Case Report: Rocky Mountain Spotted Fever with Adrenalectomy and a Hard-to-Find Tick.

BACKGROUND Rocky Mountain spotted fever (RMSF) is a potentially fatal infectious disease caused by the gram-negative intracellular bacterium Rickettsia rickettsii. The classic triad includes fever, rash, and history of tick exposure; however, the triad presents in only 3% to 18% of cases at the initial visit, and the tick bite is often painless and overlooked. RMSF can present with other manifestations, including hyponatremia, lymphopenia, thrombocytopenia, and coagulopathy. Some of these manifestations can be overlooked if they overlap with manifestations of a patient's pre-existing conditions. CASE REPORT A 43-year-old woman with RMSF presented with fever and treatment-resistant hyponatremia before developing a rash. Initially, the cause of her hyponatremia was attributed to adrenal insufficiency and dehydration. After appropriate treatments with hormone replacement therapy and intravenous hydration, her laboratory values remained relatively unchanged. A rash later appeared with an atypical RMSF pattern, warranting a detailed integumentary examination, which uncovered the culprit tick in an unusual location. After starting doxycycline, the patient's signs and symptoms, including her sodium level, improved. CONCLUSIONS We conclude that the diagnosis of RMSF is an empiric diagnosis based on clinical signs, symptoms, and appropriate epidemiologic settings for tick exposures. However, typical clinical signs do not always display at presentation. Other manifestations that a patient's pre-existing conditions can simultaneously cause should not be overlooked and should be examined holistically with other signs, symptoms, laboratory values, and physical examinations. Early treatment with doxycycline is encouraged as evidence strongly suggests that early treatment is correlated with lower mortality.

Peer Observations: Enhancing Bedside Clinical Teaching Behaviors.

Background Medical training relies on direct observations and formative feedback. After residency graduation, opportunities to receive feedback on clinical teaching diminish. Although feedback through learner evaluations is common, these evaluations can be untimely, non-specific, and potentially biased. On the other hand, peer feedback in a small group setting or lecture format has been shown to be beneficial to teaching behaviors, however, little is known if peer observation using a standardized tool followed by feedback results in improved teaching behaviors. Therefore, the objective of this study was to examine if feedback after peer observation results in improved inpatient teaching behaviors. Methods This study was conducted at a tertiary care hospital. Academic hospitalists in the Division of Hospital Medicine developed a standardized 28-item peer observation tool based on the Stanford Faculty Development Program to observe their peers during bedside teaching rounds and provide timely feedback after observation. The tool focused on five teaching domains (learning climate, control of session, promotion of understanding and retention, evaluation, and feedback) relevant to the inpatient teaching environment. Teaching hospitalists were observed at the beginning of a two-week teaching rotation, given feedback, and then observed at the end of the rotation. Furthermore, we utilized a post-observation survey to assess the teaching and observing hospitalists' comfort with observation and the usefulness of the feedback. We used mixed linear models with crossed design to account for correlations between the observations. Models were adjusted for gender, age, and years of experience. We tested the internal validity of the instrument with Cronbach's alpha. Results Seventy (range: one to four observations per faculty) observations were performed involving 27 teaching attendings. A high proportion of teachers were comfortable with the observation (79%) and found the feedback helpful (92%), and useful for their own teaching (88%). Mean scores in teaching behavior domains ranged from 2.1 to 2.7. In unadjusted and adjusted analysis, each teaching observation was followed by higher scores in learning climate (adjusted improvement = 0.09; 95% CI = 0.02-0.15; p = 0.007) and promotion of understanding and retention (adjusted improvement = 0.09; 95% CI = 0.02-0.17; p = 0.01). The standardized observation tool had Cronbach's alpha of 0.81 showing high internal validity. Conclusions Peer observation of bedside teaching followed by feedback using a standardized tool is feasible and results in measured improvements in desirable teaching behaviors. The success of this approach resulted in the expansion of peer observation to other Divisions within the Department of Internal Medicine at our Institution.

Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b.

Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast, SmegLM enhances MAPK-activated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3' UTR region of TNF mRNA and destabilizes the transcript, whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/Akt pathway. We show that macrophages incubated with TB-LM and live M.tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast, SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M.tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M.tb to subvert host immunity and potentially increase its virulence.

NOD2 controls the nature of the inflammatory response and subsequent fate of Mycobacterium tuberculosis and M. bovis BCG in human macrophages.

Mycobacterium tuberculosis (M.tb), which causes tuberculosis, is a host-adapted intracellular pathogen of macrophages. Intracellular pattern recognition receptors in macrophages such as nucleotide-binding oligomerization domain (NOD) proteins regulate pro-inflammatory cytokine production. NOD2-mediated signalling pathways in response to M.tb have been studied primarily in mouse models and cell lines but not in primary human macrophages. Thus we sought to determine the role of NOD2 in regulating cytokine production and growth of virulent M.tb and attenuated Mycobacterium bovis BCG (BCG) in human macrophages. We examined NOD2 expression during monocyte differentiation and observed a marked increase in NOD2 transcript and protein following 2-3 days in culture. Pre-treatment of human monocyte-derived and alveolar macrophages with the NOD2 ligand muramyl dipeptide enhanced production of TNF-α and IL-1ß in response to M.tb and BCG in a RIP2-dependent fashion. The NOD2-mediated cytokine response was significantly reduced following knock-down of NOD2 expression by using small interfering RNA (siRNA) in human macrophages. Finally, NOD2 controlled the growth of both M.tb and BCG in human macrophages, whereas controlling only BCG growth in murine macrophages. Together, our results provide evidence that NOD2 is an important intracellular receptor in regulating the host response to M.tb and BCG infection in human macrophages.

Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses.

Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and has high expression in alternatively activated alveolar macrophages and macrophage-derived foam cells, both cell types relevant to tuberculosis pathogenesis. In this study, we show that virulent M. tuberculosis and its cell wall mannose-capped lipoarabinomannan induce PPARgamma expression through a macrophage mannose receptor-dependent pathway. When activated, PPARgamma promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPARgamma agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A(2) activation, which is required for PPARgamma ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-kappaB activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPARgamma and preferentially uses the NF-kappaB-mediated pathway to induce IL-8 production. Finally, PPARgamma knockdown in human macrophages enhances TNF production and controls the intracellular growth of M. tuberculosis. These data identify a new molecular pathway that links engagement of the mannose receptor, an important pattern recognition receptor for M. tuberculosis, with PPARgamma activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis.