The emerging importance of lymphatics in health and disease: An NIH workshop report

The lymphatic system (LS) is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the LS has been shown to play a key role in the pathophysiology of many disease states. Thus, improved understanding of the anatomical and molecular characteristics of the LS may provide approaches for disease prevention or treatment. Recent advances harnessing single-cell technologies, clinical imaging, discovery of biomarkers, and computational tools have led to the development of strategies to study the LS. This Review summarizes the outcomes of the NIH workshop entitled Yet to be Charted: Lymphatic System in Health and Disease, held in September 2022, with emphasis on major areas for advancement. International experts showcased the current state of knowledge regarding the LS and highlighted remaining challenges and opportunities to advance the field

Worse health-related quality of life and hip function in female patients with elevated chromium levels: A prospective study of 659 patients with a recalled THR metal-on-metal implant

Background and purpose Blood metal ion levels can be an indicator for detecting implant failure in metal-on-metal (MoM) hip arthroplasties. Little is known about the effect of bilateral MoM implants on metal ion levels and patient-reported outcomes. We compared unilateral patients and bilateral patients with either an ASR hip resurfacing (HR) or an ASR XL total hip replacement (THR) and investigated whether cobalt or chromium was associated with a broad spectrum of patient outcomes. Patients and methods From a registry of 1,328 patients enrolled in a multicenter prospective follow-up of the ASR Hip System, which was recalled in 2010, we analyzed data from 659 patients (311 HR, 348 THR) who met our inclusion criteria. Cobalt and chromium blood metal ion levels were measured and a 21-item patient-reported outcome measures (PROMs) questionnaire was used mean 6 years after index surgery. Results: Using a minimal threshold of ≥7 ppb, elevated chromium ion levels were found to be associated with worse health-related quality of life (HRQoL) (p < 0.05) and hip function (p < 0.05) in women. These associations were not observed in men. Patients with a unilateral ASR HR had lower levels of cobalt ions than bilateral ASR HR patients (p < 0.001) but similar levels of chromium ions (p = 0.09). Unilateral ASR XL THR patients had lower chromium and cobalt ion levels (p < 0.005) than bilateral ASR XL THR patients. Interpretation Chromium ion levels of ≥7 ppb were associated with reduced functional outcomes in female MoM patients

Perspectives on Cognitive Phenotypes and Models of Vascular Disease

Clinical investigations have established that vascular-Associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits

Optimization of wear loss in silicon nitride (Si3N4)–hexagonal boron nitride (hBN) composite using DoE–Taguchi method

Introduction The contacting surfaces subjected to progressive loss of material known as ‘wear,’ which is unavoidable between contacting surfaces. Similar kind of phenomenon observed in the human body in various joints where sliding/rolling contact takes place in contacting parts, leading to loss of material. This is a serious issue related to replaced joint or artificial joint. Case description Out of the various material combinations proposed for artificial joint or joint replacement Si3N4 against Al2O3 is one of in ceramic on ceramic category. Minimizing the wear loss of Si3N4 is a prime requirement to avoid aseptic loosening of artificial joint and extending life of joint. Discussion and evaluation In this paper, an attempt has been made to investigate the wear loss behavior of Si3N4–hBN composite and evaluate the effect of hBN addition in Si3N4 to minimize the wear loss. DoE–Taguchi technique is used to plan and analyze experiments. Conclusion Analysis of experimental results proposes 15 N load and 8 % of hBN addition in Si3N4 is optimum to minimize wear loss against alumina

Lack of Matrilin-2 Favors Liver Tumor Development via Erk1/2 and GSK-3 beta Pathways In Vivo

Matrilin-2 (Matn2) is a multidomain adaptor protein which plays a role in the assembly of extracellular matrix (ECM). It is produced by oval cells during stem cell-driven liver regeneration. In our study, the impact of Matn2 on hepatocarcinogenesis was investigated in Matn2(-/-) mice comparing them with wild-type (WT) mice in a diethylnitrosamine (DEN) model. The liver tissue was analyzed macroscopically, histologically and immunohistochemically, at protein level by Proteome Profiler Arrays and Western blot analysis. Matn2(-/-) mice exhibited higher susceptibility to hepatocarcinogenesis compared to wild-type mice. In the liver of Matn2(-/-) mice, spontaneous microscopic tumor foci were detected without DEN treatment. After 15 mu g/g body weight DEN treatment, the liver of Matn2(-/-) mice contained macroscopic tumors of both larger number and size than the WT liver. In contrast with the WT liver, spontaneous phosphorylation of EGFR, Erk1/2 GSK-3 alpha/beta and retinoblastoma protein (p-Rb), decrease in p21/CIP1 level, and increase in beta-Catenin protein expression were detected in Matn2(-/-) livers. Focal Ki-67 positivity of these samples provided additional support to our presumption that the lack of Matn2 drives the liver into a pro-proliferatory state, making it prone to tumor development. This enhanced proliferative capacity was further increased in the tumor nodules of DEN-treated Matn2(-/-) livers. Our study suggests that Matn2 functions as a tumor suppressor in hepatocarcinogenesis, and in this process activation of EGFR together with that of Erk1/2, as well as inactivation of GSK-3 beta, play strategic roles

Mapping the lymphatic system across body scales and expertise domains: A report from the 2021 National Heart, Lung, and Blood Institute workshop at the Boston Lymphatic Symposium

Enhancing our understanding of lymphatic anatomy from the microscopic to the anatomical scale is essential to discern how the structure and function of the lymphatic system interacts with different tissues and organs within the body and contributes to health and disease. The knowledge of molecular aspects of the lymphatic network is fundamental to understand the mechanisms of disease progression and prevention. Recent advances in mapping components of the lymphatic system using state of the art single cell technologies, the identification of novel biomarkers, new clinical imaging efforts, and computational tools which attempt to identify connections between these diverse technologies hold the potential to catalyze new strategies to address lymphatic diseases such as lymphedema and lipedema. This manuscript summarizes current knowledge of the lymphatic system and identifies prevailing challenges and opportunities to advance the field of lymphatic research as discussed by the experts in the workshop