Justin E. Juskewitch

Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension

Although the two-kidney, one-clip (2K1C) model is widely used as a model of human renovascular hypertension, mechanisms leading to the development of fibrosis and atrophy in the cuffed kidney and compensatory hyperplasia in the contralateral kidney have not been defined. Based on the well-established role of the transforming growth factor (TGF)-β signaling pathway in renal fibrosis, we tested the hypothesis that abrogation of TGF-β/Smad3 signaling would prevent fibrosis in the cuffed kidney. Renal artery stenosis (RAS) was established in mice with a targeted disruption of exon 2 of the Smad3 gene (Smad3 KO) and wild-type (WT) controls by placement of a polytetrafluoroethylene cuff on the right renal artery. Serial pulse-wave Doppler ultrasound assessments verified that blood flow through the cuffed renal artery was decreased to a similar extent in Smad3 KO and WT mice. Two weeks after surgery, systolic blood pressure and plasma renin activity were significantly elevated in both the Smad3 KO and WT mice. The cuffed kidney of WT mice developed renal atrophy (50% reduction in weight after 6 wk, P < 0.0001), which was associated with the development of interstitial fibrosis, tubular atrophy, and interstitial inflammation. Remarkably, despite a similar reduction of renal blood flow, the cuffed kidney of the Smad3 KO mice showed minimal atrophy (9% reduction in weight, P = not significant), with no significant histopathological alterations (interstitial fibrosis, tubular atrophy, and interstitial inflammation). We conclude that abrogation of TGF-β/Smad3 signaling confers protection against the development of fibrosis and atrophy in RAS.

Comparative Efficacy of Group and Individual Feedback in Gross Anatomy for Promoting Medical Student Professionalism.

Professionalism is a core competency of medical training that requires students to develop the skills of providing and receiving feedback. Our study evaluated the effectiveness of delivering feedback in a group setting compared with an individual setting. The first‐year class of Mayo medical students (n = 49) enrolled in gross anatomy (in dissection teams), completed weekly anonymous evaluations of themselves and their teammates regarding seven aspects of professionalism (altruism, compassion, respect, honesty/integrity, responsibility, commitment to excellence, and self‐reflection). Professionalism scores from these surveys were calculated using a six‐point Likert scale. Students were also asked to comment on strengths and possible areas for improvement on each peer. At the midpoint of the course, peer comments and professionalism scores were shared with students in debriefing sessions either individually or with their team. Analysis of preintervention and postintervention professionalism scores indicated that the students receiving feedback in a one‐on‐one setting (student and instructor) were more likely to demonstrate higher scores on subsequent evaluations as compared with those students receiving feedback in a group setting (all team members and one instructor). Our findings suggest that providing feedback to first‐year medical students on an individual basis is the best way to improve professional attitudes and behaviors. Anat Sci Educ 3: 64–72, 2010.

Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure.

BACKGROUND Significant morbidity associated with acute liver failure (ALF) is from the systemic inflammatory response syndrome (SIRS). Toll-like receptor 4 (TLR4) has been shown to play an integral role in the modulation of SIRS. However, little is known about the mechanistic role of TLR4 in ALF. Also, no cell type has been identified as the key mediator of the TLR4 pathway in ALF. This study examines the role of TLR4 and Kupffer cells (KCs) in the development of the SIRS following acetaminophen (APAP)-induced ALF. MATERIALS AND METHODS Five groups of mice were established: untreated wild-type, E5564-treated (a TLR4 antagonist), gadolinium chloride -treated (KC-depleted), clodronate-treated (KC-depleted), and TLR4-mutant. Following APAP administration, 72-h survival, biochemical and histologic liver injury, extent of lung injury and edema, and proinflammatory gene expression were studied. Additionally, TLR4 expression was determined in livers of wild-type and KC-depleted mice. RESULTS Following APAP administration, wild-type, TLR4-mutant, E5564-treated, and KC-depleted mice had significant liver injury. However, wild-type mice had markedly worse survival compared with the other four treatment groups. TLR4-mutant, E5564-treated, and KC-depleted mice had less lung inflammation and edema than wild-type mice. Selected proinflammatory gene expression (interleukin 1β, interleukin 6, tumor necrosis factor) in TLR4-mutant, E5564-treated, and KC-depleted mice was significantly lower compared with wild-type mice after acute liver injury. CONCLUSION This study demonstrates that survival in APAP-induced ALF potentially correlates with the level of proinflammatory gene expression. This study points to a link between TLR4 and KCs in the APAP model of ALF and, more importantly, demonstrates benefits of TLR4 antagonism in ALF.

LPS-Induced Murine Systemic Inflammation Is Driven by Parenchymal Cell Activation and Exclusively Predicted by Early MCP-1 Plasma Levels

Systemic inflammation remains a major cause of morbidity and mortality in the United States, across many disease processes. One classic murine model to study this syndrome is lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4)-dependent systemic inflammation. Although most studies have focused on inflammatory cell TLR4 responses, parenchymal cells also express TLR4. Our objective was to define the in vivo role of parenchymal- versus marrow-derived cell activation via TLR4 during LPS-induced inflammation. Mice bearing TLR4 on parenchymal cells only, marrow-derived cells only, both, or neither were generated using bone marrow transplantation. Mortality occurred only in mice that had TLR4 expression on their parenchymal cells. Before onset, virtually all major plasma cytokines and blood neutrophil responses were related to marrow-derived cell activation via TLR4. The only cytokine predictive of oncoming systemic inflammation was the chemokine monocyte chemoattractant protein-1. Late blood neutrophil responses were related to the presence of TLR4 on either parenchymal or marrow cells, whereas plasma cytokine elevations late in LPS-induced systemic inflammation were dependent on mice having TLR4 in both cell compartments. Parenchymal cell activation via TLR4 is a key component of LPS-induced systemic inflammation and mortality, although most plasma cytokine levels and blood neutrophil responses were not key components. Given its unique role, future studies into monocyte chemoattractant protein-1s exact role during systemic inflammation are warranted.

Learning to Lead: Self- and Peer Evaluation of Team Leaders in the Human Structure Didactic Block.

Increasing emphasis on leadership in medical education has created a need for developing accurate evaluations of team leaders. Our study aimed to compare the accuracy of self‐ and peer evaluation of student leaders in the first‐year Human Structure block (integrated gross anatomy, embryology, and radiology). Forty‐nine first‐year medical students at Mayo Medical School were assigned to learning teams of three or four members. Teams worked together on daily laboratory dissection, clinical projects, embryology presentations, and daily group quizzes. Student team leaders were responsible for leading laboratory dissection, reviewing radiographic findings, and organizing group assignments. Weekly electronic surveys were administered to evaluate team leaders on altruism, compassion, respect, integrity, responsibility, commitment to excellence, and self‐reflection. Results demonstrated that team leaders rated themselves lower than their peers rated them in multiple aspects of leadership. Peer evaluation of team leaders was statistically higher than self‐evaluation in all traits measured except respect. Female leaders were rated higher by their peers in the areas of responsibility and self‐reflection compared to male leaders. This study demonstrates the need for increased communication between team leaders and members, along with creation of a mutually respectful environment, to improve leader awareness of their abilities and foster team success. Anat Sci Educ 2:210–217, 2009.

Reliability of the identification of the systemic inflammatory response syndrome in critically ill infants and children.

Objective: To assess interobserver reliability of the identification of episodes of the systemic inflammatory response syndrome in critically ill hospitalized infants and children. Design: Retrospective, cross-sectional study of the application of the 2005 consensus definition of systemic inflammatory response syndrome in infants and children by two independent, trained reviewers using information in the electronic medical record. Setting: Eighteen-bed pediatric multidisciplinary medical/surgical pediatric intensive care unit. Patients: A randomly selected sample of children admitted consecutively to the pediatric intensive care unit between May 1 and September 30, 2009. Interventions: None. Measurements and Main Results: Sixty infants and children were selected from a total of 343 admitted patients. Their median age was 3.9 yrs (interquartile range, 1.5–12.7), 57% were female, and 68% were Caucasian. Nineteen (32%) children were identified by both reviewers as having an episode of systemic inflammatory response syndrome (88% agreement, 95% confidence interval 78–94; &kgr; = 0.75, 95% confidence interval 0.59–0.92). Among these 19 children, agreement between the reviewers for individual systemic inflammatory response syndrome criteria was: temperature (84%, 95% confidence interval 60–97); white blood cell count (89%, 95% confidence interval 67–99); respiratory rate (84%, 95% confidence interval 60–97); and heart rate (68%, 95% confidence interval 33–87). Conclusions: Episodes of systemic inflammatory response syndrome in critically ill infants and children can be identified reproducibly using the consensus definition.

Monocyte HLA-DR expression and neutrophil CD64 expression as biomarkers of infection in critically ill neonates and infants

Background:Reduced monocyte HLA-DR expression and increased neutrophil CD64 expression have been proposed as biomarkers of infection.Methods:From 2009–2011, blood samples from neonatal intensive care unit (NICU) and pediatric intensive care unit (ICU) patients <1 y of age were collected at enrollment and during subsequent evaluation for suspected infection, if it occurred. Samples were analyzed for monocyte HLA-DR and neutrophil CD64 expression levels by flow cytometry.Results:Forty-seven infants had study samples collected at enrollment; 26 infants had study samples collected at the time of a suspected infection. At enrollment, there was an inverse relationship between neutrophil CD64 expression and age (P ≤ 0.047). At the time of suspected infection, infants with an infection demonstrated a lower percentage of HLA-DR+ monocytes (P = 0.02, area under the curve (AUC) 0.78), higher percentage of CD64+ neutrophils (P = 0.009, AUC 0.81), and higher neutrophil CD64 expression levels (P = 0.04, AUC 0.75).Conclusion:Monocyte HLA-DR and neutrophil CD64 expression in critically ill infants are related to age and infection.

Does emotional intelligence change during medical school gross anatomy course? Correlations with students' performance and team cohesion.

Emotional intelligence (EI) has been associated with increased academic achievement, but its impact on medical education is relatively unexplored. This study sought to evaluate change in EI, performance outcomes, and team cohesion within a team‐based medical school anatomy course. Forty‐two medical students completed a pre‐course and post‐course Schutte Self‐Report Emotional Intelligence Test (SSEIT). Individual EI scores were then compared with composite course performance grade and team cohesion survey results. Mean pre‐course EI score was 140.3 out of a possible 160. During the course, mean individual EI scores did not change significantly (P = 0.17) and no correlation between EI scores and academic performance was noted (P = 0.31). In addition, EI did not correlate with team cohesion (P = 0.16). While business has found significant utility for EI in increasing performance and productivity, its role in medical education is still uncertain. Anat Sci Educ 9: 143–149.

How do I … manage the platelet transfusion–refractory patient?

Platelet transfusion–refractoriness is a challenging and expensive clinical scenario seen most often in patients with hematologic malignancies. Although the majority of platelet transfusion–refractory cases are due to nonimmune causes, a significant minority are caused by alloimmunization against Class I human leukocyte antigens (HLAs) or human platelet antigens (HPAs). Such platelet transfusion–refractory patients can be effectively managed with appropriate antigen‐negative products.

Fetal and Neonatal Alloimmune Thrombocytopenia

Fetal and neonatal alloimmune thrombocytopenia [FNAIT] is a rare but potentially devastating condition that occurs when mothers form alloantibodies to paternally inherited fetal platelet antigens (often members of a human platelet antigen group). Unlike hemolytic disease of the newborn and fetus due to maternal erythrocyte alloantibodies, FNAIT commonly occurs during a mother’s very first pregnancy and thus is not realized until the birth of an affected child. Affected fetuses and neonates can suffer from mucocutaneous bleeding, intracranial hemorrhage, and even death. These same anti-platelet alloantibodies can also cause post-transfusion purpura, a rare transfusion reaction that causes isolated, unexplained, and profound thrombocytopenia several days after a blood transfusion (usually after receiving a non-platelet blood product). Post-transfusion purpura also inexplicably involves the destruction of the recipient’s own native platelets and has a 5–10% mortality rate from bleeding complications.