Spatial separation of the processing and MHC class I loading compartments for cross-presentation of the tumor-associated antigen HER2/neu by human dendritic cells.

Cross-presentation is the process by which professional antigen presenting cells (APCs) (B cells, dendritic cells (DCs) and macrophages) present endocytosed antigens (Ags) via MHC-I to CD8+ T cells. This process is crucial for induction of adaptive immune responses against tumors and infected cells. The pathways and cellular compartments involved in cross-presentation are unresolved and controversial. Among the cells with cross-presenting capacity, DCs are the most efficient, which was proposed to depend on prevention of endosomal acidification to block degradation of the epitopes. Contrary to this view, we show in this report that some cargoes induce strong endosomal acidification following uptake by human DCs, while others not. Moreover, processing of the tumor-associated antigen HER2/neu delivered in nanoparticles (NP) for cross-presentation of the epitope HER2/neu369-377 on HLA-A2 depended on endosomal acidification and cathepsin activity as well as proteasomes, and newly synthesized HLA class I. However, the HLA-A*0201/HER2/neu369-377 complexes were not found in the endoplasmic reticulum (ER) nor in endolysosomes but in hitherto not described vesicles. The data thus indicate spatial separation of antigen processing and loading of MHC-I for cross-presentation: antigen processing occurs in the uptake compartment and the cytosol whereas MHC-I loading with peptide takes place in a distinct subcellular compartment. The findings further elucidate the cellular pathways involved in the cross-presentation of a full-length, clinically relevant tumor-associated antigen by human DCs, and the impact of the vaccine formulation on antigen processing and CD8+ T cell induction.

New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.

OBJECTIVE: To assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype. METHODS: Samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject. RESULTS: A variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures. CONCLUSIONS: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase-associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.

Bullies at work: the impact of horizontal hostility in the hospital setting and intent to leave.

The phenomenon of bullying or peer incivility in nursing is not new or confined to nurses. Behaviors consistent with horizontal hostility (HH) range from overt behavioral manifestations such as infighting among nurses; sabotage (where pertinent information is intentionally withheld); passive-aggressive behavior; eye rolling in response to a question; or verbal remarks that are snide, rude, and demeaning, to more covert behaviors including failure to respect confidences and privacy. Horizontal hostility can lead to profound and long-lasting effects, including diminished productivity and increased absenteeism. This study surveyed RNs at a community hospital in the Southwest to determine (a) the degree of HH in the workplace and (b) the extent that the perception of HH affected ill calls and the likelihood of leaving their current position. The authors make recommendations about the prevention, identification, and handling of HH behaviors.

Promoting physical activity for persons with diabetes.

PURPOSE: The purpose of this study was to evaluate the effectiveness of a self-help physical activity program for persons with type 2 diabetes. Effectiveness was measured by cardiovascular indicators, hemoglobin A1C, anthropometric indicators, and activity levels. METHODS: This intervention study included 53 individuals with type 2 diabetes. Participants were randomly assigned. Participants in the intervention group attended the usual Diabetes Self-Management Education Program (DSMEP) and received a copy of the book, Manpo-kei; a concise handout summarizing the key points of Manpo-kei; and a pedometer. Participants not assigned to the intervention attended the usual DSMEP only. Data collection was completed at the beginning of the study and 3 months later using a lifestyle and diabetes questionnaire, a physical activity questionnaire, and cardiovascular and anthropometric measures. RESULTS: Those who participated in the intervention demonstrated a significant decrease in hemoglobin A1C, weight, and body fat. In addition, they increased their number of daily steps as measured by the pedometer. The control group also demonstrated a significant decrease in hemoglobin A1C and weight. Both groups demonstrated increases in their regular weekly activity. At the end of the study period, the intervention group had a significantly lower diastolic blood pressure than the control group. CONCLUSIONS: Pedometers can be a helpful strategy to motivate persons with diabetes to increase physical activity. However, it appears that attendance at DSMEP alone may be enough to increase physical activity for persons with type 2 diabetes.