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Individuals with diabetes are at a higher risk of developing foot ulcers. To better understand internal soft tissue loading and potential treatment options, subject-specific finite element (FE) foot models have been used. However, existing models typically lack subject-specific soft tissue material properties and only utilize subject-specific anatomy. Therefore, this study determined subject-specific hindfoot soft tissue material properties from one non-diabetic and one diabetic subject using inverse FE analysis. Each subject underwent cyclic MRI experiments to simulate physiological gait and to obtain compressive force and three-dimensional soft tissue imaging data at 16 phases along the loading–unloading cycles. The FE models consisted of rigid bones and nearly-incompressible first-order Ogden hyperelastic skin, fat, and muscle (resulting in six independent material parameters). Then, calcaneus and loading platen kinematics were computed from imaging data and prescribed to the FE model. Two analyses were performed for each subject. First, the skin, fat, and muscle layers were lumped into a single generic soft tissue material and optimized to the platen force. Second, the skin, fat, and muscle material properties were individually determined by simultaneously optimizing for platen force, muscle vertical displacement, and skin mediolateral bulging. Our results indicated that compared to the individual without diabetes, the individual with diabetes had stiffer generic soft tissue behavior at high strain and that the only substantially stiffer multi-material layer was fat tissue. Thus, we suggest that this protocol serves as a guideline for exploring differences in non-diabetic and diabetic soft tissue material properties in a larger population. [ABSTRACT FROM AUTHOR]

Full-contact insoles fabricated from multilayer foams are the standard of care (SoC) for offloading and redistributing high plantar pressures in individuals with diabetes at risk of plantar ulceration and subsequent lower limb amputation. These devices have regional variations in total thickness and layer thickness to create conformity with a patient's foot. Recent work has demonstrated that metamaterials can be tuned to match the mechanical properties of SoC insole foams. However, for devices fabricated using a multilayer lattice structure, having regional variations in total thickness and layer thickness may result in regional differences in mechanical properties that have yet to be investigated. Three lattices, two dual-layer and one uniform-layer lattice structure, designed to model the mechanical properties of SoC insoles, were 3D-printed at three structure/puck thicknesses representing typical regions seen in accommodative insoles. The pucks underwent cyclic compression testing, and the stiffness profiles were assessed. Three pucks at three structure/puck thicknesses fabricated from SoC foams were also tested. Initial evaluations suggested that for the latticed pucks, structure thickness and density inversely impacted puck stiffness. Behaving most like the SoC pucks, a dual-layer lattice that increased in density as structure thickness increased demonstrated consistent stiffness profiles across puck thicknesses. Identifying a lattice with constant mechanical properties at various structure thicknesses may be important to produce a conforming insole that emulates the standard of care from which patient-specific/regional lattice modulations can be made. [Display omitted] • Metamaterials were used to replicate stiffness of standard accommodative insoles. • Thickness and density impacted mechanical properties of lattice structures. • Lattice ideal for variable thickness insoles with constant stiffness was identified. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all malignancies, with a 5-year survival rate <8%.1,2 Suspicious lesions are typically diagnosed via endoscopic ultrasound–guided fine-needle aspiration or endoscopic ultrasound–guided fine-needle biopsy (EUS-FNB).3 Fewer needle passes decreases the risk of postprocedure complications, including pancreatitis and hemorrhage, while allowing additional needle passes to be used for adjuvant tissue testing, such as organoid creation and DNA sequencing. [ABSTRACT FROM AUTHOR]

Background and Aims Pancreatic cancer organoids are tumor models of individualized human pancreatic ductal adenocarcinoma (PDA), created from surgical specimens and used for personalized treatment strategies. Unfortunately, most patients with PDA are not operative candidates. Creation of human PDA organoids at the time of initial tumor diagnosis is therefore critical. Our aim was to assess the feasibility of creating human PDA organoids by EUS fine-needle biopsy (EUS-FNB) sampling in patients with PDA. Methods In this prospective clinical trial in patients referred to evaluate a pancreatic mass, EUS-FNA was performed for initial onsite diagnosis. Two additional needle passes were performed with a 22-gauge FNB needle for organoid creation. Primary outcome was successful isolation of organoids within 2 weeks of EUS-FNB sampling (P0, no passages), confirmed by organoid morphology and positive genotyping. Results Thirty-seven patients with 38 PDA tumors were enrolled. Successful isolation of organoids (P0) was achieved in 33 of 38 tumors (87%). Establishment of PDA organoid lines for ≥5 passages of growth (P5, five passages) was reached in 25 of 38 tumors (66%). In the single patient with successful P5 FNB sampling–derived and P5 surgically derived organoids, there was identical matching of specimens. There were no serious adverse events. Two patients developed bleeding at the EUS-FNB puncture site requiring hemostasis clips. Conclusions Pancreatic cancer organoids can be successfully and rapidly created by means of EUS-FNB sampling using a 22-gauge needle at the time of initial diagnosis. Successful organoid generation is essential for precision medicine in patients with pancreatic cancer in whom most are not surgically resectable. (Clinical trial registration number: NCT03140592 .) [ABSTRACT FROM AUTHOR]

The plantar aponeurosis functions to support the foot arch during weight bearing. Accurate anatomy and material properties are critical in developing analytical and computational models of this tissue. We determined the cross-sectional areas and material properties of four regions of the plantar aponeurosis: the proximal middle and distal middle portions of the tissue and the medial (to the first ray) and lateral (to the fifth ray) regions. Bone-plantar aponeurosis-bone specimens were harvested from fifteen cadaveric feet. Cross-sectional areas were measured using molding, casting, and sectioning methods. Mechanical testing was performed using displacement control triangle waves (0.5, 1, 2, 5, and 10 Hz) loaded to physiologic tension by estimating from body weight and area ratio of the region. Five specimens were tested for each region. Regional deformations were recorded by a high-speed video camera. There were overall differences in cross-sectional areas and biomechanical behavior across regions. The stress–strain responses are non-linear and mainly elastic (energy loss 3.6% to 7.2%). Moduli at the proximal middle and distal middle regions (400 and 522 MPa) were significantly higher than the medial and lateral regions (225 and 242 MPa). The effect of frequency on biomechanical outcomes was small (e.g., 3.5% change in modulus), except for energy loss (107% increase as frequency increased from 0.5 to 10 Hz). These results indicate that the plantar aponeurosis tensile response is non-linear, nearly elastic, and frequency independent. The cross-sectional area and material properties differ by region, and we suggest that such differences be included to accurately model this structure. [ABSTRACT FROM AUTHOR]

Abstract: Use of protease inhibitor (PI)–based highly active antiretroviral therapy (HAART) has been associated with altered regional fat distribution, insulin resistance, and dyslipidemias. To assess how PI-based HAART affects adipocyte gene expression in male HIV-1–infected patients, reverse transcription–polymerase chain reaction was used to quantify messenger RNA expression of adipocyte transcription factors and adipocytokines in thigh and abdominal subcutaneous adipose tissue from male (1) HIV-1 seronegative subjects (control, n = 9), (2) asymptomatic treatment-naive HIV-1–infected patients (naive, n = 6), (3) HIV-1–infected patients who were receiving antiretroviral agents but never received PIs (PI naive, n = 5), (4) HIV-1–infected patients who were receiving PI-based HAART (PI, n = 7), and (5) HIV-1–infected patients who discontinued the PI component of their antiviral therapy more than 6 months before enrollment (past PI, n =7). In the PI group, the messenger RNA expression levels of the CCAAT/enhancer–binding protein α, leptin, and adiponectin (18%, P < .01; 23%, P < .05; and 13%, P < .05, respectively) were significantly lower than the levels measured in the PI-naive group. These results are consistent with previous studies on the effects of PIs on cultured adipocytes. Prospective longitudinal studies of thigh fat adipose tissue gene expression could provide further insights on the pathogenesis of metabolic complications associated with PI-based HAART. [Copyright &y& Elsevier]

The ADHE family of enzymes are bifunctional acetaldehyde dehydrogenase (ALDH)/alcohol dehydrogenase (ADH) enzymes that probably arose from the fusion of genes encoding separate ALDH and ADH enzymes. Here we have used the Entamoeba histolytica alcohol dehydrogenase 2 (EhADH2) enzyme as a prototype to analyze the structure and function of the ALDH domain of ADHE enzymes. We find that the N-terminal domain of EhADH2, encompassing amino acids 1-446, is sufficient for ALDH activity, consistent with the concept that EhADH2, and other members of the ADHE family comprise fusion peptides. In addition, we show, using site directed mutagenesis, that the catalytic mechanism for the ALDH activity appears to be similar to that described for other members of the ALDH extended family. [Copyright &y& Elsevier]

Culture-independent microbiological technologies that interrogate complex microbial populations without prior axenic culture, coupled with high-throughput DNA sequencing, have revolutionized the scale, speed and economics of microbial ecological studies. Their application to the medical realm has led to a highly productive merger of clinical, experimental and environmental microbiology. The functional roles played by members of the human microbiota are being actively explored through experimental manipulation of animal model systems and studies of human populations. In concert, these studies have appreciably expanded our understanding of the composition and dynamics of human-associated microbial communities (microbiota). Of note, several human diseases have been linked to alterations in the composition of resident microbial communities, so-called dysbiosis. However, how changes in microbial communities contribute to disease etiology remains poorly defined. Correlation of microbial composition represents integration of only two datasets (phenotype and microbial composition). This article explores strategies for merging the human microbiome data with multiple additional datasets (e.g. host single nucleotide polymorphisms and host gene expression) and for integrating patient-based data with results from experimental animal models to gain deeper understanding of how host–microbe interactions impact disease. [ABSTRACT FROM AUTHOR]

The intestine and other tissues are able to synthesize retinyl esters in an acyl-CoA-dependent manner involving an acyl-CoA:retinol acyltransferase (ARAT). However, the molecular identity of this ARAT has not been established. Recent studies of lecithin;retinol acyltransferase (LRAT)-deficient mice indicate that LRAT is responsible for the preponderance of retinyl ester synthesis in the body, aside from in the intestine and adipose tissue. Our present studies, employing a number of mutant mouse models, identify diacylglycerol acyltransferase 1 (DGAT1) as an important intestinal ARAT in vivo. The contribution that DGAT1 makes to intestinal retinyl ester synthesis becomes greater when a large pharmacologic dose of retinol is administered by gavage to mice. Moreover, when large retinol doses are administered another intestinal enzyme(s) with ARAT activity becomes apparent. Surprisingly, although DGAT1 is expressed in adipose tissue, DGAT1 does not catalyze retinyl ester synthesis in adipose tissue in vivo. Our data also establish that cellular retinol-binding protein, type II (CRBPII), which is expressed solely in the adult intestine, in vivo channels retinol to LRAT for retinyl ester synthesis. Contrary to what has been proposed in the literature based on in vitro studies, CRBPII does not directly prevent retinol from being acted upon by DGAT1 or other intestinal ARATs in vivo. [ABSTRACT FROM AUTHOR]