Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

Toxicology Screening Testing in Patients Undergoing Spine Surgery: A Prospective Observational Pilot Study.

BACKGROUND: Chronic opioid use and polypharmacy are commonly seen in chronic pain patients presenting for spine procedures. Substance abuse and misuse have also been reported in this patient population. Negative perioperative effects have been found in patients exposed to chronic opioid, alcohol, and recreational substances. Toxicology screening testing (TST) in the perioperative period provides useful information for adequate preoperative optimization and perioperative planning. METHODS: We designed a pilot study to understand this population's preoperative habits including accuracy of self-report and TST-detected prescribed and unprescribed medications and recreational substances. We compared the results of the TST to the self-reported medications using Spearman correlations. RESULTS: Inconsistencies between TST and self-report were found in 88% of patients. Spearman correlation was 0.509 between polypharmacy and intraoperative propofol use, suggesting that propofol requirement increased as the number of substances used increased. CONCLUSIONS: TST in patients presenting for spine surgery is a useful tool to detect substances taken by patients because self-report is often inaccurate. Discrepancies decrease the opportunity for preoperative optimization and adequate perioperative preparation.

Implementation of a Standardized Protocol for Recurrent Laryngeal Nerve Monitoring Reduces False Negative Results During Neck Surgery: A Quality Control Case Study.

Recurrent laryngeal nerve (RLN) injury during neck surgery can cause significant morbidity related to vocal cord (VC) dysfunction. VC electromyography (EMG) is used to aid in the identification of the RLN and can reduce the probability of inadvertent surgical injury. Errors in the placement of specialized EMG endotracheal tubes (ETT) can result in unreliable signals, false-negative responses, or no response when stimulating the RLN. We describe a novel educational protocol developed to optimize uniformity in the placement of ETTs to improve the reliability of RLN monitoring. An intraoperative neuromonitoring database was queried for all neck surgeries requiring RLN monitoring. Data points extracted for all cases requiring EMG monitoring for neck procedures. Free running and stimulated EMG were monitored and continuously recorded by a certified technologist. Alerts were compared between 2013-14 and 2015-18 using a two-sample test of proportions. Significant reductions in alerts were demonstrated after protocol implementation (7.5% pre-implementation to 2.1% post). Alerts were compared between 2013-14 (overall alert rate of 1.8%, pre-implementation period) and 2015-18 (overall alert rate of 2.8%, post-implementation period). Protocolization for placement of EMG-ETT improved accuracy in EMG monitoring. In the follow-up cohort of 1,080 patients, use of this protocol continued to reduce the rate of alerts related to ETT malposition, confirming the sustainability of this intervention through routine education. The risk of nerve injury is reduced when the rate of alerts is minimized. Scheduled or continuous protocol education of anesthesia personnel should continue to ensure compliance with protocol.

Neuronal hypoxia induces Hsp40-mediated nuclear import of type 3 deiodinase as an adaptive mechanism to reduce cellular metabolism.

In neurons, the type 3 deiodinase (D3) inactivates thyroid hormone and reduces oxygen consumption, thus creating a state of cell-specific hypothyroidism. Here we show that hypoxia leads to nuclear import of D3 in neurons, without which thyroid hormone signaling and metabolism cannot be reduced. After unilateral hypoxia in the rat brain, D3 protein level is increased predominantly in the nucleus of the neurons in the pyramidal and granular ipsilateral layers, as well as in the hilus of the dentate gyrus of the hippocampal formation. In hippocampal neurons in culture as well as in a human neuroblastoma cell line (SK-N-AS), a 24 h hypoxia period redirects active D3 from the endoplasmic reticulum to the nucleus via the cochaperone Hsp40 pathway. Preventing nuclear D3 import by Hsp40 knockdown resulted an almost doubling in the thyroid hormone-dependent glycolytic rate and quadrupling the transcription of thyroid hormone target gene ENPP2. In contrast, Hsp40 overexpression increased nuclear import of D3 and minimized thyroid hormone effects in cell metabolism. In conclusion, ischemia/hypoxia induces an Hsp40-mediated translocation of D3 to the nucleus, facilitating thyroid hormone inactivation proximal to the thyroid hormone receptors. This adaptation decreases thyroid hormone signaling and may function to reduce ischemia-induced hypoxic brain damage.

New frontiers in intraoperative neurophysiologic monitoring: a narrative review.

Background and Objective: Neurological insults during surgery arise from anatomic and/or physiologic perturbations. Intraoperative neurophysiologic monitoring (IONM) fills a critical role of ensuring that any neurological insults during certain surgical procedures are caught in real-time to prevent patient harm. IONM provides immediate feedback to the surgeon and anesthesiologist about the need for an intervention to prevent a neurologic deficit postoperatively. As important as it seems to have IONM available to any patient having surgery where a neurological injury is possible, the truth is that IONM is unavailable to large swaths of people around the world. This review is intended to bring attention to all of the ways IONM is critically important for a variety of surgeries and highlight the barriers preventing most patients around the world from benefiting from the technology. Expansion of IONM to benefit patients from all over the world is the new frontier. Methods: We searched all English language original papers and reviews using Embase and MEDLINE/PubMed databases published from 1995 to 2022. Different combinations of the following search terms were used: intraoperative neuromonitoring, neurosurgery, low-income countries, cost, safety, and efficacy. Key Content and Findings: We describe common IONM modalities used during surgery as well as explore barriers to implementation of IONM in resource-limited regions. Additionally, we describe ongoing efforts to establish IONM capabilities in new locations around the world. Conclusions: In this paper, we performed a review of the literature on IONM with an emphasis on the basic understanding of clinical applications and the barriers for expansion into resource-limited settings. Finally, we provide our interpretation of "new frontiers" in IONM quite literally facilitating access to the tools and education so a hospital in Sub-Saharan Africa can incorporate IONM for their high-risk surgeries.

Challenges in developing Geroscience trials.

Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This unprecedented paradigm shift requires optimizing the design of future clinical studies related to aging in humans. Researchers will face a number of challenges, including ideal populations to study, which lifestyle and Gerotherapeutic interventions to test initially, selecting key primary and secondary outcomes of such clinical trials, and which age-related biomarkers are most valuable for both selecting interventions and predicting or monitoring clinical responses ("Gerodiagnostics"). This article reports the main results of a Task Force of experts in Geroscience.

Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial.

Aims: Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation. Methods and results: We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling. Conclusion: Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.Trial registration number NCT03525418.

STAT3 signaling after traumatic brain injury.

Astrocytes respond to trauma by stimulating inflammatory signaling. In studies of cerebral ischemia and spinal cord injury, astrocytic signaling is mediated by the cytokine receptor glycoprotein 130 (gp130) and Janus kinase (Jak) which phosphorylates the transcription factor signal transducer and activator of transcription-3 (STAT3). To determine if STAT3 is activated after traumatic brain injury (TBI), adult male Sprague-Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery, and then the ipsilateral cortex and hippocampus were analyzed at various post-traumatic time periods for up to 7 days. Western blot analyses indicated that STAT3 phosphorylation significantly increased at 30 min and lasted for 24 h post-TBI. A significant increase in gp130 and Jak2 phosphorylation was also observed. Confocal microscopy revealed that STAT3 was localized primarily within astrocytic nuclei. At 6 and 24 h post-TBI, there was also an increased expression of STAT3 pathway-related genes: suppressor of cytokine signaling 3, nitric oxide synthase 2, colony stimulating factor 2 receptor ß, oncostatin M, matrix metalloproteinase 3, cyclin-dependent kinase inhibitor 1A, CCAAT/enhancer-binding protein ß, interleukin-2 receptor γ, interleukin-4 receptor α, and α-2-macroglobulin. These results clarify some of the signaling pathways operative in astrocytes after TBI and demonstrate that the gp130-Jak2-STAT3 signaling pathway is activated after TBI in astrocytes.

Phosphodiesterase isoform-specific expression induced by traumatic brain injury.

Traumatic brain injury (TBI) results in significant inflammation which contributes to the evolving pathology. Previously, we have demonstrated that cyclic AMP (cAMP), a molecule involved in inflammation, is down-regulated after TBI. To determine the mechanism by which cAMP is down-regulated after TBI, we determined whether TBI induces changes in phosphodiesterase (PDE) expression. Adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury (FPI) or sham injury, and the ipsilateral, parietal cortex was analyzed by western blotting. In the ipsilateral parietal cortex, expression of PDE1A, PDE4B2, and PDE4D2, significantly increased from 30 min to 24 h post-injury. PDE10A significantly increased at 6 and 24 h after TBI. Phosphorylation of PDE4A significantly increased from 6 h to 7 days post-injury. In contrast, PDE1B, PD4A5, and PDE4A8 significantly decreased after TBI. No changes were observed with PDE1C, PDE3A, PDE4B1/3, PDE4B4, PDE4D3, PDE4D4, PDE8A, or PDE8B. Co-localization studies showed that PDE1A, PDE4B2, and phospho-PDE4A were neuronally expressed, whereas PDE4D2 was expressed in neither neurons nor glia. These findings suggest that therapies to reduce inflammation after TBI could be facilitated with targeted therapies, in particular for PDE1A, PDE4B2, PDE4D2, or PDE10A.

Adult stem cells and regenerative medicine-a symposium report.

Adult stem cells are rare, undifferentiated cells found in all tissues of the body. Although normally kept in a quiescent, nondividing state, these cells can proliferate and differentiate to replace naturally dying cells within their tissue and to repair its wounds in response to injury. Due to their proliferative nature and ability to regenerate tissue, adult stem cells have the potential to treat a variety of degenerative diseases as well as aging. In addition, since stem cells are often thought to be the source of malignant tumors, understanding the mechanisms that keep their proliferative abilities in check can pave the way for new cancer therapies. While adult stem cells have had limited practical and clinical applications to date, several clinical trials of stem cell-based therapies are underway. This report details recent research presented at the New York Academy of Sciences on March 14, 2019 on understanding the factors that regulate stem cell activity and differentiation, with the hope of translating these findings into the clinic.

Allogeneic mesenchymal stem cell therapy: A regenerative medicine approach to geroscience.

Extraordinary advances in medicine and public health have contributed to increasing life expectancy worldwide. However, health span-"healthy aging"-has paradoxically lagged to parallel this increase. Consequently, aging-associated illnesses, such as Alzheimer's disease and aging frailty, are having a growing impact on patients, their families, and entire health-care systems. Typically, such disorders have been treated as isolated disease entities. However, the inextricable links between aging-associated disorders and the aging process itself have become increasingly recognized, leading to formation of the field of geroscience. The geroscience concept is that treating the aging process itself should lead to treatment and prevention of aging-related disorders. However, the aging process is complex, dictated by highly interrelated pleiotropic processes. As such, therapeutics with pleiotropic mechanisms of action (either alone, or as part of combinatorial strategies) will be required for preventing and treating both aging and related disorders. Mesenchymal stem cells (MSCs) have multiple mechanisms of action that make these highly promising geroscience therapeutic candidates. These cells have a high safety profile for clinical use, are amenable to allogeneic use since tissue-type matching is not required, and can have sustained activity after transplantation. Herein, we review preclinical and clinical data supporting the utility of allogeneic MSCs as a geroscience therapeutic candidate.

Activated c-Jun N-terminal kinase is required for axon formation.

A critical transition in neuron development is formation of the axon, which establishes the polarized structure of the neuron that underlies its entire input and output capabilities. The morphological events that occur during axonogenesis have long been known, yet the molecular determinants underlying axonogenesis remain poorly understood. We demonstrate here that axonogenesis requires activated c-Jun N-terminal kinase (JNK). JNK is expressed throughout the neuron, but its phosphorylated, activated form is highly enriched in the axon. In young axons, activated JNK forms a proximodistal gradient of increasing intensity, beginning at about the point where the axon exceeds the lengths of the other neurites (minor processes). Treatment with SP600125, a specific inhibitor of JNK, reversibly inhibits axonogenesis but does not prevent the formation of minor processes or their differentiation into dendrites (based on their immunostaining with marker proteins). Expression of a dominant-negative construct against JNK similarly prevents axonogenesis. Investigation of JNK targets revealed that activating transcription factor-2 is phosphorylated under normal conditions in neurons, and its phosphorylation is significantly attenuated after JNK inhibition. These results demonstrate that activated JNK is required for axonogenesis but not formation of minor processes or development of dendrites.

Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty.

BACKGROUND: Impaired endogenous stem cell repair capacity is hypothesized to be a biologic basis of frailty. Therapies that restore regenerative capacity may therefore be beneficial. This Phase 1 study evaluated the safety and potential efficacy of intravenous, allogeneic, human mesenchymal stem cell (allo-hMSC)-based therapy in patients with aging frailty. METHODS: In this nonrandomized, dose-escalation study, patients received a single intravenous infusion of allo-hMSCs: 20-million (n = 5), 100-million (n = 5), or 200-million cells (n = 5). The primary endpoint was incidence of any treatment-emergent serious adverse events measured at 1 month postinfusion. The secondary endpoints were functional efficacy domains and inflammatory biomarkers, measured at 3 and 6 months, respectively. RESULTS: There were no treatment-emergent serious adverse events at 1-month postinfusion or significant donor-specific immune reactions during the first 6 months. There was one death at 258 days postinfusion in the 200-million group. In all treatment groups, 6-minute walk distance increased at 3 months (p = .02) and 6 months (p = .001) and TNF-α levels decreased at 6 months (p < .0001). Overall, the 100-million dose showed the best improvement in all parameters, with the exception of TNF-α, which showed an improvement in both the 100- and 200-million groups (p = .0001 and p = .0001, respectively). The 100-million cell-dose group also showed significant improvements in the physical component of the SF-36 quality of life assessment at all time points relative to baseline. CONCLUSIONS: Allo-hMSCs are safe and immunologically tolerated in aging frailty patients. Improvements in functional and immunologic status suggest that ongoing clinical development of cell-based therapy is warranted for frailty.

Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair. METHODS: This is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion. RESULTS: No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p = .01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in both the 100M- (p < .0001) and 200M-groups (p = .002) as well as between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy. CONCLUSION: Intravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov: CRATUS (#NCT02065245).

Traumatic Brain Injury Upregulates Phosphodiesterase Expression in the Hippocampus.

Traumatic brain injury (TBI) results in significant impairments in hippocampal synaptic plasticity. A molecule critically involved in hippocampal synaptic plasticity, 3',5'-cyclic adenosine monophosphate, is downregulated in the hippocampus after TBI, but the mechanism that underlies this decrease is unknown. To address this question, we determined whether phosphodiesterase (PDE) expression in the hippocampus is altered by TBI. Young adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. Animals were analyzed by western blotting for changes in PDE expression levels in the hippocampus. We found that PDE1A levels were significantly increased at 30 min, 1 h and 6 h after TBI. PDE4B2 and 4D2 were also significantly increased at 1, 6, and 24 h after TBI. Additionally, phosphorylation of PDE4A was significantly increased at 6 and 24 h after TBI. No significant changes were observed in levels of PDE1B, 1C, 3A, 8A, or 8B between 30 min to 7 days after TBI. To determine the spatial profile of these increases, we used immunohistochemistry and flow cytometry at 24 h after TBI. PDE1A and phospho-PDE4A localized to neuronal cell bodies. PDE4B2 was expressed in neuronal dendrites, microglia and infiltrating CD11b(+) immune cells. PDE4D was predominantly found in microglia and infiltrating CD11b(+) immune cells. To determine if inhibition of PDE4 would improve hippocampal synaptic plasticity deficits after TBI, we treated hippocampal slices with rolipram, a pan-PDE4 inhibitor. Rolipram partially rescued the depression in basal synaptic transmission and converted a decaying form of long-term potentiation (LTP) into long-lasting LTP. Overall, these results identify several possible PDE targets for reducing hippocampal synaptic plasticity deficits and improving cognitive function acutely after TBI.

Distally directed dendrotoxicity induced by kainic Acid in hippocampal interneurons of green fluorescent protein-expressing transgenic mice.

Excitotoxicity, resulting from the excessive release of glutamate, is thought to contribute to a variety of neurological disorders, including epilepsy. Excitotoxic damage to dendrites, i.e., dendrotoxicity, is often characterized by the formation of large dendritic swellings, or "beads." Here, we show that hippocampal interneurons that express the neuropeptide somatostatin are highly vulnerable to the excitotoxic effects of the ionotropic glutamate receptor agonist kainate. Brief, focal iontophoretic application of kainate rapidly induced bead formation in dendrites of somatostatinergic interneurons that express green fluorescent protein (GFP) from mice of the transgenic line GIN (GFP-expressing inhibitory neurons). Surprisingly, beads often did not form at the site of kainate application or even in the dendritic segment to which kainate was applied; instead, dendritic beading occurred more distally, often encompassing all branches distal to the application site. We have termed this phenomena, "distally directed dendrotoxicity." Distally directed beading was induced regardless of the branch order of the site of application and was found to be dependent on activation of voltage-gated sodium channels. Subsequent to induction, distally directed beading would reverse in most cells; in other cells, however, beading irreversibly invaded proximal dendritic segments and gradually encompassed the entire dendritic tree. These results demonstrate that distal dendritic segments are highly vulnerable to excitotoxic injury and imply that excessive excitatory activity originating in one synaptic pathway can impact synapses at more distal dendritic segments of the same neuron. The discovery of this phenomenon will likely be important in understanding interneuronal dysfunction following excitotoxic injury.

Professionalism in medicine: the new authority.

Examine some ways that the health care profession could regain lost ground and begin exerting more influence in the marketplace to help offset the pressures from insurance companies, consumers, and the government.

Phosphodiesterase inhibitors as therapeutics for traumatic brain injury.

Developing therapeutics for traumatic brain injury remains a challenge for all stages of recovery. The pathological features of traumatic brain injury are diverse, and it remains an obstacle to be able to target the wide range of pathologies that vary between traumatic brain injured patients and that evolve during recovery. One promising therapeutic avenue is to target the second messengers cAMP and cGMP with phosphodiesterase inhibitors due to their broad effects within the nervous system. Phosphodiesterase inhibitors have the capability to target different injury mechanisms throughout the time course of recovery after brain injury. Inflammation and neuronal death are early targets of phosphodiesterase inhibitors, and synaptic dysfunction and circuitry remodeling are late potential targets of phosphodiesterase inhibitors. This review will discuss how signaling through cyclic nucleotides contributes to the pathology of traumatic brain injury in the acute and chronic stages of recovery. We will review our current knowledge of the successes and challenges of using phosphodiesterase inhibitors for the treatment of traumatic brain injury and conclude with important considerations in developing phosphodiesterase inhibitors as therapeutics for brain trauma.