Herpes simplex encephalitis is linked with selective mitochondrial damage; a post-mortem and in vitro study

Herpes simplex virus type-1 (HSV-1) encephalitis (HSE) is the most commonly diagnosed cause of viral encephalitis in western countries. Despite antiviral treatment, HSE remains a devastating disease with high morbidity and mortality. Improved understanding of pathogenesis may lead to more effective therapies. Mitochondrial damage has been reported during HSV infection in vitro. However, whether it occurs in the human brain and whether this contributes to the pathogenesis has not been fully explored. Minocycline, an antibiotic, has been reported to protect mitochondria and limit brain damage. Minocycline has not been studied in HSV infection. In the first genome-wide transcriptomic study of post-mortem human HSE brain tissue, we demonstrated a highly preferential reduction in mitochondrial genome (MtDNA) encoded transcripts in HSE cases (n = 3) compared to controls (n = 5). Brain tissue exhibited a significant inverse correlation for immunostaining between cytochrome c oxidase subunit 1 (CO1), a MtDNA encoded enzyme subunit, and HSV-1; with lower abundance for mitochondrial protein in regions where HSV-1 was abundant. Preferential loss of mitochondrial function, among MtDNA encoded components, was confirmed using an in vitro primary human astrocyte HSV-1 infection model. Dysfunction of cytochrome c oxidase (CO), a mitochondrial enzyme composed predominantly of MtDNA encoded subunits, preceded that of succinate dehydrogenase (composed entirely of nuclear encoded subunits). Minocycline treated astrocytes exhibited higher CO1 transcript abundance, sustained CO activity and cell viability compared to non-treated astrocytes. Based on observations from HSE patient tissue, this study highlights mitochondrial damage as a critical and early event during HSV-1 infection. We demonstrate minocycline preserves mitochondrial function and cell viability during HSV-1 infection. Minocycline, and mitochondrial protection, offers a novel adjunctive therapeutic approach for limiting brain cell damage and potentially improving outcome among HSE patients

Diagnostic outcome management study in patients with clinically suspected recurrent acute pulmonary embolism with a structured algorithm

INTRODUCTION: The value of diagnostic strategies in patients with clinically suspected recurrent pulmonary embolism (PE) has not been established. The aim was to determine the safety of a simple diagnostic strategy using the Wells clinical decision rule (CDR), quantitative D-dimer testing and computed tomography pulmonary angiography (CTPA) in patients with clinically suspected acute recurrent PE. MATERIALS AND METHODS: Multicenter clinical outcome study in 516 consecutive patients with clinically suspected acute recurrent PE without using anticoagulants. RESULTS: An unlikely clinical probability (Wells rule 4 points or less) was found in 182 of 516 patients (35%), and the combination of an unlikely CDR-score and normal D-dimer result excluded PE in 88 of 516 patients (17%), without recurrent venous thromboembolism (VTE) during 3month follow-up (0%; 95% CI 0.0-3.4%). CTPA was performed in all other patients and confirmed recurrent PE in 172 patients (overall prevalence of PE 33%) and excluded PE in the remaining 253 patients (49%). During follow-up, seven of these 253 patients returned with recurrent VTE (2.8%; 95% CI 1.2-5.5%), of which in one was fatal (0.4 %; 95 % CI 0.02-1.9%). The diagnostic algorithm was feasible in 98% of patients. CONCLUSIONS: A diagnostic algorithm consisting of a clinical decision rule, D-dimer test and CTPA is effective in the management of patients with clinically suspected acute recurrent PE. CTPA provides reasonable safety in excluding acute recurrent PE in patients with a likely clinical probability or an elevated D-dimer test for recurrent PE, with a low risk for fatal PE at follow-up

The natural course of hemodynamically stable pulmonary embolism: Clinical outcome and risk factors in a large prospective cohort study

BACKGROUND: Pulmonary embolism (PE) is a potentially fatal disease with risks of recurrent venous thrombotic events (venous thromboembolism [VTE]) and major bleeding from anticoagulant therapy. Identifying risk factors for recurrent VTE, bleeding, and mortality may guide clinical decision making. OBJECTIVE: To evaluate the incidence of recurrent VTE, hemorrhagic complications, and mortality in patients with PE, and to identify risk factors and the time course of these events. DESIGN: We evaluated consecutive patients with PE derived from a prospective management study, who were followed for 3 months, treated with anticoagulants, and underwent objective diagnostic testing for suspected recurrent VTE or bleeding. RESULTS: Of 673 patients with complete follow-up, 20 patients (3.0%; 95% confidence interval [CI], 1.8 to 4.6%) had recurrent VTE. Eleven of 14 patients with recurrent PE had a fatal PE (79%; 95% CI, 49 to 95%), occurring mostly in the first week after diagnosis of initial PE. In 23 patients (3.4%; 95% CI, 2.2 to 5.1%), a hemorrhagic complication occurred, 10 of which were major bleeds (1.5%; 95% CI, 0.7 to 2.7%), and 2 were fatal (0.3%; 95% CI, 0.04 to 1.1%). During the 3-month follow-up, 55 patients died (8.2%; 95% CI, 6.2 to 10.5%). Risk factors for recurrent VTE were immobilization for > 3 days and being an inpatient; having COPD or malignancies were risk factors for bleeding. Higher age, immobilization, malignancy, and being an inpatient were risk factors for mortality. CONCLUSIONS: Recurrent VTE occurred in a small percentage of patients treated for an acute PE, and the majority of recurrent PEs were fatal. Immobilization, hospitalization, age, COPD, and malignancies were risk factors for recurrent VTE, bleeding, and mortality. Close monitoring may be indicated in these patients, precluding them from out-of-hospital start of treatmen

Safety and clinical utility of four clinical decision rules in the diagnostic management of acute pulmonary embolism-the prometheus diagnosis study

Background: Several clinical decision rules (CDRs) are available for the exclusion of acute pulmonary embolism (PE). This prospective multi-center study compared the safety and clinical utility of four CDRs (Wells rule, revised Geneva score, simplified Wells rule and simplified revised Geneva score) in excluding PE in combination with D-dimer testing. Methods: Clinical probability of patients with suspected acute PE was assessed using a computerized based “black box”, which calculated all CDRs and indicated the next diagnostic step. A “PE unlikely” result according to all CDRs in combination with a normal D-dimer result excluded PE, while patients with “PE likely” according to at least one of the CDRs or an abnormal D-dimer result underwent CT-scanning. Patients in whom PE was excluded were followed for three months. Results: 807 consecutive patients were included and PE prevalence was 23%. The number of patients categorized as “PE unlikely” ranged from 62% (simplified Wells rule) to 72% (Wells rule). Combined with a normal D-dimer level, the CDRs excluded PE in 22-24% of patients. The total failure rates of the CDR-D-dimer combinations were similar (1 failure, 0.5- 0.6%, upper 95% CI 2.9- 3.1%). Despite 30% of the patients had discordant CDR outcomes, PE was missed in none of the patients with discordant CDRs and a normal D-dimer result. Conclusions: All four CDRs show similar safety and clinical utility for exclusion of acute PE in combination with a normal D-dimer level. With this prospective validation, the more straightforward simplified scores are ready for use in clinical practice