Pulmonary Embolism during a Retrial of Low-dose Clozapine.

Pulmonary emboli (PE) are increasingly recognized as an adverse effect of clozapine. However, little is known about the characteristics or mechanisms of clozapine-associated PE. We present a case of a 34-year-old with treatment-refractory schizophrenia who developed rhabdomyolysis during his first clozapine trial. During re-trial on a lower dose than his initial trial, the patient developed chest pain that he attributed to "pacemakers." The pleuritic description and associated tachycardia prompted medical workup and the patient was ultimately diagnosed with a clozapine-associated PE. The patient's only risk factors for PE were obesity and tobacco use, while his hypercoagulability workup was unrevealing. Clozapine use was continued at a lower dose following these adverse effects given inefficacy of other agents in managing the patient's psychotic symptoms. The patient experienced significant relief of psychotic symptoms with continued clozapine therapy and a course of electroconvulsive therapy. The patient's presentation was unusual in that it occurred during a retrial of clozapine, after the initial trial was stopped when he developed rhabdomyolysis. This case demonstrates the importance of maintaining vigilance for PE in patients on clozapine as well as not dismissing somatic complaints in patients experiencing psychosis. Additionally, given his history rhabdomyolysis, an uncommon adverse effect of clozapine, the development of a second uncommon adverse effect (PE) raises the question of whether these events may be associated.

Orthodontic loading activates cell-specific autophagy in a force-dependent manner.

INTRODUCTION: Orthodontic tooth movement (OTM) relies on bone remodeling and controlled aseptic inflammation. Autophagy, a conserved homeostatic pathway, has been shown to play a role in bone turnover. We hypothesize that autophagy participates in regulating bone remodeling during OTM in a force-dependent and cell type-specific manner. METHODS: A split-mouth design was used to load molars with 1 of 3 force levels (15, 30, or 45 g of force) in mice carrying a green fluorescent protein-LC3 transgene to detect cellular autophagy. Fluorescent microscopy and quantitative polymerase chain reaction analyses were used to evaluate autophagy activation and its correlation with force level. Cell type-specific antibodies were used to identify cells with green fluorescent protein-positive puncta (autophagosomes) in periodontal tissues. RESULTS: Autophagic activity increased shortly after loading with moderate force and was associated with the expression of bone turnover, inflammatory, and autophagy markers. Different load levels resulted in altered degrees of autophagic activation, gene expression, and osteoclast recruitment. Autophagy was specifically induced by loading in macrophages and osteoclasts found in the periodontal ligament and alveolar bone. Data suggest autophagy participates in regulating bone turnover during OTM. CONCLUSIONS: Autophagy is induced in macrophage lineage cells by orthodontic loading in a force-dependent manner and plays a role during OTM, possibly through modulation of osteoclast bone resorption. Exploring the roles of autophagy in OTM is medically relevant, given that autophagy is associated with oral and systemic inflammatory conditions.

Roles of autophagy in orthodontic tooth movement.

INTRODUCTION: Orthodontic tooth movement (OTM) relies on efficient remodeling of alveolar bone. While a well-controlled inflammatory response is essential during OTM, the mechanism regulating inflammation is unknown. Autophagy, a conserved catabolic pathway, has been shown to protect cells from excess inflammation in disease states. We hypothesize that autophagy plays a role in regulating inflammation during OTM. METHODS: A split-mouth design was used to force load molars in adult male mice, carrying a GFP-LC3 transgene for in vivo detection of autophagy. Confocal microscopy, Western blot, and quantitative polymerase chain reaction analyses were used to evaluate autophagy activation in tissues of loaded and control molars at time points after force application. Rapamycin, a Food and Drug Administration-approved immunosuppressant, was injected to evaluate induction of autophagy. RESULTS: Autophagy activity increases shortly after loading, primarily on the compression side of the tooth, and is closely associated with inflammatory cytokine expression and osteoclast recruitment. Daily administration of rapamycin, an autophagy activator, led to reduced tooth movement and osteoclast recruitment, suggesting that autophagy downregulates the inflammatory response and bone turnover during OTM. CONCLUSIONS: This is the first demonstration that shows that autophagy is induced by orthodontic loading and plays a role during OTM, likely via negative regulation of inflammatory response and bone turnover. Exploring roles of autophagy in OTM holds great promise, as aberrant autophagy is associated with periodontal disease and its related systemic inflammatory disorders.