Lymphatic Fluid Mechanics: An In Situ and Computational Analysis of Lymph Flow

The lymphatic system is an extensive vascular network responsible for the transport of fluid, immune cells, proteins and lipids. It is composed of thin-walled vessels, valves, nodes and ducts, which work together to collect fluid, approximately 4 L/day, from the interstitium transporting it back to the systemic network via the great veins. The failure to transport lymph fluid results in a number of disorders and diseases. Lymphedema, for example, is a pathology characterized by the retention of fluid in limbs creating extreme discomfort, reduced mobility and impaired immunity. In general, there are two types of edema: primary edema, being those cases that are inherited (i.e. genetic predisposition), and secondary edema, which develop post-trauma or injury of the lymphatic vessels. With the onset of breast cancer and radiation therapies, the prevalence of secondary edema is on the rise. Clinical studies have shown that up to 80% of women who undergo nodal-dissection surgery develop lymphedema in their arms within 3-5 years of the surgery. Unfortunately, there is no cure or remedy for lymphedema stemming from our lack of understanding of the lymphatic system. The goal of this study was to evaluate lymph flow both experimentally and analytically to better understand the mechanisms regulating lymph transport. In particular we investigated the effects of pressure, volume loads and valve resistance on lymphatic function in the rat mesentery. Our experimental results were then used to develop computational and constitutive models to emulate the dynamic behavior of lymph transport. Collectively, the data illustrate the mechanics of lymphatic contractility and lymph flow. In particular, lymph flow and pumping significantly increased post edemagenic stress in the rat model. Furthermore, lymphangions exhibited highly nonlinear pressure-diameter responses at low pressures between 3-5 cmH2O. These experimental results strongly suggest the regulation of lymph flow via changes in pressure, shear stress and vessel diameter. Furthermore, the computational and constitutive models from this study provide great insight into lymphatic function characterizing the mechanical properties of a single pumping unit (i.e. lymphangion). These models will serve as valuable tools to further lymphatic research

Restorative dentistry considerations in the geriatric dentistry : systematic review

BACKGROUND AND AIM: As the number of elderly people visiting dental clinics increases, it is essential to have sufficient information on the correct treatment as well as the appropriate treatment plan for these patients. Therefore, the present study aimed at reviewing the most important restorative considerations for the elderly.METHOD: In this systematic review study, databases such as Pubmed, Embase, Web of Science, Scopus, ProQuest, Google scholar, as well as Iranian databases were searched with the keywords of elderly dentistry and restorative considerations. Inclusion criteria were original articles and reviews related to restorative dentistry considerations for the elderly without a time limit and being written in either English or Persian. In order to combine the results of the research, a thematic content analysis method was applied.RESULTS: The total number of documents recovered was 4208, the number of duplicate documents was 2042, and the number of documents reviewed was 17. The most important considerations related to the elderly included giving due attention to medical and social conditions, medication use, type of restorative teeth, level of restoration involved, use of dentures, age and gender, oral cancer screening, tooth decay education and prevention, and oral hygiene. The most important considerations related to restorative methods and materials were applying minimally invasive methods such as ART, more durable restorative materials, and giving due attention to the aesthetic and non-aesthetic needs of the elderly in choosing restorative materials. The most important considerations related to dentists were the differences in applying restorative methods and materials by experienced dentists in comparison younger dentists and the rate of referral of elderly people to dental centers.CONCLUSION: The most important dental considerations of the elderly are using minimally invasive methods and restorative materials with easy maintenance which are washable according to their social, economic, medical, gender, and age conditions. It is also necessary to consider the prevention of tooth decay and provide the required training for families and their caregivers in nursing homes. The elderly people are also required to avoid change their dentists frequently to maintain their oral health.peer-reviewe

Pre-hospital transfusion of plasma in hemorrhaging trauma patients independently improves hemostatic competence and acidosis

BACKGROUND: The early use of blood products has been associated with improved patient outcomes following severe hemorrhage or traumatic injury. We aimed to investigate the influence of pre-hospital blood products (i.e. plasma and/or RBCs) on admission hemostatic properties and patient outcomes. We hypothesized that pre-hospital plasma would improve hemostatic function as evaluated by rapid thrombelastography (rTEG). METHODS: We conducted a prospective observational study recruiting 257 trauma patients admitted to a Level I trauma center having received either blood products pre-hospital or in-hospital within 6 hours of admission. Clinical data on patient demographics, blood biochemistry, injury severity score and mortality were collected. Admission rTEG was conducted to characterize the coagulation profile and hemostatic function. RESULTS: 75 patients received pre-hospital plasma and/or RBCs (PH group; nearly half received both RBCs and plasma) whereas 182 patients only received in-hospital blood products (RBCs, Plasma and Platelets) within 6 hours of admission (IH group). PH patients had lower Glasgow coma scale (GCS) scores, more penetrating injuries, lower systolic blood pressures, lower hemoglobin levels, lower platelet counts and greater acidosis upon ED admission than the IH group (all p < 0.05). Despite differences in type of injury and admission vitals indicating that the PH group had more signs of bleeding than the IH group, there were no significant differences in in-hospital mortality (PH 26.7% vs. IH 20.9% p = 0.31). When comparing rTEG variables between PH patients transfused with 0, 1 or 2 units of plasma, more pre-hospital plasma transfusion was tendency towards improved rTEG variables. When adjusting for pre-hospital RBC, pre-hospital plasma was associated with significantly higher rTEG MA (p = 0.012) at hospital admission. DISCUSSION: After adjusting for pre-hospital RBCs, pre-hospital plasma transfusion was independently associated with increased rTEG MA, as well as arrival indices of shock and hemodynamic instability. Besides more severe injury and worse clinical presentation, the group that received pre-hospital transfusion had early and late mortality similar to patients not transfused pre-hospital. CONCLUSIONS: These data suggest that early administration of plasma can provide significant hemostatic and potential survival benefit to severely hemorrhaging trauma patients

Hyaluronic acid synthesis, degradation, and crosslinking in equine osteoarthritis: TNF-α-TSG-6-mediated HC-HA formation

Background TNF-α-stimulated gene 6 (TSG-6) protein, a TNF-α-responsive hyaladherin, possesses enzymatic activity that can catalyze covalent crosslinks of the polysaccharide hyaluronic acid (HA) to another protein to form heavy chain-hyaluronic acid (HC-HA) complexes in pathological conditions such as osteoarthritis (OA). Here, we examined HA synthase and inflammatory gene expression; synovial fluid HA, TNF-α, and viscosity; and TSG-6-mediated HC-HA complex formation in an equine OA model. The objectives of this study were to (1) evaluate the TNF-α-TSG-6-HC-HA signaling pathway across multiple joint tissues, including synovial membrane, cartilage, and synovial fluid, and (2) determine the impact of OA on synovial fluid composition and biophysical properties. Methods HA and inflammatory cytokine concentrations (TNF-α, IL-1β, CCL2, 3, 5, and 11) were analyzed in synovial fluid from 63 OA and 25 control joints, and HA synthase (HAS1-3), TSG-6, and hyaluronan-degrading enzyme (HYAL2, HEXA) gene expression was measured in synovial membrane and cartilage. HA molecular weight (MW) distributions were determined using agarose gel electrophoresis and solid-state nanopore measurements, and HC-HA complex formation was detected via immunoblotting and immunofluorescence. SEC-MALS was used to evaluate TSG-6-mediated HA crosslinking, and synovial fluid and HA solution viscosities were analyzed using multiple particle-tracking microrheology and microfluidic measurements, respectively. Results TNF-α concentrations were greater in OA synovial fluid, and TSG6 expression was upregulated in OA synovial membrane and cartilage. TSG-6-mediated HC-HA complex formation was greater in OA synovial fluid and tissues than controls, and HC-HA was localized to both synovial membrane and superficial zone chondrocytes in OA joints. SEC-MALS demonstrated macromolecular aggregation of low MW HA in the presence of TSG-6 and inter-α-inhibitor with concurrent increases in viscosity. Conclusions Synovial fluid TNF-α concentrations, synovial membrane and cartilage TSG6 gene expression, and HC-HA complex formation were increased in equine OA. Despite the ability of TSG-6 to induce macromolecular aggregation of low MW HA with resultant increases in the viscosity of low MW HA solutions in vitro, HA concentration was the primary determinant of synovial fluid viscosity rather than HA MW or HC-HA crosslinking. The TNF-α-TSG-6-HC-HA pathway may represent a potential therapeutic target in OA

A Pilot Study Assessing the Impact of rs174537 on Circulating Polyunsaturated Fatty Acids and the Inflammatory Response in Patients with Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability in persons under age 45. The hallmark secondary injury profile after TBI involves dynamic interactions between inflammatory and metabolic pathways including fatty acids. Omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) have been shown to provide neuroprotective benefits by minimizing neuroinflammation in rodents. These effects have been less conclusive in humans, however. We postulate genetic variants influencing PUFA metabolism in humans could contribute to these disparate findings. Therefore, we sought to (1) characterize the circulating PUFA response and (2) evaluate the impact of rs174537 on inflammation after TBI. A prospective, single-center, observational pilot study was conducted to collect blood samples from Level-1 trauma patients (N = 130) on admission and 24 h post-admission. Plasma was used to quantify PUFA levels and inflammatory cytokines. Deoxyribonucleic acid was extracted and genotyped at rs174537. Associations between PUFAs and inflammatory cytokines were analyzed for all trauma cases and stratified by race (Caucasians only), TBI (TBI: N = 47; non-TBI = 83) and rs174537 genotype (GG: N = 33, GT/TT: N = 44). Patients with TBI had higher plasma DHA levels compared with non-TBI at 24 h post-injury (p = 0.013). The SNP rs174537 was associated with both PUFA levels and inflammatory cytokines (p < 0.05). Specifically, TBI patients with GG genotype exhibited the highest plasma levels of DHA (1.33%) and interleukin-8 (121.5 ± 43.3 pg/mL), which were in turn associated with poorer outcomes. These data illustrate the impact of rs174537 on the post-TBI response. Further work is needed to ascertain how this genetic variant directly influences inflammation after trauma.12 month embargo; published online: 7 May 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes

Abstract Background Genetic variants within the fatty acid desaturase (FADS) gene cluster (human Chr11) are important regulators of long-chain (LC) polyunsaturated fatty acid (PUFA) biosynthesis in the liver and consequently have been associated with circulating LC-PUFA levels. More recently, epigenetic modifications such as DNA methylation, particularly within the FADS cluster, have been shown to affect LC-PUFA levels. Our lab previously demonstrated strong associations of allele-specific methylation (ASM) between a single nucleotide polymorphism (SNP) rs174537 and CpG sites across the FADS region in human liver tissues. Given that epigenetic signatures are tissue-specific, we aimed to evaluate the methylation status and ASM associations between rs174537 and DNA methylation obtained from human saliva, CD4+ cells and total leukocytes derived from whole blood. The goals were to (1) determine if DNA methylation from these peripheral samples would display similar ASM trends as previously observed in human liver tissues and (2) evaluate the associations between DNA methylation and circulating LC-PUFAs. Results DNA methylation at six CpG sites spanning FADS1 and FADS2 promoter regions and a putative FADS enhancer region were determined in two Caucasian cohorts of healthy volunteers: leukocytes in cohort 1 (n = 89, median age = 43, 35% male) and saliva and CD4+ cells in cohort 2 (n = 32, median age = 41, 41% male). Significant ASM between rs174537 and DNA methylation at three CpG sites located in the FADS2 promoter region (i.e., chr11:61594865, chr11:61594876, chr11:61594907) and one CpG site in the putative enhancer region (chr11:61587979) were observed with leukocytes. In CD4+ cells, significant ASM was observed at CpG sites chr11:61594876 and chr11:61584894. Genotype at rs174537 was significantly associated with DNA methylation from leukocytes. Similar trends were observed with CD4+ cells, but not with saliva. DNA methylation from leukocytes and CD4+ cells also significantly correlated with circulating omega-6 LC-PUFAs. Conclusions We observed significant ASM between rs174537 and DNA methylation at key regulatory regions in the FADS region from leukocyte and CD4+ cells. DNA methylation from leukocytes also correlated with circulating omega-6 LC-PUFAs. These results support the use of peripheral whole blood samples, with leukocytes showing the most promise for future nutrigenomic studies evaluating epigenetic modifications affecting LC-PUFA biosynthesis in humans

Additional file 3: of Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes

Table S2. Summary of plasma and serum fatty acids. Medians and IQR reported. Definitions of SFAs, MUFAs, PUFAs, and n-3/n-6 ratios are provided at the bottom of the table. (DOCX 18 kb