Strain hypothesis and additional evidence of the GluN3A deficiency-mediated pathogenesis of Alzheimer's disease.

Our recent investigation revealed that deficiency of N-methyl-D-aspartate (NMDA) receptor subunit GluN3A (NR3A) is a trigger for chronic neuronal hyperactivity and disruptionFfepspof Ca2+ homeostasis, leading to sporadic Alzheimer's disease (AD) phenotypes. The identification of the amyloid-independent pathogenesis was a surprise considering that GluN3A is a much less known NMDA receptor subunit with obscure function in aging adulthood, while the new concept of degenerative excitotoxicity as a decade-long pathogenic mechanism of AD/dementia remains to be further delineated. With negative observations in GRIN3A-/- mouse, Verhaeghe et al. in their letter challenge the "odd" idea that lasting GluN3A deficiency is detrimental and responsible for the spontaneous progression of AD and cognitive decline. We now discuss the potential mouse strain hypothesis and experimental data in these two investigations, and provide additional evidence that further supports the validity and specificity of GluN3A deficiency in the development of AD and associated dementia.

Mobile Health for Arrhythmia Diagnosis and Management.

Palpitations are a common symptom managed by general practitioners and cardiologists; atrial fibrillation (AF) is the most common arrhythmia in adults. The recent commercial availability of smartphone-based devices and wearable technologies with arrhythmia detection capabilities has revolutionized the diagnosis and management of these common medical issues, as it has placed the power of arrhythmia detection into the hands of the patient. Numerous mobile health (mHealth) devices that can detect, record, and automatically interpret irregularities in heart rhythm and abrupt changes in heart rate using photoplethysmography (PPG)- and electrocardiogram-based technologies are now commercially available. As opposed to prescription-based external rhythm monitoring approaches, these devices are more inexpensive and allow for longer-term monitoring, thus increasing sensitivity for arrhythmia detection, particularly for patients with infrequent symptoms possibly due to cardiac arrhythmias. These devices can be used to correlate symptoms with cardiac arrhythmias, assess efficacy and toxicities of arrhythmia therapies, and screen the population for serious rhythm disturbances such as AF. Although several devices have received clearance for AF detection from the United States Food & Drug Administration, limitations include the need for ECG confirmation for arrhythmias detected by PPG alone, false positives, false negatives, charging requirements for the battery, and financial cost. In summary, the growth of commercially available devices for remote, patient-facing rhythm monitoring represents an exciting new opportunity in the care of patients with palpitations and known or suspected dysrhythmias. Physicians should be familiar with the evidence that underlies their added value to patient care and, importantly, their current limitations.

Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A.

The Ca2+ hypothesis for Alzheimer's disease (AD) conceives Ca2+ dyshomeostasis as a common mechanism of AD; the cause of Ca2+ dysregulation, however, is obscure. Meanwhile, hyperactivities of N-Methyl-D-aspartate receptors (NMDARs), the primary mediator of Ca2+ influx, are reported in AD. GluN3A (NR3A) is an NMDAR inhibitory subunit. We hypothesize that GluN3A is critical for sustained Ca2+ homeostasis and its deficiency is pathogenic for AD. Cellular, molecular, and functional changes were examined in adult/aging GluN3A knockout (KO) mice. The GluN3A KO mouse brain displayed age-dependent moderate but persistent neuronal hyperactivity, elevated intracellular Ca2+ , neuroinflammation, impaired synaptic integrity/plasticity, and neuronal loss. GluN3A KO mice developed olfactory dysfunction followed by psychological/cognitive deficits prior to amyloid-ß/tau pathology. Memantine at preclinical stage prevented/attenuated AD syndromes. AD patients' brains show reduced GluN3A expression. We propose that chronic "degenerative excitotoxicity" leads to sporadic AD, while GluN3A represents a primary pathogenic factor, an early biomarker, and an amyloid-independent therapeutic target.

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice.

GPCR 37 (GPR37) is a GPCR expressed in the CNS; its physiological and pathophysiological functions are largely unknown. We tested the role of GPR37 in the ischemic brain of GPR37 knockout (KO) mice, exploring the idea that GPR37 might be protective against ischemic damage. In an ischemic stroke model, GPR37 KO mice exhibited increased infarction and cell death compared with wild-type (WT) mice, measured by 2,3,5-triphenyl-2H-tetrazolium chloride and TUNEL staining 24 h after stroke. Moreover, more severe functional deficits were detected in GPR37 KO mice in the adhesive-removal and corner tests. In the peri-infarct region of GPR37 KO mice, there was significantly more apoptotic and autophagic cell death accompanied by caspase-3 activation and attenuated mechanistic target of rapamycin signaling. GPR37 deletion attenuated astrocyte activation and astrogliosis compared with WT stroke controls 24-72 h after stroke. Immunohistochemical staining showed more ionized calcium-binding adapter molecule 1-positive cells in the ischemic cortex of GPR37 KO mice, and RT-PCR identified an enrichment of M1-type microglia or macrophage markers in the GPR37 KO ischemic cortex. Western blotting demonstrated higher levels of inflammatory factors IL-1ß, IL-6, monocyte chemoattractant protein, and macrophage inflammatory protein-1α in GPR37-KO mice after ischemia. Thus, GPR37 plays a multifaceted role after stroke, suggesting a novel target for stroke therapy.-McCrary, M. R., Jiang, M. Q., Giddens, M. M., Zhang, J. Y., Owino, S., Wei, Z. Z., Zhong, W., Gu, X., Xin, H., Hall, R. A., Wei, L., Yu, S. P. Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice.

Desflurane and Surgery Exposure During Pregnancy Decrease Synaptic Integrity and Induce Functional Deficits in Juvenile Offspring Mice.

Anesthesia in pregnant women may cause adverse effects in the hippocampus of unborn babies and fetal brain development. The mechanisms underlying pathological changes resulting from anesthetics are unclear. This study tested the hypothesis that exposure to desflurane during pregnancy may impair cognition and memory functions of juvenile offspring. Pregnant mice (at gestational day 14) were administered 10% desflurane for 3 h and compared to sham control and sciatic nerve hemi-transection surgery. Hippocampal tissues of both fetal (G14) and offspring mice (postnatal day 31) were collected and analyzed by real-time qPCR and Western blot. Functional tests were performed to assess fear and memory functions in offspring mice. Primary hippocampal neuronal cultures from postnatal day 0 (without desflurane exposure) were examined for neuronal and synaptic development under desflurane treatment in vitro. In this acute experiment, we showed that neuronal cultures exposed to desflurane significantly increased interleukin (IL)-6 expression and apoptotic gene caspase-3 activation. Desflurane exposure significantly reduced PSD-95 expression in hippocampal neurons. Similar changes were observed in hippocampal tissues from juvenile offspring mice. Inhaled desflurane impaired memory functions in offspring mice compared to sham control. These mice displayed higher sensitivity to fear conditioning. Neurons isolated from the mice exposed to desflurane exhibited significantly lower levels of synaptophysin expression. These results suggest that anesthetic exposure together with surgery during pregnancy may induce detrimental effects in juvenile offspring mice via the induction of cell death and disruption of synaptic integrity.

Increased capture threshold in permanent His-bundle pacing associated with flecainide.

A 64-year-old man underwent implantation of a permanent His-bundle pacemaker. A marked rise in the selective His-bundle capture threshold was noted 1 month after the patient started flecainide acetate for rhythm control of recurrent, symptomatic atrial flutter and atrial fibrillation. The capture threshold subsequently normalized 4 days after discontinuing flecainide and switching to dofetilide. To our knowledge, this is the first documented case of a rise in selective His-bundle capture threshold associated with flecainide acetate. Further studies are needed to characterize this association which could result in higher capture thresholds, decreased battery longevity, and mimic His-bundle lead failure.

Examining the Effect of Semantic Relatedness on the Acquisition of English Collocations.

This study examines whether semantic relatedness facilitates or impedes the acquisition of English collocations by conducting two experiments respectively on Chinese undergraduates. Each experiment was composed of a reading session, a productive test, and a receptive test. Experiment 1 began with the reading session of 28 paired-up words and their collocations (in sentence context). Those words were counterbalanced between two randomly selected groups by cross-matching on semantic relatedness. Results of the productive test revealed that the participants scored significantly higher on test items that were semantically related than the randomly cross-paired counterparts. However, for the receptive test, the participants performed significantly better on semantically unrelated items. Experiment 2 was similar to Experiment 1 except that the word pairs selected were only semantically related and did not have any shared morphemes. Experiment 2 also revealed consistent results. The results of the two experiments consistently illustrate that semantic relatedness may exert a facilitatory effect on language output but an inhibitory effect on the process of language input.

Optogenetic stimulation of glutamatergic neuronal activity in the striatum enhances neurogenesis in the subventricular zone of normal and stroke mice.

Neurogenesis in the subventricular zone (SVZ) of the adult brain may contribute to tissue repair after brain injuries. Whether SVZ neurogenesis can be upregulated by specific neuronal activity in vivo and promote functional recovery after stroke is largely unknown. Using the spatial and cell type specific optogenetic technique combined with multiple approaches of in vitro, ex vivo and in vivo examinations, we tested the hypothesis that glutamatergic activation in the striatum could upregulate SVZ neurogenesis in the normal and ischemic brain. In transgenic mice expressing the light-gated channelrhodopsin-2 (ChR2) channel in glutamatergic neurons, optogenetic stimulation of the glutamatergic activity in the striatum triggered glutamate release into SVZ region, evoked membrane currents, Ca2+ influx and increased proliferation of SVZ neuroblasts, mediated by AMPA receptor activation. In ChR2 transgenic mice subjected to focal ischemic stroke, optogenetic stimuli to the striatum started 5days after stroke for 8days not only promoted cell proliferation but also the migration of SVZ neuroblasts into the peri-infarct cortex with increased neuronal differentiation and improved long-term functional recovery. These data provide the first morphological and functional evidence showing a unique striatum-SVZ neuronal regulation via a semi-phasic synaptic mechanism that can boost neurogenic cascades and stroke recovery. The benefits from stimulating endogenous glutamatergic activity suggest a novel regenerative strategy after ischemic stroke and other brain injuries.

Reprogramming Glioblastoma Cells into Non-Cancerous Neuronal Cells as a Novel Anti-Cancer Strategy.

Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a high mortality rate. Direct reprogramming of glial cells to different cell lineages, such as induced neural stem cells (iNSCs) and induced neurons (iNeurons), provides genetic tools to manipulate a cell's fate as a potential therapy for neurological diseases. NeuroD1 (ND1) is a master transcriptional factor for neurogenesis and it promotes neuronal differentiation. In the present study, we tested the hypothesis that the expression of ND1 in GBM cells can force them to differentiate toward post-mitotic neurons and halt GBM tumor progression. In cultured human GBM cell lines, including LN229, U87, and U373 as temozolomide (TMZ)-sensitive and T98G as TMZ-resistant cells, the neuronal lineage conversion was induced by an adeno-associated virus (AAV) package carrying ND1. Twenty-one days after AAV-ND1 transduction, ND1-expressing cells displayed neuronal markers MAP2, TUJ1, and NeuN. The ND1-induced transdifferentiation was regulated by Wnt signaling and markedly enhanced under a hypoxic condition (2% O2 vs. 21% O2). ND1-expressing GBM cultures had fewer BrdU-positive proliferating cells compared to vector control cultures. Increased cell death was visualized by TUNEL staining, and reduced migrative activity was demonstrated in the wound-healing test after ND1 reprogramming in both TMZ-sensitive and -resistant GBM cells. In a striking contrast to cancer cells, converted cells expressed the anti-tumor gene p53. In an orthotopical GBM mouse model, AAV-ND1-reprogrammed U373 cells were transplanted into the fornix of the cyclosporine-immunocompromised C57BL/6 mouse brain. Compared to control GBM cell-formed tumors, cells from ND1-reprogrammed cultures formed smaller tumors and expressed neuronal markers such as TUJ1 in the brain. Thus, reprogramming using a single-factor ND1 overcame drug resistance, converting malignant cells of heterogeneous GBM cells to normal neuron-like cells in vitro and in vivo. These novel observations warrant further research using patient-derived GBM cells and patient-derived xenograft (PDX) models as a potentially effective treatment for a deadly brain cancer and likely other astrocytoma tumors.

Protocol for the development of a core outcome set and reporting guidelines for locoregional treatment in neoadjuvant systemic breast cancer treatment trials: the PRECEDENT project.

INTRODUCTION: Neoadjuvant systemic anticancer therapy (neoSACT) is increasingly used in the treatment of early breast cancer. Response to therapy is prognostic and allows locoregional and adjuvant systemic treatments to be tailored to minimise morbidity and optimise oncological outcomes and quality of life. Accurate information about locoregional treatments following neoSACT is vital to allow the translation of downstaging benefits into practice and facilitate meaningful interpretation of oncological outcomes, particularly locoregional recurrence. Reporting of locoregional treatments in neoSACT studies, however, is currently poor. The development of a core outcome set (COS) and reporting guidelines is one strategy by which this may be improved. METHODS AND ANALYSIS: A COS for reporting locoregional treatment (surgery and radiotherapy) in neoSACT trials will be developed in accordance with Core Outcome Measures in Effectiveness Trials (COMET) and Core Outcome Set-Standards for Development guidelines. Reporting guidance will be developed concurrently.The project will have three phases: (1) generation of a long list of relevant outcome domains and reporting items from a systematic review of published neoSACT studies and interviews with key stakeholders. Identified items and domains will be categorised and formatted into Delphi consensus questionnaire items. (2) At least two rounds of an international online Delphi survey in which at least 250 key stakeholders (surgeons/oncologists/radiologists/pathologists/trialists/methodologists) will score the importance of reporting each outcome. (3) A consensus meeting with key stakeholders to discuss and agree the final COS and reporting guidance. ETHICS AND DISSEMINATION: Ethical approval for the consensus process will be obtained from the Queen's University Belfast Faculty Ethics Committee. The COS/reporting guidelines will be presented at international meetings and published in peer-reviewed journals. Dissemination materials will be produced in collaboration with our steering group and patient advocates so the results can be shared widely. REGISTRATION: The study has been prospectively registered on the COMET website (https://www.comet-initiative.org/Studies/Details/2854).

Erector Spinae Plane Block as an Analgesic Intervention in Acute Rib Fractures: A Scoping Review.

Introduction: Rib fractures are a common sequelae of chest trauma and are associated with significant morbidity. The erector spinae nerve block (ESB) has been proposed as an alternative first-line regional technique for rib fractures due to ease of administration and minimal complication profile. We aimed to investigate the current literature surrounding this topic with a focus on pain and respiratory outcomes. Methods: A comprehensive literature search was performed on the Medline, Embase, Web of Science, Scopus, and Cochrane databases. Keywords of "erector spinae block" and "rib fractures" were used to form the search strategy. Papers published in English investigating ESB as an analgesic intervention for acute rib fracture were included. Exclusion criteria were operative rib fixation, or where the indication for ESB was not rib fracture. Results: There were 37 studies which met the inclusion criteria for this scoping review. Of these, 31 studies reported on pain outcomes and demonstrated a 40% decrease in pain scores post administration within the first 24 hours. Respiratory parameters were reported in 8 studies where an increase in incentive spirometry was demonstrated. Respiratory complication was not consistently reported. ESB was associated with minimal complications; only 5 cases of haematoma and infection were (incidence 0.6%) reported, none of which required further intervention. Discussion: Current literature surrounding ESB in rib fracture management provides a positive qualitative evaluation of efficacy and safety. Improvements in pain and respiratory parameters were almost universal. The notable outcome from this review was the improved safety profile of ESB. The ESB was not associated with complications requiring intervention even in the setting of anticoagulation and coagulopathy. There still remains a paucity of large cohort, prospective data. Moreover, no current studies reflect an improvement in respiratory complication rates compared to current techniques. Taken together, these areas should be the focus of any future research.

Blood Speckle Imaging: An Emerging Method for Perioperative Evaluation of Subaortic and Aortic Valvar Repair.

BACKGROUND: This article presents the use of blood speckle Imaging (BSI) as an echocardiographic approach for the pre- and post-operative evaluation of subaortic membrane resection and aortic valve repair. METHOD: BSI, employing block-matching algorithms, provided detailed visualization of flow patterns and quantification of parameters from ultrasound data. The 9-year-old patient underwent subaortic membrane resection and peeling extensions of the membrane from under the ventricular-facing surface of all three aortic valve leaflets. RESULT: Post-operatively, BSI demonstrated improvements in hemodynamic patterns, where quantified changes in flow velocities showed no signs of stenosis and trivial regurgitation. The asymmetric jet with a shear layer and flow reversal on the posterior aspect of the aorta was corrected resulting in reduced wall shear stress on the anterior aspect and reduced oscillatory shear index, which is considered a contributing element in cellular alterations in the structure of the aortic wall. CONCLUSION: This proof-of-concept study demonstrates the potential of BSI as an emerging echocardiographic approach for evaluating subaortic and aortic valvar repair. BSI enhances the quantitative evaluation of the left ventricular outflow tract of immediate surgical outcomes beyond traditional echocardiographic parameters and aids in post-operative decision-making. However, larger studies are needed to validate these findings and establish standardized protocols for clinical implementation.

Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer's disease.

Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca2+ influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca2+ overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca2+ dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca2+ influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a "gatekeeper" role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca2+-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca2+ homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke.

Pleural abrasion versus apical pleurectomy for primary spontaneous pneumothorax: a systematic review and Meta-analysis.

BACKGROUND: Surgical approach is the most effective treatment for primary spontaneous pneumothorax. The two most widely adopted surgical methods are mechanical abrasion and apical pleurectomy, in addition to bullectomy. We performed a systematic review and meta-analysis to examine which technique is superior in treating primary spontaneous pneumothorax. METHODS: PubMed, MEDLINE and EMBASE databases were searched for studies published between January 2000 to September 2022 comparing mechanical abrasion and apical pleurectomy for treatment of primary spontaneous pneumothorax. The primary outcome was pneumothorax recurrence. Secondary outcomes included post-operative chest tube duration, hospital length of stay, operative time and intra-operative of blood loss. RESULTS: Eight studies were eligible for inclusion involving 1,613 patients. There was no difference in the rate of pneumothorax recurrence between pleural abrasion and pleurectomy (RR: 1.34; 95% CI: 0.94 to 1.92). However, pleural abrasion led to shorter hospital length of stay (MD: -0.25; 95% CI: -0.51 to 0.00), post-operative chest tube duration (MD: -0.30; 95% CI: -0.56 to -0.03), operative time (MD: -13.00; 95% CI -15.07 to 10.92) and less surgical blood loss (MD: -17.77; 95% CI: -24.36 to -11.18). CONCLUSION: Pleural abrasion leads to less perioperative patient burden and shorter hospital length of stay without compromising the rate of pneumothorax recurrence when compared to pleurectomy. Thus, pleural abrasion is a reasonable first choice surgical procedure for management of primary spontaneous pneumothorax.

Quantitative three-dimensional imaging of live avian embryonic morphogenesis via micro-computed tomography.

Many clinically relevant congenital malformations arise during mid to late embryonic stages. This period is challenging to image quantitatively in live embryos, necessitating the use of multiple specimens with increased experimental variability. Here we establish X-ray and blood-pool computed tomography (CT) contrast agent toxicity and teratogenesis thresholds for 3D Micro-CT imaging of live avian embryos. Day 4 chick embryos micro-injected with Visipaque™ (VP) developed for an additional 6 days without defect. X-ray radiation up to 798 mGy was nontoxic. Peak average contrast of 1,060 HU occurred within 1 hr of imaging at 50 µm resolution. VP-enhanced contrast persisted past 24 hr with delayed accumulation in the allantois. Regional volumes of VP-injected embryos were statistically identical to those of fixed embryos perfused with osmium tetroxide. We further quantified longitudinal volumetric morphogenesis of the allantois over 30 hr. These results demonstrate the safety and efficacy of contrast enhanced quantitative micro-CT imaging for live embryos.

Calciphylaxis of the penis and distal digits: a case report.

BACKGROUND: Calciphylaxis is a rare, often fatal disease resulting from calcification of dermal arterioles and capillaries. Usually diagnosed in patients with end-stage renal disease, this disorder typically presents as necrotic, nonhealing ulcers in acral or adipose areas. Here we report the case of an elderly man who was found to have calciphylaxis of the distal digits and penis, the latter of which is an uncommon site of disease that carries a particularly poor prognosis. CASE PRESENTATION: A 73-year-old African American man with multiple medical comorbidities including dialysis-dependent end-stage renal disease presented with worsening painful, necrotic lesions on his glans penis and several distal digits over the last 2 months. The wound on the glans was foul smelling with overlying purulence and had been unsuccessfully treated with amoxicillin-clavulanic acid. Discovery of diffuse intravascular calcification on computed tomography, in addition to a markedly elevated calcium-phosphate product immediately prior to the onset of his ulcers, led to the diagnosis of calciphylaxis. The patient was initiated on sodium thiosulfate without improvement in his lesions, and he died 3 months later after another prolonged hospitalization. CONCLUSIONS: While calciphylaxis is a rare disease, involvement of the distal digits and especially the penis is even more uncommon and portends a particularly poor prognosis: 6-month mortality rates are reportedly as high as 70%. This suggests that prompt recognition and management of the disease is required; however, despite receiving standard therapy, our patient failed to experience improvement in his disease and instead developed several more fingertip ulcers at blood glucose sample points during his hospitalization. A corollary of the case presented here is the need for more effective management of calciphylaxis, especially for patients in whom uncommon sites, such as the penis, are involved.

Extensive deep venous thrombosis in a young male with absent infrarenal inferior vena cava.

A previously well, independent 20-year-old man presented with a 4-day history of progressive left lower limb pain with associated phlegmasia cerulea dolens. Duplex venous ultrasound examination and computed tomography venogram revealed extensive deep vein thrombus from the left popliteal vein to abnormal venous vasculature proximally. Notably, no infrarenal inferior vena cava was detected, with distal venous return channeled through lumbar and visceral collateral channels into the azygous system. Treatment included systemic anticoagulation, catheter-directed thrombolysis, and prolonged therapeutic anticoagulation. In the absence of other risk factors, anatomical abnormalities should be considered in young, well patients presenting with lower limb venous thrombosis.