Engineered Tissue Inhibitor of Metalloproteinases-3 Variants Resistant to Endocytosis Have Prolonged Chondroprotective Activity.

Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a central inhibitor of matrix-degrading and sheddase families of metalloproteinases. Extracellular levels of the inhibitor are regulated by the balance between its retention on the extracellular matrix and its endocytic clearance by the scavenger receptor low density lipoprotein receptor-related protein 1 (LRP1). Here, we used molecular modeling to predict TIMP-3 residues potentially involved in binding to LRP1 based on the proposed LRP1 binding motif of 2 lysine residues separated by about 21 Å and mutated the candidate lysine residues to alanine individually and in pairs. Of the 22 mutants generated, 13 displayed a reduced rate of uptake by HTB94 chondrosarcoma cells. The two mutants (TIMP-3 K26A/K45A and K42A/K110A) with lowest rates of uptake were further evaluated and found to display reduced binding to LRP1 and unaltered inhibitory activity against prototypic metalloproteinases. TIMP-3 K26A/K45A retained higher affinity for sulfated glycosaminoglycans than K42A/K110A and exhibited increased affinity for ADAMTS-5 in the presence of heparin. Both mutants inhibited metalloproteinase-mediated degradation of cartilage at lower concentrations and for longer than wild-type TIMP-3, indicating that their increased half-lives improved their ability to protect cartilage. These mutants may be useful in treating connective tissue diseases associated with increased metalloproteinase activity.

Bilateral Pulmonary Emboli and Deep Venous Thrombi in Association With Chronic Inflammatory Demyelinating Polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune neurological disorder primarily affecting the peripheral nervous system. It is important to recognize because treatment with immunomodulators can improve symptoms. We present the case of a 61-year-old man who developed a saddle pulmonary embolus as well as right-sided deep venous thrombi following left knee arthroplasty. Two months later, he had persistent pre-syncopal symptoms with exertion and had developed paraesthesias in both feet. Invasive cardiopulmonary exercise testing revealed preload failure with no evidence of pulmonary hypertension. He was then referred to neurology where clinical history, physical examination, autonomic battery, and nerve biopsy were consistent with a diagnosis of CIDP with autonomic dysfunction. Extensive venous thromboembolism may be a unique presentation of CIDP. The mechanisms, which may lead to hypercoagulability in CIDP, include the presence of systemic inflammation and denervation of peripheral vasculature leading to stasis.

Social Behaviors Associated With a Positive COVID-19 Test Result.

Objective To compare the social behaviors of individuals who were tested positive for COVID-19 relative to non-infected individuals.   Methods We sent COVID positive cases and age/gender-matched controls a survey regarding their social behaviors via MyChart (online patient portal). We called cases if they did not complete the electronic survey within two days. Data were collected from May to June 2020. Survey responses for cases without close contact and controls were compared using Pearson chi-square or Fisher's exact tests as appropriate.   Results A total of 339 participants completed the survey (113 cases, 226 controls); 45 (40%) cases had known contact with COVID-19. Cases were more likely to have recently traveled (4% vs. 0%, p = 0.01) or to work outside the home (40% vs. 25%, p = 0.02). There was no difference in the rates of attending private or public gatherings, mask/glove use, hand-washing, cleaning surfaces, and cleaning mail/groceries between cases and controls.   Conclusions Sixty percent of cases had no known contact with COVID-19, indicating ongoing community transmission and underlining the importance of contact tracing. The greater percentage of cases who work outside the home provides further evidence for social distancing and remote telework when possible.