Diagnosing and managing sleep apnea in patients with chronic cerebrovascular disease: a randomized trial of a home-based strategy.

BACKGROUND: Obstructive sleep apnea is common and associated with poor outcomes after stroke or transient ischemic attack (TIA). We sought to determine whether the intervention strategy improved sleep apnea detection, obstructive sleep apnea (OSA) treatment, and hypertension control among patients with chronic cerebrovascular disease and hypertension. METHODS: In this randomized controlled strategy trial intervention, patients received unattended polysomnography at baseline, and patients with OSA (apnea-hypopnea index ≥5 events/h) received auto-titrating continuous positive airway pressure (CPAP) for up to 1 year. Control patients received usual care and unattended polysomnography at the end of the study, to identify undiagnosed OSA. Both groups received 24-h blood pressure assessments at baseline and end of the study. "Excellent" CPAP adherence was defined as cumulative use of ≥4 h/night for ≥70% of the nights. RESULTS: Among 225 randomized patients (115 control; 110 intervention), 61.9% (120/194) had sleep apnea. The strategy successfully diagnosed sleep apnea with 97.1% (102/105) valid studies; 90.6% (48/53, 95% CI 82.7-98.4%) of sleep apnea was undiagnosed among control patients. The intervention improved long-term excellent CPAP use: 38.6% (22/57) intervention versus 0% (0/2) control (p < 0.0001). The intervention did not improve hypertension control in this population with well-controlled baseline blood pressure: intervention, 132.7 mmHg (±standard deviation, 14.1) versus control, 133.8 mmHg (±14.0) (adjusted difference, -1.1 mmHg, 95% CI (-4.2, 2.0)), p = 0.48). CONCLUSIONS: Patients with cerebrovascular disease and hypertension have a high prevalence of OSA. The use of portable polysomnography, and auto-titrating CPAP in the patients' homes, improved both the diagnosis and the treatment for sleep apnea compared with usual care but did not lower blood pressure.

Metalloproteinase inhibition has differential effects on alloimmunity, autoimmunity, and histopathology in the transplanted lung.

BACKGROUND: Upregulation of matrix metalloproteinases (MMPs) has been associated with chronic lung allograft rejection known as bronchiolitis obliterans syndrome. It has been suggested that MMP inhibition could prevent the rejection response. However, the effect of MMP inhibition on lung allograft rejection has not been reported. METHODS: Utilizing a rat model of lung transplantation, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were overexpressed by gene therapy in F344 rat lung allografts prior to transplantation into WKY recipient rats. Separately, WKY rats that received F344 lung allografts were treated systemically with COL-3, a global MMP inhibitor. RESULTS: TIMP-1 and TIMP-2 had differential effects on delayed type hypersensitivity (DTH) responses to donor antigens and type V collagen, an autoantigen involved in the rejection response. Neither TIMP-1 or TIMP-2 affected the onset of rejection pathology. COL-3 suppressed DTH responses to donor antigens and type V collagen, abrogated local production of tumor necrosis factor-alpha, and interleukin-1beta. Although it did not prevent rejection pathology, COL-3 (30 mg/kg) induced intragraft B cell hyperplasia suggestive of posttransplant proliferative disorder (PTLD). CONCLUSIONS: These data identify a complex role for MMPs and TIMPs in the immunopathogenesis of lung allograft rejection, and indicate their effects are not limited to matrix remodeling.

Viscerosomatic interaction induced by myocardial ischemia in conscious dogs.

Studies tested the hypothesis that myocardial ischemia induces increased paraspinal muscular tone localized to the T(2)-T(5) region that can be detected by palpatory means. This is consistent with theories of manual medicine suggesting that disturbances in visceral organ physiology can cause increases in skeletal muscle tone in specific muscle groups. Clinical studies in manual and traditional medicine suggest this phenomenon occurs during episodes of myocardial ischemia and may have diagnostic potential. However, there is little direct evidence of a cardiac-somatic mechanism to explain these findings. Chronically instrumented dogs [12 neurally intact and 3 following selective left ventricular (LV) sympathectomy] were examined before, during, and after myocardial ischemia. Circumflex blood flow (CBF), left ventricular contractile function, electromyographic (EMG) analysis, and blinded manual palpatory assessments (MPA) of tissue over the transverse spinal processes at segments T(2)-T(5) and T(11)-T(12) (control) were performed. Myocardial ischemia was associated with a decrease in myocardial contractile function and an increase in heart rate. MPA revealed increases in muscle tension and texture/firmness during ischemia in the T(2)-T(5) segments on the left, but not on the right or in control segments. EMG demonstrated increased amplitude for the T(4)-T(5) segments. After LV sympathectomy, MPA and EMG evidence of increased muscle tone were absent. In conclusion, myocardial ischemia is associated with significant increased paraspinal muscle tone localized to the left side T(4)-T(5) myotomes in neurally intact dogs. LV sympathectomy eliminates the somatic response, suggesting that sympathetic neural traffic between the heart and somatic musculature may function as the mechanism for the interaction.

The influence of CPAP on the neurobehavioral performance of patients with obstructive sleep apnea hypopnea syndrome: a systematic review.

OBJECTIVE: To determine what is known about neurobehavioral outcomes in patients with the obstructive sleep apnea hypopnea syndrome following treatment with continuous positive airway pressure (CPAP). DATA SOURCES: Medline was searched. Abstracts presented at international meetings were searched and authors were contacted for additional trials. Bibliographies of the retrieved articles were reviewed. STUDY SELECTION: We reviewed all prospective studies that included: 1) a target population with obstructive sleep apnea, 2) CPAP as a study intervention, 3) evidence that the CPAP level was titrated until the AHI was < 5, and 4) standardized neurobehavioral outcomes appropriate for assessing sleep apnea. DATA SYNTHESIS: Twenty-six studies contributed to this qualitative systematic review. Effect sizes were calculated and adjusted for small samples and multiple measurements. Studies were then scored according to the outcome of the study. CONCLUSIONS: This qualitative systematic review supports the assertion that CPAP has a significant and positive impact on subjective sleepiness and depression when randomized controlled trials are considered, and on fatigue, generic health-related quality of life, vigilance, and driving performance when all prospective trials are considered. These parameters appear to be sensitive to treatment duration and compliance. These results should be considered when developing health policy and designing future clinical trials.

Diagnosis and Treatment of Sleep Apnea in patients' homes: the rationale and methods of the "GoToSleep" randomized-controlled trial.

BACKGROUND: The "Diagnosis and Treatment of Sleep Apnea in Cerebrovascular Disease" (GoToSleep) study is evaluating a strategy to improve the diagnosis and treatment of sleep apnea among veterans with stroke or transient ischemic attack (TIA) who also have hypertension. Specifically, the GoToSleep study was designed to overcome some of the barriers that exist within the Veterans Health Administration (VHA) to the timely diagnosis and treatment of sleep apnea by using ambulatory home-based polysomnography and auto-titrating continuous positive airway pressure (CPAP) to reduce the reliance on laboratory-based sleep studies. METHODS: The GoToSleep study is a prospective, multi-site, randomized, controlled strategy trial among an expected 318 veterans with cerebrovascular disease and hypertension who are assigned to an intervention group or a control group. Patients in the intervention group receive unattended polysomnography at baseline, and those with sleep apnea receive auto-titrating CPAP therapy for up to one year. Patients in the control group receive usual care and unattended polysomnography at the end of the study to identify the rate of undiagnosed sleep apnea. The primary objectives of the GoToSleep study are to determine whether a diagnostic and therapeutic intervention strategy among veterans with cerebrovascular disease and hypertension improves: (1) detection of sleep apnea; (2) appropriate treatment for sleep apnea; and (3) control of hypertension. Twenty-four-hour blood pressure assessments are made at baseline and at the end of the one-year study period for both groups. Antihypertensive medications and their doses are recorded at the time of the 24-hour blood pressure measurements. DISCUSSION: This manuscript provides the rationale for 4 key components of the design of the GoToSleep trial: the inclusion of patients with cerebrovascular disease and hypertension without the use of a measure of daytime sleepiness as an eligibility criterion; the use of portable polysomnography and auto-titrating CPAP in patients' homes rather than using sleep laboratory polysomnography with fixed pressure CPAP; the analytic approach to evaluating change in blood pressure in the context of change in antihypertensive medications; and the use of a usual care control group.

Paper persistence, workarounds, and communication breakdowns in computerized consultation management.

OBJECTIVE: The consultation request process between primary care and specialty services often contains paper-based components that may be inefficient and difficult to track. Other barriers may include workarounds and communication breakdowns with the potential to adversely impact delivery of quality medical care. We investigated current challenges to the electronic outpatient consult management process in the United States Veterans Health Administration (VHA). DESIGN: We conducted ethnographic observation and semi-structured interviews in nine different specialty clinics and three primary care clinics in a large, tertiary Veterans Affairs Medical Center (VAMC). We also performed a national-level query of 'electronic error and enhancement requests' (E3Rs) related to the consult package in the VA's electronic health record (EHR) submitted over a 5-year period (2005-2009). MEASUREMENTS: Two researchers recorded the observable interactions and interview responses of 16 healthcare workers related to their work with consultations. Two separate coding schemes were applied to both the observational and the interview data. E3Rs from the national query were reviewed and categorized based on the nature of the enhancement requests. RESULTS: We identified several examples of paper persistence, as well as workarounds, communication breakdowns, and redundancies in computerized consult management. An analysis of enhancement requests for the consults also revealed three broad needs related to reporting, configuration or customization, and user interface enhancements. CONCLUSION: Understanding these challenges to the current consult management process is important to help design enhanced informatics tools integrated into workflow to support coordination of care and tracking of consults requests.

Observations from chaotic analysis of sleep EEGs.

Chaotic analysis and modeling methods were applied to a small collection of healthy individuals' sleeping EEGs in order to establish whether a common representational space could be discovered for use in comparative analysis. Common challenges were encountered and dealt with in a practical manner. The methods used and the choices made in this effort are described herein. The authors observe and describe a common representation, obtained from a delay coordinate embedding, that should be usable for comparative analysis leading to clinical utility.

Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis.

Cytochrome P450 2E1 (CYP2E1) plays an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH) in animal models, but its role in the pathogenesis of human NASH is unclear. Therefore, we measured hepatic CYP2E1 activity and its correlates in a cohort of nondiabetic patients with NASH (NDN) and controls to explore its role in the pathogenesis of human NASH. Hepatic CYP2E1 activity was assessed using the oral clearance (CL(PO)) of chlorzoxazone (CHZ) in 20 NDN and 17 age, gender, and body mass index (BMI)-matched controls. The relationship between hepatic CYP2E1 activity and demographic and anthropometric variables; fasting levels of insulin, glucose, lipids, and beta-OH butyrate; insulin resistance; and nocturnal hypoxemia was assessed. Furthermore, expression of CYP2E1 in the peripheral lymphocytes was assessed using reverse transcription-polymerase chain reaction (RT-PCR). The CL(PO) of CHZ was significantly (P =.03) greater in NDN (41 +/- 12 L/h) compared with controls (33 +/- 16 L/h). Lymphocyte CYP2E1 messenger RNA was significantly higher in NDN compared with controls (11.5 x 10(3) +/- 10 x 10(3) vs. 2.6 x 10(3) +/- 1.2 x 10(3) molecules/microg total RNA, respectively, P <.001). On univariate analysis, BMI, respiratory quotient, high-density lipoprotein, triglycerides, insulin, insulin resistance, hypoxemia, and beta-OH butyrate significantly correlated with hepatic CYP2E1 activity. However, on stepwise regression analysis, only nocturnal hypoxemia (r = 0.50, P =.009) and beta-OH butyrate (r = 0.37, P =.04) were independent predictors of hepatic CYP2E1 activity. In conclusion, hepatic CYP2E1 activity and lymphocyte CYP2E1 expression are enhanced in NDN. The significant correlations noted between CYP2E1 and hypoxemia and beta-OH butyrate suggest that these factors play a role in increased CYP2E1 activity that is seen in patients with NASH.

Olfactory system activation from sniffing: effects in piriform and orbitofrontal cortex.

Neuroimaging studies suggest that piriform cortex is activated at least in part by sniffing. We used H(2)(15)O positron emission tomography (PET) to study 15 healthy volunteers while they participated in four conditions, two of which were sniffing odorants and odorless air. The remaining two conditions involved a constant, very low flow of either odorized or odorless air during velopharyngeal closure (VPC), a technique that prevents subject-induced airflow through the nasal passages. Contrary to expectation, sniffing under odorless conditions did not induce significant piriform and surrounding cortical (PC+) activity when compared to odorless VPC, even at a liberal statistical threshold. However, a small correlation emerged in PC+ between the difference signal of [odorless sniffing - odorless VPC] and peak rate of nasal pressure change. PC+ activity was, however, strongly evoked by odorant exposure during sniffing and VPC, with neither technique showing greater activation. Activity in orbitofrontal (olfactory association) cortex was absent during odorant stimulation (OS) with VPC, but present during odorant sniffing. Sniffing may therefore play an important role in facilitating the higher-order analysis of odors. A right orbitofrontal region was also activated with odorless sniffing, which suggests a possible orbitofrontal role in guided olfactory exploration.

Macrophages exposed to lymphotropic and monocytotropic HIV induce similar CTL responses despite differences in productive infection.

Macrophages are accessory cells that are vulnerable to infection by HIV-1. HTLV-IIIB, a lymphotropic strain of HIV, infects macrophages poorly resulting in either no or low levels of virus expression compared to high levels of productive infection after exposure of macrophages to the monocytotropic HIV strain Ada-M. Whether this results in an impaired ability of HTLV-IIIB-exposed macrophages to initiate protective cytotoxic T lymphocyte (CTL) immune responses against these strains is not well defined. We investigated the ability of monocyte-derived macrophages (MDM) exposed to lymphotropic and monocytotropic HIV strains to initiate primary CTL responses in vitro. MDM exposed to HTLV-IIIB induced a specific primary CTL response that was comparable to MDM exposed to the monocytotropic strain Ada-M despite marked differences in productive HIV infection in MDM between the two strains. CTL generated in this model were MHC-restricted, strain-specific, and CD8+. These data demonstrate that high levels of productive HIV infection in accessory cells are not a prerequisite for the generation of a primary CTL response, suggesting a novel immunologic interaction between MDM and lymphotropic HIV strains.