Myocardial infarction (MI) produces acute changes in strain and stiffness within the infarct that can affect remote areas of the left ventricle (LV) and drive pathological remodeling. We hypothesized ...that intramyocardial delivery of a hydrogel within the MI region would lower wall stress and reduce adverse remodeling in Yorkshire pigs (n = 5). 99mTc-Tetrofosmin SPECT imaging defined the location and geometry of induced MI and border regions in pigs, and in vivo and ex vivo contrast cine computed tomography (cineCT) quantified deformations of the LV myocardium. Serial in vivo cineCT imaging provided data in hearts from control pigs (n = 3) and data from pigs (n = 5) under baseline conditions before MI induction, post-MI day 3, post-MI day 7, and one hour after intramyocardial delivery of a hyaluronic acid (HA)-based hydrogel with shear-thinning and self-healing properties to the central infarct area. Isolated, excised hearts underwent similar cineCT imaging using an ex vivo perfused heart preparation with cyclic LV pressurization. Deformations were evaluated using nonlinear image registration of cineCT volumes between end-diastole (ED) and end-systole (ES), and 3D Lagrangian strains were calculated from the displacement gradients. Post-MI day 3, radial, circumferential, maximum principal, and shear strains were reduced within the MI region (p < 0.04) but were unchanged in normal regions (p > 0.6), and LV end diastolic volume (LV EDV) increased (p = 0.004), while ejection fraction (EF) and stroke volume (SV) decreased (p < 0.02). Post-MI day 7, radial strains in MI border zones increased (p = 0.04) and dilation of LV EDV continued (p = 0.052). There was a significant negative linear correlation between regional radial and maximum principal/shear strains and percent infarcted tissue in all hearts (R2 > 0.47, p < 0.004), indicating that cineCT strain measures could predict MI location and degree of injury. Post-hydrogel day 7 post-MI, LV EDV was significantly reduced (p = 0.009), EF increased (p = 0.048), and radial (p = 0.021), maximum principal (p = 0.051), and shear strain (p = 0.047) increased within regions bordering the infarct. A smaller strain improvement within the infarct and normal regions was also noted on average along with an improvement in SV in 4 out of 5 hearts. CineCT provides a reliable method to assess regional changes in strains post-MI and the therapeutic effects of intramyocardial hydrogel delivery.
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•Developed novel platform to assess left ventricle deformation in vivo and ex vivo.•Local cardiac strains decreased progressively over 7 days in infarcted regions.•Measured linear correlation between local degree of infarction and strain.•Hydrogel injection improved strain in regions bordering the infarct.•Hydrogel injection resulted in less ventricle dilation and larger ejection fraction.
Nemaline myopathy (NM) is the most common of several congenital myopathies that present with skeletal muscle weakness and hypotonia. It is clinically heterogeneous and the diagnosis is confirmed by ...identification of nemaline bodies in affected muscles. The skeletal muscle α‐actin gene (ACTA1) is one of five genes for thin filament proteins identified so far as responsible for different forms of NM. We have screened the ACTA1 gene in a cohort of 109 unrelated patients with NM. Here, we describe clinical and pathological features associated with 29 ACTA1 mutations found in 38 individuals from 28 families. Although ACTA1 mutations cause a remarkably heterogeneous range of phenotypes, they were preferentially associated with severe clinical presentations (p < 0.0001). Most pathogenic ACTA1 mutations were missense changes with two instances of single base pair deletions. Most patients with ACTA1 mutations had no prior family history of neuromuscular disease (24/28). One severe case, caused by compound heterozygous recessive ACTA1 mutations, demonstrated increased α‐cardiac actin expression, suggesting that cardiac actin might partially compensate for ACTA1 abnormalities in the fetal/neonatal period. This cohort also includes the first instance of an ACTA1 mutation manifesting with adult‐onset disease and two pedigrees exhibiting potential incomplete penetrance. Overall, ACTA1 mutations are a common cause of NM, accounting for more than half of severe cases and 26% of all NM cases in this series. Ann Neurol 2004;56:86–96
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We developed a method to measure the 3-dimensional (3D) strain field in the optic nerve head (ONH) in vivo between two intraocular pressures (IOP). Radial optical coherence tomography ...(OCT) scans were taken of the ONH of 5 eyes from 5 glaucoma patients before and after IOP-lowering surgery and from 5 eyes from 3 glaucoma suspect patients before and after raising IOP by wearing tight-fitting swimming goggles. Scans taken at higher and lower IOP were compared using a custom digital volume correlation (DVC) algorithm to calculate strains in the anterior lamina cribrosa (ALC), retina, and choroid. Changes in anterior lamina depth (ALD) relative to Bruch’s membrane were also analyzed. Average displacement error was estimated to be subpixel and strain errors were smaller than 0.37%. Suturelysis decreased IOP by 9–20 mmHg and decreased compressive anterior-posterior strain Ezz in the ALC by 0.76% (p=0.002,n=5). Goggle-wearing increased IOP by 3–4 mmHg and produced compressive Ezz in the ALC (-0.32%,p=0.001,n=5). Greater IOP decrease was associated with greater ALD change (p=0.047,n=10) and greater strains in the ALC (Ezz:p=0.002,n=10). A deepening of ALD was associated with lower IOP and greater ALC strains (p⩽0.045,n=10). A DVC-based method to measure strains from OCT images caused by IOP changes as small as 2.3 mmHg provides preliminary evidence that ALD is shallower and ALC strains are less compressive at higher IOP and that ALD change is associated with ALC strains.
Glaucoma causes vision loss through progressive damage of the retinal ganglion axons at the lamina cribrosa, a connective tissue structure in the optic nerve head that supports the axons as they pass through the eye wall. It is hypothesized that strains caused by intraocular pressure (IOP) may initiate this damage, but few studies have measured the strain response to pressure of the optic nerve head in patients. We present a method to measure the 3D displacement and strain field in the optic nerve head caused by IOP alteration in glaucoma patients using clinically available images. We used this method to measure strain within the optic nerve head from IOP changes caused by glaucoma surgery and wearing tight-fitting swimming goggles.
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The objective of this study was to measure the pressure-induced deformation response of the human lamina cribrosa (LC) and analyze for variations with age and anatomical region. The ...posterior scleral cup of 8 eyes from 6 human donors was mounted onto a custom inflation chamber. A laser-scanning microscope was used for second harmonic generation (SHG) imaging of the collagen structure in the posterior volume of the LC at pressures from 5mmHg to 45mmHg. The SHG volumes were analyzed by the Fast-Fourier Iterative Digital Volume Correlation (DVC) algorithm for the three dimensional (3D) displacement field. The components of the Green–Lagrange strain tensor and the in-plane principal and maximum shear strains were evaluated from the DVC displacement field for the central and peripheral regions of the LC and the nasal, temporal, inferior, and superior quadrants surrounding the central retinal artery and vein. Among the major findings were that older age was associated with lower strains, the maximum shear strain was larger in the peripheral than central region, and the maximum principal strain was lower in the nasal quadrant. The elliptical shape of the LC was also predictive of the biaxial strain ratio. Age-related and structure-related variations in the pressure-induced strains of the LC may contribute to the susceptibility and severity of optic nerve damage in glaucoma, and regional variations may explain the progression of axonal damage and tissue remodeling observed in the LC in glaucoma.
Glaucoma causes vision loss through progressive damage of the retinal ganglion axons at the lamina cribrosa (LC), the connective tissue structure that supports the axons as they leave the eye. Mechanical characterization of the LC is challenging because of the complex 3D shape and inaccessibility of the tissue. We present a new method using digital volume correlation to map the 3D displacement and strain fields in the LC under inflation. We report for the first time significant regional variations in the strains that are consistent with the pattern of optic nerve damage in early glaucoma. Thus regional strain variations may be predictive of the progression of axonal damage in glaucoma.
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This study investigated the inflation response of the lamina cribrosa (LC) and adjacent peripapillary sclera (PPS) in post-mortem human eyes with no history of glaucoma. The posterior ...sclera of 13 human eyes from 7 donors was subjected to controlled pressurization between 5–45 mmHg. A laser-scanning microscope (LSM) was used to image the second harmonic generation (SHG) response of collagen and the two-photon fluorescent (TPF) response of elastin within the volume of the LC and PPS at each pressure. Image volumes were analyzed using digital volume correlation (DVC) to calculate the three-dimensional (3D) deformation field between pressures. The LC exhibited larger radial strain, Err, and maximum principal strain, Emax, (p < 0.0001) and greater posterior displacement (p=0.0007) compared to the PPS between 5–45 mmHg, but had similar average circumferential strain, Eθθ, and maximum shear strain, Γmax. The Emax and Γmax were highest near the LC-PPS interface and lowest in the nasal quadrant of both tissues. Larger LC area was associated with smaller Emax in the peripheral LC and larger Emax in the central LC (p ≤ 0.01). The Emax, Γmax, and Eθθ in the inner PPS increased with increasing strain in adjacent LC regions (p ≤ 0.001). Smaller strains in the PPS were associated with a larger difference in the posterior displacement between the PPS and central LC (p < 0.0001 for Emax and Err), indicating that a stiffer pressure-strain response of the PPS is associated with greater posterior bowing of the LC.
Glaucoma causes vision loss through progressive damage of the retinal ganglion axons at the lamina cribrosa (LC), a connective tissue structure that supports the axons as they pass through the eye wall. It is hypothesized that strains caused by intraocular pressure may initiate this damage and that these strains are modulated by the combined deformation of the LC and adjacent peripapillary sclera (PPS). In this study we present a method to measure the pressure-induced 3D displacement and strain field in the LC and PPS simultaneously. Regional strain variation in the LC and PPS was investigated and compared and strains were analyzed for associations with age, LC area, LC strain magnitude, and LC posterior motion relative to the PPS.
The purpose of this study was to measure the 2D collagen network structure of the human lamina cribrosa (LC), analyze for the correlations with age, region, and LC size, as well as the correlations ...with pressure-induced strains.
The posterior scleral cups of 10 enucleated human eyes with no known ocular disease were subjected to ex vivo inflation testing from 5 to 45 mm Hg. The optic nerve head was imaged by using second harmonic generation imaging (SHG) to identify the LC collagen structure at both pressures. Displacements and strains were calculated by using digital volume correlation of the SHG volumes. Nine structural features were measured by using a custom Matlab image analysis program, including the pore area fraction, node density, and beam connectivity, tortuosity, and anisotropy.
All strain measures increased significantly with higher pore area fraction, and all but the radial-circumferential shear strain (Erθ) decreased with higher node density. The maximum principal strain (Emax) and maximum shear strain (Γmax) also increased with larger beam aspect ratio and tortuosity, respectively, and decreased with higher connectivity. The peripheral regions had lower node density and connectivity, and higher pore area fraction, tortuosity, and strains (except for Erθ) than the central regions. The peripheral nasal region had the lowest Emax, Γmax, radial strain, and pore area fraction.
Features of LC beam network microstructure that are indicative of greater collagen density and connectivity are associated with lower pressure-induced LC strain, potentially contributing to resistance to glaucomatous damage.
In this study, we measured the effect of the removal of sulfated glycosaminoglycans (sGAGs) on the pressure-induced strains of the human lamina cribrosa (LC).
We applied an ex vivo inflation method ...to measure the three-dimensional (3D) deformation response of six human LCs to pressure, before and after the degradation of chondroitin and dermatan sulfates. The experiment used a laser-scanning microscope (LSM) to acquire the second harmonic generation (SHG) signal of the collagen structure in the LC. Digital volume correlation (DVC) was used to calculate the deformation in the LC after a change in pressure from 5 to 45 mm Hg.
The average strains between 5 and 45 mm Hg in the LC decreased significantly after sGAG degradation (P ≤ 0.03), with the greatest change occurring in regions of previously high strain (P ≤ 0.003) and the peripheral regions of the LC (P ≤ 0.02). The stiffening effect was greater in the LC of middle-aged (42-49 years) donors compared with those of older (64-88 years) donors (P < 0.0001).
The LC experienced less strain at the same pressures after most sGAGs were removed. These results suggest that the natural decrease in sGAGs within the LC with age may contribute to the stiffer inflation response of older LC to IOP. Likewise, the increase in the amount of sGAGs observed in the LC of glaucomatous eyes, may contribute to a more compliant LC, which may affect the susceptibility and progression of axon damage.
The chiral conformation that palmitoleic acid takes when it is bound to ToxT, the master regulator of virulence genes in the bacterial pathogen Vibrio cholerae, was used as inspiration to design a ...novel class of fatty acid mimetics. The best mimetic, based on a chiral hydrindane, was found to be a potent inhibitor of this target. The synthetic chemistry that enabled these studies was based on the sequential use of a stereoselective annulative cross-coupling reaction and dissolving metal reduction to establish the C13 and C9 stereocenters, respectively.
Abstract
Structural and social determinants of health (SSDoH) are environmental conditions in which individuals are born, live, learn, work, play, worship, and age that affect health, functioning, ...and quality-of-life outcomes across the life course. Growing evidence suggests that SSDoH can help to explain heterogeneity in outcomes in Alzheimer’s disease and Alzheimer’s disease and related dementias (AD/ADRD) research and clinical practice. The National Institute on Aging has prioritized collecting SSDoH data to elucidate disease mechanisms and aid discovery of disease-modifying treatments. However, a major nexus of AD/ADRD research, the national network of Alzheimer’s Disease Research Centers (ADRCs), collects few SSDoH data. We describe a framework for feasibly gathering and modeling SSDoH data across ADRCs. We lay out key constructs, their measures, and empirical evidence for their importance in elucidating disease and prevention mechanisms. Toward a goal of translation, the framework proposes a modular structure with a core set of measures and options for adjunctive modules. We describe considerations for measuring SSDoH in existing geographically and culturally diverse research cohorts. We also outline a rationale for universal implementation of a set of SSDoH measures and juxtapose the approach with alternatives aimed at collecting SSDoH data.
After a sudden infant death, parents and caregivers need accurate and open communication about why their infant died. Communicating tragic news about a child's death to families and caregivers is ...difficult. Shared and consistent terminology is essential for pediatricians, other physicians, and nonphysician clinicians to improve communication with families and among themselves. When families do not have complete information about why their child died, pediatricians will not be able to support them through the process and make appropriate referrals for pediatric specialty and mental health care. Families can only speculate about the cause and may blame themselves or others for the infant's death. The terminology used to describe infant deaths that occur suddenly and unexpectedly includes an assortment of terms that vary across and among pediatrician, other physician, or nonphysician clinician disciplines. Having consistent terminology is critical to improve the understanding of the etiology, pathophysiology, and epidemiology of these deaths and communicate with families. A lack of consistent terminology also makes it difficult to reliably monitor trends in mortality and hampers the ability to develop effective interventions. This report describes the history of sudden infant death terminology and summarizes the debate over the terminology and the resulting diagnostic shift of these deaths. This information is to assist pediatricians, other physicians, and nonphysician clinicians in caring for families during this difficult time. The importance of consistent terminology is outlined, followed by a summary of progress toward consensus. Recommendations for pediatricians, other physicians, and nonphysician clinicians are proposed.
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