Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation.

In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporters function at peri-synaptic contact. Here, we report that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synapse formation and function in the developing cerebellum. Dscam-mutant mice show defects in CF synapse translocation as is observed in loss of function mutations in the astrocytic glutamate transporter GLAST expressed in Bergmann glia. These mice show impaired glutamate clearance and the delocalization of GLAST away from the cleft of parallel fibre (PF) synapse. GLAST complexes with the extracellular domain of DSCAM. Riluzole, as an activator of GLAST-mediated uptake, rescues the proximal impairment in CF synapse formation in Purkinje cell-selective Dscam-deficient mice. DSCAM is required for motor learning, but not gross motor coordination. In conclusion, the intercellular association of synaptic and astrocyte proteins is important for synapse formation and function in neural transmission.

Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. METHODS: We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. RESULTS: Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. CONCLUSIONS: We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

Transcriptional features of low-grade neuroepithelial tumors with the BRAF V600E mutation associated with epileptogenicity.

Low-grade neuroepithelial tumors are major causes of drug-resistant focal epilepsy. Clinically, these tumors are defined as low-grade epilepsy-associated neuroepithelial tumors (LEATs). The BRAF V600E mutation is frequently observed in LEAT and linked to poor seizure outcomes. However, its molecular role in epileptogenicity remains elusive. To understand the molecular mechanism underlying the epileptogenicity in LEAT with the BRAF V600E genetic mutation (BRAF V600E-LEAT), we conducted RNA sequencing (RNA-seq) analysis using surgical specimens of BRAF V600E-LEAT obtained and stored at a single institute. We obtained 21 BRAF V600E-LEAT specimens and 4 control specimens, including 24 from Japanese patients and 1 from a patient of Central Asian origin, along with comprehensive clinical data. We submitted the transcriptome dataset of 21 BRAF V600E-LEAT plus 4 controls, as well as detailed clinical information, to a public database. Preliminary bioinformatics analysis using this dataset identified 2134 differentially expressed genes between BRAF V600E-LEAT and control. Additionally, gene set enrichment analysis provided novel insights into the association between estrogen response-related pathways and the epileptogenicity of BRAF V600E-LEAT patients. Our datasets and findings will contribute toward the understanding of the pathology of epilepsy caused by LEAT and the identification of new therapeutic targets.

Attenuated cerebellar phenotypes in Inpp4a truncation mutants with preserved phosphatase activity.

Phosphoinositides (PIPs) act as intracellular signaling molecules that regulate various cellular processes. Abnormalities in PIP metabolism cause various pathological conditions, including neurodegenerative diseases, cancer and immune disorders. Several neurological diseases with diverse phenotypes, such as ataxia with cerebellar atrophy or intellectual disability without brain malformation, are caused by mutations in INPP4A, which encodes a phosphoinositide phosphatase. We examined two strains of Inpp4a mutant mice with distinct cerebellar phenotypes: the Inpp4aΔEx1,2 mutant exhibited striatal degeneration without cerebellar atrophy, and the Inpp4aΔEx23 mutant exhibited a severe striatal phenotype with cerebellar atrophy. Both strains exhibited reduced expression of Inpp4a mutant proteins in the cerebellum. N-terminal-truncated Inpp4a proteins were expressed from the Inpp4aΔEx1,2 allele by alternative translation initiation and had phosphatase activity for PI(3,4)P2, whereas the Inpp4a mutant protein encoded by Inpp4aΔEx23 completely lacked phosphatase activity. Our results indicate that the diverse phenotypes observed in Inpp4a-related neurological diseases could be due to the varying protein expression levels and retained phosphatase activity in different Inpp4a variants. These findings provide insights into the role of INPP4A mutations in disease pathogenesis and may help to develop personalized therapy.

Effects of bariatric surgery on cardiovascular-related acute care use in patients with hypertrophic cardiomyopathy.

AIMS: Prior studies have suggested causal relationships between obesity and acute cardiovascular events. It has been also known that the risk of acute cardiovascular events is reduced by bariatric surgery. However, little is known about whether bariatric surgery lowers the risk of acute cardiovascular events in patients with obesity and hypertrophic cardiomyopathy (HCM). In this context, we aimed to investigate whether bariatric surgery is associated with a reduced risk of cardiovascular-related acute care use in patients with HCM. METHODS AND RESULTS: In this population-based study, the bariatric surgery group consisted of patients with HCM who underwent bariatric surgery from January 2004 to December 2014. The control group included those who have obesity and HCM and received non-bariatric elective intra-abdominal surgery during the same period. The outcome was cardiovascular-related acute care use (i.e. emergency department (ED) visits or unplanned hospitalizations for cardiovascular disease) during a 1-year post-surgery period. We used the SPARCS database, a population-based ED and inpatient database in New York State. We constructed logistic regression models with generalized estimating equations to compare the risk of the outcome events during sequential 6-month post-surgery periods. We adjusted for age, sex, number of ED visits and hospitalizations for cardiovascular disease within 2 years before the index surgery, and the Elixhauser co-morbidity measures. We also performed propensity score (PS)-matching and inverse probability treatment weighting analyses using these variables. The analytic cohort consisted of 207 adults with obesity and HCM, including 147 patients who underwent bariatric surgery and 60 in the control group. The risk was not significantly different in the 1-6 months post-surgery period. By contrast, in the 7-12 months post-surgery period, the risk of cardiovascular-related acute care use was significantly lower in the bariatric surgery group (adjusted odds ratio 0.23; 95% CI 0.068-0.71; P = 0.01) compared with the control group. In the PS-matched cohort, there were no significant differences in the baseline characteristics. The PS-matched analysis demonstrated lower risk of the outcome event in the bariatric surgery group in the 7-12 months post-surgery period. The inverse probability treatment weighting analysis replicated the findings. CONCLUSIONS: Bariatric surgery was associated with a lower risk of cardiovascular-related acute care use in the 7-12 months post-surgery period in this population-based study.

A rare case of echo enhancing agent anaphylaxis complicated by acute coronary syndrome.

Enhancing agents in echocardiography are used frequently to improve endocardial border visualization and assessment of structural heart disease. We present a unique case of anaphylactic shock with acute coronary syndrome following administration of sulfur hexafluoride echo enhancing agent. This case emphasizes the importance of recognizing anaphylaxis to enhancing agents, as well as recognizing the potential relationship between anaphylaxis and acute coronary syndrome with in-stent thrombosis.

Clinical impact of pulmonary artery catheter in patients with cardiogenic shock: A systematic review and meta-analysis.

BACKGROUND: The clinical utility of the pulmonary artery catheter (PAC) for the management of cardiogenic shock (CS) remains controversial. We performed a systematic review and meta-analysis exploring the association between PAC use and mortality among patients with CS. METHODS: Published studies of patients with CS treated with or without PAC hemodynamic guidance were retrieved from MEDLINE and PubMed databases from January 1, 2000, to December 31, 2021. The primary outcome was mortality, which was defined as a combination of in-hospital mortality and 30-day mortality. Secondary outcomes assessed 30-day and in-hospital mortality separately. To assess the quality of nonrandomized studies, the Newcastle-Ottawa Scale (NOS), a well-established scoring system was used. We analyzed outcomes for each study using NOS with a threshold value of >6, indicating high quality. We also performed analyses based on the countries of the studies conducted. RESULTS: Six studies with a total of 930,530 patients with CS were analyzed. Of these, 85,769 patients were in the PAC-treated group, and 844,761 patients did not receive a PAC. PAC use was associated with a significantly lower risk of mortality (PAC: 4.6 % to 41.5 % vs control: 18.8 % to 51.0 %) (OR 0.63, 95 % CI: 0.41-0.97, I2 = 0.96). Subgroup analyses demonstrated no difference in the risk of mortality between NOS ≥ 6 studies and NOS < 6 studies (p-interaction = 0.57), 30-day and in-hospital mortality (p-interaction = 0.83), or the country of origin of studies (p-interaction = 0.08). CONCLUSIONS: The use of PAC in patients with CS may be associated with decreased mortality. These data support the need for a randomized controlled trial testing the utility of PAC use in CS.

Cerebrospinal fluid-contacting neuron tracing reveals structural and functional connectivity for locomotion in the mouse spinal cord.

Cerebrospinal fluid-contacting neurons (CSF-cNs) are enigmatic mechano- or chemosensory cells lying along the central canal of the spinal cord. Recent studies in zebrafish larvae and lampreys have shown that CSF-cNs control postures and movements via spinal connections. However, the structures, connectivity, and functions in mammals remain largely unknown. Here we developed a method to genetically target mouse CSF-cNs that highlighted structural connections and functions. We first found that intracerebroventricular injection of adeno-associated virus with a neuron-specific promoter and Pkd2l1-Cre mice specifically labeled CSF-cNs. Single-cell labeling of 71 CSF-cNs revealed rostral axon extensions of over 1800 µm in unmyelinated bundles in the ventral funiculus and terminated on CSF-cNs to form a recurrent circuitry, which was further determined by serial electron microscopy and electrophysiology. CSF-cNs were also found to connect with axial motor neurons and premotor interneurons around the central canal and within the axon bundles. Chemogenetic CSF-cNs inactivation reduced speed and step frequency during treadmill locomotion. Our data revealed the basic structures and connections of mouse CSF-cNs to control spinal motor circuits for proper locomotion. The versatile methods developed in this study will contribute to further understanding of CSF-cN functions in mammals.

Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin.

BACKGROUND: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. METHODS: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. RESULTS: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. CONCLUSIONS: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.

Do Patients With Non-Viable Myocardium From Ischemic Cardiomyopathy Benefit From Revascularization? A Systematic Review And Meta-Analysis.

BACKGROUND: Myocardial viability assessment is used to select patients who will derive the greatest benefit from revascularization. It remains controversial whether revascularization only benefits patients with ischemic cardiomyopathy who have viable myocardium. The objective of this meta-analysis was to compare mortality between patients with ischemic cardiomyopathy and non-viable myocardium who underwent revascularization and those who underwent medical therapy alone. METHODS: The MEDLINE database was searched using PubMed to retrieve studies published up to December 2021. Inclusion criteria were 1. studies that evaluated the impact of revascularization (revascularization group) versus medical therapy alone (control group) following myocardial viability assessment; 2. patients who had coronary artery disease that was amenable to coronary artery bypass grafting or percutaneous coronary intervention; and 3. patients who had non-viable myocardium. The main outcome measure was all-cause mortality. RESULTS: A total of 12 studies were included, evaluating 1363 patients with non-viable myocardium, of whom 501 patients underwent revascularization and 862 patients received medical therapy alone. There was a significant reduction in all-cause mortality (RR 0.76, 95 % CI: 0.62-0.93, I2 = 0) in the revascularization group compared to the control group. There was no association between the type of viability imaging modality and the risk of all-cause mortality (P-interaction = 0.58). CONCLUSIONS: The findings of this meta-analysis suggest a benefit from revascularization compared to medical therapy in patients with ischemic cardiomyopathy despite the lack of myocardial viability.

Real-time PCR method for detection of short DNA using a deoxyuridine probe and application for detection of fomivirsen.

This study sought to develop a short DNA detection method using a deoxyuridine probe and polymerase chain reaction. The probe was hybridized to the target short DNA, which was then extended by DNA polymerase. The extended DNA was used for real-time PCR after the probe was removed by uracil DNA glycosylase. This method measured from 0.01 to 10 nM of a model short DNA sequence of 17 nucleotides. The method was then used to detect the nucleic acid medicine fomivirsen, as well as 21 phosphorothioate nucleotides, and to quantify 0.1-100 nM of fomivirsen. This method may be useful for detecting short DNA fragments, such as functional nucleotides.

An Insight Into Pathophysiology, Epidemiology, and Management of Cardiovascular Complications of SARS-CoV-2 Infection, Post-acute COVID Syndrome, and COVID Vaccine.

Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic health emergency in March 2020. Elderly patients and those with pre-existing medical conditions including cardiovascular disease are at increased risk of developing severe disease. Not only is the viral infection with SARS-CoV-2 associated with higher mortality in patients with underlying cardiovascular disease, but development of cardiovascular complications is also common in patients with COVID-19. Even after recovery from the acute illness, post-acute COVID syndrome with cardiopulmonary manifestations can occur in some patients. Additionally, there are rare but increasingly recognized adverse events, including cardiovascular side effects, reported with currently available COVID-19 vaccines. In this review, we discuss the most common cardiovascular complications of SARS-CoV-2 and COVID-19 vaccines, cardiopulmonary manifestations of post-acute COVID syndrome and the current evidence-based guidance on the management of such complications.

Transit Amplifying Progenitors in the Cerebellum: Similarities to and Differences from Transit Amplifying Cells in Other Brain Regions and between Species.

Transit amplification of neural progenitors/precursors is widely used in the development of the central nervous system and for tissue homeostasis. In most cases, stem cells, which are relatively less proliferative, first differentiate into transit amplifying cells, which are more proliferative, losing their stemness. Subsequently, transit amplifying cells undergo a limited number of mitoses and differentiation to expand the progeny of differentiated cells. This step-by-step proliferation is considered an efficient system for increasing the number of differentiated cells while maintaining the stem cells. Recently, we reported that cerebellar granule cell progenitors also undergo transit amplification in mice. In this review, we summarize our and others' recent findings and the prospective contribution of transit amplification to neural development and evolution, as well as the molecular mechanisms regulating transit amplification.

Left Ventricular Unloading Before Percutaneous Coronary Intervention is Associated With Improved Survival in Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock: A Systematic Review and Meta-Analysis.

BACKGROUND: Left ventricular unloading with Impella may improve survival outcomes in patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS). However, the optimal timing to initiate left ventricular unloading has yet to be established. Therefore, we conducted a systematic review and meta-analysis to compare survival in patients with AMI-CS who were supported with Impella prior to PCI (pre-PCI) to those in whom support was initiated following PCI (post-PCI). METHODS: All studies that evaluated the impact of pre-PCI versus post-PCI Impella placement in patients with AMI-CS were included. Primary endpoints included in-hospital, 30-day, and 6-month survival rates. RESULTS: We identified five observational studies comparing outcomes in 432 patients with AMI-CS, of which 173 patients were treated with Impella pre-PCI and 259 patients post-PCI. Patients in the pre-PCI group had lower in-hospital mortality compared to patients in the post-PCI group (RR 0.62, 95% CI: 0.50-0.76, I2 = 0%). The lower mortality rate in the pre-PCI group remained evident at 30 days (HR 0.60, 95% CI: 0.47-0.78, I2 = 0%) and at 6 months (HR 0.66, 95% CI: 0.44-0.97, I2 = 0%). There was no difference in the risk of adverse events including reinfarction, stroke, major bleeding, acute ischemic limb, access site bleeding, and hemolysis. CONCLUSIONS: In this meta-analysis of studies evaluating survival among AMI-CS patients with left ventricular unloading initiated pre- versus post-PCI, Impella placement prior to PCI was associated with improved survival.

A prediction model using 2-propanol and 2-butanone in urine distinguishes breast cancer.

Safe and noninvasive methods for breast cancer screening with improved accuracy are urgently needed. Volatile organic compounds (VOCs) in biological samples such as breath and blood have been investigated as noninvasive novel markers of cancer. We investigated volatile organic compounds in urine to assess their potential for the detection of breast cancer. One hundred and ten women with biopsy-proven breast cancer and 177 healthy volunteers were enrolled. The subjects were divided into two groups: a training set and an external validation set. Urine samples were collected and analyzed by gas chromatography and mass spectrometry. A predictive model was constructed by multivariate analysis, and the sensitivity and specificity of the model were confirmed using both a training set and an external set with reproducibility tests. The training set included 60 breast cancer patients (age 34-88 years, mean 60.3) and 60 healthy controls (age 34-81 years, mean 58.7). The external validation set included 50 breast cancer patients (age 35-85 years, mean 58.8) and 117 healthy controls (age 18-84 years, mean 51.2). One hundred and ninety-one compounds detected in at least 80% of the samples from the training set were used for further analysis. The predictive model that best-detected breast cancer at various clinical stages was constructed using a combination of two of the compounds, 2-propanol and 2-butanone. The sensitivity and specificity in the training set were 93.3% and 83.3%, respectively. Triplicated reproducibility tests were performed by randomly choosing ten samples from each group, and the results showed a matching rate of 100% for the breast cancer patient group and 90% for the healthy control group. Our prediction model using two VOCs is a useful complement to the current diagnostic tools. Further studies inclusive of benign tumors and non-breast malignancies are warranted.

Identification of the Core Activate Position for a Seated Subject: Proposal of a new Exercise Method for Maintenance Rehabilitation.

OBJECTIVES: This study aimed to identify a position for core muscle activation (core activate position) for a seated subject and to design an exercise method using this position for rehabilitation during the daily maintenance or maintenance stages. METHODS: Thirteen young men participated as subjects in this study. We manufactured a chair in which the seat had an adjustable forward tilt angle. The subjects underwent ultrasonographic measurements of the thickness of the transversus abdominis, internal oblique, and external oblique muscles while sitting in the chair with the seat angle adjusted to 0°, 6°, or 12°. Further, we conducted image analysis to determine the positional relationships of these muscles using the following four points as landmarks: the anterior superior iliac spine, the posterior superior iliac spine, the fourth lumbar vertebra, and the seventh thoracic vertebra. RESULTS: Significant increases in the thickness of the transversus abdominis and external oblique muscles were observed when the seat forward tilt angle was adjusted to 12° (P <0.05). In the core activate position (which demonstrated effective activation of the transversus abdominis), the posterior superior iliac spine, the fourth lumbar vertebra, and the seventh thoracic vertebra were aligned in a straight line that was nearly perpendicular to the line connecting the anterior superior iliac spine and the posterior superior iliac spine. CONCLUSIONS: This postural guidance can be applied to core exercise methods during maintenance rehabilitation.