The stress-activated transcription factor, heat shock factor-1 (HSF1), regulates many genes including cytoprotective heat shock proteins (HSPs). We hypothesized that polymorphisms in HSF1 may alter the level or function of HSF1 protein accounting for interindividual viability in disease susceptibility or prognosis. We searched for exomic variants in HSF1 by querying human genome databases and directly sequencing DNA from 80 anonymous genomic DNA samples. Overall, HSF1 sequence was highly conserved, with no common variations. We found 31 validated deviations from a reference sequence in the dbSNP database and an additional 5 novel variants by sequencing, with allele frequencies that were 0.06 or less. Of these 36, 2 were in 5′-untranslated region (5′UTR), 10 in 3′UTR, and 24 in the coding region. The potential effects of 5′UTR on secondary structure, protein structure/function, and 3′UTR targets of microRNAs were analyzed using RNAFold, PolyPhen-2, SIFT, and MicroSNiper. One of the 5′UTR variants was predicted to strengthen secondary structure. Eight of 3′UTR variants were predicted to modify microRNA target sequences. Eight of the coding region variants were predicted to modify HSF1 structure/function. Reducing HSF1 levels in A549 cells using short hairpin RNA (shRNA) increased sensitivity to heatinduced killing demonstrating the impact that genetic variants that reduce HSF1 levels might have. Using the pmirGLO expression system, we found that the wild-type HSF1 3′ UTR suppressed translation of a firefly luciferase reporter plasmid by 65 %. Introducing two of four 3′UTR single nucleotide polymorphisms (SNPs) increased HSF1 3′UTR translational suppression by 27-44 % compared with the wild-type HSF1 3′UTR sequence while a third SNP reduced suppression by 25 %. HSF1 variants may alter HSF1 protein levels or function with potential effects on cell functions, including sensitivity to stress.
Introduction: Pulmonary equipment has become ubiquitous in clinical care. Basic device troubleshooting and mechanical manipulation skills are crucial to the practicing physician yet are frequently neglected in standard pulmonary curricula. Methods: We developed a hands-on pulmonary curriculum for medical residents and students, focusing on oxygen delivery, spirometry, positive airway pressure devices, thoracostomy, and tracheostomy knowledge. The curriculum, consisting of five 1-hour sessions, offers hands-on experience with basic pulmonary equipment relevant to the ICU and/or pulmonary clinic. Each session is led by a pulmonologist or critical care facilitator and designed for a learning audience of 10-15 internal medicine trainees and medical students. More than 11 sessions have been conducted since curriculum implementation. Results: Voluntary, immediate, pre-and postsession surveys assessed objective subject knowledge, perceived subject understanding, and perceived effectiveness of this handson format versus a conventional lecture style. A total of 52 learners returned surveys. Aggregate responses demonstrated that these sessions were typically the first formal training learners had received in these subject areas. Subject knowledge and perceived level of subject understanding both improved, and respondents reported the hands-on style of teaching was more effective than conventional lecture format. Discussion: Focused on practical knowledge, this pulmonary hands-on curriculum addresses a knowledge gap for medical trainees, has been enthusiastically received by trainees, and provides a useful resource for faculty wishing to teach about these devices.
Introduction Two-stage revision is frequently used for the treatment of periprosthetic joint infection (PJI). Because antibiotic-loaded cement spacers are constructed and implanted as temporary devices, mechanical complications are possible. The purpose of our study was to define the incidence of such mechanical complications, determine associated risk factors, and establish if such complications influence the subsequent success of PJI treatment. Methods We identified patients who received an antibiotic spacer for the treatment of PJI at a single center over a six-year timeframe. Medical records and all radiographs were collected and reviewed. Radiographic changes over time were recorded, and mechanical complications were noted. We used multivariate logistic regression analysis to assess risk factors for mechanical spacer complications and assess whether such complications influence the likelihood of subsequent reimplantation and ultimate component retention. Results A total of 236 patients were included in the study. There were 82 hip spacers (28% dynamic and 72% static) with a mechanical complication rate of 8.5% and 154 knee spacers (44% dynamic and 56% static) with a mechanical complication rate of 18.2%. Knee spacers were significantly more likely to have mechanical complications than hip spacers. Other risk factors for mechanical complications included bone loss and elevated body mass index (BMI). Bone loss and advanced age were found to be independent risk factors for failure to undergo second-stage reimplantation. Mechanical spacer failure was not an independent risk factor for the likelihood of subsequent reimplantation or ultimate component retention. Conclusions Mechanical complications of antibiotic spacers are common but do not appear to negatively impact the likelihood of subsequent reimplantation or component retention. In knee spacers and in patients with bone loss or elevated BMI, appropriate patient counseling and strategies to prevent such complications are recommended.
This study reveals previously unknown and potentially important differences between male and female mice in physiological and cellular responses to chronic heat exposure, which had consequences for survival. Future studies may identify biomarkers of differential heat tolerance and treatments to improve heat tolerance in humans.
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