Comorbidities in patients with vascular dementia and Alzheimer's disease with Neuropsychiatric symptoms.

INTRODUCTION: This study aimed to examine baseline risk factors in Alzheimer's Disease (AD) and Vascular dementia (VaD) patients with neuropsychiatry symptoms (NPS), and determine whether specific risk factors differ by subtypes of dementia for AD and VaD patients with NPS. METHODS: A retrospective data analysis was conducted to evaluate similarities and differences in the risk factors for AD and VaD with NPS. The analysis included 2949 patients with VaD and 6341 patients with clinical confirmation of AD and VaD with or without NPS collected between February 2016 and August 2021. The multivariate logistic regression analysis was used to determine the risk factors associated with AD and VaD with NPS, by predicting the increasing odds (odds ratios (ORs) of an association of a specific baseline risk factor with AD or VaD with NPS. The validity of the regression models was tested using a Hosmer-Lemeshow test, while the Receiver Operating Curve (ROC) was used to test the sensitivity of the models. RESULTS: In the adjusted analysis TSH (OR = 1.781, 95 % CI, p = 0.0025) and CHF (OR = 1.620, 95 %, p = 0.016) were associated with VaD with NPS, while a history of emergency department(ED) admission (OR = 0.277, 95 % CI, p = 0.003) likely to be associated with VaD patients without NPS. For AD patients, a history of CVA (OR = 1.395, 95 % CI, p = 0.032) and cancer (OR = 1.485, 95 % CI, p = 0.013) were associated with AD patients with NPS. DISCUSSION: The findings of this study indicate that an abnormal thyroid gland and CHF were linked to VaD patients with behavioral disturbances, while CVA and cancer were linked to AD patients with behavioral disturbances. These findings suggest the need to develop management strategies for the care of patients with AD and VaD with NPS.

Integrating basic, clinical, and health system science in a medical neuroscience course of an integrated pre-clerkship curriculum.

Basic science, clinical science, and health system science (HSS) have become three pillars of integration upon which modern, post-Flexner, medical education is now based. Because of this new approach to curricular integration in a clinical presentation curruculum, medical training is now placed in the context of healthcare delivery. This study described the design, implementation, and assessment of an integrated teaching strategy, including the effect on students' performance in a medical neuroscience course's summative and formative examinations of an integrated clinical presentation curriculum. The integrated teaching of basic science content, clinical case discussion, and HSS was performed in the first year of an allopathic integrated pre-clerkship curriculum. The two cohorts were from two different years, spring 2018 and 2019. The acceptance of the integrated teaching strategy by medical students was above 80% in all categories that were assessed, including enhancing the integrated experience in learning basic and clinical science materials in the context of HSS; understanding of the learning lessons; facilitation of self-directed learning; provision of a better learning environment; and a holistic understanding of materials including the relevance of HSS issues in the discussion of neurological cases in the medical career of the students. More than 90% of the students scored ≥70% in summative questions mapped to the four learning objectives of the integrated teaching session. The objectives are the correlation of structure to specific functions (94.0 ± 0.21), clinical anatomical features of the nervous system (95.0 ± 0.27), cross-sectional features of the nervous system (96.0 ± 0.31), and the effect of lesions on the structure and functional pathways of the nervous system (97.0 ± 0.34). This result was significantly higher when compared to students' performance in the non-integrated teaching cohort (p < 0.05). Formative assessments (F(7,159) = 92.52, p < 0.001) were significantly different between the two groups. When medical students were evaluated using the same questions for formative assessment, they performed better in the integrated teaching cohort (*p < 0.05) compared to the non-integrated teaching cohort (**p < 0.05).

Effective Feedback Strategy for Formative Assessment in an Integrated Medical Neuroscience Course.

Purpose: Despite the different benefits of formative assessments in an integrated medical curriculum, the effective strategies to provide feedback to medical students to benefit from the different merits of formative assessment are not fully understood. This study aims to determine the effect of different strategies of formative feedback on students' outcomes in a medical neuroscience course. Method: We compared medical students' performance in summative examinations in the academic year that formative feedback was provided using in-person discussion and compared such performances with the academic year when the feedback was provided by written rationales or a combination of written rationales and in-person discussion. We also surveyed medical students' preferences for whether written or in-person formative feedback is a better strategy to provide feedback at the end of each course. Results: ANOVA found a significant difference in summative performance scores for those scoring ≥ 70% when formative feedback was provided by providing a rationale, in-person, and a combination of both ([F (2,80) = 247.60, P < 0.001]. Post hoc analysis revealed a significant and highest performance when feedback was provided using the written rationale approach (***P < 0.05), followed by in-person (**P < 0.05). In contrast, the least performance was recorded when formative feedback was provided using a combination of providing a written rationale for the answers to the questions and in-person discussion of the questions (*P < 0.05). Students' preferred approach for receiving formative feedback for their formative assessment was highest for written rationale (***P < 0.05), followed by in-person or a combination of in-person and written rationale (**P < 0.05). Conclusion: Our results found that medical students preferred a written formative feedback approach, which was associated with better student performance on the summative examination. This study reveals the importance of developing effective strategies to provide formative feedback to medical students for medical students to fully benefit from the merits of formative assessment in an integrated medical school curriculum.

Obstetric Neuropathy in Diabetic Patients: The "Double Hit Hypothesis".

The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal damage during the delivery process. However, the anatomical and pathophysiological mechanisms are not well understood. Our overarching hypothesis in this review paper is that pregnant women who are diabetic have a damaged peripheral nervous system, constituting the "first hit" hypothesis. The delivery process itself-the "second hit"-can produce neurological damage to the mother. Women with diabetes mellitus (DM) are at risk for neurological damage during both hits, but the cumulative effects of both "hits" pose a greater risk of neurological damage and pathophysiological changes during delivery. In our analysis, we introduce the different steps of our concept paper. Subsequently, we describe each of the topics. First, we outline the mechanisms by which diabetes acts as a detrimental variable in neuropathy by focusing on the most common form of diabetic neuropathy, diabetic distal symmetrical polyneuropathy, also known as distal sensorimotor neuropathy. The possible role of macrosomia in causing diabetic neuropathy and obstetric neurological injury is discussed. Second, we describe how vaginal delivery can cause various obstetrical neurological syndromes and pathophysiological changes. Third, we highlight the risk of obstetric neuropathy and discuss anatomical sites at which lesions may occur, including lesions during delivery. Fourth, we characterize the pathophysiological pathways involved in the causation of diabetic neuropathy. Finally, we highlight diabetic damage to sensory vs. motor nerves, including how hyperglycemia causes different types of damage depending on the location of nerve cell bodies.

Autophagy and the Bone Marrow Microenvironment: A Review of Protective Factors in the Development and Maintenance of Multiple Myeloma.

The role of the unfolded protein response (UPR) in plasma cells (PC) and their malignant multiple myeloma (MM) counterparts is a well described area of research. The importance of autophagy in these cells, as well as the interplay between autophagy and the UPR system, has also been well studied. In this review, we will discuss the relationship between these two cellular responses and how they can be utilized in MM to account for the high levels of monoclonal immunoglobulin (Ig) protein synthesis that is characteristic of this disease. Interactions between MM cells and the bone marrow (BM) microenvironment and how MM cells utilize the UPR/autophagy pathway for their survival. These interacting pathways form the foundation for the mechanism of action for bortezomib, a proteasome inhibitor used to modify the progression of MM, and the eventual drug resistance that MM cells develop. One important resistance pathway implicated in MM progression is caspase 10 which attenuates autophagy to maintain its prosurvival function and avoid cell death. We lay a groundwork for future research including 3D in vitro models for better disease monitoring and personalized treatment. We also highlight pathways involved in MM cell survival and drug resistance that could be used as new targets for effective treatment.

Sex Differences in Demographic and Pharmacological Factors in Alzheimer Patients With Dementia and Cognitive Impairments.

Objective: The current study investigates sex differences associated with pharmacological and demographic characteristics in Alzheimer patients (AD) with dementia (ADD) or mild cognitive impairment (MCI). Method: A retrospective analytical approach was used to analyze data from 45,696 AD patients with MCI or ADD. The univariate analysis was used to determine differences in demographic, and pharmacological characteristics for male and female ADD and MCI-AD patients. Multivariate analysis was used to predict specific pharmacological and demographic factors that are associated with male and female MCI and ADD patients. Result: In the adjusted analysis for male patients, Hispanics [0.166,0.020 - 1.355, P = 0.094] or African Americans [OR = 2.380, 95% CI,2.120 - 2.674, P < 0.001], were more likely to have MCI-AD and be treated with galantamine [OR = 0.559, 95% CI, 0.382 - 0.818, P = 0.003], donepezil [OR = 1.639, 95% CI,1.503 - 1.787, P < 0.001], rivastigmine [OR = 1.394, 95% CI,1.184 - 1.642, P < 0.001], olanzapine [OR = 2.727, 95% CI,2.315 - 3.212, P < 0.001], risperidone [OR = 2.973, 95% CI,2.506 - 3.526, P < 0.001], present with increasing age [1.075,1.071 - 1.079, P < 0.001], and are on tobacco use [OR = 1.150, 95% CI,1.054 - 1.254, P = 0.002]. For female patients, buspirone [OR = 0.767, 95% CI, 0.683 - 0.861, P < 0.001] and a history of alcohol (ETOH) use [OR = 0.484, 95% CI, 0.442 - 0.529, P < 0.001] were associated with MCI-AD. Increasing age [OR = 1.096, 95% CI, 1.093 - 1.100, P < 0.001], donepezil [OR = 2.185, 95% CI, 2.035 - 2.346, P < 0.001], memantine [OR = 2.283, 95% CI, 2.104 - 2.477, P < 0.001] aripiprazole [OR = 1.807, 95% CI, 1.544 - 2.113, P < 0.001] olanzapine [OR = 2.289, 95% CI, 1.986 - 2.640, P < 0.001] risperidone [OR = 2.548, 95% CI, 2.246 - 2.889, P < 0.001] buspirone [OR = 0.767, 95% CI, 0.683 - 0.861, P < 0.001] escitalopram [OR = 1.213, 95% CI,1.119 - 1.315, P < 0.001] African Americans [OR = 1.395, 95% CI, 1.268 - 1.535, P < 0.001] and tobacco use [OR = 1.150, 95% CI, 1.073 - 1.233, P < 0.001] were associated with ADD. Conclusion: Our findings reveal that MCI-AD patients were more likely to be Hispanics or African American males treated with rivastigmine, olanzapine and citalopram. African American females were associated with ADD and more likely to be treated with buspirone and presented with a history of ETOH. This finding suggests the need for a pharmacological treatment approach encompassing sex-sensitive strategies for MCI-AD and ADD patients.

Gender Differences in Demographic and Pharmacological Factors in Patients Diagnosed with Late-Onset of Alzheimer's Disease.

BACKGROUND: Whether gender differences exist in late-onset of Alzheimer's disease (LOAD) treated with cholinesterase inhibitors (ChEIs) is not fully understood. This study investigated demographic and pharmacological characteristics in LOAD patients to determine gender differences in LOAD patients treated with ChEIs alone and ChEIs with other medications. METHODS: This 5-year retrospective data analysis included 9290 LOAD AD patients with 2949 men patients and 6341 women. Potential predictors of demographic and pharmacological characteristics associated gender differences in patients treated with and without ChEIs therapy were determined using univariate analysis, while multivariable models adjusted for demographic and pharmacological variables. RESULTS: In the adjusted analysis, men patients with LOAD that presented with a history of alcohol use (ETOH) (OR = 1.339, 95% CI, 1.072-1.672, p = 0.010), treated with second generation antipsychotics (SGAs) (OR = 1.271, 95% CI, 1.003-1.610, p = 0.047), citalopram (OR = 5.103, 95% CI, 3.423-7.607, p < 0.001), memantine (OR = 4.409, 95% CI, 3.704-5.249, p < 0.001), and buspirone (OR = 2.166, 95% CI, 1.437-3.264, p < 0.001) were more likely to receive ChEIs therapy, whereas older men were less likely to be treated with ChEIs therapy. Women who were African Americans (OR = 1.387, 95% CI, 1.168-1.647, p < 0.001), that received memantine (OR = 3.412, 95% CI, 3.034-3.837, p < 0.001), selective serotonin reuptake inhibitor (SSRIs) (OR = 1.143, 95% CI, 1.016-1.287, p = 0.026), and a history of ETOH (OR = 2.109, 95% CI, 1.724-2.580, p < 0.001) were more likely to receive ChEIs therapy, whereas older women were less likely to receive ChEIs therapy. CONCLUSION: In both men and women patients, those with increasing age were less likely to be treated with ChEI therapy, while patients treated with memantine were also likely to receive ChEI therapy. Our findings highlight the importance for clinicians to optimize ChEI in LOAD to improve treatment effectiveness and eliminate gender differences in ChEI therapy.

Structural and Ultrastructural Analysis of the Multiple Myeloma Cell Niche and a Patient-Specific Model of Plasma Cell Dysfunction.

Multiple myeloma (MM) is a deadly, incurable malignancy in which antibody-secreting plasma cells (PCs) become neoplastic. Previous studies have shown that the PC niche plays a role cancer progression. Bone marrow (BM) cores from MM and a premalignant condition known as monoclonal gammopathy of unknown significance (MGUS) patients were analyzed with confocal and transmission electron microscopy. The BM aspirates from these patients were used to generate 3D PC cultures. These in vitro cultures were then assayed for the molecular, cellular, and ultrastructural hallmarks of dysfunctional PC at days 1 and 5. In vivo, evidence of PC endoplasmic reticulum stress was found in both MM and MGUS BM; however, evidence of PC autophagy was found only in MM BM. Analysis of in vitro cultures found that MM PC can survive and maintain a differentiated phenotype over an unprecedented 5 days, had higher levels of paraprotein production when compared to MGUS-derived cultures, and showed evidence of PC autophagy as well. Increased fibronectin deposition around PC associated with disease severity and autophagy dysregulation was also observed. 3D cultures constructed from BM aspirates from MGUS and MM patients allow for long-term culture of functional PC while maintaining their distinct morphological phenotypes.

The role of ethnicity, biological sex, and psychotropic agents in early and late onset Alzheimer's disease.

Objective: This study investigates differences in pharmacological and demographic factors among male and female patients with Late-onset Alzheimer's disease (LOAD) and Early-onset Alzheimer's disease (EOAD). Method: Data are from 10,126 AD patients, 9,290 were diagnosed with LOAD, while 836 were diagnosed with EOAD. Data were collected from the Prisma Health Upstate Alzheimer's patients' registry between 2016 and 2021. The logistic regression analysis was used to assess the association between pharmacological and demographic factors in males and females with LOAD and EOAD. Results: In the adjusted analysis for males, patients that were administered memantine [odd ratio (OR) = 1.588, 95% CI, 1.175-2.145, p = 0.003], and buspirone [OR = 1.971, 95% CI, 1.221-3.183, p = 0.006] were more likely to be associated with EOAD, while increasing age [OR = 0.816, 95% CI, 0.799-0.834, p < 0.001] was associated with LOAD. Female patients with a history of alcohol (ETOH) use were more likely to be associated with EOAD while increasing age [OR = 0.845, 95% CI, 0.834-0.857, p < 0.001], treatment with memantine [OR = 0.774, 95% CI, 0.627-0.956, p = 0.017], African Americans [OR = 0.621, 95% CI, 0.462-0.835, p = 0.002] and tobacco use [OR = 0.529, 95% CI, 0.424-0.660, p < 0.001] were associated with LOAD. Conclusion: Our findings identified specific demographic and pharmacological factors associated with males and females with LOAD and EOAD. These findings suggest the need to develop strategies to eliminate disparity in the care of LOAD or EOAD patients.

Metabolomic Profiles of Men and Women Ischemic Stroke Patients.

BACKGROUND: Stroke is known to affect both men and women; however, incidence and outcomes differ between them. Therefore, the discovery of novel, sex-specific, blood-based biomarkers for acute ischemic stroke (AIS) patients has the potential to enhance the understanding of the etiology of this deadly disease in the content of sex. The objective of this study was to identify serum metabolites associated with male and female AIS patients. METHODS: Metabolites were measured with the use of untargeted, reverse-phase ultra-performance liquid chromatography-tandem mass spectrometry quantification from blood specimens collected from AIS patients. Samples were collected from 36 patients comprising each of 18 men and women with matched controls. Metabolic pathway analysis and principal component analysis (PCA) was used to differentiate metabolite profiles for male and female AIS patients from the control, while logistic regression was used to determine differences in metabolites between male and female AIS patients. RESULTS: In female AIS patients, 14 distinct altered metabolic pathways and 49 corresponding metabolites were identified, while 39 metabolites and 5 metabolic pathways were identified in male patients. Metabolites that are predictive of ischemic stroke in female patients were 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC (P-16:0/20:4) (AUC = 0.914, 0.765-1.000), 1-(1-enyl-palmitoyl)-2-palmitoyl-GPC (P-16:0/16:0) (AUC = 0.840, 0.656-1.000), and 5,6-dihydrouracil (P-16:0/20:2) (AUC = 0.815, 0.601-1.000). Significant metabolites that were predictive of stroke in male patients were 5alpha-androstan-3alpha,17beta-diol disulfate (AUC = 0.951, 0.857-1.000), alpha-hydroxyisocaproate (AUC = 0.938, 0.832-1.000), threonate (AUC = 0.877, 0.716-1.000), and bilirubin (AUC = 0.817, 0.746-1.000). CONCLUSIONS: In the current study, the untargeted serum metabolomics platform identified multiple pathways and metabolites associated with male and female AIS patients. Further research is necessary to characterize how these metabolites are associated with the pathophysiology in male and female AIS patients.

Collagen Fibrillogenesis in the Mitral Valve: It's a Matter of Compliance.

Collagen fibers are essential structural components of mitral valve leaflets, their tension apparatus (chordae tendineae), and the associated papillary muscles. Excess or lack of collagen fibers in the extracellular matrix (ECM) in any of these structures can adversely affect mitral valve function. The organization of collagen fibers provides a sophisticated framework that allows for unidirectional blood flow during the precise opening and closing of this vital heart valve. Although numerous ECM molecules are essential for the differentiation, growth, and homeostasis of the mitral valve (e.g., elastic fibers, glycoproteins, and glycans), collagen fibers are key to mitral valve integrity. Besides the inert structural components of the tissues, collagen fibers are dynamic structures that drive outside-to-inside cell signaling, which informs valvular interstitial cells (VICs) present within the tissue environment. Diversity of collagen family members and the closely related collagen-like triple helix-containing proteins found in the mitral valve, will be discussed in addition to how defects in these proteins may lead to valve disease.

An Adaptive Blended Learning Model for the Implementation of an Integrated Medical Neuroscience Course During the Covid-19 Pandemic.

The implementation of an integrated medical neuroscience course by technologically pivoting an in-person neuroscience course to online using an adaptive blended method may provide a unique approach for teaching a medical neuroscience course during the Covid-19 pandemic. An adaptive blended learning method was developed in response to the requirements necessitated by the Covid-19 pandemic. This model combined pedagogical needs with digital technology using online learning activities to implement student learning in a medical neuroscience course for year one medical students. This approach provided medical students with an individually customized learning opportunity in medical neuroscience. The students had the complete choice to engage the learning system synchronously or asynchronously and learn neuroscience materials at different locations and times in response to the demands required to deal with the pandemic. Students' performance in summative and formative examinations of the adaptive blended learning activities were compared with the previous performance obtained the previous year when the contents of the medical neuroscience course were implemented using the conventional "face-to-face" learning approach. While the cohort of our students in 2019 and 2020 changed, the contents, sessions, volume of material, and assessment were constant. This enabled us to compare the results of the 2019 and 2020 classes. Overall, students' performance was not significantly different between the adaptive blended learning and the in-person approach. More students scored between 70% and 79% during the adaptive blended learning compared with in-class teaching, while more students scored between 80% and 89% during the in-person learning than during the adaptive blended learning. Finally, the percentage of students that scored >90% was not significantly different for both Years 2019 and 2020. The adaptive blended learning approach was effective in enhancing academic performance for high-performing medical students. It also permitted the early identification of underachieving students, thereby serving as an early warning sign to permit timely intervention.

Therapeutic Engineered Hydrogel Coatings Attenuate the Foreign Body Response in Submuscular Implants.

BACKGROUND: Biomedical devices are implanted into mammalian soft tissues to improve, monitor, or restore form or function. The utility of these implants is limited by the subsequent foreign body response (FBR), beginning with inflammation and terminating in a collagen envelope around the device, known as the capsule. This capsule then can contract and distort the shape of the device or limit its effectiveness in interacting with the surrounding host tissues. In the current study, we investigated the effect of therapeutic collagen-coated silicone discs in a rat model of the FBR. METHODS: A 3-dimensional printed mold was used to fabricate collagen-coated silicone discs incorporating 3 therapeutic agents: colchicine, a function-blocking antibody against interleukin 8 (IL-8) receptor B, and a powerful anti-inflammatory steroid, dexamethasone. Discs were implanted submuscularly into a well-characterized rat model of the FBR and evaluated for inflammatory response, fibrotic development, and cytokine release. RESULTS: Coated silicone discs exhibited reduced collagen deposition and little to no foreign body giant cells at the host-silicone interface when compared with the silicone-only group. Therapeutic hydrogels demonstrate a significant decrease in cellular infiltration into the coatings over the 2-week time point in contrast to therapeutic-free hydrogel coatings. Cytokine analysis revealed significant differences between therapeutic-free and therapeutic-containing coatings when compared with silicone-only controls. Levels of IL-1ß, IL-6, monocyte chemotactic protein 1, and macrophage inflammatory protein 3α were affected 48 hours after implantation, while differences in IL-18, growth-regulated oncogene/keratinocyte chemoattractant, and macrophage inflammatory protein 3α were observed 1 week after implantation. CONCLUSIONS: By utilizing the host's innate immune response, our engineered hydrogel coatings delivered therapeutic moieties directly to the implant microenvironment, thus delaying the FBR up to 2 weeks.

Constitutive modeling of compressible type-I collagen hydrogels.

Collagen hydrogels have been used ubiquitously as engineering biomaterials with a biphasic network of fibrillar collagen and aqueous-filled voids that contribute to a complex, compressible, and nonlinear mechanical behavior - not well captured within the infinitesimal strain theory. In this study, type-I collagen, processed from a bovine corium, was fabricated into disks at 2, 3, and 4% (w/w) and exposed to 0, 105, 106, and 107 microjoules of ultraviolet light or enzymatic degradation via matrix metalloproteinase-2. Fully hydrated gels were subjected to unconfined, aqueous, compression testing with experimental data modeled within a continuum mechanics framework by employing the uncommon Blatz-Ko material model for porous elastic materials and a nonlinear form of the Poisson's ratio. From the Generalized form, the Special Blatz-Ko, compressible Neo-Hookean, and incompressible Mooney-Rivlin models were derived and the best-fit material parameters reported for each. The average root-mean-squared (RMS) error for the General (RMS = 0.13 ±â€¯0.07) and Special Blatz-Ko (RMS = 0.13 ±â€¯0.07) were lower than the Neo-Hookean (RMS = 0.23 ±â€¯0.10) and Mooney-Rivlin (RMS = 0.18 ±â€¯0.08) models. We conclude that, with a single fitted-parameter, the Special Blatz-Ko sufficiently captured the salient features of collagen hydrogel compression over most examined formulations and treatments.

Design and Fabrication of a Three-Dimensional In Vitro System for Modeling Vascular Stenosis.

Vascular stenosis, the abnormal narrowing of blood vessels, arises from defective developmental processes or atherosclerosis-related adult pathologies. Stenosis triggers a series of adaptive cellular responses that induces adverse remodeling, which can progress to partial or complete vessel occlusion with numerous fatal outcomes. Despite its severity, the cellular interactions and biophysical cues that regulate this pathological progression are poorly understood. Here, we report the design and fabrication of a three-dimensional (3D) in vitro system to model vascular stenosis so that specific cellular interactions and responses to hemodynamic stimuli can be investigated. Tubular cellularized constructs (cytotubes) were produced, using a collagen casting system, to generate a stenotic arterial model. Fabrication methods were developed to create cytotubes containing co-cultured vascular cells, where cell viability, distribution, morphology, and contraction were examined. Fibroblasts, bone marrow primary cells, smooth muscle cells (SMCs), and endothelial cells (ECs) remained viable during culture and developed location- and time-dependent morphologies. We found cytotube contraction to depend on cellular composition, where SMC-EC co-cultures adopted intermediate contractile phenotypes between SMC- and EC-only cytotubes. Our fabrication approach and the resulting artery model can serve as an in vitro 3D culture system to investigate vascular pathogenesis and promote the tissue engineering field.

Animal Models for Heart Valve Research and Development.

Valvular heart disease is the third-most common cause of heart problems in the United States. Malfunction of the valves can be acquired or congenital and each may lead either to stenosis or regurgitation, or even both in some cases. Heart valve disease is a progressive disease, which is irreversible and may be fatal if left untreated. Pharmacological agents cannot currently prevent valvular calcification or help repair damaged valves, as valve tissue is unable to regenerate spontaneously. Thus, heart valve replacement/repair is the only current available treatment. Heart valve research and development is currently focused on two parallel paths; first, research that aims to understand the underlying mechanisms for heart valve disease to emerge with an ultimate goal to devise medical treatment; and second, efforts to develop repair and replacement options for a diseased valve. Studies that focus on developmental malformation, genetic and disease epigenetics usually employ small animal models that are easy to access for in vivo imaging that minimally disturbs their environment during early stages of development. Alternatively, studies that aim to develop novel device for replacement and repair of diseased valves often employ large animals whose heart size and anatomy closely replicate human's. This paper aims to briefly review the current state-of-the-art animal models, and justification to use an animal model for a particular heart valve related project.

Altered Hemodynamics in the Embryonic Heart Affects Outflow Valve Development.

Cardiac valve structure and function are primarily determined during early development. Consequently, abnormally-formed heart valves are the most common type of congenital heart defects. Several adult valve diseases can be backtracked to abnormal valve development, making it imperative to completely understand the process and regulation of heart valve development. Epithelial-to-mesenchymal transition (EMT) plays an important role in the development of heart valves. Though hemodynamics is vital to valve development, its role in regulating EMT is still unknown. In this study, intracardiac hemodynamics were altered by constricting the outflow tract (OFT)/ventricle junction (OVJ) of HH16-17 (Hamilton and Hamburger (HH) Stage 16-17) chicken embryos, ex ovo for 24 h. The constriction created an increase in peak and time-averaged centerline velocity along the OFT without changes to volumetric flow or heart rate. Computational fluid dynamics was used to estimate the level of increased spatially-averaged wall shear stresses on the OFT cushion from AMIRA reconstructions. OFT constriction led to a significant decrease in OFT cushion volume and the number of invaded mesenchyme in the OFT cushion. qPCR analysis revealed altered mRNA expression of a representative panel of genes, vital to valve development, in the OFT cushions from banded hearts. This study indicates the importance of hemodynamics in valve development.

Asymmetric cell-matrix and biomechanical abnormalities in elastin insufficiency induced aortopathy.

Aortopathy is characterized by vascular smooth muscle cell (VSMC) abnormalities and elastic fiber fragmentation. Elastin insufficient (Eln (+/-)) mice demonstrate latent aortopathy similar to human disease. We hypothesized that aortopathy manifests primarily in the aorto-pulmonary septal (APS) side of the thoracic aorta due to asymmetric cardiac neural crest (CNC) distribution. Anatomic (aortic root vs. ascending aorta) and molecular (APS vs. non-APS) regions of proximal aorta tissue were examined in adult and aged wild type (WT) and mutant (Eln (+/-)) mice. CNC, VSMCs, elastic fiber architecture, proteoglycan expression, morphometrics and biomechanical properties were examined using histology, 3D reconstruction, micropipette aspiration and in vivo magnetic resonance imaging (MRI). In the APS side of Eln (+/-) aorta, Sonic Hedgehog (SHH) is decreased while SM22 is increased. Elastic fiber architecture abnormalities are present in the Eln (+/-) aortic root and APS ascending aorta, and biglycan is increased in the aortic root while aggrecan is increased in the APS aorta. The Eln (+/-) ascending aorta is stiffer than the aortic root, the APS side is thicker and stiffer than the non-APS side, and significant differences in the individual aortic root sinuses are observed. Asymmetric structure-function abnormalities implicate regional CNC dysregulation in the development and progression of aortopathy.

Biomedical implant capsule formation: lessons learned and the road ahead.

Clinicians and investigators have been implanting biomedical devices into patients and experimental animals for centuries. There is a characteristic complex inflammatory response to the presence of the biomedical device with diverse cell signaling, followed by migration of fibroblasts to the implant surface and the eventual walling off of the implant in a collagen capsule. If the device is to interact with the surrounding tissues, the collagen envelope will eventually incapacitate the device or myofibroblasts can cause capsular contracture with resulting distortion, migration, or firmness. This review analyzes the various tactics used in the past to modify or control capsule formation with suggestions for future investigative approaches.

The impact of flow-induced forces on the morphogenesis of the outflow tract.

One percent of infants are born with congenital heart disease (CHD), which commonly involves outflow tract (OFT) defects. These infants often require complex surgeries, which are associated with long term adverse remodeling effects, and receive replacement valves with limited strength, biocompatibility, and growth capability. To address these problematic issues, researchers have carried out investigations in valve development and valve mechanics. A longstanding hypothesis is that flow-induced forces regulate fibrous valve development, however, the specific mechanisms behind this mechanotransduction remain unclear. The purpose of this study was to implement an in vitro system of outflow tract development to test the response of embryonic OFT tissues to fluid flow. A dynamic, three-dimensional bioreactor system was used to culture embryonic OFT tissue under different levels of flow as well as the absence of flow. In the absence of flow, OFT tissues took on a more primitive phenotype that is characteristic of early OFT cushion development where widely dispersed mesenchymal cells are surrounded by a sparse, disorganized extracellular matrix (ECM). Whereas OFT tissues subjected to physiologically matched flow formed compact mounds of cells, initated, fibrous ECM development, while prolonged supraphysiological flow resulted in abnormal tissue remodeling. This study indicates that both the timing and magnitude of flow alter cellular processes that determine if OFT precursor tissue undergoes normal or pathological development. Specifically, these experiments showed that flow-generated forces regulate the deposition and localization of fibrous ECM proteins, indicating that mechanosensitive signaling pathways are capable of driving pathological OFT development if flows are not ideal.