Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.

High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.

Venous thromboembolism related to cytomegalovirus infection: A case report and literature review.

RATIONALE: Herein, we present a case of seemingly unprovoked portal vein thrombosis (PVT) occurring in the context of an acute cytomegalovirus (CMV) infection and prolonged debilitating fatigue. PATIENT CONCERNS: A 46-year-old male airline pilot presented with a 2 week history of abdominal pain, nausea, vomiting, watery diarrhea, and daily recurrent fevers. This was in the context of progressive, debilitating fatigue for 3 months forcing the patient to leave his job. DIAGNOSES: Computed tomography of the abdomen revealed PVT, which was managed initially by heparin infusion. Cefepime was ordered for broad-spectrum antibiotic management of sepsis and possible septic thrombosis. Further workup exposed elevated transaminases consistent with mild hepatitis without synthetic dysfunction and colonoscopy revealed colitis. A comprehensive evaluation for liver disease was notable for a markedly elevated ferritin level. Spiking fevers and neutrophilia persisted for several days despite empiric antimicrobial treatment, but eventually resolved. The remainder of the workup was negative except for positive CMV IgM titer and viral load. This raised suspicion for a hypercoagulable state caused by CMV hepatitis with CMV-induced PVT. Heparin was transitioned to warfarin at the time of discharge. INTERVENTIONS: Given the patient's immunocompetent state and resolution of fevers, antiviral therapy for CMV infection was not initiated. OUTCOMES: The patient continued to improve with a normalization of the serum ferritin level and anticoagulation therapy was stopped after 6 months. LESSONS: There is mounting support for infectious causes of venous thromboembolism (VTE) based on existing molecular biology and clinical research. Meta-analysis of existing data showed that between 1.9% and 9.1% of patients hospitalized with VTE had concurrent acute CMV infection. Theoretical mechanisms for this association include transient formation of antiphospholipid antibodies, transient formation of antibodies targeting CMV capsule phospholipids with procoagulant properties, and direct infection of the endothelial cells. We hope this case will serve as a reminder to consider CMV as a transient cause of PVT and VTE, particularly in light of 2016 guidelines for unprovoked VTE recommending lifelong anticoagulation. We also plan to prospectively study the association of unprovoked VTE and acute CMV infection in our own hospital system.

Spindle cell sarcomatoid carcinoma of the trachea: first case report of surgical resection.

BACKGROUND: Primary malignant tracheal tumors are rare, accounting for approximately 0.2 % of respiratory tract tumors yearly, with squamous cell carcinomas and adenoid cystic carcinomas accounting for two-thirds of these cases. Sarcomatoid carcinomas are a group of poorly differentiated non-small cell lung carcinomas containing a component of sarcoma or sarcoma-like (spindle and/or giant cell) differentiation, categorized into five morphologic subgroups. Spindle cell sarcomatoid carcinoma is a rare variant of sarcomatoid carcinomas, consisting of only spindle-shaped tumor cells. Only one other case has been reported as a primary tracheal tumor. CASE PRESENTATION: We present a 75-year-old male, having progressive dyspnea and cough, with a spindle cell sarcomatoid carcinoma tumor visualized on chest computed tomography scan and confirmed with biopsy. CONCLUSIONS: Due to its low incidence, knowledge of treatment methods, prognostic factors, and etiology is limited thus approaches to eradication have widely varied. We are reporting the second published case of spindle cell sarcomatoid carcinoma of the trachea and the first reported successful outcome of definitive treatment with tracheal resection.