Impaired Recovery Research Articles

P-092: Multiple Myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival

<h3>Background</h3> Multiple myeloma (MM) cells depend on the ubiquitin-proteasome system for survival. Proteasome inhibitors (PIs) are FDA-approved in MM and have radically improved patient survival. However, acquisition of resistance is inevitable. The proteasome stress response (PSR) contributes to proteostasis via de novo proteasome biogenesis. The PSR master regulator NRF1 is constitutively degraded by the proteasome in homeostatic conditions, but in face of proteasomal insufficiency, it is deglycosylated by NGLY1, cleaved by the aspartic protease DDI2, and translocates to the nucleus, to induce proteasome subunit gene transcription. Pharmacological targeting of NGLY1 was recently shown to sensitize cells to PIs. <h3>Hypothesis</h3> We hypothesize that blocking DDI2 or NRF1 could target an intrinsic vulnerability of MM and represent an innovative therapeutic strategy to overcome PI resistance. <h3>Methods</h3> We used MM cell lines with distinct baseline sensitivity to PIs, including AMO1-VR, an isogenic AMO1 cell line adapted to grow in continuous bortezomib. NRF1 cleavage and nuclear localization were assessed via western blotting. We used CRISPR-Cas9 to knock out (KO) DDI2/NRF1. Cell viability or tumor growth of DDI2/NRF1 KO versus non-targeting gRNA-edited cells were compared in in vitro and in vivo growth competition studies, respectively. Addback studies were performed by stably expressing WT or aspartic protease dead DDI2 in DDI2 KO AMO1-VR monoclones. Chymotryptic-like proteasome activity was measured via cleavage of a fluorescent substrate. Proteasome subunit PSMA7, PSMB5, PSMB6 and PSMD11 transcription was evaluated via real time PCR. <h3>Results</h3> Full length and cleaved NRF1 is detectable in MM cell lines and positively correlates with polyubiquitinated proteins, suggesting constitutively active PSR in MM. DDI2/NRF1 KO is cytotoxic alone or in combination with PI carfilzomib in MM cells with distinct PI sensitivity, including de-novo PI-resistant KMS20. In vivo, DDI2 KO leads to reduced plasmacytoma formation in NSG mice and results in prolongation of animal survival. DDI2 KO in AMO1-VR sensitizes to carfilzomib. Further, DDI2 KO blocks NRF1 cleavage and nuclear import, thereby impairing proteasome subunit transcription and CT-L proteasome activity in baseline conditions and following carfilzomib treatment, resulting in increased sensitivity to PI. Wild-type, but not catalytically-dead DDI2 addback rescues these phenotypes, confirming a causative link. <h3>Conclusions</h3> MM cells exhibit baseline activation of NRF1 and are dependent upon DDI2 for survival. DDI2 KO blocks NRF1 cleavage and nuclear translocation, causing impaired proteasome subunit biogenesis and recovery of CT-L proteasome activity, thereby increasing sensitivity to PI. Add-back of wild-type, but not of catalytically-dead DDI2 fully rescues these phenotypes. Our study provides the preclinical rationale for development of novel therapeutics targeting DDI2/NRF1 in MM.

Memantine Improves Recovery After Spreading Depolarization in Brain Slices and can be Considered for Future Clinical Trials.

Spreading depolarization (SD) has been identified as a key mediator of secondary lesion progression after acute brain injuries, and clinical studies are beginning to pharmacologically target SDs. Although initial work has focused on the N-Methyl-D-aspartate receptor antagonist ketamine, there is also interest in alternatives that may be better tolerated. We recently showed that ketamine can inhibit mechanisms linked to deleterious consequences of SD in brain slices. The present study tested the hypothesis that memantine improves recovery of brain slices after SD and explored the effects of memantine in a clinical case targeting SD. For mechanistic studies, electrophysiological and optical recordings were made from hippocampal area CA1 in acutely prepared brain slices from mice. SDs were initiated by localized microinjection of K+ in conditions of either normal or reduced metabolic substrate availability. Memantine effects were assessed from intrinsic optical signals and extracellular potential recordings. For the clinical report, a subdural strip electrode was used for continuous electrocorticographic recording after the surgical evacuation of a chronic subdural hematoma. In brain slice studies, memantine (10-300µM) did not prevent the initiation of SD, but impaired SD propagation rate and recovery from SD. Memantine reduced direct current (DC) shift duration and improved recovery of synaptic potentials after SD. In brain slices with reduced metabolic substrate availability, memantine reduced the evidence of structural disruption after the passage of SD. In our clinical case, memantine did not noticeably immediately suppress SD; however, it was associated with a significant reduction of SD duration and a reduction in the electrocorticographic (ECoG) suppression that occurs after SD. SD was completely suppressed, with improvement in neurological examination with the addition of a brief course of ketamine. These data extend recent work showing that N-Methyl-D-aspartate receptor antagonists can improve recovery from SD. These results suggest that memantine could be considered for future clinical trials targeting SD, and in some cases as an adjunct or alternative to ketamine.

Neural correlates of walking post-stroke: neuroimaging insights from the past decade.

Walking dysfunction such as slow walking speed and reduced independent mobility are common impairments following stroke. Neural mechanisms of upper limb impairment and motor recovery have been highly studied, while less is known about the neural correlates of walking dysfunction and rehabilitation after stroke. Our objective was to review the literature on neuroimaging correlates of walking and walking recovery post-stroke to provide a more comprehensive picture of neurological regions of interest. We searched the databases PubMed, CINAHL, Web of Science, and Cochrane Trials for articles published in English between January 1, 2010 and November 30, 2020 that assessed walking after stroke through neuroimaging and various clinical measures. The following key words were used: stroke, gait, walking, rehabilitation, brain mapping, neuroimaging, neural control of walking, motor recovery and motor function, and resulted in eighteen articles included in this review. These articles revealed regions of interest associated with lower extremity impairment and walking post-stroke to include the putamen, caudate, insula, pallidum, superior temporal gyrus, internal capsule, superior longitudinal fasciculus, corticospinal tract, corona radiata, and white matter associated with the pedunculopontine nucleus. This information strengthens our understanding of supraspinal control of walking post-stroke. However, future research on lesion location, functional and structural connectivity, and walking deficits is needed to confidently associate specific brain regions and white matter tracts/connectivity with specific impairments. Greater insight into neuromechanisms associated with response to neurorehabilitation post-stroke could improve treatment selection and prediction of motor recovery.

Measuring the human immune response to surgery: multiomics for the prediction of postoperative outcomes.

Postoperative complications including infections, cognitive impairment, and protracted recovery occur in one-third of the 300 million surgeries performed annually worldwide. Complications cause personal suffering along with a significant economic burden on our healthcare system. However, the accurate prediction of postoperative complications and patient-targeted interventions for their prevention remain as major clinical challenges. Although multifactorial in origin, the dysregulation of immunological mechanisms that occur in response to surgical trauma is a key determinant of postoperative complications. Prior research, primarily focusing on inflammatory plasma markers, has provided important clues regarding their pathogenesis. However, the recent advent of high-content, single-cell transcriptomic, and proteomic technologies has considerably improved our ability to characterize the immune response to surgery, thereby providing new means to understand the immunological basis of postoperative complications and to identify prognostic biological signatures. The comprehensive and single-cell characterization of the human immune response to surgery has significantly advanced our ability to predict the risk of postoperative complications. Multiomic modeling of patients' immune states holds promise for the discovery of preoperative predictive biomarkers, ultimately providing patients and surgeons with actionable information to improve surgical outcomes. Although recent studies have generated a wealth of knowledge, laying the foundation for a single-cell atlas of the human immune response to surgery, larger-scale multiomic studies are required to derive robust, scalable, and sufficiently powerful models to accurately predict the risk of postoperative complications in individual patients.

Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart.

Type 2 diabetes (T2D) impairs hypoxia-inducible factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischemic remodeling observed following myocardial infarction in T2D. Molidustat is an HIF stabilizer currently undergoing clinical trials for the treatment of renal anemia associated with chronic kidney disease; however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. In human cardiomyocytes, molidustat stabilized HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signaling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, while suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. In conclusion, pharmacological HIF1α stabilization can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart.

Presence of Anti-Thyroid Antibodies Correlate to Worse Outcome of Anti-NMDAR Encephalitis.

ObjectiveTo investigate the characteristics and prognosis of anti-NMDAR encephalitis with the prevalence of anti-thyroid antibodies (ATAbs).MethodsThe clinical data of anti-NMDAR encephalitis patients admitted to Xuanwu Hospital from January 2012 to August 2018 was prospectively analyzed, and the patients were followed up for 24 months.ResultsA total of 120 patients were enrolled, of which 34.2% (41/120) were positive for ATAbs. The antibodies were more frequent in patients with severe disease compared to the non-severe group (51.4% vs. 25.6%, P=0.008). In addition, prevalence of ATAbs correlated with a higher incidence of disturbed consciousness, autonomic dysfunction, central hypoventilation and mechanical ventilation. The ATAbs-positive patients were also more likely to receive intravenous gamma immunoglobulin and immunosuppressor compared to the ATAbs-negative cases (P=0.006; P=0.035). Although the presence of ATAbs was associated with longer hospital stays and worse prognosis at 6 months (P=0.006; P=0.038), it had no impact on long-term patient prognosis. Positive status of anti-thyroglobulin antibody was an independent risk factor for worse prognosis at 6 months [odds ratio (OR)= 3.907, 95% CI: 1.178-12.958, P=0.026].ConclusionATAbs are prevalent in patients with anti-NMDAR encephalitis, especially in severe cases, and correlate with poor prognosis and impaired short-term neurological recovery.

Effect of Polyphenol-Rich Foods, Juices, and Concentrates on Recovery from Exercise Induced Muscle Damage: A Systematic Review and Meta-Analysis.

Objectives. To determine the effects of consuming polyphenol-rich foods, juices and concentrates on recovery from exercise-induced muscle damage (EIMD). Method. Eligibility criteria. Randomised and quasi-randomised placebo-controlled trials with a parallel or cross-over design evaluating the effects of consuming polyphenol-rich foods, juices and concentrates on recovery from EIMD in humans. Eligible studies included at least one of the primary outcome measures: maximal isometric voluntary contraction; MIVC, delayed onset muscle soreness; DOMS, or countermovement jump; CMJ. Information sources. AMED, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, PUBMED, SCOPUS (Elsevier), SPORTDiscus (EBSCO), and the UK Clinical Trials Gateway were searched from inception to September 2020. Risk of bias and quality of evidence. Risk of bias was assessed using Cochrane Risk of Bias 2 tool. Quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation framework. Synthesis of results. Random effects models were used to determine the effect of polyphenol supplementation on recovery from EIMD. Data are presented as standardised mean differences (SMD) with 95% confidence intervals (CI). Results. Included studies. Twenty-five studies were included; 15 had a parallel, and 10 had a cross-over design. A total of 527 participants (male: n = 425; female: n = 102) were included in the meta-analysis. Synthesis of results. Consumption of polyphenol-rich foods, juices and concentrates accelerated recovery of MIVC immediately post-exercise (SMD = 0.23, 95% CI 0.04, 0.42; p = 0.02; low-quality evidence), 24 h (SMD = 0.39, 95% CI 0.15, 0.62; p = 0.001; low-quality evidence), 48 h (SMD = 0.48, 95% CI 0.28, 0.67; p < 0.001; moderate-quality evidence), 72 h (SMD = 0.29, 95% CI 0.11, 0.46; p = 0.001; low-quality evidence) and 96 h post-exercise (SMD = 0.50, 95% CI 0.16, 0.83; p = 0.004; very low-quality evidence). DOMS was reduced at 24 h (SMD = −0.29, 95% CI −0.47, −0.11; p = 0.002; low-quality evidence), 48 h (SMD = −0.28, 95% CI −0.46, −0.09; p = 0.003; low-quality evidence) and 72 h post-exercise (SMD = −0.46, 95% CI −0.69, −0.24; p < 0.001; very low-quality evidence). CMJ height was greater immediately post-exercise (SMD = 0.27, 95% CI 0.01, 0.53; p = 0.04; low-quality evidence), at 24 h (SMD = 0.47, 95% CI 0.11, 0.83; p = 0.01; very low-quality evidence), 48 h (SMD = 0.58, 95% CI 0.24, 0.91; p < 0.001; very low-quality evidence) and 72 h post-exercise (SMD = 0.57, 95% CI 0.03, 1.10; p = 0.04; very low-quality evidence). Polyphenol supplementation did not alter creatine kinase, c-reactive protein, and interleukin−6 at any time points. At 72 h post-exercise, protein carbonyls (SMD = −0.64, 95% CI −1.14, −0.14; p = 0.01) were reduced. Discussion. Limitations of evidence. Risk of bias was high for 10 studies and moderate for 15. Sensitivity analyses excluding the high risk of bias studies reduced the SMDs for MIVC and DOMS, and for CMJ effects at 24 and 48 h were no longer statistically significant. Interpretation. Consuming polyphenol-rich foods, juices and concentrates accelerated recovery of muscle function while reducing muscle soreness in humans. Maximal benefit occurred 48–72 h post-exercise, however, the certainty of the evidence was moderate to very low. Supplementation could be useful when there is limited time between competitive events and impaired recovery could negatively impact performance.

Exercise, but Not Metformin Prevents Loss of Muscle Function Due to Doxorubicin in Mice Using an In Situ Method.

Though effective in treating various types of cancer, the chemotherapeutic doxorubicin (DOX) is associated with skeletal muscle wasting and fatigue. The purpose of this study was to assess muscle function in situ following DOX administration in mice. Furthermore, pre-treatments with exercise (EX) or metformin (MET) were used in an attempt to preserve muscle function following DOX. Mice were assigned to the following groups: control, DOX, DOX + EX, or DOX + MET, and were given a single injection of DOX (15 mg/kg) or saline 3 days prior to sacrifice. Preceding the DOX injection, DOX + EX mice performed 60 min/day of running for 5 days, while DOX + MET mice received 5 daily oral doses of 500 mg/kg MET. Gastrocnemius–plantaris–soleus complex function was assessed in situ via direct stimulation of the sciatic nerve. DOX treatment increased time to half-relaxation following contractions, indicating impaired recovery (p < 0.05). Interestingly, EX prevented any increase in half-relaxation time, while MET did not. An impaired relaxation rate was associated with a reduction in SERCA1 protein content (p = 0.07) and AMPK phosphorylation (p < 0.05). There were no differences between groups in force production or mitochondrial respiration. These results suggest that EX, but not MET may be an effective strategy for the prevention of muscle fatigue following DOX administration in mice.

Intranasal delivery of exosomes from human adipose derived stem cells at forty-eight hours post injury reduces motor and cognitive impairments following traumatic brain injury

The neuroprotective role of human adipose-derived stems cells (hASCs) has raised great interest in regenerative medicine due to their ability to modulate their surrounding environment. Our group has demonstrated that exosomes derived from hASC (hASCexo) are a cell-free regenerative approach to long term recovery following traumatic brain injury (TBI). Previously, we demonstrated the efficacy of exosome treatment with intravenous delivery at 3 h post TBI in rats. Here, we show efficacy of exosomes through intranasal delivery at 48 h post TBI in mice lengthening the therapeutic window of treatment and therefore increasing possible translation to clinical studies.Our findings demonstrate significant recovery of motor impairment assessed by an elevated body swing test in mice treated with exosomes containing MALAT1 compared to both TBI mice without exosomes and exosomes depleted of MALAT1. Significant cognitive improvement was seen in the reversal trial of 8 arm radial arm water maze in mice treated with exosomes containing MALAT1. Furthermore, cortical damage was significantly reduced in mice treated with exosomes containing MALAT1 as well as decreased MHCII+ staining of microglial cells. Mice without exosomes or treated with exosomes depleted of MALAT1 did not show similar recovery. Results demonstrate both inflammation related genes and NRTK3 (TrkC) are target genes modulated by hASC exosomes and further that MALAT1 in hASC exosomes regulates expression of full length TrkC thereby activating the MAPK pathway and promoting recovery.Exosomes are a promising therapeutic approach following TBI with a therapeutic window of at least 48 h and contain long noncoding RNA's, specifically MALAT1 that play a vital role in the mechanism of action.

Difference between psychostimulant users and opioid users in recovery of cognitive impairment, measured with the Montreal Cognitive Assessment (MoCA®)

ABSTRACT Objective Substance use disorder (SUD) can lead to cognitive impairment. The objective of our study is to investigate differences in cognitive impairment between psychostimulant users and opioid users after long-term abstinence. Specifically, we expected patients with a mainly high-frequency use of psychostimulants to show less improvement on the Montreal Cognitive Assessment (MoCA®) screening. Methods The overall analyses include patients (N = 91) having MoCA® scores from both the time of admission and before discharge from long-term treatment. The studied subgroups comprised 21 participants each. Results The MoCA® sum-scores were statistically equal in the groups both at admission and at discharge. Within-subjects t-tests of the sum-score suggest a significant change from admission to discharge for the opiate group, but not for the psychostimulant group. The psychostimulant users were also tested later than the opioid users. Conclusion Our data indicate that there may be differences in how mainly psychostimulant-using patients recover in cognitive functioning compared to patients mainly using opioids. There should be a heightened focus on cognitive function, and adaptation of the treatment content may be warranted for patients with mainly psychostimulant use.

Metformin and leucine increase satellite cells and collagen remodeling during disuse and recovery in aged muscle.

Loss of muscle mass and strength after disuse followed by impaired muscle recovery commonly occurs with aging. Metformin (MET) and leucine (LEU) individually have shown positive effects in skeletal muscle during atrophy conditions but have not been evaluated in combination nor tested as a remedy to enhance muscle recovery following disuse atrophy in aging. The purpose of this study was to determine if a dual treatment of metformin and leucine (MET + LEU) would prevent disuse-induced atrophy and/or promote muscle recovery in aged mice and if these muscle responses correspond to changes in satellite cells and collagen remodeling. Aged mice (22-24 months) underwent 14days of hindlimb unloading (HU) followed by 7 or 14days of reloading (7 or 14days RL). MET, LEU, or MET + LEU was administered via drinking water and were compared to Vehicle (standard drinking water) and ambulatory baseline. We observed that during HU, MET + LEU resolved whole body grip strength and soleus muscle specific force decrements caused by HU. Gastrocnemius satellite cell abundance was increased with MET + LEU treatment but did not alter muscle size during disuse or recovery conditions. Moreover, MET + LEU treatment alleviated gastrocnemius collagen accumulation caused by HU and increased collagen turnover during 7 and 14days RL driven by a decrease in collagen IV content. Transcriptional pathway analysis revealed that MET + LEU altered muscle hallmark pathways related to inflammation and myogenesis during HU. Together, the dual treatment of MET and LEU was able to increase muscle function, satellite cell content, and reduce collagen accumulation, thus improving muscle quality during disuse and recovery in aging.

Cognitive improvement among abstinent methamphetamine users: A 2-year prospective longitudinal study.

The adverse impact of chronic methamphetamine (MA) use on cognitive function has been described in previous studies, but limited evidence is available for abstinent users from prospective longitudinal studies. The aim of the present study was to assess cognitive function of varying abstinent duration. This prospective longitudinal study was conducted with baseline and four follow-up interviews every 6 months over 2 years in 358 MA users in Guangdong province, China. The Montreal Cognitive Assessment (MoCA) was used to measure cognitive function. Generalized estimating equation (GEE) analysis was used to examine within-subjects relationships between abstinence and cognitive consequences over time. The repeated measure analysis of variance showed significant differences in the total MoCA score and all subscale scores (except Orientation) in the 24 months follow-up. The GEE model showed that abstinence from MA in the past 6 months predicted an increase of 0.66 (95% confidence interval [CI] = 0.29 to 1.05, p = .002) in MoCA score changes compared with the nonabstinence MA users. Abstinence in the past 12, 18, and 24 months predicted an increase in MoCA total score changes of 1.25 (95% CI = -0.23 to 2.74), 2.15 (95% CI = -0.79 to 5.09), and 5.28 (95% CI = -2.01 to 12.58), respectively, but none of these was statistically significant. Cognitive function was potentially improved following 6 months of MA abstinence. This study extends prior research by long-term follow-up in big sample MA abstinence users. Findings from study support the need for a comprehensive measure to decrease MA use and promote the recovery of cognitive impairment.

Arhgef2 regulates mitotic spindle orientation in hematopoietic stem cells and is essential for productive hematopoiesis

AbstractHow hematopoietic stem cells (HSCs) coordinate their divisional axis and whether this orientation is important for stem cell–driven hematopoiesis is poorly understood. Single-cell RNA sequencing data from patients with Shwachman-Diamond syndrome (SDS), an inherited bone marrow failure syndrome, show that ARHGEF2, a RhoA-specific guanine nucleotide exchange factor and determinant of mitotic spindle orientation, is specifically downregulated in SDS hematopoietic stem and progenitor cells (HSPCs). We demonstrate that transplanted Arhgef2−/− fetal liver and bone marrow cells yield impaired hematopoietic recovery and a production deficit from long-term HSCs, phenotypes that are not the result of differences in numbers of transplanted HSCs, their cell cycle status, level of apoptosis, progenitor output, or homing ability. Notably, these defects are functionally restored in vivo by overexpression of ARHGEF2 or its downstream activated RHOA GTPase. By using live imaging of dividing HSPCs, we show an increased frequency of misoriented divisions in the absence of Arhgef2. ARHGEF2 knockdown in human HSCs also impairs their ability to regenerate hematopoiesis, culminating in significantly smaller xenografts. Together, these data demonstrate a conserved role for Arhgef2 in orienting HSPC division and suggest that HSCs may divide in certain orientations to establish hematopoiesis, the loss of which could contribute to HSC dysfunction in bone marrow failure.

Contralateral and Ipsilateral Interactions in the Somatosensory Pathway in Healthy Humans.

Hyper-adaptability, the ability to adapt to changes in the internal environment caused by neurological disorders, is necessary to recover from various disabilities, such as motor paralysis and sensory impairment. In the recovery from motor paralysis, the pre-existing neural pathway of the ipsilateral descending pathway, which is normally suppressed and preserved in the course of development, is activated to contribute to the motor control of the paretic limb. Conversely, in sensory pathways, it remains unclear whether there are compensatory pathways which are beneficial for the recovery of sensory impairment due to damaged unilateral somatosensory pathways, such as thalamic hemorrhage. Here, we investigated the interaction between the left and right somatosensory pathways in healthy humans using paired median nerve somatosensory evoked potentials (SEPs). Paired median nerve SEPs were recorded at CP3 and CP4 with a reference of Fz in the International 10–20 System. The paired median nerve stimulation with different interstimulus intervals (ISIs; 1, 2, 3, 5, 10, 20, 40, 60, and 100 ms) was performed to test the influence of the first stimulus (to the right median nerve) on the P14, P14/N20, and N20/P25 components induced by the second stimulus (left side). Results showed that the first stimulation had no effect on SEP amplitudes (P14, P14/N20, and N20/P25) evoked by the second stimulation in all ISI conditions, suggesting that there might not be a neural connectivity formed by a small number of synapses in the left–right interaction of the somatosensory pathway. Additionally, the somatosensory pathway may be less diverse in healthy participants.

Investigating the dose-response relationship between motor imagery and motor recovery of upper-limb impairment and function in chronic stroke: A scoping review.

The recovery of upper-limb impairment and dysfunction post-stroke is often incomplete owing to the limited time in therapy focused on upper-limb recovery and the severity of the impairment. In these cases, motor imagery (MI) may be used as a precursor to physical therapies to initiate rehabilitation early on when it would be otherwise impossible to engage in therapy, as well as to increase the dose of therapy when MI is used in adjunct to physical therapy. While previous reviews have shown MI to be effective as a therapeutic option, disparity in findings exists, with some studies suggesting MI is not an effective treatment for post-stroke impairment and dysfunction. One factor contributing to these findings is inconsistency in the dose of MI applied. To explore the relationship between MI dose and recovery, a scoping review of MI literature as a treatment for adult survivors of stroke with chronic upper-limb motor deficit was performed. Embase, Medline and CINHAL databases were searched for articles related to MI and stroke. Following a two-phase review process, 21 papers were included, and data related to treatment dose and measures of impairment and function were extracted. Effect sizes were calculated to investigate the effect of dosage on motor recovery. Findings showed a high degree of variability in dosage regimens across studies, with no clear pattern for the effect of dose on outcome. The present review highlights the gaps in MI literature, including variables that contribute to the dose-response relationship, that future studies should consider when implementing MI.

Endothelial Hyaluronan Synthase 3 Augments Postischemic Arteriogenesis Through CD44/eNOS Signaling.

Objective: The dominant driver of arteriogenesis is elevated shear stress sensed by the endothelial glycocalyx thereby promoting arterial outward remodeling. Hyaluronan, a critical component of the endothelial glycocalyx, is synthesized by 3 HAS isoenzymes (hyaluronan synthases 1-3) at the plasma membrane. Considering further the importance of HAS3 for smooth muscle cell and immune cell functions we aimed to evaluate its role in collateral artery growth. Approach and Results: Male Has3-deficient (Has3-KO) mice were subjected to hindlimb ischemia. Blood perfusion was monitored by laser Doppler perfusion imaging and endothelial function was assessed by measurement of flow-mediated dilation in vivo. Collateral remodeling was monitored by high resolution magnetic resonance angiography. A neutralizing antibody against CD44 (clone KM201) was injected intraperitoneally to analyze hyaluronan signaling in vivo. After hindlimb ischemia, Has3-KO mice showed a reduced arteriogenic response with decreased collateral remodeling and impaired perfusion recovery. While postischemic leukocyte infiltration was unaffected, a diminished flow-mediated dilation pointed towards an impaired endothelial cell function. Indeed, endothelial AKT (protein kinase B)-dependent eNOS (endothelial nitric oxide synthase) phosphorylation at Ser1177 was substantially reduced in Has3-KO thigh muscles. Endothelial-specific Has3-KO mice mimicked the hindlimb ischemia-induced phenotype of impaired perfusion recovery as observed in global Has3-deficiency. Mechanistically, blocking selectively the hyaluronan binding site of CD44 reduced flow-mediated dilation, thereby suggesting hyaluronan signaling through CD44 as the underlying signaling pathway. Conclusions: In summary, HAS3 contributes to arteriogenesis in hindlimb ischemia by hyaluronan/CD44-mediated stimulation of eNOS phosphorylation at Ser1177. Thus, strategies augmenting endothelial HAS3 or CD44 could be envisioned to enhance vascularization under pathological conditions.

Loss of skeletal muscle mass can be predicted by sarcopenia and reflects poor functional recovery at one year after surgery for geriatric hip fractures

IntroductionHip fractures in the elderly impact negatively on functional dependence, and carry great social costs and morbidity. We assessed the decline in muscle mass and functional outcomes following hip fracture surgery . Material and methodsThirty patients with a hip fracture (mean age: 80.8 years) were assessed using dual-energy X-ray absorptiometry and reassessed for changes in body composition 1 year after hip surgery. Baseline demographic data, sarcopenia, and bone mineral density were recorded. Body mass index (BMI), handgrip strength, appendicular skeletal muscle mass (ASM), total body fat percentage, and responses to questionnaires measuring quality of life and activities of daily living (ADL) before injury and 1 year after hip surgery were analyzed to identify changes. Associations with changes in ADL or quality of life were analyzed with time-variant independent variables. ResultsSignificant losses in ADL were identified at the 1-year follow-up, at which time only 43% of patients had regained their preinjury ADL status. Additionally, the participants had lost an average of 4.63% of ASM. ASM loss was significantly higher in patients with baseline sarcopenia than in those without (mean loss: 9.18% and 1.15%, respectively). When confounders were controlled for, a greater loss of ASM and handgrip strength and larger increase in BMI were associated with greater decrease in ADL 1 year after hip surgery. ConclusionGeriatric hip fracture patients may experience a significant loss of muscle mass, associated with impaired functional recovery 1 year after hip surgery, highlighting a potential treatment target of maintaining muscle mass to improve prognosis in these patients.

Relationship Between Somatosensory and Motor Recovery From Acute Hospital Admission to 3 Months Poststroke

Abstract Date Presented Accepted for AOTA INSPIRE 2021 but unable to be presented due to online event limitations. Upper extremity (UE) functional recovery after stroke requires the integration of motor and sensory systems. We describe the relationship among recovery of somatosensation, motor impairment, and manual dexterity from acute to 3 months poststroke. Sensory retraining emphasized in conjunction with motor interventions after stroke may improve functional UE outcomes. Primary Author and Speaker: Isha Vora Contributing Authors: David Lin, Julie DiCarlo, Jessica Ranford, and Teresa J. Kimberley

Recovery of limb perfusion and function after hindlimb ischemia is impaired by arterial calcification.

Medial artery calcification results from deposition of calcium hydroxyapatite crystals on elastin layers, and osteogenic changes in vascular smooth muscle cells. It is highly prevalent in patients with chronic kidney disease, diabetes, and peripheral artery disease (PAD), and when identified in lower extremity vessels, it is associated with increased amputation rates. This study aims to evaluate the effects of medial calcification on perfusion and functional recovery after hindlimb ischemia in rats. Medial artery calcification and acute limb ischemia were induced by vitamin D3 (VitD3) injection and femoral artery ligation in rats. VitD3 injection robustly induced calcification in the medial layer of femoral arteries in vivo. Laser Doppler perfusion imaging revealed that perfusion decreased and then partially recovered after hindlimb ischemia in vehicle‐injected rats. In contrast, VitD3‐injected rats showed markedly impaired recovery of perfusion following limb ischemia. Accordingly, rats with medial calcification showed worse ischemia scores and delayed functional recovery compared with controls. Immunohistochemical and histological staining did not show differences in capillary density or muscle morphology between VitD3‐ and vehicle‐injected rats at 28 days after femoral artery ligation. The evaluation of cardiac and hemodynamic parameters showed that arterial stiffness was increased while cardiac function was preserved in VitD3‐injected rats. These findings suggest that medial calcification may contribute to impaired perfusion in PAD by altering vascular compliance, however, the specific mechanisms remain poorly understood. Reducing or slowing the progression of arterial calcification in patients with PAD may improve clinical outcomes.

Impaired Stabilization of Orthostatic Cerebral Oxygenation Is Associated With Slower Gait Speed: Evidence From The Irish Longitudinal Study on Ageing.

BackgroundCerebral autoregulation (CAR) systems maintain blood flow to the brain across a wide range of blood pressures. Deficits in CAR have been linked to gait speed (GS) but previous studies had small sample sizes and used specialized equipment which impede clinical translation. The purpose of this work was to assess the association between GS and orthostatic cerebral oxygenation in a large, community-dwelling sample of older adults.MethodData for this study came from the Irish Longitudinal Study on Ageing. A near-infrared spectroscopy (NIRS) device attached to the forehead of each participant (n = 2 708) was used to track tissue saturation index (TSI; the ratio of oxygenated to total hemoglobin) during standing. GS was assessed using a portable walkway.ResultsRecovery was impaired in slower GS participants with a TSI value at 20 seconds (after standing) of −0.55% (95% CI: −0.67, −0.42) below baseline in the slowest GS quartile versus −0.14% (95% CI: −0.25, −0.04) in the fastest quartile. Slower GS predicted a lower TSI throughout the 3-minute monitoring period. Results were not substantially altered by adjusting for orthostatic hypotension. Adjustment for clinical and demographic covariates attenuated the association between but differences remained between GS quartiles from 20 seconds to 3 minutes after standing.ConclusionThis study reported evidence for impaired recovery of orthostatic cerebral oxygenation depending on GS in community-dwelling older adults. Future work assessing NIRS as a clinical tool for monitoring the relationship between GS and cerebral regulation is warranted.