Early out-of-hospital non-invasive ventilation is superior to standard medical treatment in patients with acute respiratory failure: a pilot study.

OBJECTIVE: To assess in patients with acute respiratory failure (ARF) whether out-of-hospital (OOH) non-invasive ventilation (NIV) is feasible, safe and more effective compared with standard medical therapy (SMT). PATIENTS AND INTERVENTIONS: Patients with OOH ARF were randomly assigned to receive either SMT or NIV. MEASUREMENTS AND RESULTS: Fifty-one patients were enrolled, 26 of whom were randomly assigned to SMT and 25 of whom received NIV. Two patients were excluded because of protocol violations. OOH NIV was safe and effective in all patients. In the SMT group, treatment was not effective in five of 25 patients who required OOH mechanical ventilation (p=0.05). Patients in the SMT group were admitted to an intensive care unit (ICU) more frequently (n=17) (p<0.05) and for longer periods (3.7±6.4 days) (p=0.03) compared with patients in the NIV group (n=9, 1.3±2.6 days). Six patients in the SMT group required subsequent inhospital intubation and invasive ventilation during their hospital stays; only one patient in the NIV group required intubation (p=0.10). In contrast, patients in the NIV group received NIV more frequently (n=14) in hospital compared with patients in the SMT group (n=5) (p<0.01). CONCLUSIONS: OOH NIV proved to be feasible, safe and more effective for the treatment of ARF compared with SMT. OOH NIV promotes inhospital treatment with NIV and may reduce the frequency and length of ICU stays. Because the risks of OOH emergency intubation can be avoided, NIV should be the first-line treatment in OOH ARF if no contraindications are present.

Racial disparities in blood pressure control and treatment differences in a Medicaid population, North Carolina, 2005-2006.

INTRODUCTION: Racial disparities in prevalence and control of high blood pressure are well-documented. We studied blood pressure control and interventions received during the course of a year in a sample of black and white Medicaid recipients with high blood pressure and examined patient, provider, and treatment characteristics as potential explanatory factors for racial disparities in blood pressure control. METHODS: We retrospectively reviewed the charts of 2,078 black and 1,436 white North Carolina Medicaid recipients who had high blood pressure managed in primary care practices from July 2005 through June 2006. Documented provider responses to high blood pressure during office visits during the prior year were reviewed. RESULTS: Blacks were less likely than whites to have blood pressure at goal (43.6% compared with 50.9%, P = .001). Blacks above goal were more likely than whites above goal to have been prescribed 4 or more antihypertensive drug classes (24.7% compared with 13.4%, P < .001); to have had medication adjusted during the prior year (46.7% compared with 40.4%, P = .02); and to have a documented provider response to high blood pressure during office visits (35.7% compared with 30.0% of visits, P = .02). Many blacks (28.0%) and whites (34.3%) with blood pressure above goal had fewer than 2 antihypertensive drug classes prescribed. CONCLUSION: In this population with Medicaid coverage and access to primary care, blacks were less likely than whites to have their blood pressure controlled. Blacks received more frequent intervention and had greater use of combination antihypertensive therapy. Care patterns observed in the usual management of high blood pressure were not sufficient to achieve treatment goals or eliminate disparities.

Localization and MHC class II presentation of antigens targeted for macroautophagy.

Intracellular antigens can be presented on major histocompatibility complex (MHC) class II molecules after degradation via macroautophagy. To enhance MHC class II presentation of potential vaccine antigens, we have developed a method to target antigens for autophagic degradation via fusion to the Atg8/LC3 protein: Atg8/LC3 is specifically incorporated into autophagosomes via coupling to phosphatidylethanolamine, and subsequently degraded in MHC class II loading compartments (MIICs). Antigens fused to the N-terminus of Atg8/LC3 follow the same pathway and get preferentially presented on MHC class II molecules. The localization of Atg8/LC3 fusion antigens in MIICs can be visualized by confocal microscopy, and MHC class II presentation can be quantified in a presentation assay with antigen-specific CD4(+) T-cell clones. These assays are good measures of autophagosome formation and lysosomal degradation of macroautophagy cargo and therefore are useful for studying regulation of the autophagic pathway under various experimental conditions and physiological perturbations.

Autophagy in innate and adaptive immunity against intracellular pathogens.

Autophagy delivers cytoplasmic constituents for lysosomal degradation. Recent studies have demonstrated that this pathway mediates resistance to pathogens and is targeted for immune evasion by viruses and bacteria. Lysosomal degradation products, including pathogenic determinants, are then surveyed by the adaptive immune system to elicit antigen-specific T cell responses. CD4(+) T helper cells have been shown to recognize nuclear and cytosolic antigens via presentation by major histocompatibility complex (MHC) class II molecules after autophagy. Furthermore, some sources of natural MHC class II ligands display characteristics of autophagy substrates, and autophagosomes fuse with late endosomes, in which MHC class II loading is thought to occur. Although MHC class II antigen processing via autophagy has so far mainly been described for professional antigen-presenting cells like B cells, macrophages, and dendritic cells, it might be even more important for cells with less endocytic potential, like epithelial cells, when these express MHC class II at sites of inflammation. Therefore, autophagy might contribute to immune surveillance of intracellular pathogens via MHC class II presentation of intracellular pathogen-derived peptides.

Management of cardiovascular risk in the usual care of Medicaid recipients.

Uncontrolled risk factors contribute substantially to cardiovascular disease burden. With retrospective chart review, we examined rates of cardiovascular risk factor assessment and intervention during the course of usual care for a representative sample of 3,742 adult North Carolina Medicaid recipients with diagnosed hypertension managed by a primary care provider. Most patients had been established with their provider for at least three years. Ninety-six percent had multiple modifiable risk factors. Blood pressure and cholesterol were above goal for 52.9% and 37.2% of patients, respectively. Among those with uncontrolled blood pressure, only 44.3% had intensification of therapy within the prior year. Half of patients with cholesterol above goal were treated with medication; and half of current smokers had documented advice to quit. Documentation of aspirin use or counseling was rare. Despite Medicaid coverage and access to care, many effective strategies to prevent cardiovascular events were underutilized, even among patients at highest risk.

Prevention and treatment of childhood obesity: care received by a state medicaid population.

Based on chart review for a representative cluster sample of North Carolina Medicaid enrollees aged 3 to 5 years (n = 1951) and 13 to 16 years (n = 1922) years, this study describes prevalence, practice patterns, and comorbidities related to overweight/obese immediately prior to 2007 Expert Recommendations. In total, 16% of children in both age groups were overweight, and 20% (ages 3-5 years) and 25% (ages 13-16 years) were obese. For 3- to 5-year-olds, body mass index percentile was infrequently recorded (22%) or plotted on growth charts (24%), and weight status category was rarely documented (10%). Results were similar for adolescents (21%, 20%, and 12%, respectively). In both groups, documentation of counseling in nutrition or physical activity was rare (16% for ages 3-5 years; 7% for ages 13-16 years). In adolescents, approximately 20% received recommended laboratory screening and overweight/ obesity was significantly associated with chart-documented asthma, back pain, prediabetes, gastroesophageal reflux disease, hypertension, and sleep apnea. Whether improvements in documentation of care followed these new guidelines deserves further research.

Level of blood pressure above goal and clinical inertia in a Medicaid population.

Failure to adjust hypertension therapy despite elevated blood pressure (BP) levels is an important contributor to lack of BP control. One possible explanation is that small elevations above goal BP are not concerning to clinicians. BP levels farther above goal, however, should be more likely to prompt clinical action. We reviewed 1 year's worth of primary care records of 3742 North Carolina Medicaid recipients 21 years and older with hypertension (a total of 15,516 office visits) to examine variations in hypertension management stratified by level of BP above goal and the association of BP level above goal with documented antihypertensive medication change. Among the 53% of patients not at goal BP, 42% were within 10/5 mm Hg of goal; 11% had a BP 40/20 mm Hg or higher above goal. Higher level of BP above goal was independently associated with antihypertensive medication change. Compared with visits at which BP was less than 10/5 mm Hg above goal, the adjusted odds of medication change were 7.9 (95% Confidence Interval 6.2-10.2) times greater at visits when patients' BP was 40/20 mm Hg or higher above goal. However, even when BP was above goal at this level, treatment change occurred only 46% (95% Confidence Interval 40.2-51.8) of the time.

Recommendation for and receipt of cancer screenings among medicaid recipients 50 years and older.

BACKGROUND: Persons of low socioeconomic status, including those with Medicaid coverage, are more likely to be diagnosed with cancer at an advanced stage, but little is known about cancer screening practices among Medicaid recipients. Our objective was to identify cancer screening rates among older Medicaid recipients seen in a primary care setting, and to identify patient and physician characteristics associated with screening. METHODS: We used a stratified cluster sampling design to select a representative sample of 1951 North Carolina Medicaid recipients 50 years and older. Medical records were reviewed in the office of the primary care provider. Principal outcomes were the documentation of physician recommendations for and patient receipt of screening examinations for colorectal, breast, and cervical cancer. RESULTS: Documentation that colorectal, breast, and cervical cancer screening was recommended by the primary care provider was found for only 52.7%, 60.4%, and 51.5% of eligible patients, respectively. Documented rates of adequate screening were 28.2% for colorectal cancer, 31.7% for mammography within 2 years, and 31.6% for Papanicolaou test within 3 years. When medical record and claims data were combined, approximately half of eligible patients had evidence of screening. Length of the patient-physician relationship and African American race were positively associated with screening. CONCLUSIONS: Cancer screening rates among older Medicaid recipients fall far short of national objectives. Lack of a screening recommendation by the physician, rather than patient refusal of recommended tests, accounted for most instances of screening delinquency. Efforts to increase cancer screening rates among Medicaid recipients must address patient, physician, and organizational barriers to the routine identification and delivery of preventive services.

Innate and adaptive immunity through autophagy.

The two main proteolytic machineries of eukaryotic cells, lysosomes and proteasomes, receive substrates by different routes. Polyubiquitination targets proteins for proteasomal degradation, whereas autophagy delivers intracellular material for lysosomal hydrolysis. The importance of autophagy for cell survival has long been appreciated, but more recently, its essential role in both innate and adaptive immunity has been characterized. Autophagy is now recognized to restrict viral infections and replication of intracellular bacteria and parasites. Additionally, this pathway delivers cytoplasmic antigens for MHC class II presentation to the adaptive immune system, which then in turn is able to regulate autophagy. At the same time, autophagy plays a role in the survival and the cell death of T cells. Thus, the immune system utilizes autophagic degradation of cytoplasmic material, to both restrict intracellular pathogens and regulate adaptive immunity.

Immune surveillance via self digestion.

The adaptive immune system is orchestrated by CD4+ T cells. These cells detect peptides presented on Major Histocompatibility Complex (MHC) class II molecules, which are loaded in late endosomes with products of lysosomal proteolysis. One pathway by which proteins gain access to degradation in lysosomes is macroautophagy. We recently showed that constitutive macroautophagy can be detected in cells relevant for the immune system, including dendritic cells. In these antigen presenting cells, autophagosomes frequently fused with MHC class II antigen loading compartments and targeting of Influenza matrix protein 1 (MP1) for macroautophagy enhanced MHC class II presentation to MP1-specific CD4+ T cell clones up to 20 fold. Our findings indicate that macroautophagy is a constitutive and efficient pathway of antigen delivery for MHC class II presentation. We suggest that this pathway samples intracellular proteins for immune surveillance and induction of tolerance in CD4+ T cells, and could be targeted for improved MHC class II presentation of vaccine antigens.

Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes.

Major histocompatibility complex (MHC) class II molecules present products of lysosomal proteolysis to CD4(+) T cells. Although extracellular antigen uptake is considered to be the main source of MHC class II ligands, a few intracellular antigens have been described to gain access to MHC class II loading after macroautophagy. However, the general relevance and efficacy of this pathway is unknown. Here we demonstrated constitutive autophagosome formation in MHC class II-positive cells, including dendritic, B, and epithelial cells. The autophagosomes continuously fuse with multivesicular MHC class II-loading compartments. This pathway was of functional relevance, because targeting of the influenza matrix protein 1 to autophagosomes via fusion to the autophagosome-associated protein Atg8/LC3 led to strongly enhanced MHC class II presentation to CD4(+) T cell clones. We suggest that macroautophagy constitutively and efficiently delivers cytosolic proteins for MHC class II presentation and can be harnessed for improved helper T cell stimulation.

Beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis.

OBJECTIVE: Sporadic Inclusion Body Myositis (sIBM) is the most common acquired muscle disease in patients above 50 years of age. Apart from inflammation in the skeletal muscle, overexpression of amyloid precursor protein (APP) and intracellular accumulation of its proteolytic fragment beta-amyloid play a central role in the pathogenesis of sIBM. In neurodegenerative disorders, similar aggregations of aberrant proteins have recently been shown to be susceptible to autophagic degradation. Therefore, we analyzed macroautophagy of APP in human muscle cell lines and sIBM muscle biopsies. METHODS: Colocalization of APP with the essential autophagy protein Atg8/LC3, which associates with preautophagosomal and autophagosomal membranes via lipidation, was analyzed in the CCL-136 muscle cell line and muscle biopsies by immunofluorescence. While APP was visualized with specific antibodies in the muscle cell line and in tissue sections. Atg8/LC3 localization was analyzed after GFP-Atg8/LC3 transfection or with an Atg8/LC3 specific antiserum, respectively. RESULTS: We demonstrate here that Atg8/LC3 colocalizes with APP in cultured human muscle cells. In addition, APP/beta-amyloid-containing autophagosomes can be observed at increased frequency in muscle fibers of sIBM muscle biopsies, but not in non-myopathic muscle or non-vacuolated myopathic controls. APP/beta-amyloid and Atg8/LC3 double-positive compartments were almost exclusively observed in degenerating muscle fibers of the type II (fast-twitching) and were in part associated with overexpression of major histocompatibility complex (MHC) class I and II on myofibers and invasion by CD4(+) and CD8(+) cells. INTERPRETATION: These findings indicate that APP/beta-amyloid is targeted for lysosomal degradation via macroautophagy and suggest that the autophagy pathway should be explored for its potential therapeutic merit in sIBM.

Endogenous MHC class II processing of a viral nuclear antigen after autophagy.

CD4+ T cells classically recognize antigens that are endocytosed and processed in lysosomes for presentation on major histocompatibility complex (MHC) class II molecules. Here, endogenous Epstein-Barr virus nuclear antigen 1 (EBNA1) was found to gain access to this pathway by autophagy. On inhibition of lysosomal acidification, EBNA1, the dominant CD4+ T cell antigen of latent Epstein-Barr virus infection, slowly accumulated in cytosolic autophagosomes. In addition, inhibition of autophagy decreased recognition by EBNA1-specific CD4+ T cell clones. Thus, lysosomal processing after autophagy may contribute to MHC class II-restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease.

Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs.

Dendritic cells (DCs) are known to induce the growth and function of natural killer (NK) cells. Here, we address the capacity of DCs to interact with NK cells in human lymphoid organs and identify the role of specific DC-derived cytokines. We demonstrate that DCs colocalize with NK cells in the T cell areas of lymph nodes. In culture, DCs from either blood or spleen primarily stimulate the CD56(bright)CD16- NK cell subset, which is enriched in secondary lymphoid tissues. Blocking of IL-12 abolished DC-induced IFN-gamma secretion by NK cells, whereas membrane-bound IL-15 on DCs was essential for NK cell proliferation and survival. Maturation by CD40 ligation promoted the highest IL-15 surface presentation on DCs and led to the strongest NK cell proliferation induced by DCs. These results identify secondary lymphoid organs as a potential DC/NK cell interaction site and identify the distinct roles for DC-derived IL-12 and IL-15 in NK cell activation.