Production of nitric oxide elevates nitrosothiol formation resulting in decreased glutathione in macrophages exposed to asbestos or asbestos substitutes

The purpose of this study was to investigate the effects of pneumoconiogenic particles, such as asbestos, on nitrosothiol formation in macrophages. In addition, the effects of man-made mineral fibers (MMMFs) were also evaluated, because they have come into heavy use as substitutes for asbestos. RAW264.7 cells and J774 cells of murine macrophage cell lines were cultured with chrysotile B (CH) asbestos, crocidolite (CR) asbestos, or MMMFs comprised of glass wool (GW), rock wool (RW), or ceramic (RF1). All of these fibers significantly increased nitric oxide (NO) production in the culture with macrophages. Chrysotile B, CR, and GW significantly decreased the level of reduced glutathione (GSH) in RAW264.7 cells. S-nitrosothiol (RS-NO) formation was increased by both types of cells on exposure to every fiber. A large portion of this increased RS-NO may be in the form of S-nitrosoglutathione (GS-NO), because GSH is the most abundant thiol substance in the cell. Both CH and GW significantly increased superoxide anion in the media cultured of RAW264.7 cells. These results indicate that macrophages exposed to asbestos or MMMFs are subject to oxidative stress, not only through the generation of reactive oxygen and nitrogen species, but also through decreases in the level of the cellular antioxidant, GSH, by GS-NO formation. The increase of RS-NO in macrophages exposed to asbestos or MMMFs may deserve more attention as the indicator of continuous oxidative stress by NO on cells and tissues, which causes inflammation and involves the development of asbestos-induced diseases.     

Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS

The long-term effects of the sodium salt of dichloroacetic acid (DCA) were evaluated in four patients with mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS) carrying A3243G mutation. Oral administration of DCA in MELAS patients was followed for an average of 5 years 4 months. Serum levels of lactate and pyruvate were maintained at around 10 and 0.6 mg/dl, respectively. Serum levels of DCA were 40-136 microg/ml. Symptoms responding to treatment included persistent headache, abdominal pain, muscle weakness, and stroke-like episodes. In contrast, no improvements in mental status, deafness, short stature, or neuroelectrophysiological findings were observed. Adverse effects included mild liver dysfunction in all patients, hypocalcemia in three and peripheral neuropathy in one. None of these adverse events was severe enough to require discontinuation of treatment. To determine suitable indications for DCA therapy, analysis of many more patients who have undergone DCA administration is required.     

Mosaic trisomy of a small r(1) with an abnormal phenotype

Cytogenetic studies of a mildly dysmorphic 10-year-old male with mild developmental delay and learning difficulties revealed mosaicism for a supernumerary ring chromosome in approximately half of the cells. The karyotype of this patient was established as 47,XY,+r[15]/46,XY[15].ish r(1)(D1Z7+,wcp1-). Although the presence of euchromatic material was shown by C banding, the lack of hybridization with the whole chromosome paint 1 (wcp1) probe suggests that few unique sequences are contained in the ring and that these sequences likely explain the child's dysmorphic features and developmental delay. A review of the literature, including the present case, suggests that the significance of euchromatin in supernumerary r(1) as determined by both C banding and fluorescence in situ hybridization (FISH) with chromosome 1 painting probes can be used as a prognostic indicator for potential severity of the clinical phenotype.     

Student perceptions of assessment and feedback in longitudinal integrated clerkships

Objectives This study was conducted to elucidate how the learning environment and the student–preceptor relationship influence student experiences of being assessed and receiving feedback on performance. Thus, we examined how long‐term clinical clerkship placements influence students’ experiences of and views about assessment and feedback. Methods We took a constructivist grounded approach, using authentic assessment and communities of practice as sensitising concepts. We recruited and interviewed 13 students studying in longitudinal integrated clerkships across two medical schools and six settings, using a semi‐structured interview framework. We used an iterative coding process to code the data and arrive at a coding framework and themes. Results Students valued the unstructured assessment and informal feedback that arose from clinical supervision, and the sense of progress derived from their increasing responsibility for patients and acceptance into the health care community. Three themes emerged from the data. Firstly, students characterised their assessment and feedback as integrated, developmental and longitudinal. They reported authenticity in the monitoring and feedback that arose from the day‐to‐day delivery of patient care with their preceptors. Secondly, students described supportive and caring relationships and a sense of safety. These enabled them to reflect on their strengths and weaknesses and to interpret critical feedback as supportive. Students developed similar relationships across the health care team. Thirdly, the long‐term placement provided for multiple indicators of progress for students. Patient outcomes were perceived as representing direct feedback about students’ development as doctors. Taking increasing responsibility for patients over time is an indicator to students of their increasing competence and contributes to the developing of a doctor identity. Conclusions Clerkship students studying for extended periods in one environment with one preceptor perceive assessment and feedback as authentic because they are embedded in daily patient care, useful because they are developmental and longitudinal, and constructive because they occur in the context of a supportive learning environment and relationship.     

What are the features of targeted or system-wide initiatives that affect diversity in health professions trainees? A BEME systematic review: BEME Guide No. 50

Abstract

Background/purpose: There is interest to increase diversity among health professions trainees. This study aims to determine the features/effects of interventions to promote recruitment/admission of under-represented minority (URM) students to health professions programs.

Methodology: This registered BEME review applied systematic methods to: title/full-text inclusion review, data extraction, and quality assessment (QA). Included studies reported outcomes for interventions designed to increase diversity of health professions education (HPE) programs’ recruitment and admissions.

Results: Of 7225 studies identified 86 met inclusion criteria. Interventions addressed: admissions (34%), enrichment (19%), outreach (15%), curriculum (3%), and mixed (29%). They were mostly single center (76%), from the United States (81%), in medicine (45%) or dentistry (22%). URM definition was stated in only 24%. The dimension most commonly considered was ethnicity/race (88%). The majority of studies (81%) found positive effects. Heterogeneity precluded meta-analysis. Qualitative analysis identified key features: admissions studies points systems and altered weightings; enrichment studies highlighted academic, application and exam preparation, and workplace exposure.

Discussion/conclusions: Several intervention types may increase diversity. Limited applicant pools were a rate-limiting feature, suggesting efforts earlier in the continuum are needed to broaden applicant pools. There is a need to examine underlying cultural and external pressures that limit programs’ acceptance of initiatives to increase diversity.     

Outcomes in esophageal atresia and tracheoesophageal fistula

Background/Purpose: The purpose of this analysis was to investigate outcomes in newborns with esophageal atresia (EA) or tracheoesophageal fistula (TEF) with respect to prognostic classifications and complications.Methods: Charts of all 144 infants with EA/TEF treated at British Columbia Children’s Hospital (BCCH) from 1984 to 2000 were reviewed. Patient demographics, frequency of associated anomalies, and details of management and outcomes were examined.Results: Applying the Waterston prognostic classification to our patient population, survival rate was 100% for class A, 100% for class B, and 80% for class C. The Montreal classification survival rate was 92% for class I and 71% for class II (P = .08). Using the Spitz classification, survival rate was 99% for type I, 84% for type II, and 43% for type III (P < .05). The Bremen classification survival rate was 95% “without complications” and 71% “with complications.” Complications included stricture (52%), gastroesophageal reflux (31%), anastomotic leakage (8%), recurrent fistula (8%), and pneumonia (6%). Seventeen patients underwent fundoplication for gastroesophageal reflux, 16 pre-1992 and one post-1992.Conclusions: Comparing the major prognostic classifications, the Spitz classification scheme was found to be most applicable. In our institution, the trend in management of gastroesophageal reflux after repair of EA/TEF has moved away from fundoplication toward medical management.     

Traffic of endogenous, transduced, and endocytosed prolactin in rabbit lacrimal acinar cells

The rabbit lacrimal gland undergoes an immunophysiological transformation during pregnancy, reminiscent of that of the mammary gland as it prepares to deliver secretory IgA into the nascent fluid product. The contents of TGF-beta and prolactin (PRL) within ductal epithelial cells increase, and their primary localizations shift from the apical to the basal cytoplasm, suggesting a transformation from exocrine to paracrine secretion. Studies with ex vivo acinar cell models demonstrated that elevated PRL suppresses traffic of secretory proteins into the regulated exocrine apparatus and directs them into a novel, induced, regulated paracrine apparatus [Wang, Y., Chiu, C.T., Nakamura, T., Walker, A.M., Petridou, B., Trousdale M.D., Hamm-Alvarez S.F., Schechter J.E., Mircheff A.K., 2007. Elevated prolactin redirects secretory vesicle traffic in rabbit lacrimal acinar cells. Am. J. Physiol. Endocrinol. Metab. 292, E1122-E1134]. However, it was not clear whether PRL itself entered the induced paracrine apparatus. In the present study, confocal immunofluorescence microscopy revealed that natively expressed PRL and over-expressed PRL co-localized with PRL receptors (PRLR); rab11, a marker for the recycling endosome; gamma-adaptin, a marker for the Golgi complex and trans-Golgi network; and rab7, a marker for the autophagic lysosomal apparatus. Natively expressed, over-expressed, and endocytosed PRL also co-localized with rab4 and rab5A, markers for the early endosome, and with rab3D, a marker for regulated exocrine secretory vesicles. Endocytosed PRL was stored in intact form and released in response to stimulation with carbachol. Subcellular fractionation analysis detected relative excesses of PRL over PRLR in fractions that contained fragments of the recycling endosome and fractions that contained both secretory vesicle fragments and prelysosomal and autolysosomal fragments. EM-gold microscopy demonstrated PRL within small vesicles, consistent with endosomes or secondary lysosomes, and in large vesicles, consistent with regulated secretory vesicles. The secretory vesicles were preponderantly localized in the apical cytoplasm of control cells, and in the basal cytoplasm of PRL over-expressing cells. These results indicate that when lacrimal epithelial cells synthesize PRL, and when they endocytose it from their ambient medium, they traffic it both into the endosomes that constitute the constitutive transcytotic paracrine apparatus and also into regulated secretory vesicles, which are associated with the exocrine apparatus at low PRL levels and with the induced paracrine apparatus at high PRL levels.     

Population-based analysis of severe injuries from nonmotorized wheeled vehicles

BACKGROUND: Bicycling, skateboarding, and inline skating are popular recreational activities, with the potential of causing severe injury. METHODS: A retrospective, population-based, trauma registry analysis of severe injuries and deaths from nonmotorized wheeled vehicles (NMWV) over a 10-year period was performed. RESULTS: During the study period, 1475 cyclists, 141 skateboarders, and 112 inline skaters sustained injury meeting registry criteria (length of stay > or = 3 days or death). The majority were male. Lone crashes were the most common mechanism of injury, although collisions with motor vehicles accounted for 63.6% (n = 44) of observed deaths. Thoracic trauma and head injuries were more common in nonsurvivors. CONCLUSION: NMWV injuries pose a public health concern. We recommend enforcement of mandatory helmet laws and expansion of the existing law to include skateboarders and inline skaters. Education initiatives should also be expanded to include the adult population. NMWV should be separated from motorized vehicles as much as possible.