Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats.

OBJECTIVE Sleep disruption in the acute phase after stroke has detrimental effects on recovery in both humans and animals. Conversely, the effect of sleep promotion remains unclear. Baclofen (Bac) is a known non-rapid eye movement (NREM) sleep-promoting drug in both humans and animals. The aim of this study was to investigate the effect of Bac on stroke recovery in a rat model of focal cerebral ischemia (isch). METHODS Rats, assigned to three experimental groups (Bac/isch, saline/isch, or Bac/sham), were injected twice daily for 10 consecutive days with Bac or saline, starting 24 h after induction of stroke. The sleep-wake cycle was assessed by EEG recordings and functional motor recovery by single pellet reaching test (SPR). In order to identify potential neuroplasticity mechanisms, axonal sprouting and neurogenesis were evaluated. Brain damage was assessed by Nissl staining. RESULTS Repeated Bac treatment after ischemia affected sleep, motor function, and neuroplasticity, but not the size of brain damage. NREM sleep amount was increased significantly during the dark phase in Bac/isch compared to the saline/isch group. SPR performance dropped to 0 immediately after stroke and was recovered slowly thereafter in both ischemic groups. However, Bac-treated ischemic rats performed significantly better than saline-treated animals. Axonal sprouting in the ipsilesional motor cortex and striatum, and neurogenesis in the peri-infarct region were significantly increased in Bac/isch group. CONCLUSION Delayed repeated Bac treatment after stroke increased NREM sleep and promoted both neuroplasticity and functional outcome. These data support the hypothesis of the role of sleep as a modulator of poststroke recovery.

Baclofen and gamma-hydroxybutyrate differentially altered behavior, EEG activity and sleep in rats.

OBJECTIVES Animal and human studies have shown that sleep may have an impact on functional recovery after brain damage. Baclofen (Bac) and gamma-hydroxybutyrate (GHB) have been shown to induce physiological sleep in humans, however, their effects in rodents are unclear. The aim of this study is to characterize sleep and electroencelphalogram (EEG) after Bac and GHB administration in rats. We hypothesized that both drugs would induce physiological sleep. METHODS Adult male Sprague-Dawley rats were implanted with EEG/electromyogram (EMG) electrodes for sleep recordings. Bac (10 or 20 mg/kg), GHB (150 or 300 mg/kg) or saline were injected 1 h after light and dark onset to evaluate time of day effect of the drugs. Vigilance states and EEG spectra were quantified. RESULTS Bac and GHB induced a non-physiological state characterized by atypical behavior and an abnormal EEG pattern. After termination of this state, Bac was found to increase the duration of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep (∼90 and 10 min, respectively), reduce sleep fragmentation and affect NREM sleep episode frequency and duration (p<0.05). GHB had no major effect on vigilance states. Bac drastically increased EEG power density in NREM sleep in the frequencies 1.5-6.5 and 9.5-21.5 Hz compared to saline (p<0.05), while GHB enhanced power in the 1-5-Hz frequency band and reduced it in the 7-9-Hz band. Slow-wave activity in NREM sleep was enhanced 1.5-3-fold during the first 1-2 h following termination of the non-physiological state. The magnitude of drug effects was stronger during the dark phase. CONCLUSION While both Bac and GHB induced a non-physiological resting state, only Bac facilitated and consolidated sleep, and promoted EEG delta oscillations thereafter. Hence, Bac can be considered a sleep-promoting drug and its effects on functional recovery after stroke can be evaluated both in humans and rats.

Adaptive servo-ventilation as treatment of persistent central sleep apnea in post-acute ischemic stroke patients.

BACKGROUND Adaptive servo-ventilation (ASV) is a well-established treatment of central sleep apnea (CSA) related to congestive heart failure (CHF). Few studies have evaluated the effectiveness and adherence in patients with CSA of other etiologies, and even less is known about treatment of CSA in patients of post ischemic stroke. METHODS A single-centre retrospective analysis of ASV treatment for CSA in post-acute ischemic stroke patients without concomitant CHF was performed. Demographics, clinical data, sleep studies, ventilator settings, and adherence data were evaluated. RESULTS Out of 154 patients on ASV, 15 patients had CSA related to ischemic stroke and were started on ASV a median of 11 months after the acute cerebrovascular event. Thirteen out of the 15 patients were initially treated with continuous positive airway pressure (11/15) and bilevel positive airway pressure (2/15) therapy with unsatisfactory control of CSA. ASV significantly improved AHI (46.7 ± 24.3 vs 8.5 ± 12/h, P = 0.001) and reduced ESS (8.7 ± 5.7 vs 5.6 ± 2.5, P = 0.08) with a mean nightly use of ASV of 5.4 ± 2.4 h at 3 months after the initiation of treatment. Results were maintained at 6 months. CONCLUSION ASV was well tolerated and clinically effective in this group of patients with persistent CSA after ischemic stroke.

Sleep disordered breathing and vascular function in patients with chronic mountain sickness and healthy high-altitude dwellers.

Background Chronic mountain sickness (CMS) is often associated with vascular dysfunction, but the underlying mechanism is unknown. Sleep disordered breathing (SDB) frequently occurs at high altitude. At low altitude SDB causes vascular dysfunction. Moreover, in SDB, transient elevations of right-sided cardiac pressure may cause right-to-left shunting in the presence of a patent foramen ovale (PFO) and, in turn, further aggravate hypoxemia and pulmonary hypertension. We speculated that compared to healthy high-altitude dwellers, in patients with CMS, SDB and nocturnal hypoxemia are more pronounced and related to vascular dysfunction. Methods We performed overnight sleep recordings, and measured systemic and pulmonary-artery pressure in 23 patients with CMS (mean±SD age 52.8±9.8 y) and 12 healthy controls (47.8±7.8 y) at 3600 m. In a subgroup of 15 subjects with SDB, we searched for PFO with transesophagal echocardiography. Results The major new findings were that in CMS patients, a) SDB and nocturnal hypoxemia was more severe (P<0.01) than in controls (apnea/hypopnea index, AHI, 38.9±25.5 vs. 14.3±7.8[nb/h]; SaO2, 80.2±3.6 vs. 86.8±1.7[%], CMS vs. controls), and b) AHI was directly correlated with systemic blood pressure (r=0.5216, P=0.001) and pulmonary-artery pressure (r=0.4497, P=0.024). PFO was associated with more severe SDB (AHI 48.8±24.7 vs. 14.8±7.3[nb/h], P=0.013, PFO vs. no PFO) and hypoxemia. Conclusion SDB and nocturnal hypoxemia are more severe in CMS patients than in controls and are associated with systemic and pulmonary vascular dysfunction. The presence of a PFO appeared to further aggravate SDB. Closure of PFO may improve SDB, hypoxemia and vascular dysfunction in CMS patients. Clinical Trials Gov Registration NCT01182792.

Physician and patient determinants of the treatment of sleep difficulties in U.S. outpatient settings

The prevalence of sleep difficulties among the patients seen in the primary care settings is about 30%. This problem increases with age and is more common among females than males. Variations are noticed in prescription choices for different patients with sleep difficulties. Many factors affect a physician's prescription decision while chosen from a wide array of available medications. Both pharmacological and behavioral therapies are available for the treatment of sleep difficulties. It is important to know the impact of use of different types of prescriptions on health outcomes related to sleep difficulties. Thus the knowledge of prescription patterns among different types of patients (e.g. age, gender, race, insurance type etc.) becomes important for determining a clinical guideline. This study is designed to assist in evidence-based policymaking on understanding the variations in physician prescriptions for sleep difficulties and reasons for such variations. ^ A modified version of the model suggested by Eisenberg was used as a theoretical framework for this study to predict the factors influencing treatment of sleep difficulties. Multivariate logistic regression methods were used to analyze the 1996–2001 National Ambulatory Medical Care Survey data. ^ This study found that increased age, female gender, white race, established patients, and mental comorbidity were associated with significantly increased likelihood for prescription of some type of therapy for sleep difficulties in US outpatient settings. Patients with private insurance were associated with lower likelihood of receipt of many therapies. Psychiatrists were more likely to prescribe some kind of treatment as well as more expensive therapies for sleep difficulty as compared to other physician specialties. HMO enrolled patient visits were more likely to be associated with receipt of behavioral therapy. This study also found that 32% of patients with sleep difficulties received no type of therapy during their visits. Only 5% of the patients received behavioral therapy only. Almost three-quarters of the patients receiving some kind of medication prescription were prescribed benzodiazepines. The study results also suggest a need for wider coverage of behavioral therapy by payers in US outpatient settings. ^

Sleep quality and quantity and associated factors among high school students from south Texas

Background. Insufficient and poor quality sleep among adolescents affects not only the cognitive functioning, but overall health of the individual. Existing research suggests that adolescents from varying ethnic groups exhibit differing sleep patterns. However, little research focuses on sleep patterns and associated factors (i.e. tobacco use, mental health indicators) among Hispanic youth. ^ Methods. The study population (n=2,536) included students in grades 9-12 who attended one of the three public high schools along the Texas-Mexico border in 2003. This was a cross sectional study using secondary data collected via a web-based, confidential, self-administered survey. Separate logistic regression models were estimated to identify factors associated with reduced (<9 hours/night) and poor quality sleep on average during weeknights. ^ Results. Of participants, 49.5% reported reduced sleep while 12.8% reported poor quality sleep. Factors significantly (p<0.05) associated with poor quality sleep were: often feeling stressed or anxious (OR=5.49), being born in Mexico (OR=0.65), using a computer/playing video games 15+ hours per week (OR=2.29), working (OR=1.37), being a current smoker (OR=2.16), and being a current alcohol user (OR=1.64). Factors significantly associated with reduced quantity of sleep were: often feeling stressed or anxious (OR=2.74), often having headaches/stomachaches (OR=1.77), being a current marijuana user (OR=1.70), being a current methamphetamine user (OR=4.92), and being a current alcohol user (OR=1.27). ^ Discussion. Previous research suggests that there are several factors that can influence sleep quality and quantity in adolescents. This paper discusses these factors (i.e. work, smoking, alcohol, etc.) found to be associated with poor sleep quality and reduced sleep quantity in the Hispanic adolescent population. A reduced quantity of sleep (81.20% of the participants) and a poor quality of sleep (12.80% of the participants) were also found in high school students from South Texas. ^

Comparison of methods for assessing in home night time crying in healthy infants

Background. Infant colic is a common condition that is thought to put infants at risk for Shaken Baby Syndrome, a particularly devastating form of child abuse. However, little research has been done on techniques parents can use to deal with infant colic. This pilot study was conducted to assess the equipment that will be used in a randomized control trial that will compare the results for two different techniques that parents can use to reduce crying in infants with colic. ^ Methods. A total of 11 healthy infants, between one and five months of age, were recruited into this pilot study. All infants had a dosimeter, actiwatch and maternal log placed into the home and a subset of infants (N=3) were also recorded by a video camera. The equipment recorded between 6pm and 6am for at least two and up to five nights. The maternal log and video log were compared with one another to determine if the maternal log provides an accurate representation of the infant's night-time activities (i.e. sleep, awake, crying, feeding). The maternal log was then compared to the dosimeter and actiwatch data to determine if the dosimeter/actiwatch accurately reproduce the maternal log. ^ Results. Data from 10 infants were included in the analyses. The maternal log and video log were in full or partial agreement 90% of the time. When comparing events noted by the mother, the maternal log and dosimeter data were in agreement 84% of the time, and the maternal log and actiwatch data were in agreement 87% of the time. In combination, the dosimeter and/or actiwatch data agreed with the maternal log 90% of the time. ^ Conclusions. Our preliminary analyses of these data suggest the dosimeter and actiwatch will be useful tool for defining infant sleep patterns relative to the maternal log. However further analysis will be required to develop threshold values that can be used to objectively define events in the proposed RCT. Such analyses will need to integrate data from multiple dosimeters and deal with the shifting baselines observed for both the dosimeter and actiwatch.^

Sleep-wake disorders persist 18 months after traumatic brain injury but remain underrecognized

OBJECTIVE This study is a prospective, controlled clinical and electrophysiologic trial examining the chronic course of posttraumatic sleep-wake disturbances (SWD). METHODS We screened 140 patients with acute, first-ever traumatic brain injury of any severity and included 60 patients for prospective follow-up examinations. Patients with prior brain trauma, other neurologic or systemic disease, drug abuse, or psychiatric comorbidities were excluded. Eighteen months after trauma, we performed detailed sleep assessment in 31 participants. As a control group, we enrolled healthy individuals without prior brain trauma matched for age, sex, and sleep satiation. RESULTS In the chronic state after traumatic brain injury, sleep need per 24 hours was persistently increased in trauma patients (8.1 ± 0.5 hours) as compared to healthy controls (7.1 ± 0.7 hours). The prevalence of chronic objective excessive daytime sleepiness was 67% in patients with brain trauma compared to 19% in controls. Patients significantly underestimated excessive daytime sleepiness and sleep need, emphasizing the unreliability of self-assessments on SWD in trauma patients. CONCLUSIONS This study provides prospective, controlled, and objective evidence for chronic persistence of posttraumatic SWD, which remain underestimated by patients. These results have clinical and medicolegal implications given that SWD can exacerbate other outcomes of traumatic brain injury, impair quality of life, and are associated with public safety hazards.

Sleep-disordered breathing among acute ischemic stroke patients in Brazil.

OBJECTIVES Sleep-disordered breathing (SDB) is very common in acute stroke patients and has been related to poor outcome. However, there is a lack of data about the association between SDB and stroke in developing countries. The study aims to characterize the frequency and severity of SDB in Brazilian patients during the acute phase of ischemic stroke; to identify clinical and laboratorial data related to SDB in those patients; and to assess the relationship between sleep apnea and functional outcome after six months of stroke. METHODS Clinical data and laboratorial tests were collected at hospital admission. The polysomnography was performed on the first night after stroke symptoms onset. Functional outcome was assessed by the modified Rankin Scale (mRS). RESULTS We prospectively evaluated 69 patients with their first-ever acute ischemic stroke. The mean apnea-hypopnea index (AHI) was 37.7 ± 30.2. Fifty-three patients (76.8%) exhibited an AHI ≥ 10 with predominantly obstructive respiratory events (90.6%), and thirty-three (47.8%) had severe sleep apnea. Age (OR: 1.09; 95% CI: 1.03-1.15; p= 0.004) and hematocrit (OR: 1.18; 95% CI: 1.03-1.34; p= 0.01) were independent predictors of sleep apnea. Age (OR: 1.13; 95% CI: 1.03-1.24; p= 0.01), body mass index (OR: 1.54; 95% CI: 1.54-2.18; p= 0.01), and hematocrit (OR: 1.19; 95% CI: 1.01-1.40; p= 0.04) were independent predictors of severe sleep apnea. The National Institutes of Health Stroke Scale (NIHSS; OR: 1.30; 95% CI: 1.1-1.5; p= 0.001) and severe sleep apnea (OR: 9.7; 95% CI: 1.3-73.8; p= 0.03) were independently associated to mRS >2 at six months, after adjusting for confounders. CONCLUSION Patients with acute ischemic stroke in Brazil have a high frequency of SDB. Severe sleep apnea is associated with a poor long-term functional outcome following stroke in that population.

The High Frequency Component of Heart Rate Variability and Delta EEG Power during Sleep in Healthy Women and Women with Irritable Bowel Syndrome

Thesis (Ph.D.)--University of Washington, 2016-06

Sleep Patterns and Parents’ Experience in Caring for Young Children Newly Diagnosed with Juvenile Idiopathic Arthritis

Thesis (Ph.D.)--University of Washington, 2016-05

Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer

Purpose: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. Methods: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. Results: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. Conclusion: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo-adjuvant MAD was not perceived by patients to be a major inconvenience. If neo-adjuvant MAD in the way tested can be demonstrated to lead to improved biochemical control and/or survival, then patients would view these therapeutic gains as worthwhile. Compliance with short-term goserelin was excellent, confirming that LH-RH analogues have a potential role in more long-term adjuvant treatment. However, for more protracted androgen deprivation, survival advantages and deleterious effects need to be assessed in parallel, in order to determine the optimal duration of treatment. (C) 2003 Elsevier Ireland Ltd. All fights reserved.

Equine laminitis: glucose deprivation and MMP activation induce dermo-epidermal separation in vitro

Reasons for performing study: Acute laminitis is characterised by hoof lamellar dermal-epidermal separation at the basement membrane (BM) zone. Hoof lamellar explants cultured in vitro can also be made to separate at the basement membrane zone and investigating how this occurs may give insight into the poorly understood pathophysiology of laminitis. Objectives: To investigate why glucose deprivation and metalloproteinase (MMP) activation in cultured lamellar explants leads to dermo-epidermal separation. Methods: Explants, cultured without glucose or with the MMP activator p-amino-phenol-mercuric acetate (APMA), were subjected to tension and processed for transmission electron microscopy (TEM). Results: Without glucose, or with APMA, explants under tension separated at the dermo-epidermal junction. This in vitro separation occurred via 2 different ultrastructural processes. Lack of glucose reduced hemidesmosomes (HDs) numbers until they disappeared and the basal cell cytoskeleton collapsed. Anchoring filaments (AFs), connecting the basal cell plasmalemma to the BM, were unaffected although they failed under tension. APMA activation of constituent lamellar MMPs did not affect HDs but caused AFs to disappear, also leading to dermo-epidermal separation under tension. Conclusions: Natural laminitis may occur in situations where glucose uptake by lamellar basal cells is compromised (e.g. equine Cushing's disease, obesity, hyperlipaemia, ischaemia and septicaemia) or when lamellar MMPs are activated (alimentary carbohydrate overload). Potential relevance: Therapies designed to facilitate peripheral glucose uptake and inhibit lamellar MMP activation may prevent or ameliorate laminitis.

Frequency of insomnia report in patients with obstructive sleep apnoea hypopnea syndrome (OSAHS)

Background and purpose: Insomnia and Obstructive Sleep Apnoea Hypopnea Syndrome (OSAHS) are the two most common sleep disorders, and both have significant associated health costs. Despite this, relatively little is known about the prevalence or impact of insomnia in those with OSAHS, although a recent study suggested there may be substantial comorbidity between these disorders [Chest 120 (2001) 1923-9]. The primary aim of this study was to further explore the prevalence of insomnia in OSAHS. A secondary aim was to assess the effect of factors that may impact on both conditions, including mood and sleep-beliefs. Patients and methods: Consecutive patients referred to an accredited Sleep Investigations Unit (n = 105) completed a brief standardized battery of validated questionnaires assessing sleep-related variables and mood. Results: Results showed a high rate of prevalence of clinical insomnia in this OSAHS population, and a strong positive correlation between OSAHS and insomnia symptom severity. Further, OSAHS patients with comorbid insomnia had increased levels of depression, anxiety and stress compared to patients with OSAHS-only, and both patient groups reported similar and significant levels of dysfunctional beliefs about sleep. Findings in relation to habitual sleep, assessed using subjective (diary) and objective criteria (polysomnogram), were mixed but generally showed greater sleep disturbance among those with OSAHS-insomnia compared to those with OSAHS-only. Conclusions: Overall these findings suggest that comorbidity of insomnia in OSAHS patients may lead to increased OSAHS severity and that patients with both conditions may experience more symptoms relating to depression, anxiety and stress. These findings underscore the need for insomnia assessment and management services, even in clinics that primarily service patients with OSAHS. (C) 2004 Elsevier B.V. All rights reserved.

Two new tools for assessing patients' knowledge and beliefs about obstructive sleep apnea and continuous positive airway pressure therapy

Background and purpose: Patients' knowledge and beliefs about their illnesses are known to influence a range of health related variables, including treatment compliance. It may, therefore, be important to quantify these variables to assess their impact on compliance, particularly in chronic illnesses such as Obstructive Sleep Apnea (OSA) that rely on self-administered treatments. The aim of this study was to develop two new tools, the Apnea Knowledge Test (AKT) and the Apnea Beliefs Scale (ABS), to assess illness knowledge and beliefs in OSA patients. Patients and methods: The systematic test construction process followed to develop the AKT and the ABS included consultation with sleep experts and OSA patients. The psychometric properties of the AKT and ABS were then investigated in a clinical sample of 81 OSA patients and 33 healthy, non-sleep disordered adults. Results: Results suggest both measures are easily understood by OSA patients, have adequate internal consistency, and are readily accepted by patients. A preliminary investigation of the validity of these tools, conducted by comparing patient data to that of the 33 healthy adults, revealed that apnea patients knew more about OSA, had more positive attitudes towards continuous positive airway pressure (CPAP) treatment, and attributed more importance to treating sleep disturbances than non-clinical groups. Conclusions: Overall, the results of psychometric analyses of these tests suggest these measures will be useful clinical tools with numerous beneficial applications, particularly in CPAP compliance studies and apnea education program evaluations. (C) 2004 Elsevier B.V. All rights reserved.