Variant Creutzfeldt-Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrP(Sc) type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure.

Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion disease associated with infection with bovine spongiform encephalopathy (BSE)-like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.

All neuropathologically confirmed cases of variant CreutzfeldtJakob disease (vCJD), characterized by abundant florid plaques and type 4 disease-related prion protein (PrP Sc ) in the brain, have been homozygous for methionine at polymorphic residue 129 of PRNP. The distinctive neuropathological and molecular phenotype of vCJD can be faithfully recapitulated in Prnp-null transgenic mice homozygous for human PrP M129 but not V129, where a distinct prion strain is propagated. Here we model susceptibility of 129MV heterozygotes, the most common PRNP genotype, in transgenic mice and show that, remarkably, propagation of type 4 PrP Sc was not associated with characteristic vCJD neuropathology. Depending on the source of the inoculum these mice can develop four distinct disease phenotypes after challenge with bovine spongiform encephalopathy (BSE) prions or vCJD (human-passaged BSE) prions. vCJD-challenged mice had higher attack rates of prion infection than BSE-challenged recipients. These data argue that human PRNP 129 heterozygotes will be more susceptible to infection with vCJD prions than to cattle BSE prions and may present with a neuropathological phenotype distinct from vCJD.bovine spongiform encephalopathy ͉ prion disease ͉ prion strains ͉ florid plaques ͉ subclinical infection

Background Women in medicine report many gender-specific barriers to their career success and satisfaction, including a lack of mentors and role models. The literature calls for innovative strategies to enhance mentorship for women in medicine. Objective To describe the content, perceived value, and ongoing achievements of a mentoring program for women in emergency medicine. Methods The program offered mentoring for female faculty and residents in an academic emergency medicine department. Volunteers participated in group mentoring sessions using a mosaic of vertical and peer mentoring. Sessions focused on topics specific to women in medicine. An anonymous, electronic survey was sent to women who participated during 2004–2010 to assess the perceived value of the program and to collect qualitative feedback. Preliminary achievements fulfilling the program's goals were tracked. Results A total of 46 women (64%) completed the survey. The results showed a positive perceived value of the program (average, 4.65 on a 5-point Likert scale) in providing mentors and role models (4.41), in offering a supportive environment (4.39), in providing discussions pertinent to both personal (4.22) and professional development (4.22), while expanding networking opportunities (4.07). Notable achievements included work on the creation of a family leave policy, establishing lactation space, collaboration on projects, awards, and academic advancement. Conclusion This innovative model for mentoring women is perceived as a valuable asset to the academic department and residency. It offers the unique combination of expanding a female mentor pool by recruiting alumni and using a mosaic of vertical and peer mentoring.

PRO 2000 Gel was safe and well tolerated in sexually active HIV-uninfected and sexually abstinent HIV-infected women, enabling the product to be considered for evaluation in efficacy trials.

Background and Purpose-Hyperbaric oxygen therapy (HBO) has promise as a treatment for acute stroke. This study was conducted to evaluate the efficacy, safety, and feasibility of using HBO in acute ischemic stroke. Methods-We conducted a randomized, prospective, double-blind, sham-controlled pilot study of 33 patients presenting with acute ischemic stroke who did not receive thrombolytics over a 24-month period. Patients were randomized to treatment for 60 minutes in a monoplace hyperbaric chamber pressurized with 100% O 2 to 2.5-atm absolute (ATA) in the HBO group or 1.14 ATA in the sham group. Primary outcomes measured included percentage of patients with improvement at 24 hours (National Institutes of Health Stroke Scale [NIHSS]) and 90 days (NIHSS, Barthel Index, modified Rankin Scale, Glasgow Outcome Scale). Secondary measurements included complications of treatment and mortality at 90 days. Results-Baseline demographics were similar in both groups. There were no differences between the groups at 24 hours (Pϭ0.44). 4 and maintenance of blood-brain barrier integrity. 5 HBO has been shown in animal models of both focal and global ischemia to reduce the volume of brain infarction and improve outcome. 6 -8 There have been Ͼ400 cases of ischemic strokes in humans treated with HBO, with more than half of these cases claiming improvement on clinical or experimental grounds. 9 -12 Despite this result, there have been only 2 controlled pilot studies in humans, both using multiple treatments at 1.5-atm pressure absolute (ATA). 13,14 We conducted a pilot study to prospectively assess the efficacy, safety, and feasibility of a 1-time treatment with hyperbaric oxygen at 2.5 ATA in patients with acute ischemic stroke. MethodsThis study was a prospective, sham-controlled, double-blind pilot study comparing HBO with sham in the treatment of ischemic stroke. This study was approved by the Methodist Hospital Institutional Review Board, with patient or proxy consent obtained before enrollment. ParticipantsParticipants included adults Ͼ18 years of age presenting to an emergency department within 24 hours after stroke onset with a measurable deficit on the National Institutes of Health Stroke Scale (NIHSS) and without evidence of hemorrhage on CT scan. Patients waking up with symptoms had time of onset defined as the time they went to sleep. Patients were excluded if they received thrombolytics, had a seizure at onset, had a stroke within 3 months, had improvement on the NIHSS score before treatment, or had an NIHSS score Ͼ22. Patients were also excluded if they had risk factors for HBO, including a history of severe chronic obstructive pulmonary disease, pneumothorax, bowel obstruction, sickle cell disease, or evidence of cardiac arrhythmia deemed by an investigator as potentially mandating emergent intervention. InterventionsSubjects were stratified on the basis of time since symptom onset (0 to 12 or 12 to 24 hours) and subsequently randomized to receive either HBO or sham treatment. The HBO group underwent a 1-time trea...

BackgroundIn the highly competitive environment of academic medicine, junior faculty investigators face high attrition rates due to challenges in finding effective mentorship, securing grant funding, and obtaining resources to support their career development and research productivity. The purpose of this study was to describe the centralized, cost-sharing design of the Independent Investigator Incubator (I3) program as a novel approach to junior faculty mentoring and to evaluate quantitative outcomes for program improvement.MethodsIn September 2014, the I3 pilot program, a comprehensive mentorship program targeting junior faculty pursuing research careers, was launched. Participants included junior faculty during the crucial first three years of their research careers or during their transition from career development awards to more independent research. Following initial screening, the I3 mentees were paired with a senior faculty “super-mentor” with expertise in either basic science or clinical research. Mentees were provided with robust traditional one-on-one mentoring, targeted feedback from a super-mentor review committee, as well as biostatistician and grant writing support. To assess the effectiveness of the I3 program, we tracked outcome measures via baseline and 12-month mentee surveys. Data collected assessed program diversity, mentee self-assessments, evaluation of the mentoring relationship, scholarship and productivity metrics. Raw data were analyzed using a paired t-test in Excel (P < 0.05).ResultsResults of the baseline mentee self-assessment survey found that the I3 mentees indicated common “perceive deficits” including navigating the organizational and institutional culture, clear direction in achieving promotion and tenure, among others. When baseline mentee survey responses were compared to 12-month responses, we identified strong “perceived growth” in categories, such as Research and Interpersonal Skills and Career Development Skills. Further, productivity metrics at 12-months revealed that roughly 80% of I3 mentees successfully published a manuscript(s). The I3 program has helped generate roughly $12.1 million dollars in investigator-initiated funding after two years in the program.ConclusionThe I3 program allows for shared costs between institutions and increased availability of successful subject matter experts. Study results imply that the I3 mentoring program provides transformative mentorship for junior faculty. Using our findings, we developed courses and an annual “snapshot” of mentee performance for mentors.Electronic supplementary materialThe online version of this article (10.1186/s12909-018-1290-3) contains supplementary material, which is available to authorized users.

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