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Behavioral Paradigm for the Evaluation of Stimulation-Evoked Somatosensory Perception Thresholds in Rats
Get PDFIntracortical microstimulation (ICMS) of the somatosensory cortex via penetrating microelectrode arrays (MEAs) can evoke cutaneous and proprioceptive sensations for restoration of perception in individuals with spinal cord injuries. However, ICMS current amplitudes needed to evoke these sensory percepts tend to change over time following implantation. Animal models have been used to investigate the mechanisms by which these changes occur and aid in the development of new engineering strategies to mitigate such changes. Non-human primates are commonly the animal of choice for investigating ICMS, but ethical concerns exist regarding their use. Rodents are a preferred animal model due to their availability, affordability, and ease of handling, but there are limited choices of behavioral tasks for investigating ICMS. In this study, we investigated the application of an innovative behavioral go/no-go paradigm capable of estimating ICMS-evoked sensory perception thresholds in freely moving rats. We divided animals into two groups, one receiving ICMS and a control group receiving auditory tones. Then, we trained the animals to nose-poke – a well-established behavioral task for rats – following either a suprathreshold ICMS current-controlled pulse train or frequency-controlled auditory tone. Animals received a sugar pellet reward when nose-poking correctly. When nose-poking incorrectly, animals received a mild air puff. After animals became proficient in this task, as defined by accuracy, precision, and other performance metrics, they continued to the next phase for perception threshold detection, where we varied the ICMS amplitude using a modified staircase method. Finally, we used non-linear regression to estimate perception thresholds. Results indicated that our behavioral protocol could estimate ICMS perception thresholds based on ~95% accuracy of rat nose-poke responses to the conditioned stimulus. This behavioral paradigm provides a robust methodology for evaluating stimulation-evoked somatosensory percepts in rats comparable to the evaluation of auditory percepts. In future studies, this validated methodology can be used to study the performance of novel MEA device technologies on ICMS-evoked perception threshold stability using freely moving rats or to investigate information processing principles in neural circuits related to sensory perception discrimination
Layer Multiplication Co-Extrusion of Cross-Linked Polymer Microsphere-Filled Systems
No full textLayer multiplication co-extrusion allows for creation of advance structures with highly tunable properties, with relative ease. Multi-layer co-extrusion using the layer multiplication technique was used to create 33-layered structures of polymer microsphere-filled layers alternating with unfilled layers. Cross-linked polyurethane (PU) microspheres (of two different rigidities) and ultra-highly cross-linked polymethylmethacrylate (PMMA) microspheres were used to examine the effect of particle rigidity in confinement on overall mechanical properties. Layer structures were successfully created with particle-filled layers; once layer size approaches the particle size, the particles deform the unfilled counter-layer. In certain conditions, impingement of the counter-layer occurs, decreasing the mechanical properties. High-density polyethylene-grafted-maleic anhydride (HDPE-g-MA) was subsequently utilized as a compatibilizer to improve the interface between the particles and the matrix. The HDPE-g-MA was effective in increasing the mechanical performance of the co-extruded product made with the PU microspheres but inefficient in improving the product made with the PMMA microspheres
Peroxisome Biogenesis Initiated by Protein Phase Separation
Get PDFPeroxisomes are organelles that carry out β-oxidation of fatty acids and amino acids. Both rare and prevalent diseases are caused by their dysfunction. Among disease-causing variant genes are those required for protein transport into peroxisomes. The peroxisomal protein import machinery, which also shares similarities with chloroplasts, is unique in transporting folded and large, up to 10 nm in diameter, protein complexes into peroxisomes. Current models postulate a large pore formed by transmembrane proteins; however, so far, no pore structure has been observed. In the budding yeast Saccharomyces cerevisiae, the minimum transport machinery includes the membrane proteins Pex13 and Pex14 and the cargo-protein-binding transport receptor, Pex5. Here we show that Pex13 undergoes liquid–liquid phase separation (LLPS) with Pex5–cargo. Intrinsically disordered regions in Pex13 and Pex5 resemble those found in nuclear pore complex proteins. Peroxisomal protein import depends on both the number and pattern of aromatic residues in these intrinsically disordered regions, consistent with their roles as ‘stickers’ in associative polymer models of LLPS. Finally, imaging fluorescence cross-correlation spectroscopy shows that cargo import correlates with transient focusing of GFP–Pex13 and GFP–Pex14 on the peroxisome membrane. Pex13 and Pex14 form foci in distinct time frames, suggesting that they may form channels at different saturating concentrations of Pex5–cargo. Our findings lead us to suggest a model in which LLPS of Pex5–cargo with Pex13 and Pex14 results in transient protein transport channels
Unmet Needs With Antipsychotic Treatment in Schizophrenia and Bipolar I Disorder: Patient Perspectives from Qualitative Focus Groups
No full textBackground: Schizophrenia (SZ) and bipolar I disorder (BD-I) are chronic mental health disorders often treated with antipsychotic medications. This qualitative study sought to better understand disease burden and treatment experiences with oral antipsychotic medications in participants living with SZ or BD-I. Methods: Six 90-min focus groups were conducted with participants diagnosed with SZ or BD-I. Trained moderators facilitated discussions using a semistructured guide. Participants described symptoms, impacts of disease, and experiences with oral antipsychotic medications, whether favourable or unfavourable. Results: Among participants with SZ (n = 15; 3 groups, 5 per group), 53% were male and 33% were white, with a mean of 18.6 years since diagnosis. Of participants with BD-I (n = 24; 3 groups, 8 per group), 33% were male and 42% were white, with a mean of 13.0 years since diagnosis. Participants described numerous symptoms of their illnesses that impacted relationships and daily life, including effects on emotional health, the ability to work, and encounters with law enforcement. Previous antipsychotic medications were deemed effective by 14/15 (93%) participants with SZ and 12/16 (75%) participants with BD-I. Most participants with SZ (13/15; 87%) or with BD-I (16/24; 67%) reported discontinuing their antipsychotic medication at some point. Side effects were a common reason for discontinuing or switching medications for participants with SZ (8/15; 53%) and for those with BD-I (11/24; 46%). The most common side effects reported in both cohorts were weight gain, drowsiness, sexual problems, and neurologic symptoms. Side effects negatively affected quality of life, leading to serious health problems and issues with self-esteem. Conclusions: People living with SZ or BD-I cited a range of favourable and unfavourable experiences with oral antipsychotic medications. Most participants reported that their antipsychotics were effective at controlling their symptoms, but multiple side effects impacted their quality of life, caused additional serious health problems, and often led to discontinuation of or switching antipsychotics. Findings from this study contribute to a better understanding of patients’ experiences with antipsychotics and highlight a need for new medications with favourable benefit/risk profiles
Racial Differences in Time to Blood Pressure Control of Aneurysmal Subarachnoid Hemorrhage Patients: A Single-Institution Study
No full textBackground and purpose Aneurysmal subarachnoid hemorrhage occurs in approximately 30,000 patients annually in the United States. Uncontrolled blood pressure is a major risk factor for aneurysmal subarachnoid hemorrhage. Clinical guidelines recommend maintaining blood pressure control until definitive aneurysm securement occurs. It is unknown whether racial differences exist regarding blood pressure control and outcomes (HLOS, discharge disposition) in aneurysmal subarachnoid hemorrhage. Here, we aim to assess whether racial differences exist in 1) presentation, 2) clinical course, and 3) outcomes, including time to blood pressure stabilization, for aSAH patients at a large tertiary care medical center. Methods We conducted a retrospective review of adult aneurysmal subarachnoid hemorrhage cases from 2013 to 2019 at a single large tertiary medical center. Data extracted from the medical record included sex, age, race, insurance status, aneurysm location, aneurysm treatment, initial systolic and diastolic blood pressure, Hunt Hess grade, modified Fisher score, time to blood pressure control (defined as time in minutes from first blood pressure measurement to the first of three consecutive systolic blood pressure measurements under 140mmHg), hospital length of stay, and final discharge disposition. Results 194 patients met inclusion criteria; 140 (72%) White and 54 (28%) Black. While White patients were more likely than Black patients to be privately insured (62.1% versus 33.3%, p \u3c 0.001), Black patients were more likely than White patients to have Medicaid (55.6% versus 15.0%, p \u3c 0.001). Compared to White patients, Black patients presented with a higher median systolic (165 mmHg versus 148 mmHg, p = 0.004) and diastolic (93 mmHg versus 84 mmHg, p = 0.02) blood pressure. Black patients had a longer median time to blood pressure control than White patients (200 minutes versus 90 minutes, p = 0.001). Black patients had a shorter median hospital length of stay than White patients (15 days versus 18 days, p \u3c 0.031). There was a small but statistically significant difference in modified Fisher score between black and white patients (3.48 versus 3.17, p = 0.04).There were no significant racial differences present in sex, Hunt Hess grade, discharge disposition, complications, or need for further interventions. Conclusion Black race was associated with higher blood pressure at presentation, longer time to blood pressure control, but shorter hospital length of stay. No racial differences were present in aneurysmal subarachnoid hemorrhage associated complications or interventions
Blood Pressure Variability and Early Neurological Outcomes in Acute and Subacute Stroke in Southwestern Uganda
No full textBackground: Greater blood pressure variability has detrimental effects on clinical outcome after a stroke; its effects are controversial and have not been evaluated in Sub-Saharan Africa (SSA). Methods: We conducted a prospective study of patients with CT head confirmed ischemic and hemorrhagic strokes admitted to a tertiary hospital within 7 days of onset of unilateral neurological deficits. Blood pressure variability indices, standard deviation (SD) and coefficient of variation (CV) of systolic and diastolic blood pressure between day 0 and day 7, were calculated with a subsequent modified Rankin Scale (mRS) score on day 14 post-stroke. Linear regression was performed to determine the exponential coefficients of mortality at 14 days post- stroke. Results: Out of 120 patients, 51.7% were female, 52.5% had ischemic stroke and the overall median age was 65 (IQR 54–80) years. Twenty (16.7%) patients died within a median survival time of 7 days, while 32 (26.7%) died by day 14 post-stroke. Patients with hemorrhagic stroke had an overall SDSBP of 16.44 mmHg while those with ischemic stroke had an overall SDSBP of 14.05 mmHg. In patients with ischemic stroke, SDSBP had adjusted coefficients of 1, p = 0.004 with C·I: 1.01–1.04 and NIHSS had adjusted coefficients of 1, p = 0.019 with C·I: 1.00–1.03 while in patients with hemorrhagic stroke, SDSBP had adjusted coefficients of 1, p = 0.045 with C·I: 1.00–1.04 and NIHSS had adjusted coefficients of 1, p ≤0.001 with C·I: 1.01–1.03. Conclusion: Exponential increase in Blood Pressure Variability (BPV) and stroke severity scale were independently associated with early mortality among all stroke patients in our study. We recommend future studies to evaluate whether controlling BPV among patients with stroke in Sub-Saharan Africa can reduce mortality
Demographic and Clinical Associations to Employment Status in older-Age Bipolar Disorder: Analysis from the GAGE-BD Database Project
No full textObjective: The current literature on employment in older adults with bipolar disorder (OABD) is limited. Using the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE-BD), we examined the relationship of occupational status in OABD to other demographic and clinical characteristics. Methods: Seven hundred and thirty-eight participants from 11 international samples with data on educational level and occupational status were included. Employment status was dichotomized as employed versus unemployed. Generalized linear mixed models with random intercepts for the study cohort were used to examine the relationship between baseline characteristics and employment. Predictors in the models included baseline demographics, education, psychiatric symptom severity, psychiatric comorbidity, somatic comorbidity, and prior psychiatric hospitalizations. Results: In the sample, 23.6% (n = 174) were employed, while 76.4% were unemployed (n = 564). In multivariable logistic regression models, less education, older age, a history of both anxiety and substance/alcohol use disorders, more prior psychiatric hospitalizations, and higher levels of BD depression severity were associated with greater odds of unemployment. In the subsample of individuals less than 65 years of age, findings were similar. No significant association between manic symptoms, gender, age of onset, or employment status was observed. Conclusion: Results suggest an association between educational level, age, psychiatric severity and comorbidity in relation to employment in OABD. Implications include the need for management of psychiatric symptoms and comorbidity across the lifespan, as well as improving educational access for people with BD and skills training or other support for those with work-life breaks to re-enter employment and optimize the overall outcome
Donepezil-Associated Survival Benefits among Alzheimer’s Disease Patients are Retained but not Enhanced during COVID-19 Infections
Get PDFBackground and Aim: Donepezil is a front-line treatment for Alzheimer’s disease. Donepezil treatment is associated with decreased risk of all-cause mortality. Specific protection is observed in pneumonia and cardiovascular disease. We hypothesized that donepezil treatment would improve mortality among Alzheimer’s patients following infection with COVID-19. The objective of this study is to assess the influence of ongoing donepezil treatment on survival in Alzheimer’s disease patients after polymerase chain reaction (PCR)-confirmed COVID-19 infection. Methods: This is a retrospective cohort study. We conducted a national survey of Veterans with Alzheimer’s disease to assess the influence of ongoing donepezil treatment on survival in Alzheimer’s disease patients after PCR-confirmed COVID-19 infection. We assessed all-cause 30-day mortality stratified by COVID-19 infection and donepezil use, estimating odds ratios using multivariate logistic regression. Results: Among people with Alzheimer’s disease and COVID-19, all-cause 30-day mortality was 29% (47/163) for people taking donepezil compared with 38% (159/419) for those who were not. Among people with Alzheimer’s disease without COVID-19, all-cause 30-day mortality was 5% (189/4189) for people taking donepezil compared with 7% (712/10,241) for those who were not. Adjusting for covariates, the decrease in mortality associated with donepezil did not differ between people with and without COVID-19 (interaction p = 0.710) Conclusion: The known survival benefits of donepezil were retained but not found to be specific to COVID-19 among people with Alzheimer’s disease
Membrane Bending and Sphingomyelinase-Associated, Sulfatide-Dependent Hypoxic Adhesion of Sickle Mature Erythrocytes
Get PDFAbnormal erythrocyte adhesion owing to polymerization of sickle hemoglobin is central to the pathophysiology of sickle cell disease (SCD). Mature erythrocytes constitute \u3e80% of all erythrocytes in SCD; however, the relative contributions of erythrocytes to acute and chronic vasculopathy in SCD are not well understood. Here, we showed that bending stress exerted on the erythrocyte plasma membrane by polymerization of sickle hemoglobin under hypoxia, enhances sulfatide-mediated abnormal mature erythrocyte adhesion. We hypothesized that sphingomyelinase (SMase) activity, which is upregulated by accumulated bending energy, leads to elevated membrane sulfatide availability, and thus, hypoxic mature erythrocyte adhesion. We found that mature erythrocyte adhesion to laminin in controlled microfluidic experiments is significantly greater under hypoxia than under normoxia (1856 ± 481 vs 78 ± 23, mean ± SEM), whereas sickle reticulocyte (early erythrocyte) adhesion, high to begin with, does not change (1281 ± 299 vs 1258 ± 328, mean ± SEM). We showed that greater mean accumulated bending energy of adhered mature erythrocytes was associated with higher acid SMase activity and increased mature erythrocyte adhesion (P = .022, for acid SMase activity and P = .002 for the increase in mature erythrocyte adhesion with hypoxia, N = 5). In addition, hypoxia results in sulfatide exposure of the erythrocyte membrane, and an increase in SMase, whereas anti-sulfatide inhibits enhanced adhesion of erythrocytes. These results suggest that the lipid components of the plasma membrane contribute to SCD complications. Therefore, sulfatide and the components of its upregulation pathway, particularly SMase, should be further explored as potential therapeutic targets for inhibiting sickle erythrocyte adhesion
Microfluidic Concurrent Assessment of Red Blood Cell Adhesion and Microcapillary Occlusion: Potential Hemorheological Biomarkers in Sickle Cell Disease
Get PDFDeformability and non-adherence are two fundamental functional properties of red blood cells (RBCs), which allow them to move unimpeded through the microvasculature. In sickle cell disease (SCD), polymerization of abnormal sickle hemoglobin leads to decreased deformability and increased membrane adhesiveness in RBCs. This contributes to abnormal blood vessel occlusion, which is central to the underlying pathophysiology. RBC deformability and adhesiveness are, therefore key hemorheological biomarkers in characterizing disease states as well as in evaluating novel therapeutics. To date, these important interrelated biomarkers have been assessed in distinct laboratory assays, without integration or concurrent assessment in vitro. To this end, we present a novel microfluidic assay in which laminin (LN, a sub-endothelial matrix protein that mimics microvascular damage and extracellular matrix exposure)functionalized microcapillaries ranging from 20 μm to 4 μm are embedded in microchannels, for simultaneous assessment of microcapillary occlusion mediated by RBC deformability and vascular cellular adhesion mediated by pathologic RBC membrane changes. We show that RBC adhesion to LN or microcapillary occlusion can be associated with markers for intravascular hemolysis or iron overload in SCD. Following allogeneic hematopoietic stem cell transplant (HSCT), which is a curative therapy, in a single subject with SCD, RBC-mediated microcapillary occlusion fell into the healthy range, but RBC adhesion to LN, albeit significantly decreased, remained outside the healthy range. Our findings demonstrate the potential of this bifunctional assay, in both monitoring the clinical course and supplementing clinical observations with comprehensive evaluation of two functional hemorheological properties
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