density in frontal and centroparietal regions. Further analysis demonstrated temazepam both slowed the average frequency of spindle waveforms and increased the relative proportion of spindles at peak frequencies in frontal and centroparietal regions. These findings suggest that benzodiazepines have diverse effects on sleep spindles that vary by frequency and cortical topography. Further research that explores the relationships between topographic and frequency-dependent changes in pharmacologically-induced sleep spindles and the functional effects of these waveforms is indicated.

Altered overnight modulation of spontaneous waking EEG reflects altered sleep homeostasis in major depressive disorder: a high-density EEG investigation.

BACKGROUND: Prior investigations have suggested sleep homeostasis is altered in major depressive disorder (MDD). Low frequency activity (LFA) in the electroencephalogram during waking has been correlated with sleep slow wave activity (SWA), suggesting that waking LFA reflects sleep homeostasis in healthy individuals. This study investigated whether the overnight change in waking LFA and its relationship with sleep SWA are altered in MDD. METHODS: 256-channel high-density electroencephalography (hdEEG) recordings during waking (pre- and post-sleep) and during sleep were collected in 14 unmedicated, unipolar MDD subjects (9 women) and age- and sex-matched healthy controls (HC). RESULTS: Waking LFA (3.25-6.25 Hz) declined significantly overnight in the HC group, but not in the group of MDD subjects. Overnight decline of waking LFA correlated with sleep SWA in frontal brain regions in HC, but a comparable relationship was not found in MDD. LIMITATIONS: This study is not able to definitely segregate overnight changes in the waking EEG that may occur due to homeostatic and/or circadian factors. CONCLUSIONS: MDD involves altered overnight modulation of waking low frequency EEG activity that may reflect altered sleep homeostasis in the disorder. Future research is required to determine the functional significance and clinical implications of these findings.

Topographic and sex-related differences in sleep spindles in major depressive disorder: a high-density EEG investigation.

BACKGROUND: Sleep spindles are believed to mediate several sleep-related functions including maintaining disconnection from the external environment during sleep, cortical development, and sleep-dependent memory consolidation. Prior studies that have examined sleep spindles in major depressive disorder (MDD) have not demonstrated consistent differences relative to control subjects, which may be due to sex-related variation and limited spatial resolution of spindle detection. Thus, this study sought to characterize sleep spindles in MDD using high-density electroencephalography (hdEEG) to examine the topography of sleep spindles across the cortex in MDD, as well as sex-related variation in spindle topography in the disorder. METHODS: All-night hdEEG recordings were collected in 30 unipolar MDD participants (19 women) and 30 age and sex-matched controls. Topography of sleep spindle density, amplitude, duration, and integrated spindle activity (ISA) were assessed to determine group differences. Spindle parameters were compared between MDD and controls, including analysis stratified by sex. RESULTS: As a group, MDD subjects demonstrated significant increases in frontal and parietal spindle density and ISA compared to controls. When stratified by sex, MDD women demonstrated increases in frontal and parietal spindle density, amplitude, duration, and ISA; whereas MDD men demonstrated either no differences or decreases in spindle parameters. LIMITATIONS: Given the number of male subjects, this study may be underpowered to detect differences in spindle parameters in male MDD participants. CONCLUSIONS: This study demonstrates topographic and sex-related differences in sleep spindles in MDD. Further research is warranted to investigate the role of sleep spindles and sex in the pathophysiology of MDD.

Overnight changes in waking auditory evoked potential amplitude reflect altered sleep homeostasis in major depression.

OBJECTIVE: Sleep homeostasis is altered in major depressive disorder (MDD). Pre- to postsleep decline in waking auditory evoked potential (AEP) amplitude has been correlated with sleep slow wave activity (SWA), suggesting that overnight changes in waking AEP amplitude are homeostatically regulated in healthy individuals. This study investigated whether the overnight change in waking AEP amplitude and its relation to SWA is altered in MDD. METHOD: Using 256-channel high-density electroencephalography, all-night sleep polysomnography and single-tone waking AEPs pre- and postsleep were collected in 15 healthy controls (HC) and 15 non-medicated individuals with MDD. RESULTS: N1 and P2 amplitudes of the waking AEP declined after sleep in the HC group, but not in MDD. The reduction in N1 amplitude also correlated with fronto-central SWA in the HC group, but a comparable relationship was not found in MDD, despite equivalent SWA between groups. No pre- to postsleep differences were found for N1 or P2 latencies in either group. These findings were not confounded by varying levels of alertness or differences in sleep variables between groups. CONCLUSION: MDD involves altered sleep homeostasis as measured by the overnight change in waking AEP amplitude. Future research is required to determine the clinical implications of these findings.

The use of bovine serum albumin to improve the RT-qPCR detection of foodborne viruses rinsed from vegetable surfaces.

AIMS: To demonstrate that produce rinsates used for RT-qPCR detection of foodborne viruses may cause significant PCR inhibition and propose a means to reduce its impact on sensitivity. METHODS AND RESULTS: Here, it is shown that rinsing and concentration from spinach and precut lettuce have the potential to generate RNA extracts that are inhibitory to RT-qPCRs assembled from commercial kits for the detection of norovirus GII (NoV GII), hepatitis A virus (HAV), hepatitis E virus (HEV), rotavirus (RV) and feline calicivirus (FCV) as sample process control. It is further shown that the addition of bovine serum albumin (BSA) to those reactions restored a positive signal in all cases. The effect of BSA was dependent upon the primer/probe combination. Moreover, two of the detection systems (FCV and HAV) strongly benefited from the addition of BSA even in the absence of PCR inhibitors. CONCLUSIONS: BSA was shown to restore positive signals in five different RT-qPCR systems that were otherwise completely inhibited by produce rinsate extracts. It is therefore suggested to consider the addition of BSA to RT-qPCRs for the detection of foodborne viruses when inhibition is observed. SIGNIFICANCE AND IMPACT OF THE STUDY: This study clearly demonstrates the potency of PCR inhibitors generated during routine virus concentration from produce and that it can be alleviated by the addition of BSA to the RT-qPCRs. Although used elsewhere, the addition of BSA to PCRs is not a common practice in this growing field of research.

Comparative analysis of different TaqMan real-time RT-PCR assays for the detection of swine Hepatitis E virus and integration of Feline calicivirus as internal control.

AIMS: The aim of this study was to compare the performance of four TaqMan RT-PCR assays with a commonly used nested RT-PCR and to include the Feline calicivirus (FCV) as an internal control. METHODS AND RESULTS: RNA extracted from 87 swine faecal samples and 103 swine blood samples was subjected to different detection systems. Faecal samples naturally contaminated with Hepatitis E virus (HEV) and negative samples were artificially inoculated with 3.2 x 10(3) PFU of FCV. Detection results obtained on faecal and plasma samples were 35.6% and 4.9% with the nested RT-PCR assay, 8.0% and 0%, 0% and 0%, 13.8% and 0% and 36.8% and 3.9% with TaqMan systems A, B, C and D respectively. The Ct means obtained with the multiplex TaqMan assay were 30.11 and 30.43 for the detection of FCV with HEV contaminated samples and negative samples. CONCLUSIONS: The TaqMan system D was more suitable for the detection of swine HEV strains than the three others and FCV was integrated successfully as an internal control. SIGNIFICANCE AND IMPACT OF THE STUDY: FCV was demonstrated as an efficient control to monitor the RNA extraction process and HEV amplification procedure in a multiplex HEV/FCV TaqMan assay. This control would be helpful in limiting false negative results.

Complex formation between potyvirus VPg and translation eukaryotic initiation factor 4E correlates with virus infectivity.

The interaction between the viral protein linked to the genome (VPg) of turnip mosaic potyvirus (TuMV) and the translation eukaryotic initiation factor eIF(iso)4E of Arabidopsis thaliana has previously been reported. eIF(iso)4E binds the cap structure (m(7)GpppN, where N is any nucleotide) of mRNAs and has an important role in the regulation in the initiation of translation. In the present study, it was shown that not only did VPg bind eIF(iso)4E but it also interacted with the eIF4E isomer of A. thaliana as well as with eIF(iso)4E of Triticum aestivum (wheat). The interaction domain on VPg was mapped to a stretch of 35 amino acids, and substitution of an aspartic acid residue found within this region completely abolished the interaction. The cap analogue m(7)GTP, but not GTP, inhibited VPg-eIF(iso)4E complex formation, suggesting that VPg and cellular mRNAs compete for eIF(iso)4E binding. The biological significance of this interaction was investigated. Brassica perviridis plants were infected with a TuMV infectious cDNA (p35Tunos) and p35TuD77N, a mutant which contained the aspartic acid substitution in the VPg domain that abolished the interaction with eIF(iso)4E. After 20 days, plants bombarded with p35Tunos showed viral symptoms, while plants bombarded with p35TuD77N remained symptomless. These results suggest that VPg-eIF(iso)4E interaction is a critical element for virus production.

Life expectancy estimation with breast cancer: bias of the declining exponential function and an alternative to its use.

BACKGROUND: Life expectancy gain (LEG) is an outcome measure commonly estimated with a declining exponential function in a Markov model. The accuracy of such estimates has not been objectively evaluated. PURPOSE: To compare LEGs from declining exponential function estimates with those calculated from population data, using published screening mammography studies as examples. METHOD: SEER-based population data are used to compare LEG calculation with declining exponential function estimation and empiric population data in a new model, the "nested" Markov. RESULTS: Analyses of the LEG of mammographic screening based on the declining exponential function significantly overestimate LEGs for younger women and underestimate them for older women. Because of offsetting errors, all-age analyses paradoxically appear accurate. CONCLUSION: Declining exponential function estimates of LEGs for chronic diseases with low mortality rates and long time horizons are liable to significant bias, especially with limited age cohorts.

Screening for breast cancer: time, travel, and out-of-pocket expenses.

BACKGROUND: We estimated the personal costs to women found to have a breast problem (either breast cancer or benign breast disease) in terms of time spent, miles traveled, and cash payments made for detection, diagnosis, initial treatment, and follow-up. METHODS: We analyzed data from personal interviews with 465 women from four communities in Florida. These women were randomly selected from those with a recent breast biopsy (within 6-8 months) that indicated either breast cancer (208 women) or benign breast disease (257 women). One community was the site of a multifaceted intervention to promote breast screening, and the other three communities were comparison sites for evaluation of that intervention. All P values are two-sided. RESULTS: In comparison with time spent and travel distance for women with benign breast disease (13 hours away from home and 56 miles traveled), time spent and travel distance were statistically significantly higher (P<.001) for treatment and follow-up of women with breast cancer (89 hours and 369 miles). Personal financial costs for treatment of women with breast cancer were also statistically significantly higher (breast cancer = $604; benign breast disease = $76; P < .001) but were statistically significantly lower for detection and diagnosis (breast cancer = $170; benign breast disease = $310; P < .001). Among women with breast cancer, time spent for treatment was statistically significantly lower (P = .013) when their breast cancer was detected by screening (68.9 hours) than when it was detected because of symptoms (84.2 hours). Personal cash payments for detection, diagnosis, and treatment were statistically significantly lower among women whose breast problems were detected by screening than among women whose breast problems were detected because of symptoms (screening detected = $453; symptom detected = $749; P = .045). CONCLUSION: There are substantial personal costs for women who are found to have a breast problem, whether the costs are associated with problems identified through screening or because of symptoms.

Complications associated with therapeutic neck radiation.

PURPOSE: This retrospective study of patients who underwent neck radiation as part of their treatment for squamous cell carcinoma of the oral cavity sought to identify and quantify the morbidity associated with this treatment. PATIENTS AND METHODS: Thirty-five patients who received neck radiation between 1985 and 1992 were randomly recalled for examination. All patients had been treated in a standardized fashion by the Department of Radiation Oncology. The long-term effects of neck radiation on skin changes, thyroid function, and neck range of motion, of atherosclerotic carotid artery disease, xerostomia, and glottic structures were measured. RESULTS: Fifty-seven percent of patients demonstrated grade 1 skin changes. No severe changes were noted, and no development of secondary neoplasia was observed. There was no linear trend observed between radiation dose and skin changes. Hypothyroidism developed in 14.3% of patients within 3.5 years posttreatment. Logistic regression demonstrated a significant association between hypothyroidism and radiation dose. Limitation of neck mobility was the most significant complication with deficits demonstrated in all ranges of motion. Carotid bruits were documented in 14.3% of patients, with a significant association between the higher neck dosage in N+ cases. Xerostomia was found in 68% of patients. There was persistent glottic erythema in 11.4% of patients. CONCLUSIONS: The results of this study indicate that there are persistent complications after neck radiation, which include limitation of neck movement, diminished thyroid function, accelerated carotid artery narrowing, and skin and salivary changes.

Laser and daunomycin chemophototherapy of human carcinoma cells.

Adriamycin and daunomycin anticancer drugs are detectable in leukemias and solid tumors by cell fluorescence. We observed initial cytoplasmic fluorescence followed by slow nuclear localization of adriamycin and daunomycin after incubation with cultured human squamous cell (P3, FADU) and adenocarcinoma (HT29, SW620) lines by digital video imaging microscopy. Tumor cells incubated with 10 mug/ml of these drugs exhibited increased uptake for more than 3 h with intracellular levels in the range 0.5-2.5 mug/10 6 cells measured by dimethyl sulfoxide (DMSO) extraction and fluorescence spectrophotometry. Daunomycin had 10- to 100-fold higher toxicity for these carcinoma cells than for normal human epithelial keratinocytes measured by in vitro MTT tetrazolium assays. The viability of daunomycin-sensitized carcinoma cells was decreased 2- to 10-fold further by argon laser illumination at 488 nm (5W, T max = 8 degrees C) for 2-3 minutes. The results suggest that adriamycin derivatives may be useful targeting agents for adjuvant treatment and chemophototherapy of human solid tumors by MR-guided laser fiberoptic endoscopy.

Wooden transnasal intracranial penetration: an unusual presentation.

A 2 1/2-year-old child presented to the emergency department with a wooden stick lodged firmly in her right nares. No nasal discharge or neurological abnormalities were noted at presentation. After plain radiographs failed to demonstrate any evidence of a foreign body, computed tomography (CT scan) was obtained that revealed a hypodense region in the right frontal lobe corresponding to the projected tract of the branch. The patient underwent a right frontal craniotomy with debridement of her contused right frontal lobe. She was discharged 8 days postoperatively without evidence of neurologic sequelae. This case illustrates an unusual presentation of intracranial penetration, with only six similar cases found in the literature. It also highlights the need for the emergency physician to be concerned about intracranial penetration when treating intranasal foreign bodies, particularly those of the nonmetallic type. The literature is reviewed regarding transnasal intracranial penetration by wooden foreign bodies.

Pharmacokinetics of intravenous diltiazem and five of its metabolites in patients with chronic renal failure and in healthy volunteers.

The pharmacokinetics of diltiazem were studied in seven patients with chronic renal failure (CRF) not requiring dialysis and in three healthy volunteers after a rapid i.v. infusion of 20 mg. Mean plasma concentrations at the end of infusion were 3.15 times higher in patients with CRF than in healthy volunteers. From 0.5 to 12 h post-infusion, the difference remained between 25 per cent and 73 per cent. Mean AUC0-infinity was statistically greater in patients than in volunteers while mean V area, CLtot, and CLren were statistically lower. The t1/2 alpha and t1/2 beta values were not significantly (p greater than 0.05) different between patients and volunteers. Renal excretion was statistically more important in volunteers (6.6 per cent of the dose) than in patients (1.2 per cent of the dose). We therefore conclude that CRF does not influence t1/2 beta of diltiazem but it interferes with the extent and possibly the rate of its extravascular distribution. That could result in transient high plasma concentrations after rapid i.v. infusion.

Pharmacokinetics of oral diltiazem and five of its metabolites in patients with chronic renal failure.

The pharmacokinetics of oral diltiazem were studied in 10 patients with chronic renal failure not requiring dialysis and in five healthy volunteers after a single dose of 120 mg. We found that patients with chronic renal failure had lower amounts of unchanged diltiazem and of its main metabolite (MA) in urine and a trend to have slightly higher values of plasma concentration. Since the terminal elimination phase is not affected by chronic renal failure we conclude that this trend is probably the result of alterations in the volume of distribution of diltiazem in these patients.

Establishing a quality improvement process for identification of psychosocial problems in a primary care practice.

OBJECTIVES: A quality improvement process that will significantly increase the rate of identification of psychosocial problems through routine use of case-finding instruments can be established in a general medicine practice. DESIGN: Two groups of patient examination reports written by physicians were retrospectively compared with the patients' responses on the case-finding database instrument. The samples were obtained by sequential selection in four time periods. SETTING AND PATIENTS: The study occurred in a university general internal medicine practice that utilizes the problem-oriented record. The patients studied were seen for first-time comprehensive examinations designed to identify all important health problems, including psychosocial problems. INTERVENTION: The authors compared performances of the physicians in identification of psychosocial problems before and after the intervention, which consisted of a pilot study audit of psychosocial problem identification, establishment of standards for interpretation of the case-finding instrument, design of a flow sheet to make case-finding data clearly available to the physician at each comprehensive examination, and feedback of physician performance according to practice-adopted standards for identification of psychosocial problems. MEASUREMENT: The result of the intervention was an increase in psychosocial problem identification from 67% to 90% of problems present, p less than 0.05 by chi-square distribution; or a decrease from 33% to 10% in psychosocial problems missed by the physicians. CONCLUSION: The quality improvement process for identification of psychosocial problems described in this report significantly increased the rate of identification of psychosocial problems by general internists.