Adam Reinhardt

Effect of Simvastatin Injections on Temporomandibular Joint Inflammation in Growing Rats

PURPOSE Juvenile idiopathic arthritis often affects the temporomandibular joint (TMJ), resulting in facial deformities, and intra-articular injections of anti-inflammatory steroids used in treatment may inhibit bone growth in the developing condyle. The purpose of this pilot study was to evaluate the anti-inflammatory properties of simvastatin (SIM), a bone anabolic drug, compared with the common steroid triamcinolone hexacetonide (TH) in experimental TMJ arthritis of growing rats. METHODS Joint inflammation was induced by injecting complete Freunds adjuvant (CFA) into the TMJs of 32 growing (4-week-old) Sprague-Dawley rats while simultaneously receiving 1) ethanol drug carrier, 2) 0.1 mg of SIM, 3) 0.5 mg of SIM, or 4) 0.15 mg of TH. Six rats had no treatment to the TMJ. Animals were euthanized 28 days later, and TMJs were decalcified and stained with hematoxylin-eosin. RESULTS Histopathologic TMJ results showed that CFA injection along with drug carrier induced increased thickness of the articular layer on the head of the condyle and inflammation of the retrodiscal area (CFA and ethanol). Although both TH and SIM reduced the articular layer thickness, 0.5 mg of SIM was more effective at reducing subsynovial inflammation. CONCLUSIONS Intra-articular simvastatin showed anti-inflammatory properties in this TMJ model, prompting its further study in the growing TMJ, where bone anabolic properties would be important.

Preliminary response to Janus kinase inhibition with baricitinib in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE)

Preliminary response to Janus kinase inhibition with baricitinib in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) G Montealegre, A Reinhardt, P Brogan, Y Berkun, A Zlotogorski, D Brown, P Chira, L Gao, J Dare, S Schalm, R Merino, D Chapelle, H Kim, S Judd, M O’Brien, A Almeida De Jesus, Y Kim, B Kost, Y Huang, S Paul, A Brofferio, C-C Lee, C Hadigan, T Heller, C Minniti, K Rother, R Goldbach-Mansky

Impact of local steroid or statin treatment of experimental temporomandibular joint arthritis on bone growth in young rats

INTRODUCTION Juvenile idiopathic arthritis in temporomandibular joints (TMJs) is often treated with intra-articular steroid injections, which can inhibit condylar growth. The purpose of this study was to compare simvastatin (a cholesterol-lowering drug that reduces TMJ inflammation) with the steroid triamcinolone hexacetonide in experimental TMJ arthritis. METHODS Joint inflammation was induced by injecting complete Freunds adjuvant (CFA) into the TMJs of 40 growing Sprague Dawley rats; 4 other rats were left untreated. In the same intra-articular injection, one of the following was applied: (1) 0.5 mg of simvastatin in ethanol carrier, (2) ethanol carrier alone, (3) 0.15 mg of triamcinolone hexacetonide, (4) 0.5 mg of simvastatin and 0.15 mg of triamcinolone hexacetonide, or (5) nothing additional to the CFA. The animals were killed 28 days later, and their mandibles were evaluated morphometrically and with microcomputed tomography. RESULTS The analysis showed that the TMJs subjected to CFA alone had decreased ramus height compared with those with no treatment (P <0.05). Groups that had injections containing the steroid overall had decreases in weight, ramus height, and bone surface density when compared with the CFA-alone group (P <0.0001). Groups that had injections containing simvastatin, however, had overall increases in weight (P <0.0001), ramus height (P <0.0001), condylar width (P <0.05), condylar bone surface density (P <0.05), and bone volume (P <0.0001) compared with the groups receiving the steroid injections, and they were not different from the healthy (no treatment) group. CONCLUSIONS Treatment of experimentally induced arthritis in TMJs with intra-articular simvastatin preserved normal condylar bone growth.

Erratum: Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production (Journal of Clinical Investigation (2015) 125:11 (4196-4211) DOI: 10.1172/JCI81260)

Autosomal recessive mutations in proteasome subunit b 8 (PSMB8), which encodes the inducible proteasome subunit b5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes a7), PSMB4 (encodes b7), PSMB9 (encodes b1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical [...] Research Article Immunology

Stratification of patients with autoinflammatory phenotypes by interferon (IFN) score suggests a new group of IFN mediated autoinflammatory diseases with overlapping clinical phenotypes

Stratification of patients with autoinflammatory phenotypes by interferon (IFN) score suggests a new group of IFN mediated autoinflammatory diseases with overlapping clinical phenotypes A Almeida de Jesus, Z Deng, S Brooks, H Kim, G Montealegre, D Chapelle, Y Liu, B Marrero, L Malle, M O’Brien, W Goodspeed, Y Huang, P Hashkes, G Nasrullayeva, MT Terreri, C Silva, B Arabshahi, K O’Neill, M Punaro, L Moorthy, A Reinhardt, V Lilleby, J Niemela, S Rosenzweig, T Fleisher, R Goldbach-Mansky

Feedback Quality Using an Observation Form

Background: Direct observations with focused feedback are critical components for medical student education. Numerous challenges exist in providing useful comments to students during their clerkships. Students’ evaluations of the clerkship indicated they were not receiving feedback from preceptors or house officers. Objective: To encourage direct observation with feedback, Structured Patient Care Observation (SPCO) forms were used to evaluate third-year medical students during patient encounters. Design: In 2014-2015, third-year medical students at a Midwestern medical school completing an 8-week pediatrics clerkship provided experiences on inpatient wards and in ambulatory clinics. Students were expected to solicit feedback using the SPCO form. Results/Findings: A total of 121 third-year medical students completed the pediatrics clerkship. All of the students completed at least one SPCO form. Several students had more than one observation documented, resulting in 161 SPCOs submitted. Eight were excluded for missing data, leaving 153 observations for analysis. Encounter settings included hospital (70), well-child visits (34), sick visits (41), not identified (8). Observers included attending physicians (88) and residents (65). The SPCOs generated 769 points of feedback, comments coalesced into themes of patient interviews, physical examination, or communication with patients and family. Once themes were identified, comments within each theme were further categorized as either actionable or reinforcing feedback. Discussion: SPCOs provided a structure to receive formative feedback from clinical supervisors. Within each theme, reinforcing feedback and actionable comments specific enough to be useful in shaping future encounters were identified.