Mechanical loading modulates glutamate receptor subunit expression in bone.

The cellular mechanisms coupling mechanical loading with bone remodeling remain unclear. In the CNS, the excitatory amino acid glutamate (Glu) serves as a potent neurotransmitter exerting its effects via various membrane Glu receptors (GluR). Nerves containing Glu exist close to bone cells expressing functional GluRs. Demonstration of a mechanically sensitive glutamate/aspartate transporter protein and the ability of glutamate to stimulate bone resorption in vitro suggest a role for glutamate linking mechanical load and bone remodeling. We used immunohistochemical techniques to identify the expression of N-methyl-d-aspartate acid (NMDA) and non-NMDA (AMPA or kainate) ionotropic GluR subunits on bone cells in vivo. In bone sections from young adult rats, osteoclasts expressed numerous GluR subunits including AMPA (GluR2/3 and GluR4), kainic acid (GluR567) and NMDA (NMDAR2A, NMDAR2B and NMDAR2C) receptor subtypes. Bone lining cells demonstrated immunoexpression for NMDAR2A, NMDAR2B, NMDAR2C, GluR567, GluR23, GluR2 and GluR4 subunits. Immunoexpression was not evident on osteocytes, chondrocytes or vascular channels. To investigate the effects of mechanical loading on GluR expression, we used a Materials Testing System (MTS) to apply 10 N sinusoidal axial compressive loads percutaneously to the right limbs (radius/ulna, tibia/fibula) of rats. Each limb underwent 300-load cycles/day (cycle rate, 1 Hz) for 4 consecutive days. Contralateral, non-loaded limbs served as controls. Mechanically loaded limbs revealed a load-induced loss of immunoexpression for GluR2/3, GluR4, GluR567 and NMDAR2A on osteoclasts and NMDAR2A, NMDAR2B, GluR2/3 and GluR4 on bone lining cells. Both neonatal rabbit and rat osteoclasts were cultured on bone slices to investigate the effect of the NMDA receptor antagonist, MK801, and the AMPA/kainic acid receptor antagonist, NBQX, on osteoclast resorptive activity in vitro. The inhibition of resorptive function seen suggested that both NMDAR and kainic acid receptor function are required for normal osteoclast function. While the exact role of ionotropic GluRs in skeletal tissue remains unclear, the modulation of GluR subunit expression by mechanical loading lends further support for participation of Glu as a mechanical loading effector. These ionotropic receptors appear to be functionally relevant to normal osteoclast resorptive activity.

DNA microarray analysis of hippocampal gene expression measured twelve hours after hypoxia-ischemia in the mouse.

Cell death from cerebral ischemia is a dynamic process. In the minutes to days after an ischemic insult, progressive changes in cellular morphology occur. Associated with these events is the regulation of competing programs of gene expression; some are protective against ischemic insult, and others contribute to delayed cell death. Many genes involved in these processes have been identified, but individually, these findings have provided only limited insight into the systems biology of cerebral ischemia. Attempts to characterize the coordinated expression of large numbers of genes in cerebral ischemia has only recently become possible. Today, DNA microarray technology provides a powerful tool for investigating parallel expression changes for thousands of genes at one time. In this study, adult mice were subjected to 30 minutes of hypoxia-ischemia (HI), and the hippocampus was examined 12 hours later for differential gene expression using a 15K high-density mouse EST array. The genomic response to HI is complex, affecting approximately 7% of the total number of ESTs examined. Assigning differentially expressed ESTs to molecular functional groups revealed that HI affects many pathways including the molecular chaperones, transcription factors, kinases, and calcium ion binding genes. A comprehensive list of regulated genes should prove valuable in advancing our understanding of the pathogenesis of cerebral ischemia.

Analysis of hospital discharge data to characterize obstructive sleep apnea and its management in adult patients hospitalized in Canada: 2006 to 2007.

BACKGROUND: Diagnosed obstructive sleep apnea (OSA) affects 2% to 7% of middle-age persons worldwide and represents a substantial health care burden. The gold standard for treating OSA in adults is continuous positive airway pressure (CPAP) therapy. Compliance with this treatment is especially important in OSA patients experiencing concomitant acute and chronic disease or illness, and those undergoing procedures associated with sedation, analgesia and anesthesia. OBJECTIVE: To describe the clinical characteristics and management of hospitalized OSA patients in Canada. METHODS: Using the Canadian Institute for Health Information's hospital Discharge Abstract Database (fiscal year 2006/2007), a retrospective cohort study of all acute care patients discharged with a diagnosis that included OSA was performed. RESULTS: An examination of the discharge data of 2,400,245 acute care hospital abstracts identified 8823 cases of OSA. The mean age of OSA patients was 45.7 years and 66.5% were men. The most common comorbidities in the adult OSA population were obesity, cardiovascular disease, type 2 diabetes mellitus and chronic obstructive pulmonary disease. In adult OSA patients, the reported surgical intervention rate using uvulopalatopharyngoplasty (9.6%) was much higher than interventional CPAP therapy (4.8%). CONCLUSIONS: Only a small percentage of hospitalized OSA patients were documented as having received CPAP therapy during their stay. Issues relating to the accuracy, specificity and completeness of the Canadian Institute for Health Information's hospital Discharge Abstract Database specific to OSA and its management were identified. Practices pertaining to the reporting, coding and management of hospitalized adult OSA patients warrant further investigation and research.

Prevalence of unspecified sleep apnea and the use of continuous positive airway pressure in hospitalized patients, 2004 National Hospital Discharge Survey.

Diagnosed obstructive sleep apnea affects 2-4% of middle aged Americans and represents a substantial health care burden. Despite its prevalence, little is known about the demographic characteristics or clinical management of sleep apnea patients hospitalized for other comorbidities and surgeries. The aim of this study was to provide a broad characterization of the epidemiology of sleep apnea in hospitalized patients in the United States and to describe the trends in the management of their sleep apnea during their hospitalizations. Using the 2004 National Hospital Discharge Survey (NHDS), a nationally representative sample of discharges from nonfederal acute care hospitals in the United States, cases of sleep apnea were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The specific objectives of this study were to: (1) describe the prevalence of hospitalized unspecified sleep apnea individuals according to age, gender, and comorbidities; (2) estimate prevalence of the use of continuous positive airway pressure (CPAP) therapy during hospitalization and describe those uses according to hospital ownership and size. A retrospective analysis of data of hospitalized patients with unspecified sleep apnea from the 2004 National Hospital Discharge Survey (NHDS) was completed. In 2004, the NHDS collected data for approximately 371,000 discharges from a sample of 439 nonfederal short-stay hospitals. An estimated 34.9 million inpatients were discharged from nonfederal short-stay hospitals in 2004. Patients diagnosed with unspecified sleep apnea were identified using the International Classification of Diseases (Ninth Revision), Clinical Modification (ICD-9-CM) code of 780.57, which, before 2005, was the sole diagnostic code under which obstructive sleep apnea was listed. A subset of these patients, those receiving CPAP therapy, was further identified using the ICD-9-CM procedural code 93.90. Review of weighted discharge data identified a total of 293,478 estimated cases of unspecified sleep apnea. Approximately 64% of these individuals were between the ages 40 and 69 years old with a gender distribution of 55.3% males. The most common diagnoses in hospitalized sleep apnea patients were morbid obesity, congestive heart failure, coronary artery disease, exacerbation of COPD, and pneumonia. Sleep apnea was managed through the standardized therapy, CPAP, in 5.8% of hospitalized patients and CPAP therapy was more likely to be utilized in sleep apnea patients hospitalized in a government hospital than in a for-profit hospital. In conclusion, only a small percentage (5.8%) of patients diagnosed with unspecified sleep apnea in the 2004 NHDS were provided with CPAP therapy during hospitalization. There appear to be institutional differences in the utilization of CPAP therapy in hospitals across the United States. These findings suggest that in the United States, the management of sleep apnea in hospitalized patients is deficient, and the use of CPAP therapy in the hospital warrants further investigation.