Astrocyte-Derived Exosomes in an iPSC Model of Bipolar Disorder.

Bipolar I Disorder (BP) is a serious, recurrent mood disorder that is characterized by alternating episodes of mania and depression. To begin to identify novel approaches and pathways involved in BP, we have obtained skin samples from BP patients and undiagnosed control (C) individuals, reprogrammed them to form induced pluripotent stem cells (iPSC), and then differentiated the stem cells into astrocytes. RNAs from BP and C astrocytes were extracted and RNAseq analysis carried out. 501 differentially expressed genes were identified, including genes for cytoskeletal elements, extracellular matrix, signaling pathways, neurodegeneration, and notably transcripts that identify exosomes. When we compared highly expressed genes using hierarchial cluster analysis, "Exosome" was the first and most highly significant cluster identified, p < 5 × 10-13, Benjamini correction. Exosomes are membrane-bound vesicles that package and remove toxic proteins from cells and also enable cell to cell communication. They carry genetic material, including DNA, mRNA and microRNAs, proteins, and lipids to target cells throughout the body. Exosomes are released by cortical neurons and astrocytes in culture and are present in BP vs C postmortem brain tissue. Little is known about what transcripts and proteins are targeted to neurons, how they regulate biological functions of the acceptor cell, or how that may be altered in mood disorders. Since astrocyte-derived exosomes have been suggested to promote neuronal plasticity, as well as to remove toxic proteins in the brain, alterations in their function or content may be involved in neurodevelopmental, neuropathological, and neuropsychiatric conditions. To examine exosome cargos and interactions with neural precursor cells, astrocytes were differentiated from four bipolar disorder (BP) and four control (C) iPSC lines. Culture supernatants from these astrocytes were collected, and exosomes isolated by ultra-centrifugation. Western blot analysis demonstrated the presence of the exosome markers CD9, CD81, and Hsp70. Nanosight technology was used to characterize exosomes from each astrocyte cell line, suggesting that exosomes were slightly more concentrated in culture supernatants derived from BP compared with C astrocytes but there was no difference in the mean sizes of the exosomes. Analysis of their function in neuronal differentiation is being carried out by labeling exosomes derived from bipolar patient and control astrocytes and adding them to control neural progenitor cells. Given the current interest in clearing toxic proteins from brains of patients with neurodegenerative disorders, exosomes may present similar opportunities in BP.

A descriptive study of work aggravated asthma.

BACKGROUND AND AIMS: Work related asthma (WRA) is one of the most frequently reported occupational lung diseases in a number of industrialised countries. A better understanding of work aggravated asthma (WAA), as well as work related new onset asthma (NOA), is needed to aid in prevention efforts. METHODS: WAA and NOA in the United States were compared using cases reported to the National Institute for Occupational Safety and Health (NIOSH) from four state Sentinel Event Notification Systems for Occupational Risks (SENSOR) surveillance programmes for 1993-95. RESULTS: A total of 210 WAA cases and 891 NOA cases were reported. WAA cases reported mineral and inorganic dusts as the most common exposure agent, as opposed to NOA cases, in which diisocyanates were reported most frequently. A similar percentage of WAA and NOA cases still experienced breathing problems at the time of the interview or had visited a hospital or emergency room for work related breathing problems. NOA cases were twice as likely to have applied for workers' compensation compared with WAA cases. However, among those who had applied for worker compensation, approximately three-fourths of both WAA and NOA cases had received awards. The services and manufacturing industrial categories together accounted for the majority of both WAA (62%) and NOA (75%) cases. The risk of WAA, measured by average annual rate, was clearly the highest in the public administration (14.2 cases/10(5)) industrial category, while the risk of NOA was increased in both the manufacturing (3.2 cases/10(5)) and public administration (2.9 cases/10(5)) categories. CONCLUSIONS: WAA cases reported many of the same adverse consequences as NOA cases. Certain industries were identified as potential targets for prevention efforts based on either the number of cases or the risk of WAA and NOA.

Surveillance of work-related asthma in selected U.S. states using surveillance guidelines for state health departments--California, Massachusetts, Michigan, and New Jersey, 1993-1995.

PROBLEM/CONDITION: Cases of work-related asthma (WRA) are sentinel health events that indicate the need for preventive intervention. WRA includes new-onset asthma caused by workplace exposure to sensitizers or irritants and preexisting asthma exacerbated by workplace exposures. REPORTING PERIOD: This report reviews cases of WRA identified by state health departments from January 1, 1993, through December 31, 1995, as well as follow-up investigations of cases and associated workplaces conducted through June 30, 1998. DESCRIPTION OF THE SYSTEMS: State-based surveillance and intervention programs for WRA are conducted in California, Massachusetts, Michigan, and New Jersey as part of the Sentinel Event Notification Systems for Occupational Risks (SENSOR) cooperative agreement program, initiated by CDC's National Institute for Occupational Safety and Health (NIOSH). RESULTS: From 1993 through 1995, a total of 1,101 cases of WRA were identified by SENSOR surveillance staff members in California, Massachusetts, Michigan, and New Jersey. Of these 1,101 cases, 19.1% were classified as work-aggravated asthma, and 80.9% were classified as new-onset asthma. Objective evidence substantiating asthma work-relatedness was documented in the medical records of 3.4% of WRA cases identified in the two states (Michigan and New Jersey) where medical records are routinely reviewed for this information. Indoor air pollutants, dusts, cleaning materials, lubricants (e.g., metalworking fluids), and diisocyanates were among the most frequently reported causes of WRA. In addition, a well-recognized cause of occupational asthma - natural rubber latex - was identified in a new setting, the healthcare industry. The most common industries associated with WRA cases included transportation equipment manufacturing (19.3%), health services (14.2%), and educational services (8.7%). Air sampling for agents known to induce occupational asthma was performed in Michigan for comparison with established federal time-weighted average exposure limits. Sixteen (13.4%) of 119 workplaces tested had airborne concentrations exceeding NIOSH recommended exposure limits (RELs); 11 (9.1%) of 121 workplaces had concentrations exceeding permissible exposure limits (PELs) of the Michigan Occupational Safety and Health Act (MIOSHA) program. INTERPRETATION: The surveillance data findings confirm well-recognized causes of asthma and have identified new putative causes (e.g., cleaning materials and metalworking fluids). Because the surveillance program depends on physicians' recognizing asthma work-relatedness and reporting diagnosed cases, the data are considered an underestimate of the magnitude of the WRA problem. The data also indicate that physicians are not commonly performing objective physiologic tests to substantiate a WRA diagnosis. Workplace findings suggest a need to evaluate existing exposure standards for specific agents known to induce occupational asthma (e.g., diisocyanates). Case-based surveillance can help improve the recognition, control, and prevention of WRA. The SENSOR model also provides a mechanism for workers and physicians to request workplace investigations aimed at primary prevention for other workers. PUBLIC HEALTH ACTION: NIOSH and state health department representatives are working to establish a long-term agenda for state-based surveillance of work-related conditions and hazards. The results from the SENSOR WRA programs described in this report support inclusion of WRA as a priority condition warranting surveillance at the state level.

Surveillance for occupational asthma--Michigan and New Jersey, 1988-1992.

PROBLEM/CONDITION: A case of occupational asthma is a sentinel health event indicating a need for preventive intervention. REPORTING PERIOD COVERED: 1988-1992. DESCRIPTION OF SYSTEMS: As part of the Sentinel Event Notification System for Occupational Risks (SENSOR) Program, initiated by CDC's National Institute for Occupational Safety and Health in 1987, state-based surveillance and intervention programs for occupational asthma (OA) have been under development in Michigan and New Jersey. The initial 5-year projects in these states have been completed. RESULTS: From 1988 through 1992, the SENSOR programs in these states identified a total of 535 cases of occupational asthma and related conditions. Of these 535 cases, 328 cases met the SENSOR surveillance case definition for OA. In addition, 128 cases were classified as possible OA, 42 as reactive airways dysfunction syndrome, and 37 as occupationally aggravated asthma. In both Michigan and New Jersey, manufacturing was the industrial sector with the largest proportion of cases. In Michigan, > 40% of the case-patients worked in transportation equipment manufacturing. In New Jersey, 15% of case-patients worked in manufacturing of chemicals and allied products. Overall, isocyanates were the most frequently reported asthma-causing agents (19.4% of cases). Follow-up industrial hygiene sampling measured suspect agents at airborne concentrations generally below the permissible exposure limits established by the Occupational Safety and Health Administration. INTERPRETATION: In its first 5 years, the SENSOR system has led to the identification of previously unrecognized causes of occupational asthma. Overall findings indicate the need for more comprehensive control of such well-known occupational allergens as the isocyanates. In addition, SENSOR interventions have prompted improvements in protection for workers. ACTIONS TAKEN: Approaches to state-based surveillance and intervention for OA are being developed through newly funded 5-year SENSOR projects in four states (California, Massachusetts, Michigan, and New Jersey). The goal is to develop a model for effective state-based OA surveillance that can be applied by any state health department.