Adaptation to host temperature is a prerequisite for any pathogen capable of causing deep infection in humans. Our previous studies demonstrated that a Cryptococcus neoformans ccr4⌬ mutant lacking the major deadenylase involved in regulated mRNA decay was defective in host temperature adaptation and therefore virulence. In this study, the ccr4⌬ mutant was found to exhibit characteristics of chronic unfolded-protein response (UPR) engagement in both the gene expression profile and phenotype. We demonstrate that host temperature adaptation in C. neoformans is accompanied by transient induction of the endoplasmic reticulum (ER) stress response and that Ccr4-dependent posttranscriptional gene regulation contributes to resolution of ER stress during host temperature adaptation.The pathogenic fungus Cryptococcus neoformans is one of two species of cryptococci commonly associated with infection in humans (2, 6). Unifying characteristics of the pathogenic cryptococci include the production of a polysaccharide capsule, the ability to form melanin pigments through the activity of the multicopper oxidase laccase, and the ability to adapt to and thrive at mammalian host temperature. Adaptation of C. neoformans to the host temperature is accompanied by major changes in gene expression as measured by microarray analysis and serial analysis of gene expression (SAGE) (5,19,29). This modulation of gene expression likely requires alterations in mRNA synthesis rates through activation of transcriptional transactivators and repressors, as well as alterations in chromatin structure. In addition to mRNA synthesis, our previous studies of a C. neoformans ccr4⌬ mutant lacking the major mRNA deadenylase involved in regulated mRNA turnover suggest a role for posttranscriptional regulation of gene expression in C. neoformans host temperature adaptation (24).Destabilization of specific transcripts in response to stress is highly conserved. In the model yeast Saccharomyces cerevisiae, deletion of CCR4 results in stabilization of transcripts encoding distinct functional classes (ribosome biogenesis, translation initiation, and tRNA synthesis) in response to temperature stress (13). In mammalian cells, subsets of transcripts were destabilized in response to heat shock, and induction of endoplasmic reticulum (ER) stress by treatment with tunicamycin or potentiation of ER calcium release by thapsigargin treatment triggered destabilization of a subset of mRNAs in which are included several transcripts encoding ribosomal proteins (8). This suggests that in response to heat shock and ER stress, distinct pools of transcripts representing specific cellular processes are targeted for degradation.The conserved ER stress response involves engagement of the unfolded-protein response (UPR) and the ER-associated degradation (ERAD) pathway (18). The UPR serves to retool the ER for enhanced protein folding, and ERAD serves to remove unfolded proteins from the ER lumen and shunt them into a degradative pathway. Microarray analyses performed in S. cerevisiae ...
IntroductionMetabolic bone disease is a malady that causes significant morbidity and mortality to a patient who has sustained a fragility fracture. There is currently no protocol to prevent secondary fragility fracture at our institution. The objective of this study was to create an appropriate protocol for implementing clinical pathways for physicians to diagnose and treat osteoporosis and fragility fractures by educating patients.MethodsA multidisciplinary team created an appropriate protocol that could be implemented in an inpatient setting. A thorough literature review was conducted to evaluate potential barriers and efficacious methods of protocol design.ResultsA bone health improvement protocol was developed. Any patient over the age of 50 who sustains a fracture from low energy trauma, such as a fall from standing or less, should be considered to place into this protocol. These patients received education on metabolic bone disease, a prescription for high dose vitamin D therapy, and laboratory testing to determine the etiology of their metabolic bone disease. Continuity of care of these patients with their primary care provider was provided for further management of their metabolic bone disease and evaluation of their disease after discharged from the hospital.DiscussionComprehensive secondary prevention should consist of osteoporosis assessment and treatment together with a fall risk assessment. With this protocol, secondary fragility fractures potentially could be prevented.
Introduction. The initial treatment for many orthopaedic injuries is splinting. Unfortunately, formal musculoskeletal training is limited in primary care leading to deficiencies in competency and confidence. Suboptimal splints can result in complications such as skin breakdown, worsening of deformity, and increased pain. Our orthopaedic surgery clinic often cares for patients who initially present to an emergency department or primary care clinic for their orthopaedic injury. Previous studies have shown that a high number of splints are applied improperly in the primary care setting, which could result in in avoidable skin complications and fracture instability. Methods. Orthopaedic surgery residents held a splinting workshop for family medicine residents. The workshop involved didactic and skills portions. Pre- and post-surveys were administered using a 10-point scale to assess confidence in applying three common splints. The data were analyzed using student’s t-test and qualitative feedback. Results. Confidence in applying and molding each splint type improved significantly (p < 0.05). Knowledge in splint construction improved significantly as well (p < 0.05). Subjective feedback was positive. Conclusion. These results showed inter-residency education can increase residents’ confidence in skill-based medical care significantly. The results are encouraging and should facilitate further collaboration between multispecialty residency programs to improve patient care. Further investigation is needed to determine how well skills gained in workshop are retained.
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