Similar Impairment Research Articles

Postnatal Phencyclidine-Induced Deficits in Decision Making Are Ameliorated by Optogenetic Inhibition of Ventromedial Orbitofrontal Cortical Glutamate Neurons

BackgroundThe orbitofrontal cortex (OFC) is essential for decision making, and functional disruptions within the OFC are evident in schizophrenia. Postnatal phencyclidine (PCP) administration in rats is a neurodevelopmental manipulation that induces schizophrenia-relevant cognitive impairments. We aimed to determine whether manipulating OFC glutamate cell activity could ameliorate postnatal PCP-induced deficits in decision making. MethodsMale and female Wistar rats (n = 110) were administered saline or PCP on postnatal days 7, 9, and 11. In adulthood, we expressed YFP (yellow fluorescent protein) (control), ChR2 (channelrhodopsin-2) (activation), or eNpHR 3.0 (enhanced halorhodopsin) (inhibition) in glutamate neurons within the ventromedial OFC (vmOFC). Rats were tested on the probabilistic reversal learning task once daily for 20 days while we manipulated the activity of vmOFC glutamate cells. Behavioral performance was analyzed using a Q-learning computational model of reinforcement learning. ResultsCompared with saline-treated rats expressing YFP, PCP-treated rats expressing YFP completed fewer reversals, made fewer win-stay responses, and had lower learning rates. We induced similar performance impairments in saline-treated rats by activating vmOFC glutamate cells (ChR2). Strikingly, PCP-induced performance deficits were ameliorated when the activity of vmOFC glutamate cells was inhibited (halorhodopsin). ConclusionsPostnatal PCP-induced deficits in decision making are associated with hyperactivity of vmOFC glutamate cells. Thus, normalizing vmOFC activity may represent a potential therapeutic target for decision-making deficits in patients with schizophrenia.

Loss of microRNA-30a and sex-specific effects on the neonatal hyperoxic lung injury

BackgroundBronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.MethodsWild-type and miR-30a−/− neonatal mice were exposed to hyperoxia [95% FiO2, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a−/− mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a−/− male and female lung transcriptome data.ResultsSignificantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a−/− mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a−/− female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand–receptor interaction. Gene expression signature in the miR-30a−/− female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium.ConclusionsmiR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.

More extensive structural damage in temporal lobe epilepsy with hippocampal sclerosis type 1

ObjectiveTo explore clinical and structural differences between mesial temporal lobe epilepsy (mTLE) patients with different hippocampal sclerosis (HS) subtypes. MethodsHigh-resolution T1-weighted MRI and diffusion tensor imaging data were obtained in 41 refractory mTLE patients and 52 age- and sex-matched healthy controls. Postoperative histopathological examination confirmed HS type 1 in 30 patients and HS type 2 in eleven patients. Clinical features, postoperative seizure outcomes, hippocampal subfields volumes, fractional anisotropy (FA) values of white matter regions and graph theory parameters were explored and compared between the HS type 1 and HS type 2 groups. ResultsNo significant differences in clinical features and postsurgical seizure outcomes were found between the HS type 1 and type 2 groups. However, the HS type 1 group showed extra atrophy in ipsilateral parasubiculum than healthy controls and more severe atrophy in contralateral hippocampal fissure than the HS type 2 group. More extensive FA decrease were also observed in the HS type 1 group, involving ipsilateral optic radiation, superior fronto-occipital fasciculus, contralateral uncinate fasciculus, tapetum, bilateral hippocampal cingulum, corona radiata, etc. Furthermore, in spite of similar impairments in characteristic path length, global efficiency and local efficiency in two HS groups, the HS type 1 group showed additional decrease of clustering coefficient than healthy controls. ConclusionsHS type 1 and 2 groups had similar clinical characteristics and postoperative seizure outcomes. More widespread neuronal cell loss in the HS type 1 group contributed to more extensive structural damage and connectivity abnormality. These results shed new light on the imaging correlates of different HS pathology.

Early cellular and synaptic changes in dopaminoceptive forebrain regions of juvenile mice following gestational exposure to valproate.

Gestational exposure of mice to valproic acid (VPA) is one currently used experimental model for the investigation of typical failure symptoms associated with autism spectrum disorder (ASD). In the present study we hypothesized that the reduction of dopaminergic source neurons of the VTA, followed by perturbed growth of the mesotelencephalic dopamine pathway (MT), should also modify pattern formation in the dopaminoceptive target regions (particularly its mesoaccumbens/mesolimbic portion). Here, we investigated VPA-evoked cellular morphological (apoptosis-frequency detected by Caspase-3, abundance of Ca-binding proteins, CaBP), as well as synaptic proteomic (western blotting) changes, in selected dopaminoceptive subpallial, as compared to pallial, regions of mice, born to mothers treated with 500 mg/kg VPA on day 13.5 of pregnancy. We observed a surge of apoptosis on VPA treatment in nearly all investigated subpallial and pallial regions; with a non-significant trend of similar increase the nucleus accumbens (NAc) at P7, the age at which the MT pathway reduction has been reported (also supplemented by current findings). Of the CaBPs, calretinin (CR) expression was decreased in pallial regions, most prominently in retrosplenial cortex, but not in the subpallium of P7 mice. Calbindin-D 28K (CB) was selectively reduced in the caudate-putamen (CPu) of VPA exposed animals at P7 but no longer at P60, pointing to a potency of repairment. The VPA-associated overall increase in apoptosis at P7 did not correlate with the abundance and distribution of CaBPs, except in CPu, in which the marked drop of CB was negatively correlated with increased apoptosis. Abundance of parvalbumin (PV) at P60 showed no significant response to VPA treatment in any of the observed regions we did not find colocalization of apoptotic (Casp3+) cells with CaBP-immunoreactive neurons. The proteomic findings suggest reduction of tyrosine hydroxylase in the crude synaptosome fraction of NAc, but not in the CPu, without simultaneous decrease of the synaptic protein, synaptophysin, indicating selective impairment of dopaminergic synapses. The morpho-functional changes found in forebrain regions of VPA-exposed mice may signify dendritic and synaptic reorganization in dopaminergic target regions, with potential translational value to similar impairments in the pathogenesis of human ASD.

A mutation responsible for impaired detection by the Xpert SARS-CoV-2 assay independently emerged in different lineages during the SARS-CoV-2 pandemic

BackgroundCOVID-19 diagnosis lies on the detection of SARS-CoV-2 on nasopharyngeal specimens by RT-PCR. The Xpert-Xpress SARS-CoV-2 assay provides results in less than one hour from specimen reception, which makes it suitable for clinical/epidemiological circumstances that require faster responses. The analysis of a COVID-19 outbreak suspected in the neonatology ward from our institution showed that the Ct values obtained for the targeted genes in the Xpert assay were markedly different within each specimen (N Ct value > 20 cycles above the E Ct value).ResultsWe identified the mutation C29200T in the N gene as responsible for an impairment in the N gene amplification by performing whole genome sequencing of the specimens involved in the outbreak (Omicron variant). Subsequently, a retrospective analysis of all specimens sequenced in our institution allowed us to identify the same SNP as responsible for similar impairments in another 12 cases (42% of the total cases reported in the literature). Finally, we found that the same SNP emerged in five different lineages independently, throughout almost all the COVID-19 pandemic.ConclusionsWe demonstrated for the first time the impact of this SNP on the Xpert assay, when harbored by new Omicron variants. We extend our observation period throughout almost all the COVID-19 pandemic, offering the most updated observations of this phenomenon, including sequences from the seventh pandemic wave, until now absent in the reports related to this issue. Continuous monitoring of emerging SNPs that could affect the performance of the most commonly used diagnostic tests, is required to redesign the tests to restore their correct performance.

The role of corneal endothelium in macular corneal dystrophy development and recurrence.

Macular corneal dystrophy (MCD) is a progressive, bilateral stromal dystrophic disease that arises from mutations in carbohydrate sulfotransferase 6 (CHST6). Corneal transplantation is the ultimate therapeutic solution for MCD patients. Unfortunately, postoperative recurrence remains a significant challenge. We conducted a retrospective review of a clinical cohort comprising 102 MCD patients with 124 eyes that underwent either penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK). Our results revealed that the recurrence rate was nearly three times higher in the DALK group (39.13%, 9/23 eyes) compared with the PKP group (10.89%, 11/101 eyes), suggesting that surgical replacement of the corneal endothelium for treating MCD is advisable to prevent postoperative recurrence. Our experimental data confirmed the robust mRNA and protein expression of CHST6 in human corneal endothelium and the rodent homolog CHST5 in mouse endothelium. Selective knockdown of wild-type Chst5 in mouse corneal endothelium (ACsiChst5), but not in the corneal stroma, induced experimental MCD with similar extracellular matrix synthesis impairments and corneal thinning as observed in MCD patients. Mice carrying Chst5 point mutation also recapitulated clinical phenotypes of MCD, along with corneal endothelial abnormalities. Intracameral injection of wild-type Chst5 rescued the corneal impairments in ACsiChst5 mice and retarded the disease progression in Chst5 mutant mice. Overall, our study provides new mechanistic insights and therapeutic approaches for MCD treatment by high-lighting the role of corneal endothelium in MCD development.

Chronic inhibition of astrocytic aquaporin-4 induces autistic-like behavior in control rat offspring similar to maternal exposure to valproic acid

Social communication and interaction deficits, memory impairment, and anxiety-like behavior are characterized in many people identified with autism spectrum disorder (ASD). A thorough understanding of the specific aspects that contribute to the deficiencies associated with ASD can aid research into the etiology of the disorder while also providing targets for more effective intervention. As part of the ASD pathophysiology, alterations in synaptogenesis and abnormal network connections were seen in high-order brain areas, which control social behavior and communication. The early emergence of microglia during nervous system development may contribute to synaptic dysfunction and the pathobiology of ASD. Since aquaporin-4 (AQP4) appears to be required for the basic procedures of synapse activation, certain behavioral and cognitive impairments as well as disturbance in water homeostasis might likely arise from AQP4 deficiency. Here, through the measurement of the water content of the hippocampus and behavioral experiments we aim to explore the contribution of astrocytic AQP4 to the autism-like behavior induced by prenatal valproic acid (VPA) exposure and whether inhibition of AQP4 per se can induce autistic-like behavior in control rats.Microinjection of TGN-020 (10 µM, i.c.v), a specific AQP4 inhibitor, for 7 successive days before behavioral tasks from postnatal day 28 to 35 revealed that inhibition of AQP4 in the control offspring caused lower social interaction and locomotor activity, higher anxiety, and decreased ability to recognize novel objects, very similar to the behavioral changes observed in offspring prenatally exposed to VPA. However, VPA-exposed offspring treated with TGN-020, showed no further remarkable behavioral impairments than those detected in the autistic-like rats. Furthermore, both control offspring treated with TGN-020 and offspring exposed to VPA had a considerable accumulation of water in their hippocampi. But AQP4 inhibition did not affect the water status of the autistic-like rats.The findings of this study revealed that control offspring exhibited similar hippocampal water retention and behavioral impairments that were observed in maternal VPA-exposed offspring following inhibition of astrocytic AQP4, whereas, in autistic-like rats, it did not produce any significant change in water content and behaviors. Findings suggest that AQP4 deficiency could be associated with autistic disorder and may be a potential pharmaceutical target for treating autism in the future.

#5621 BENEFICIAL EFFECTS OF CHRONIC INTRADIALYTIC EXERCISE TRAINING ON HEMODIALYSIS-INDUCED-MYOCARDIAL STUNNING

Abstract Background and Aims Hemodialysis (HD) induces left ventricular (LV) segmental regional wall motion abnormalities (RWMAs) due to hypoperfusion, leading to acute LV transient dysfunction, well known as myocardial stunning. Repeated episodes of HD-related myocardial stunning contribute directly to the development of heart failure and increased mortality in patients receiving HD (Burton et al., 2009). Exercise training exert pleiotropic favorable effects on the cardiovascular system. No study has however investigated its impact on the kinetics of regional myocardial function during HD. This study aims to evaluate the effect of intradialytic exercise (IDE) on RWMAs compared with standard care. Method This was a prospective, open-label, two-center trial (clinicaltrials.gov NCT04697459) with two parallel groups: 31 patients (ENT) undergoing a 4-month IDE program (30min of cycling + 30min of resistance training starting 30 min after HD onset) and 21 patients continuing usual care (CTRL). Untrained adults, aged 20-79 years, undertaking maintenance HD for >3 months were eligible to participate. Exclusion criteria were poor echogenicity, contraindication to exercise, orthopedic complications, severe heart (ischemic, valvular, ...), vascular or respiratory diseases, ejection fraction <45% and body mass index >35. Longitudinal strain (LS) using speckle-tracking echocardiography were measured during a standard HD session, just before HD onset (HDT0) and at peak stress of HD (30 min before HD-ending, HDPeak). The same procedure was used before and after 4-months of IDE or usual care. LS from a 18 LV segment model were used to assess the presence of HD-induced RWMAs, defined as a ≥20% reduction in LS at peak stress compared to baseline. A generalized linear mixed model (Poisson model) was used to analyze the effect of IDE on RWMAs. Results After 4 months of IDE, we observed a significant reduction of RWMAs at HDPeak (mean before: 6.03±3.19 vs after: 4.55±2.26; point estimate: -1.48, 95% confident interval CI: -0.39/-2.57, p = 0.03), whereas its occurrence remained unchanged in CTRL (mean before: 6.14±3.51 vs after: 6.09±3.16; point estimate: -0.05; 95% CI: 1.45/-1.54, p = 0.96). There was also evidence that IDE program significantly attenuated the decline of global LS observed during HD (before: 2.11±2.39% vs after: 1.10±1.95%; point estimate: -1.01%; 95% CI: -1.86/-0.13, p = 0.02) compared to the similar impairment in CTRL (before: 1.60±2.30% vs after: 1.79±2.08%; point estimate: +0.18%; 95% CI: +1.20/-0.85 p = 0.72). Conclusion There is clear evidence that chronic IDE is cardioprotective. Identifying the underlying mechanisms responsible for exercise-induced cardioprotection was beyond the scope of our study, but we can reasonably assume that structural and/or functional changes in the coronary arteries, especially in microcirculatory territories (i.e. increased collateral circulation due to angiogenesis/arteriogenesis, improved endothelial function, reduced blood viscosity) and/or intrinsic changes in the cardiac myocyte (reduced fibrosis, enhanced calcium handling/sensitivity, altered mitochondrial turnover and phenotype), related among others to reduced oxidative stress and/or inflammation, might play a role (Powers et al 2014). Whether our results translate to longer-term reduction in clinical outcomes and cardiovascular mortality in end-stage renal disease patients require further studies.

Potential direct role of synuclein in dopamine transport and its implications for Parkinson's disease pathogenesis

Parkinson Disease (PD) is a progressive neurodegenerative disorder that is caused by dysfunction and death of dopaminergic neurons. Mutations in the gene encoding α-synuclein (ASYN) have been linked with familial PD (FPD). Despite important role of ASYN in PD pathology, its normal biological function has not been clarified, although direct action of ASYN in synaptic transmission and dopamine (DA+) release have been proposed. In the present report we propose a novel hypothesis that ASYN functions as DA+/H+ exchanger that can facilitate transport of dopamine across synaptic vesicle (SV) membrane by taking advantage of proton gradient between SV lumen and cytoplasm. According to this hypothesis, normal physiological role of ASYN consists of fine-tuning levels of dopamine in the SVs based on cytosolic concentration of dopamine and intraluminal pH. This hypothesis is based on similarity in domain structure of ASYN and pHILP, a designed peptide developed to mediate loading of lipid nanoparticles with the cargo molecules. We reason that carboxy-terminal acidic loop D2b domain in both ASYN and pHILP binds cargo molecules. By mimicking DA+ association with E/D residues in D2b domain of ASYN using Tyrosine replacement approach (TR) we have been able to estimate that ASYN is able to transfer 8–12 molecules of dopamine across SV membrane on each DA+/H+ exchange cycle. Our results suggest that familial PD mutations (A30P, E46K, H50Q, G51D, A53T and A53E) will interfere with different steps of the exchange cycle, resulting in partial loss of dopamine transport function phenotype. We also predict that similar impairment in ASYN DA+/H+ exchange function also occurs as a result on neuronal aging due to changes in SV lipid composition and size and also dissipation of pH gradient across SV membrane. Proposed novel functional role of ASYN provides novel insights into its biological role and its role in PD pathogenesis.

Inverse relationship between education and amyloid burden in individuals with subjective cognitive decline plus and mild cognitive impairment

AbstractBackgroundHigher educated patients with MCI can tolerate more neuropathology than lower educated patients with similar clinical impairment. It is not known whether this observation also accounts for potential preclinical stages of AD, namely subjective cognitive decline plus (SCD+).MethodData of 197 SCD+ individuals, 227 MCI and 157 AD patients were included, which were collected as part of the AMYPAD‐DPMS cohort (https://amypad.eu/). First, median education in years was computed across the AD‐spectrum groups for each of the 8 European sites. Next, using a median split, the SCD+, MCI and AD cohort were separately categorized into a higher and lower educated group, excluding subjects with median education. Afterwards, the higher and lower educated AD‐spectrum groups were matched for age, sex and cognitive function (MMSE) using propensity score matching in R, leading to the following sample (low/high education): 54/54 SCD+, 70/81 MCI and 56/65 AD patients. Global amyloid load was compared between education groups using Centiloid (CL) information derived from Flutemetamol and Florbetaben PET scans. To confirm the results of the stringent group comparison, partial correlations between years of education and CL values correcting for age, sex and tracer type were performed for each AD‐spectrum group. All analyses were conducted in SPSS 28 and significance level was set to p < .05.ResultHigher educated SCD+ subjects presented significantly (p <. 001) lower CL values (M(CL) = 16.48) than lower educated SCD+ subjects (M(CL) = 32.17), whereas the opposite effect (p < .046) was observed in the MCI cohort with higher educated MCI patients presenting greater CL values (M(CL) = 57.08) compared to the lower educated MCI group (M(CL) = 41.74). No difference was found in the AD group. Results were further confirmed by the correlation approach across the unmatched sample yielding a negative association between years of education and CL values in the SCD+ group (r = ‐.159, p = .027) and a positive association in the MCI group (r = .153, p = .022).ConclusionThese results indicate that sensitivity to early amyloid accumulation may possibly increase with higher education in potential preclinical stages of AD, whereas in clinical stages of AD higher education may support compensatory mechanisms against amyloid burden.

Novel c.2654+1G>A mutation in the CSF1R gene in a family with CSF1R‐microglial encephalopathy

AbstractBackgroundThe colony‐stimulating factor‐1 receptor (CSF1R) is a transmembrane tyrosine kinase receptor that is mainly expressed in the brain‐resident microglia. Thus, microglial dysfunction due to CSF1R mutation may play a primary and pivotal role in the pathogenesis of CSF1R‐microglial encephalopathy. Neither the functional consequences of all known CSF1R mutations nor the full genetic spectrum of mutations causing CSF1R‐microglial encephalopathy have been fully elucidated. We aimed to describe a novel heterozygous splicing variant of the CSF1R gene that caused CSF1R‐microglial encephalopathy in a Han Chinese family.MethodThe demographic data, detailed medical history, and clinical manifestations were collected from a family with CSF1R‐microglial encephalopathy. Some family members also underwent neuropsychological evaluation, structural and functional magnetic resonance imaging (MRI), and whole‐exome sequence analyses.ResultFour generations of this family, including 27 members, presented with a medical history of a dominant hereditary pattern (Figure 1). Seven of these 27 individuals had died, while five presented with similar cognitive impairments clinically, including the proband, and his sister, father, uncle, and grandmother during their life. Brain MRI of the proband (Figure 2) and his sister (Figure 3) depicted symmetric confluent and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The brother of the proband remained asymptomatic, and the structural brain MRI only revealed minimal white matter changes; however, pseudo‐continuous arterial spin labeling (pCASL) demonstrated marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum (Figure 4). Whole‐exome sequencing was performed for seven family members, which identified a novel splice‐site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members (Figure 5).ConclusionWe identified a novel splicing mutation (c.2319+1C>A) in intron 20 of CSF1R as the cause of CSF1R‐microglial encephalopathy in a Han Chinese family, which broadens the genetic spectrum of CSF1R‐microglial encephalopathy. We opine that clinically feasible pCASL techniques may be more sensitive to the alterations in CBF of associated with microglial density and cellular changes. This study highlights the potential value of pCASL techniques to improve the clinical diagnostic accuracy of CSF1R‐microglial encephalopathy.

Creating the Phenotype of Preeclamptic Endothelial Dysfunction in Placental Vessels

Objective: To determine if placental vessel endothelial dysfunction can be produced in control vessels by exposure to preeclamptic plasma, establishing a model to further explore the mechanisms of dysfunction and therapeutics to restore function in preeclampsia. Hypothesis: Preeclamptic plasma administered to unaffected vessels induces endothelial dysfunction. Methods: Placental microvessels were dissected from the maternal side of placentas from patients consented to the Medical College of Wisconsin Maternal Research Placenta and Cord Blood Bank. Control vessels were treated with 10% healthy maternal plasma or 10% preeclamptic (PreE) maternal plasma within the vessel lumen for 12-16 hours[MJ1]. PreE vessels were not treated with plasma. Microvessels were then cannulated on glass micropipettes, pressurized to 60mmHg and constricted with 0.1-1.0 nM Endothelin-1 (ET-1). A 1-100cm H2O pressure gradient was applied and the inner diameter of the vessel was measured by video microscopy. The change in diameter was calculated as a % of maximum diameter as assessed by exposure to 100μM papaverine. Flow mediated dilation (FMD) was evaluated by a two-way ANOVA test with Dunnett’s multiple comparisons. The maximum dilation values were evaluated by a Kruskal-Wallis test with Dunn’s multiple comparative test or t-test as appropriate. FMD is evaluated as mean +/- SEM. Data: Control vessels at maximum flow dilated to 81.1 % ± 7.1 % (n=5), whereas vessel from PreE placentas dilated to 36.9 % ± 8.6% (n=3,). Incubation of control vessels with normal plasma resulted in maximal dilation of 80.6% ± 3.3%, n=3. Control vessels incubated with plasma from PreE patients dilated to 44.7% ± 4.7%. n=3). Summary of Results: Control vessels dilated significantly more than PreE vessels when evaluated by t-test (p=0.05). Incubation of control vessels with normal plasma did not change maximal dilation (p>0.99). Control vessels incubated with PreE plasma demonstrated a near significant drop in dilatory capacity (p=0.05). PreE plasma exposed vessels compared to untreated PreE vessels showed no significant difference (p=0.46[DDG2] ).When comparing overall flow mediated dilatory responses in these vessels there is a significant difference observed between control vessels, control vessels treated with PreE plasma, and PreE vessels at 50cm H2O (p<0.05). This difference is even more significant (p<0.01) at the maximum pressure gradient when analyzed by two-way ANOVA. There is no significant difference at any point between control vessels and control vessels treated with normal plasma as evaluated by two-way ANOVA (p>0.99). Conclusions: The addition of PreE plasma to control vessels demonstrates similar impairment in endothelium-dependent vasodilation as seen in untreated PreE vessels. Future directions will include evaluation of the mechanisms of vasodilation and therapeutic options that could restore endothelial function in PreE vessels. NHLBI 1K08HL150340-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Leveraging patient-reported outcomes to discern mobility trajectories in Parkinson’s disease (P10-11.003)

<h3>Objective:</h3> To characterize subgroups of persons with Parkinson’s disease (PWP) with similar longitudinal mobility impairment patterns based on an easy-to-use patient-reported outcome (PRO) measure. <h3>Background:</h3> Mobility impairments are common, complex symptoms experienced by PWP. The underlying mechanisms and accrual patterns are not well understood, which impedes therapeutic shared-decision making. <h3>Design/Methods:</h3> Latent class growth analysis (LCGA) uses finite mixture models to estimate discrete groups of trajectory parameters using maximum likelihoods. Using longitudinal data available through Fox Insight Data Exploration Network, LCGA was applied to 16,863 PWP stratified by early (N=8612; &lt;3 years), mid (N=6181; 3–10 years) and later (N=2070; &gt;10 years) disease duration spanning ~4.5 years, to empirically discern clusters of PWP with similar longitudinal mobility impairment patterns. Mobility impairment was measured using a generic health-related quality of life tool that has shown construct validity in PWP (EuroQol 5 dimensions [EQ-5D-5L] mobility component). Associations were evaluated between latent trajectory classes and sociodemographic/clinical factors. <h3>Results:</h3> In the early and mid-disease duration strata, four clusters were identified, while a fifth cluster was identified in the later disease duration strata. The subgroup trajectories ranged from none to moderate mobility problems, with a smaller cluster of subjects with severe mobility problems. The percentage of subjects with moderate (early=17.5%, mid=26.4%, later=32.5%) and severe (early=3.8%, mid=7.4%, later=15.4%) mobility problems at baseline increased across disease duration groups. The trajectories tended to be variable or slightly worsening in the early and later duration group and more stable in the mid-duration group. Across strata, the clusters with moderate to severe mobility problems were associated with more severe impairment, depression, anxiety and arthritis, higher BMI, lower income, and lower education. There were no differences by race. <h3>Conclusions:</h3> The approach described and applied to PWP provides a novel template for using a easy-to-use PRO to improve our understanding of mobility trajectories in Parkinson’s disease. <b>Disclosure:</b> Doug Gunzler has nothing to disclose. Dr. Gunzler has received research support from NIH/NINDS. The institution of Dr. Gunzler has received research support from Biogen. The institution of Dr. Gunzler has received research support from Amneal. Dr. Gunzler has received research support from Michael J Fox Foundation. The institution of Prof. Briggs has received research support from NIH. The institution of Prof. Briggs has received research support from Michael J. Fox Foundation.

Data-driven deep phenotyping of multiple sclerosis patients using patient-reported outcome measures (P3-3.015)

<h3>Objective:</h3> To identify distinct clusters of persons with multiple sclerosis (PwMS) with shared impairment patterns across 11 functional domains. <h3>Background:</h3> PwMS experience wide-ranging symptoms across multiple domains, alone or in combination, with varied severity. We sought to characterize naturally occurring clusters of MS using seemingly heterogeneous longitudinal patient-reported outcome measure (PROMs) responses, which are increasingly used in clinical trials and practice. <h3>Design/Methods:</h3> From the electronic health records of 6,619 MS patients with extended care (≥2 encounters 6 months apart) at a tertiary referral center between 2008–2015, we abstracted responses for 11 validated MS-PROMs include 8 MS Performance Scales© (mobility, hand function, vision, fatigue, cognition, bladder/bowel, sensory, spasticity) and 3 MS Functional Scales (pain, depression, tremor/coordination). We applied unsupervised machine learning through mixture modeling (latent profile analysis) to the 11 MS-PROMs at baseline, to identify a set of discrete and non-overlapping clusters of MS patients with similar impairment patterns. <h3>Results:</h3> Nine patient clusters were detected, and were differentiated by low (4 clusters), medium (1 cluster), and high (4 clusters) levels of mobility impairment. The low mobility impairment clusters were differentiated by low impairment across domains (31.7%), to moderate fatigue (18.7%), to moderate fatigue + moderately-high sensory dysfunction (7.9%), and to moderately-high fatigue + pain (10%). The medium mobility cluster had moderately-high impairment across domains (10.2%). The clusters with high mobility impairments varied with mild impairment (8.3%) to high impairment (4.1%) across all domains, and two clusters with moderate impairment across domains but not sensory dysfunction (low [3.9%] vs high [5.1%]). The clusters also varied by sociodemographic and clinical attributes. The most impaired cluster had the highest proportion of Black patients, the lowest quality of life, and lived in ZIP codes with the highest levels of deprivation. <h3>Conclusions:</h3> We leveraged PROMs to innovatively deep phenotype MS patients into distinct subgroups with varying levels of disability and symptomatology. <b>Disclosure:</b> The institution of Prof. Briggs has received research support from NIH. The institution of Prof. Briggs has received research support from Michael J. Fox Foundation. Doug Gunzler has nothing to disclose. Dr. Ontaneda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Ontaneda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech/Roche. Dr. Ontaneda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen Idec. Dr. Ontaneda has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech/Roche. The institution of Dr. Ontaneda has received research support from NIH. The institution of Dr. Ontaneda has received research support from PCORI. The institution of Dr. Ontaneda has received research support from NMSS. The institution of Dr. Ontaneda has received research support from Genetech. Dr. Miller has received intellectual property interests from a discovery or technology relating to health care. Mr. Zamora has nothing to disclose. Alessandro De Nadai has nothing to disclose.

Differences in clinical characteristics and quantitative lung CT features between vaccinated and not vaccinated hospitalized COVID-19 patients in Italy

BackgroundTo evaluate the differences in the clinical characteristics and severity of lung impairment, assessed by quantitative lung CT scan, between vaccinated and non-vaccinated hospitalized patients with COVID-19; and to identify the variables with best prognostic prediction according to SARS-CoV-2 vaccination status. We recorded clinical, laboratory and quantitative lung CT scan data in 684 consecutive patients [580 (84.8%) vaccinated, and 104 (15.2%) non-vaccinated], admitted between January and December 2021.ResultsVaccinated patients were significantly older 78 [69–84] vs 67 [53–79] years and with more comorbidities. Vaccinated and non-vaccinated patients had similar PaO2/FiO2 (300 [252–342] vs 307 [247–357] mmHg; respiratory rate 22 [8–26] vs 19 [18–26] bpm); total lung weight (918 [780–1069] vs 954 [802–1149] g), lung gas volume (2579 [1801–3628] vs 2370 [1675–3289] mL) and non-aerated tissue fraction (10 [7.3–16.0] vs 8.5 [6.0–14.1] %). The overall crude hospital mortality was similar between the vaccinated and non-vaccinated group (23.1% vs 21.2%). However, Cox regression analysis, adjusted for age, ethnicity, age unadjusted Charlson Comorbidity Index and calendar month of admission, showed a 40% reduction in hospital mortality in the vaccinated patients (HRadj = 0.60, 95%CI 0.38–0.95).ConclusionsHospitalized vaccinated patients with COVID-19, although older and with more comorbidities, presented a similar impairment in gas exchange and lung CT scan compared to non-vaccinated patients, but were at a lower risk of mortality.

Impact of muscular symptoms and/or pain on disease characteristics, disability, and quality of life in adult patients with hypophosphatasia: A cross-sectional analysis from the Global HPP Registry.

Hypophosphatasia (HPP) manifests in adults as fractures/pseudofractures, pain, muscle weakness, and other functional impairments. Better phenotypic disease characterization is needed to help recognize disability and treat patients with HPP. Baseline/pretreatment demographic, clinical characteristic, and patient-reported disability/health-related quality-of-life (HRQoL) data from adults (≥18 y) in the Global HPP Registry (NCT02306720) were stratified by presence of overt skeletal manifestations (skeletal group) versus muscular/pain manifestations without skeletal manifestations (muscular/pain group) and summarized descriptively. Disability was measured using the Health Assessment Questionnaire-Disability Index (HAQ-DI), and HRQoL using the 36-item Short Form Health Survey (SF-36v2). Of 468 adults, 300 were classified into the skeletal group and 73 into the muscular/pain group. The skeletal group had a higher median age at baseline (50.1 vs 44.4 y; P=0.047) but a lower median age at first HPP manifestation (12.3 vs 22.1 y; P=0.0473), with more signs and symptoms (median, 4 vs 3; P<0.0001) and involved body systems (median, 3 vs 2; P<0.0001) than the muscular/pain group. More patients in the skeletal group required any use of mobility aids (22.6% vs 3.5%, respectively; P=0.001). Six-Minute Walk test distances walked were similar between groups. SF-36v2 and HAQ-DI scores were similar between groups for physical component summary (n=238; mean [SD]: 40.2 [11.0] vs 43.6 [11.2]; P=0.056), mental component summary (n=238; mean [SD]: 43.6 [11.3] vs 43.8 [11.8]; P=0.902), and HAQ-DI (n=239; median [minimum, maximum]: 0.4 [0.0, 2.7] vs 0.3 [0.0, 2.1]; P=0.22). Adults with HPP experience similar QoL impairment regardless of skeletal involvement. https://clinicaltrials.gov/ct2/show/NCT02306720 and https://www.encepp.eu/encepp/viewResource.htm?id=47907, identifier NCT02306720; EUPAS13514.

Age-related differences in reactive balance control and fall-risk in people with chronic stroke

BackgroundImpaired reactive responses to sudden environmental perturbations contribute to heightened fall-risk in healthy aging and neurologically impaired populations. Previous studies have demonstrated individual contributions of paretic and non-paretic sides to fall-risk in people with stroke with variable levels of motor impairment. However, the combined effect of aging and unilateral cortical lesion on reactive balance control is not clearly understood. We therefore aimed to examine age-related differences in reactive balance control and fall-risk during laboratory-induced gait-slips in people with comparable stroke-related motor impairments. MethodsThirteen younger (45.61 ± 4.61 years) and thirteen older (71.92 ± 6.50 years) adults with similar stroke-related impairment (on Fugl-Meyer Lower Extremity Assessment) were exposed to one overground gait-slip under each limb (paretic and non-paretic). Center of mass state stability and slipping kinematics (slip displacement and velocity) were computed. Clinical balance and mobility were also assessed. ResultsOn non-paretic slips, older adults with chronic stroke demonstrated greater falls and lower center of mass stability (its position and velocity) at post-slip touchdown compared to younger adults with chronic stroke (p < 0.01). This was accompanied with a greater peak slip displacement and faster peak slip velocity (p < 0.01). However, there were no such group differences noted on the paretic slips (p > 0.01). ConclusionAging may have an independent, detrimental effect on reactive balance control in people with chronic stroke. Non-paretic deficits in controlling slip intensities (slip displacement and velocity) can accentuate fall-risk in older adults with chronic stroke. Further investigation is necessary to identify additional factors attributing to heightened fall-risk in older adults with chronic stroke.

Impaired gating of γ- and ε-AChR respectively causes Escobar syndrome and fast-channel myasthenia.

To dissect the kinetic defects of acetylcholine receptor (AChR) γ subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR ε subunit in a congenital myasthenic syndrome (CMS). Whole exome sequencing, α-bungarotoxin binding assay, single channel patch-clamp recordings, and maximum likelihood analysis of channel kinetics. We identified compound heterozygous variants in AChR γ and ε subunits in three Escobar syndrome (1-3) and three CMS patients (4-6), respectively. Each Escobar syndrome patient carries γP121R along with γV221Afs*44 in patients 1 and 2, and γY63* in patient 3. Three CMS patients share εP121T along with εR20W, εG-8R, and εY15H in patients 4, 5, and 6, respectively. Surface expressions of γP121R- and εP121T-AChR were 80% and 138% of the corresponding wild-type AChR, whereas εR20W, εG-8R, and εY15H reduced receptor expression to 27%, 35%, and 30% of wild-type εAChR, respectively. γV221Afs*44 and γY63* are null variants. Thus, γP121R and εP121T determine the phenotype. γP121R and εP121T shorten channel opening burst duration to 28% and 18% of corresponding wild-type AChR by reducing the channel gating equilibrium constant 44- and 63-fold, respectively. Similar impairment of channel gating efficiency of a corresponding P121 residue in the acetylcholine-binding site of the AChR γ and ε subunits causes Escobar syndrome without pterygium and fast-channel CMS, respectively, suggesting that therapy for the fast-channel CMS will benefit Escobar syndrome.

Regulation of XPC Binding Dynamics and Global Nucleotide Excision Repair by p63 and Vitamin D Receptor.

p63 and the vitamin D receptor (VDR) play important roles in epidermal development and differentiation, but their roles and relationship in the response to ultraviolet (UV) radiation are less clear. Using TERT-immortalized human keratinocytes expressing shRNA targeting p63 in concert with exogenously applied siRNA targeting VDR, we assessed p63 and VDR's separate and combined effect on nucleotide excision repair (NER) of UV-induced 6-4 photoproducts (6-4PP). Knockdown of p63 reduced VDR and XPC expression relative to nontargeting controls, while knockdown of VDR had no effect on p63 and XPC protein expression, though alone it modestly reduced XPC mRNA. Upon UV irradiation through filters with 3 μm pores to create spatially discrete spots of DNA damage, keratinocytes depleted of p63 or VDR exhibited slower removal of 6-4PP than control cells over the first 30 min. Costaining of control cells with antibodies to XPC revealed that XPC accumulated at DNA damage foci, peaking within 15 min and gradually fading over 90 min as NER proceeded. In either p63- or VDR-depleted keratinocytes, XPC overaccumulated at spots of DNA damage so that 50% more XPC was retained at 15 min and 100% more XPC was retained at 30 min than in control cells, suggesting dissociation of XPC after binding was also delayed. Concurrent knockdown of VDR and p63 resulted in similar impairment of 6-4PP repair and XPC overaccumulation but even slower release of XPC from DNA damage sites such that 200% more XPC was retained relative to controls at 30 min post-UV. These results suggest that VDR accounts for some of p63's effects in delaying 6-4PP repair associated with overaccumulation and slower dissociation of XPC, though p63's regulation of basal XPC expression appears to be VDR-independent. The results are consistent with a model where XPC dissociation is an important step during NER and that failure to do so may inhibit subsequent repair steps. This work further links two important regulators of epidermal growth and differentiation to the DNA repair response to UV.

Autoimmunity and Frontotemporal Lobar Degeneration: From Laboratory Study to Clinical Practice.

Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases with heterogenous clinical, genetic, and pathological characteristics that show similar impairment of areas in the frontal and/or temporal lobes. Prime doctors' lack of awareness of this complex disease makes early identification and accurate intervention difficult. Autoimmune diseases and autoantibodies are manifestations of different levels of autoimmune reactions. This review presents research findings examining the relationship between autoimmunity and FTLD in terms of autoimmune diseases and autoantibodies with a focus on identifying potential diagnosis and treatment approaches. The findings indicate that the same or similar pathophysiological mechanisms may exist from clinical, genetic, and pathological perspectives. However, the existing evidence is not sufficient to extract substantial conclusions. On the basis of the current situation, we propose future research patterns using prospective studies on large populations and combined clinical and experimental research. Autoimmune reactions or, more generally, inflammatory reactions should receive increased attention from doctors and scientists of all disciplines.