Changes in components of energy regulation in mouse cortex with increases in wakefulness.

STUDY OBJECTIVES: Increases in ATP production machinery have been described in brain after 3 h of sleep deprivation. Whether this is sustained with longer durations of extended wakefulness is unknown. We hypothesized that energy depletion could be a mechanism leading to difficulty maintaining wakefulness and assessed changes in components of the electron transport chain. DESIGN: Protein levels of key subunits of complexes IV and V of the electron transport chain (COXI, COXIV, ATP5B) and uncoupling protein 2 (UCP2) in isolated mitochondria by Westerns in mouse cerebral cortex after 3 and 12 h of sleep deprivation were compared to that in control mice. Activity of complex IV enzyme and relevant transcription factors-Nrf1, Nrf2 (Gabp), and phosphorylation of AMP-dependent kinase (AMPK)-were also assessed. PARTICIPANTS: 8-10 week old C57BL/6J male mice (n = 91). INTERVENTIONS: 3, 6, and 12 h of sleep deprivation. MEASUREMENTS AND RESULTS: After both 3 and 12 h of sleep deprivation, complex IV proteins and enzyme activity were significantly increased. The complex V catalytic subunit was significantly increased after 12 h of sleep deprivation only. Increased levels of UCP2 protein after 12 h of sleep deprivation suggests that there might be alterations in the ATP/AMP ratio as wakefulness is extended. That phosphorylation of AMPK is increased after 6 h of sleep deprivation supports this assertion. The increase in Nrf1 and Nrf2 (Gabp) mRNA after 6 h of sleep deprivation provides a mechanism by which there is up-regulation of key proteins. CONCLUSIONS: There are complex dynamic changes in brain energy regulation with extended wakefulness.

Breast cancer: education, counseling, and adjustment among patients and partners: a randomized clinical trial.

BACKGROUND: Although various forms of psychoeducation and counseling interventions have been examined among patients with a variety of diagnoses, the unique contribution of phase-specific psychoeducation and telephone counseling (TC) to the ongoing process of adjustment has not been explored among patients with breast cancer and their partners. OBJECTIVE: To conduct a randomized controlled clinical trial of phase-specific evidence-based psychoeducation and TC interventions to enhance emotional, physical, and social adjustments in patients with breast cancer and their partners. METHODS: A purposive sample of 249 patient-partner dyads were assigned randomly to one of four groups: (a) control group receiving disease management (DM), (b) standardized psychoeducation (SE), (c) TC, or (d) standardized psychoeducation plus telephone counseling (SE + TC). Data were collected at baseline, diagnostic, postsurgery, adjuvant therapy, and ongoing recovery phases measuring emotional, physical, and social adjustments. RESULTS: Patients showed poorer adjustment over time in the DM group relative to those receiving interventions on selected measures of emotional adjustment. All patients showed improvement over time in overall health and adjustment in social and vocational environments. Partners in all groups exhibited improvement over time for measures of adjustment in the social environment but no changes in psychological well-being or overall health. Partners in the TC group had poorer scores on physical symptoms compared with the SE + TC group and poorer vocational scores compared with the DM group. DISCUSSION: Findings from this study provide preliminary support for the value of phase-specific SE and TC interventions to enhance selected adjustment outcomes for patients with breast cancer and their partners.

Ziprasidone in adolescents with autism: an open-label pilot study.

INTRODUCTION: The antipsychotic drugs are the best-studied agents shown to reduce symptoms in autism, including hyperactivity, aggression, self-abusive behavior, temper tantrums, lability, irritability, social withdrawal, and stereotypical behaviors. However, significant weight gain has been associated with use of many atypical agents. Ziprasidone has been weight neutral in adult populations, but data from adolescents and patients with autism are sparse. However, ziprasidone administration has been associated with increases in the QTc. The purpose of this study was to collect pilot data on the efficacy and safety of ziprasidone in adolescents with autism, focusing on safety issues of weight gain and QTc. METHODS: Twelve adolescents with autism (mean age 14.5 +/- 1.8 years) were treated in a 6-week open pilot study. Ziprasidone dosage ranged from 20 to 160 mg/day (mean, 98.3 +/- 40.4 mg/day). The primary efficacy measure was the Clinical Global Impressions-Improvement item (CGI-I); other efficacy measures included the Aberrant Behavior Checklist and the Children's Psychiatric Rating Scale. RESULTS: Based on the CGI-I, 9 of 12 (75%) patients were treatment responders. Ziprasidone was weight neutral, and the QTc increased by a mean of 14.7 msec. Two subjects had acute dystonic reactions. Cholesterol decreased and prolactin remained the same. CONCLUSIONS: Ziprasidone shows promise as a treatment for adolescents with autism. More definitive trials are needed.

Macular cystoid spaces in patients with retinal dystrophy.

BACKGROUND: Non leaking macular cystoid spaces (MCS) are seen in some retinal dystrophies. Carbonic anhydrase inhibitor (CAI) treatment may reduce the size of MSC and improve vision. METHODS: A retrospective study of patients with retinal dystrophy with MCS seen between 2009 and 2013 at two sites. Patients had ophthalmic examination, optical coherence tomography (OCT) and genetic testing. Patients with vision worse than 20/30 were treated with CAI. Post treatment visual acuity (VA), central foveal zone (CFZ) thickness, and qualitative estimation of MCS size were assessed. RESULTS: Eighteen patients, 6-47 years old, were included. IVFA was performed in 15 (83%) patients. Of the 26 eyes in 13 patients who were treated and followed, VA improved in 15 eyes (58%) of 10 patients. Ten of these 15 eyes had decreased CFZ thickness and 9/10 showed qualitative MCS improvement. Regression analysis showed that change in CFZ thickness was not significantly predictive of change in final visual acuity (p = 0.405). Five of 15 eyes with improved VA had paradoxically increased CFZ thickness and 2/5 had enlarged MCS. Three of the treated eyes (11%) in two patients had decreased VA with decreased CFZ thickness and improved MCS in 2/3 eyes. Eight eyes (31%) in six patients showed no change in VA with decreased CFZ thickness in 6/8 eyes with improved MCS. Genetic testing showed mutations of NR2E3, XLRS, CRB1, GPR98 and CNGB1. CONCLUSION: Non-leaking MCS occur in a variety of retinal dystrophies. Therapy with topical or systemic CAI has variable efficacy and may result in VA improvement with or without qualitative improvement in MCS and CFZ thickness.

Differences in activity of cytochrome C oxidase in brain between sleep and wakefulness.

STUDY OBJECTIVES: Increased mRNA level of subunit 1 cytochrome c oxidase (COXI) during wakefulness and after short-term sleep deprivation has been described in brain. We hypothesized that this might contribute to increased activity of cytochrome oxidase (COX) enzyme during wakefulness, as part of the mechanisms to provide sufficient amounts of adenosine triphosphate to meet increased neuronal energy demands. DESIGN: COX activity was measured in isolated mitochondria from different brain regions in groups of rats with 3 hours of spontaneous sleep, 3 hours of spontaneous wake, and 3 hours of sleep deprivation. The group with 3 hours of spontaneous wake was added to delineate the circadian component of changes in the enzyme activity. Northern blot analysis was performed to examine the mRNA levels of 2 subunits of the enzyme COXI and COXIV, encoded by mitochondrial and nuclear DNA, respectively. SETTING: Laboratory of Biochemistry, Department of Animal Biology, and Center for Sleep and Respiratory Neurobiology, University of Pennsylvania. PARTICIPANTS: 2-month-old male Fischer rats (N = 21) implanted for polygraphic recording. MEASUREMENTS AND RESULTS: For COX activity, there was a main effect by analysis of variance of experimental group (P < .0001) with significant increases in COX activity in wake and sleep-deprived groups as compared to the sleep group. A main effect of brain region was also significant (P < .001). There was no difference between brain regions in the degree of increase in enzyme activity in wakefulness. Both COXI and COXIV mRNA were increased with wakefulness as compared to sleep. CONCLUSIONS: There is an increase in COX activity after both 3 hours of spontaneous wake and 3 hours of sleep deprivation as compared with 3 hours of spontaneous sleep in diverse brain regions, which could be, in part, explained by the increased levels of bigenomic transcripts of the enzyme. This likely contributes to increased adenosine triphosphate production during wakefulness. ABBREVIATIONS: ADP, adenosine diphosphate; ATP, adenosine triphosphate; COXI, cytochrome c oxidase subunit 1 mRNA; COX, cytochrome c oxidase (protein); CREB, cyclic AMP response element binding protein; DNA, deoxyribonucleic acid; EDTA, ethylenediaminetetraacetic acid; EEG, electroencephalography; EMG, electromyography; GABP, GA binding protein; HEPES, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; mRNA, messenger ribonucleic acid; NADH, nicotinamid adenine dinucleotide, reduced; NDII, NADH dehydrogenase subunit 2 mRNA; NRF, nuclear respiratory factor.

Functional outcomes of excessive daytime sleepiness in older adults.

OBJECTIVES: To describe the effect of self-reported excessive daytime sleepiness (EDS) on functional outcomes. DESIGN: Case-control study designed to examine differences in functional status between cases (with daytime sleepiness) and controls (no daytime sleepiness) with regard to demographic factors, general health, sleep history, and medications. SETTING: Retirement communities in southeastern Pennsylvania, Delaware, and New Jersey. PARTICIPANTS: Seventy-six nondepressed, nondemented adults, aged 65 and older, were cases (had daytime sleepiness) and 38 were controls (had no daytime sleepiness). MEASUREMENTS: Standardized questionnaires to assess disease-specific functional status (Functional Outcomes of Sleepiness Questionnaire (FOSQ) and Epworth Sleepiness Scale (ESS)), depression (Geriatric Depression Scale-Short Form and the Center for Epidemiologic Studies-Depression Scale), dementia (Short Blessed Test), demographic factors, current medical history, and sleep complaints. RESULTS: There was a significant difference in functional status between sleepy cases and nonsleepy controls. Sleepiness had a moderate to large negative effect (effect size range from 0.59 to 0.83, P <.005) on the following functional domains of the FOSQ: social outcome, general productivity, vigilance, activity level, and global assessment of functional status. Correlation between ESS and FOSQ subscales were -0.31 to -0.67, P <.05. Examination of cases with daytime sleepiness revealed increased functional impairment in individuals with more than three medical conditions or those taking more than four medications (P <.001 and P =.03, respectively). CONCLUSION: Daytime sleepiness is associated with functional impairments in a broad range of activities. The decrease in daily functioning noted in the sleepy subjects has implications for deconditioning and related comorbidity. These findings suggest that exploration of daytime sleepiness should be part of the ongoing assessment of the elderly, particularly those with multiple medical conditions.

Comparative evaluation of dual Scheimpflug imaging parameters in keratoconus, early keratoconus, and normal eyes.

PURPOSE: To determine the efficacy of various parameters measured by dual Scheimpflug imaging technology in differentiating eyes with keratoconus or early keratoconus from normal eyes. SETTING: Cornea Service, Wills Eye Institute, Philadelphia, Pennsylvania, USA. DESIGN: Comparative case series. METHODS: A retrospective evaluation was performed of the parameters provided by the Galilei dual Scheimpflug analyzer in keratoconus, early keratoconus, and normal eyes. Logistic regression and receiver operating characteristic curve analysis were used to compare the mean values and to calculate the sensitivity and specificity of these parameters. RESULTS: Many parameters were statistically significantly different between keratoconus and normal eyes compared with early keratoconus eyes (P<.05). Total cornea power-steep and posterior curvature-steep keratometry had the highest area under the curve (AUC) score (0.99) for differentiating keratoconus eyes from normal eyes. All anterior curvature parameters were statistically significant in differentiating keratoconus eyes from normal eyes, whereas only the anterior curvature-steep was statistically significant in differentiating early keratoconus eyes from normal eyes. The central pachymetry and thinnest pachymetry were statistically significant in differentiating keratoconus and early keratoconus eyes from normal eyes. Third-order root mean square (RMS) and total RMS had the highest AUC scores (0.83 and 0.82, respectively) for differentiating early keratoconus eyes from normal eyes. CONCLUSION: Total corneal power, anterior curvature, posterior curvature, pachymetry, and corneal aberration data generated from the dual Scheimpflug analyzer showed promising results in differentiating keratoconus and early keratoconus eyes from normal eyes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Tongue fat infiltration in obese versus lean Zucker rats.

STUDY OBJECTIVES: Obesity is the most important risk factor for obstructive sleep apnea (OSA), and the effects of obesity may be mediated by tongue fat. Our objective was to examine the effects of obesity on upper airway structures in obese (OBZ) and non-obese (NBZ) Zucker rats. DESIGN: Animal study. SETTING: Academic Medical Center. PARTICIPANTS: OBZ (638.2 ± 39 g; 14.9 ± 1.1 w) and age-matched NBZ Zucker (442.6 ± 37 g, 15.1 ± 1.5 w) rats. INTERVENTIONS: TONGUE FAT AND VOLUME AND WERE ASSESSED USING: in vivo magnetic resonance spectroscopy (MRS), magnetic resonance imaging including Dixon imaging for tongue fat volume, ex vivo biochemistry (fat quantification; triglyceride (mg)/tissue (g), and histology (Oil Red O stain). MEASUREMENTS AND RESULTS: MRS: overall OBZ tongue fat/water ratio was 2.9 times greater than NBZ (P < 0.002) with the anterior OBZ tongue up to 3.3 times greater than NBZ (P < 0.002). Biochemistry: Triglyceride (TG) in the tongue was 4.4 times greater in OBZ versus NBZ (P < 0.0006). TG was greater in OBZ tongue (3.57 ± 1.7 mg/g) than OBZ masseter muscle (0.28 ± 0.1; P < 0.0001) but tongue and masseter TG were not different in NBZ rats (0.82 ± 0.3 versus 0.28 ± 0.1 mg/g, P = 0.67). Dixon fat volume was significantly increased in OBZ (56 ± 15 mm3) versus NBZ (34 ± 5 mm3, P < 0.004). Histology demonstrated a greater degree of intracellular muscle fat and extramuscular fat infiltration in OBZ versus NBZ rats. CONCLUSIONS: Genetically obese rats had a large degree of fat infiltration in the tongue compared to both skeletal muscle and tongue tissues of the non-obese age-matched littermates. The significant fat increase and sequestration in the obese tongue may play a role in altered tongue neuromuscular function, tongue stiffness or metabolic function.

Sleep in children with Williams Syndrome.

OBJECTIVE: To analyze sleep in children with Williams Syndrome (WS) compared to normal healthy controls in order to determine whether particular sleep features are characteristic of WS, and to explore associations between disturbed sleep and behavior. METHODS: Thirty-five children with genetically-confirmed WS and 35 matched controls underwent overnight polysomnography and performance testing in the Sleep Center at the Children's Hospital of Philadelphia. Parents completed questionnaires regarding the subjects' sleep and behavior. RESULTS: WS subjects had significantly different sleep than controls, with decreased sleep efficiency, increased respiratory-related arousals and increased slow wave sleep on overnight polysomnography. WS subjects were also noted to have more difficulty falling asleep, with greater restlessness and more arousals from sleep than controls. Fifty-two percent of WS subjects had features of attention deficit-hyperactivity disorder. CONCLUSION: Children with WS had significantly different sleep than controls in our sample. These differences demonstrated in our study may reflect genetic influences on sleep.

Phasic respiratory pharyngeal mechanics by magnetic resonance imaging in lean and obese zucker rats.

RATIONALE: Although obstructive sleep apnea is strongly associated with obesity, we have little understanding of how obesity may alter the mechanical properties of the pharynx and the role of obesity in the pathogenesis of sleep apnea. OBJECTIVES: The overall objective of this study was to determine the effect of obesity on pharyngeal airway size and pharyngeal wall tissue strain in lean and obese Zucker rats. METHODS: Respiratory-gated magnetic resonance imaging with noninvasive tissue tagging was performed in anesthetized, spontaneously breathing lean (n = 9) and obese (n = 9) Zucker rats. Images acquired during expiration and inspiration of the rostral, mid-, and caudal pharynx were analyzed for airway size and pharyngeal wall tissue strain, using planimetry, optical flow, and finite element analyses. Differences in cross-sectional airway area, lateral and anteroposterior airway diameters, and tissue strain (stretch, compression, and direction of stretch) in the lateral and ventral pharyngeal walls were compared by analysis of variance (significance at p < 0.05). MEASUREMENTS AND MAIN RESULTS: Compared with their lean littermates, obese rats had the following significant findings: reduced pharyngeal airway cross-sectional area during inspiration and expiration, smaller increases in airway area during inspiration, and decreased lateral airway dilation during inspiration. Tissue strain in the pharyngeal walls showed no significant differences between obese and lean rats. CONCLUSIONS: These findings suggest that obesity results in a mechanical abnormality that decreases pharyngeal airway size and prevents a normal airway response to a given change in pharyngeal wall tissue strain.

Screening for risk of rehospitalization from home care: use of the outcomes assessment information set and the probability of readmission instrument.

The purpose of this study was to evaluate the Outcomes Assessment Information Set (OASIS) compared with the Probability of Readmission (P(ra)) instrument for use in predicting rehospitalization during home care. Using logistic regression and receiver operating characteristic (ROC) curve analysis, the P(ra) instrument was found to be significantly better at predicting rehospitalization than the OASIS case mix weight, clinical, or service scores. The area under the curve (AUC) for the P(ra) was .686 compared with .549 for the OASIS case mix weight (p =.010). Similar results were found for the OASIS clinical and service scores. The AUC for the function score of >/=2 (.599) provided the closest approximation to the P(ra) (.686), and the difference between the two was not statistically significant (p =.120). The OASIS function score could be used to identify at-risk home care patients without having to also use the P(ra) instrument.

Pharyngeal airway wall mechanics using tagged magnetic resonance imaging during medial hypoglossal nerve stimulation in rats.

To better understand pharyngeal airway mechanics as it relates to the pathogenesis and treatment of obstructive sleep apnoea, we have developed a novel application of magnetic resonance imaging (MRI) with non-invasive tissue tagging to measure pharyngeal wall tissue motion during active dilatation of the airway. Eleven anaesthetized Sprague-Dawley rats were surgically prepared with platinum electrodes for bilateral stimulation of the medial branch of the hypoglossus nerve that supplies motor output to the protrudor and intrinsic tongue muscles. Images of the pharyngeal airway were acquired before and during stimulation using a gated multislice, spoiled gradient recalled (SPGR) imaging protocol in a 4.7 T magnet. The tag pulses, applied before stimulation, created a grid pattern of magnetically imbedded dark lines that revealed tissue motion in images acquired during stimulation. Stimulation significantly increased cross-sectional area, and anteroposterior and lateral dimensions in the oropharyngeal and velopharyngeal airways when results were averaged across the rostral, mid- and caudal pharynx (P < 0.001). Customized software for tissue motion-tracking and finite element-analysis showed that changes in airway size were associated with ventral displacement of tissues in the ventral pharyngeal wall in the rostral, mid- and caudal pharyngeal regions (P < 0.0032) and ventral displacement of the lateral walls in the mid- and caudal regions (P < 0.0001). In addition, principal maximum stretch was significantly increased in the lateral walls (P < 0.023) in a ventral-lateral direction in the mid- and caudal pharyngeal regions and principal maximum compression (perpendicular to stretch) was significantly increased in the ventral walls in all regions (P < 0.0001). Stimulation did not cause lateral displacement of the lateral pharyngeal walls at any level. The results reveal that the increase in pharyngeal airway size resulting from stimulation of the medial branch of the hypoglossal nerve is predominantly due to ventral displacement of the ventral and lateral pharyngeal walls.

Enzymes of adenosine metabolism in the brain: diurnal rhythm and the effect of sleep deprivation.

Adenosine plays a role in promoting sleep, an effect that is thought to be mediated in the basal forebrain. Adenosine levels vary in this region with prolonged wakefulness in a unique way. The basis for this is unknown. We examined, in rats, the activity of the major metabolic enzymes for adenosine - adenosine deaminase, adenosine kinase, ecto- and cytosolic 5'-nucleotidase - in sleep/wake regulatory regions as well as cerebral cortex, and how the activity varies across the day and with sleep deprivation. There were robust spatial differences for the activity of adenosine deaminase, adenosine kinase, and cytosolic and ecto-5'-nucleotidase. However, the basal forebrain was not different from other sleep/wake regulatory regions apart from the tuberomammillary nucleus. All adenosine metabolic enzymes exhibited diurnal variations in their activity, albeit not in all brain regions. Activity of adenosine deaminase increased during the active period in the ventrolateral pre-optic area but decreased significantly in the basal forebrain. Enzymatic activity of adenosine kinase and cytosolic-5'-nucleotidase was higher during the active period in all brain regions tested. However, the activity of ecto-5'-nucleotidase was augmented during the active period only in the cerebral cortex. This diurnal variation may play a role in the regulation of adenosine in relationship to sleep and wakefulness across the day. In contrast, we found no changes specifically with sleep deprivation in the activity of any enzyme in any brain region. Thus, changes in adenosine with sleep deprivation are not a consequence of alterations in adenosine enzyme activity.