UW Neurological Surgery Recent PubMed Publications

Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus.

J Neurosci. 2019 02 13;39(7):1320-1331

Authors: Khuu MA, Pagan CM, Nallamothu T, Hevner RF, Hodge RD, Ramirez JM, Garcia AJ

Abstract
Individuals with sleep apnea often exhibit changes in cognitive behaviors consistent with alterations in the hippocampus. It is hypothesized that adult neurogenesis in the dentate gyrus is an ongoing process that maintains normal hippocampal function in many mammalian species, including humans. However, the impact of chronic intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal adult neurogenesis remains unclear. Using a murine model, we examined the impact of 30 d of IH (IH30) on adult neurogenesis and synaptic plasticity in the dentate gyrus. Although IH30 did not affect paired-pulse facilitation, IH30 suppressed long-term potentiation (LTP). Immunohistochemical experiments also indicate that IH perturbs multiple aspects of adult neurogenesis. IH30 increased the number of proliferating Sox2+ neural progenitor cells in the subgranular zone yet reduced the number of doublecortin-positive neurons. Consistent with these findings, cell lineage tracing revealed that IH30 increased the proportion of radial glial cells in the subgranular zone, yet decreased the proportion of adult-born neurons in the dentate gyrus. While administration of a superoxide anion scavenger during IH did not prevent neural progenitor cell proliferation, it mitigated the IH-dependent suppression of LTP and prevented adult-born neuron loss. These data demonstrate that IH causes both reactive oxygen species-dependent and reactive oxygen species-independent effects on adult neurogenesis and synaptic plasticity in the dentate gyrus. Our findings identify cellular and neurophysiological changes in the hippocampus that may contribute to cognitive and behavioral deficits occurring in sleep apnea.SIGNIFICANCE STATEMENT Individuals with sleep apnea experience periods of intermittent hypoxia (IH) that can negatively impact many aspects of brain function. Neurons are continually generated throughout adulthood to support hippocampal physiology and behavior. This study demonstrates that IH exposure attenuates hippocampal long-term potentiation and reduces adult neurogenesis. Antioxidant treatment mitigates these effects indicating that oxidative signaling caused by IH is a significant factor that impairs synaptic plasticity and reduces adult neurogenesis in the hippocampus.

PMID: 30587544 [PubMed - indexed for MEDLINE]

Age and sex-mediated differences in six-month outcomes after mild traumatic brain injury in young adults: a TRACK-TBI study.

Neurol Res. 2019 Jul;41(7):609-623

Authors: Yue JK, Levin HS, Suen CG, Morrissey MR, Runyon SJ, Winkler EA, Puffer RC, Deng H, Robinson CK, Rick JW, Phelps RRL, Sharma S, Taylor SR, Vassar MJ, Cnossen MC, Lingsma HF, Gardner RC, Temkin NR, Barber J, Dikmen SS, Yuh EL, Mukherjee P, Stein MB, Cage TA, Valadka AB, Okonkwo DO, Manley GT, TRACK-TBI Investigators

Abstract
Introduction: Risk factors for young adults with mTBI are not well understood. Improved understanding of age and sex as risk factors for impaired six-month outcomes in young adults is needed. Methods: Young adult mTBI subjects aged 18-39 years (18-29y; 30-39y) with six-month outcomes were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study. Multivariable regressions were performed for outcomes with age, sex, and the interaction factor age-group*sex as variables of interest, controlling for demographic and injury variables. Mean-differences (B) and 95% CIs are reported. Results: One hundred mTBI subjects (18-29y, 70%; 30-39y, 30%; male, 71%; female, 29%) met inclusion criteria. On multivariable analysis, age-group*sex was associated with six-month post-traumatic stress disorder (PTSD; PTSD Checklist-Civilian version); compared with female 30-39y, female 18-29y (B= -19.55 [-26.54, -4.45]), male 18-29y (B= -19.70 [-30.07, -9.33]), and male 30-39y (B= -15.49 [-26.54, -4.45]) were associated with decreased PTSD symptomatology. Female sex was associated with decreased six-month functional outcome (Glasgow Outcome Scale-Extended (GOSE): B= -0.6 [1.0, -0.1]). Comparatively, 30-39y scored higher on six-month nonverbal processing speed (Wechsler Adult Intelligence Scale-Processing Speed Index (WAIS-PSI); B= 11.88, 95% CI [1.66, 22.09]). Conclusions: Following mTBI, young adults aged 18-29y and 30-39y may have different risks for impairment. Sex may interact with age for PTSD symptomatology, with females 30-39y at highest risk. These results may be attributable to cortical maturation, biological response, social modifiers, and/or differential self-report. Confirmation in larger samples is needed; however, prevention and rehabilitation/counseling strategies after mTBI should likely be tailored for age and sex.

PMID: 31007155 [PubMed - indexed for MEDLINE]

Effects of Electronic Cigarettes on Oral Cavity: A Systematic Review.

J Evid Based Dent Pract. 2019 12;19(4):101318

Authors: Ralho A, Coelho A, Ribeiro M, Paula A, Amaro I, Sousa J, Marto C, Ferreira M, Carrilho E

Abstract
INTRODUCTION: The increase in the use of electronic cigarettes (e-cigs) in young people and the lack of knowledge of the health effects of smoking in the short and long term are worrying. Although the oral cavity is the first to interact directly with the e-cig aerosol, studies on potential oral cavity lesions are still limited and there is some controversy about safety.
OBJECTIVE: To perform a systematic review to evaluate the adverse effects of e-cigs on oral health.
MATERIALS AND METHODS: The research was conducted using Cochrane Library, Embase, PubMed, and Web of Science. The research was limited to articles in English, Portuguese, and Spanish, published between January 2003 and November 2018. The research question was formulated according to the population, intervention, comparison, outcome (PICO) strategy. The quality of the methodology of each study was evaluated following the guidelines described in the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool.
RESULTS: The initial search resulted in 432 articles, of which only eight were included for analysis. Periodontal and peri-implant clinical and radiographic parameters (plaque index, clinical attachment loss, probing depth, peri-implant bone loss, and radiographic bone level) are worse, and proinflammatory cytokine levels are higher among electronic and conventional cigarette smokers than among nonsmokers. Bleeding on probing was higher in nonsmokers than in conventional cigarette smokers and e-cig users. Nine different lesions of the oral mucosa were detected, with nicotinic stomatitis, hairy tongue, and angular cheilitis being more prevalent in e-cig consumers.
CONCLUSION: The results suggest that e-cigs are less harmful than conventional cigarettes. However, there is also a greater susceptibility of e-cig consumers to developing alterations in oral biological tissues than ex-smokers or nonsmokers. There is still a clear need for the development of new studies.

PMID: 31843181 [PubMed - indexed for MEDLINE]

The role of prefrontal cortex in the control of feature attention in area V4.

Nat Commun. 2019 12 16;10(1):5727

Authors: Bichot NP, Xu R, Ghadooshahy A, Williams ML, Desimone R

Abstract
When searching for an object in a cluttered scene, we can use our memory of the target object features to guide our search, and the responses of neurons in multiple cortical visual areas are enhanced when their receptive field contains a stimulus sharing target object features. Here we tested the role of the ventral prearcuate region (VPA) of prefrontal cortex in the control of feature attention in cortical visual area V4. VPA was unilaterally inactivated in monkeys performing a free-viewing visual search for a target stimulus in an array of stimuli, impairing monkeys' ability to find the target in the array in the affected hemifield, but leaving intact their ability to make saccades to targets presented alone. Simultaneous recordings in V4 revealed that the effects of feature attention on V4 responses were eliminated or greatly reduced while leaving the effects of spatial attention on responses intact. Altogether, the results suggest that feedback from VPA modulates processing in visual cortex during attention to object features.

PMID: 31844117 [PubMed - indexed for MEDLINE]

Magnetic resonance vessel wall imaging in cerebrovascular diseases

Neurosurg Focus. 2019 12 13;47(6):E4

Authors: Young CC, Bonow RH, Barros G, Mossa-Basha M, Kim LJ, Levitt MR

Abstract
Cerebrovascular diseases manifest as abnormalities of and disruption to the intracranial vasculature and its capacity to carry blood to the brain. However, the pathogenesis of many cerebrovascular diseases begins in the vessel wall. Traditional luminal and perfusion imaging techniques do not provide adequate information regarding the differentiation, onset, or progression of disease. Intracranial high-resolution MR vessel wall imaging (VWI) has emerged as an invaluable technique for understanding and evaluating cerebrovascular diseases. The location and pattern of contrast enhancement in intracranial VWI provides new insight into the inflammatory etiology of cerebrovascular diseases and has potential to permit earlier diagnosis and treatment. In this report, technical considerations of VWI are discussed and current applications of VWI in vascular malformations, blunt cerebrovascular injury/dissection, and steno-occlusive cerebrovascular vasculopathies are reviewed.

PMID: 31846249 [PubMed - indexed for MEDLINE]

Quantifying neurologic disease using biosensor measurements in-clinic and in free-living settings in multiple sclerosis.

NPJ Digit Med. 2019;2:123

Authors: Chitnis T, Glanz BI, Gonzalez C, Healy BC, Saraceno TJ, Sattarnezhad N, Diaz-Cruz C, Polgar-Turcsanyi M, Tummala S, Bakshi R, Bajaj VS, Ben-Shimol D, Bikhchandani N, Blocker AW, Burkart J, Cendrillon R, Cusack MP, Demiralp E, Jooste SK, Kharbouch A, Lee AA, Lehár J, Liu M, Mahadevan S, Murphy M, Norton LC, Parlikar TA, Pathak A, Shoeb A, Soderberg E, Stephens P, Stoertz AH, Thng F, Tumkur K, Wang H, Rhodes J, Rudick RA, Ransohoff RM, Phillips GA, Bruzik E, Marks WJ, Weiner HL, Snyder TM

Abstract
Technological advances in passive digital phenotyping present the opportunity to quantify neurological diseases using new approaches that may complement clinical assessments. Here, we studied multiple sclerosis (MS) as a model neurological disease for investigating physiometric and environmental signals. The objective of this study was to assess the feasibility and correlation of wearable biosensors with traditional clinical measures of disability both in clinic and in free-living in MS patients. This is a single site observational cohort study conducted at an academic neurological center specializing in MS. A cohort of 25 MS patients with varying disability scores were recruited. Patients were monitored in clinic while wearing biosensors at nine body locations at three separate visits. Biosensor-derived features including aspects of gait (stance time, turn angle, mean turn velocity) and balance were collected, along with standardized disability scores assessed by a neurologist. Participants also wore up to three sensors on the wrist, ankle, and sternum for 8 weeks as they went about their daily lives. The primary outcomes were feasibility, adherence, as well as correlation of biosensor-derived metrics with traditional neurologist-assessed clinical measures of disability. We used machine-learning algorithms to extract multiple features of motion and dexterity and correlated these measures with more traditional measures of neurological disability, including the expanded disability status scale (EDSS) and the MS functional composite-4 (MSFC-4). In free-living, sleep measures were additionally collected. Twenty-three subjects completed the first two of three in-clinic study visits and the 8-week free-living biosensor period. Several biosensor-derived features significantly correlated with EDSS and MSFC-4 scores derived at visit two, including mobility stance time with MSFC-4 z-score (Spearman correlation -0.546; p = 0.0070), several aspects of turning including turn angle (0.437; p = 0.0372), and maximum angular velocity (0.653; p = 0.0007). Similar correlations were observed at subsequent clinic visits, and in the free-living setting. We also found other passively collected signals, including measures of sleep, that correlated with disease severity. These findings demonstrate the feasibility of applying passive biosensor measurement techniques to monitor disability in MS patients both in clinic and in the free-living setting.

PMID: 31840094 [PubMed]

Chemotherapy in Esthesioneuroblastoma/Olfactory Neuroblastoma: An Analysis of the Surveillance Epidemiology and End Results (SEER) 1973-2015 Database.

Am J Clin Oncol. 2020 03;43(3):203-209

Authors: Cranmer LD, Chau B, Rockhill JK, Ferreira M, Liao JJ

Abstract
OBJECTIVE: Chemotherapy has been proposed as an adjunct to primary local therapy in esthesioneuroblastoma (ENB)/olfactory neuroblastoma (ON), but its role has not been precisely defined. Here, we evaluated its role in ENB treatment.
MATERIALS AND METHODS: The Surveillance Epidemiology and End Results (SEER) database was queried for ENB/ON (International Classification of Diseases-3 9522). Cases met criteria for inclusion if they were unique, had a primary location in the nasal cavity, and had adequate information for Kadish staging derivation. Univariable and multivariable Cox analyses assessed chemotherapy treatment effect on disease-specific survival (DSS) and overall survival (OS). Multiple imputation addressed missing data. A P<0.05 was designated for statistical significance.
RESULTS: In adjusted multivariable analyses, chemotherapy treatment was associated with inferior DSS (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.21-2.51; P=0.003) and OS (HR, 1.71; 95% CI, 1.26-2.32; P=0.001). Among the subset with local or regional disease treated with surgery and/or radiation therapy, chemotherapy remained associated with inferior outcomes DSS (HR, 2.78; 95% CI, 1.63-4.74; P<0.001) and OS (HR, 2.18; 95% CI, 1.45-3.27; P<0.001). Chemotherapy treatment misclassification did not explain these findings.
CONCLUSIONS: This analysis does not support chemotherapy to improve either DSS or OS in primary ENB/ON treatment, after controlling for known ENB prognostic factors available from SEER. Other prognostic and treatment selection factors could exist which were not controlled in these analyses. Chemotherapy could beneficially affect outcomes other than DSS or OS. Although the concerns have been expressed regarding chemotherapy treatment misclassification in SEER, their analyses did not identify such misclassification as an explanation for our findings.

PMID: 31842117 [PubMed - indexed for MEDLINE]

Modulating neuroinflammation and oxidative stress to prevent epilepsy and improve outcomes after traumatic brain injury.

Neuropharmacology. 2019 Dec 06;:107907

Authors: Eastman CL, D'Ambrosio R, Ganesh T

Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability in young adults worldwide. TBI survival is associated with persistent neuropsychiatric and neurological impairments, including posttraumatic epilepsy (PTE). To date, no pharmaceutical treatment has been found to prevent PTE or ameliorate neurological/neuropsychiatric deficits after TBI. Brain trauma results in immediate mechanical damage to brain cells and blood vessels that may never be fully restored given the limited regenerative capacity of brain tissue. This primary insult unleashes cascades of events, prominently including neuroinflammation and massive oxidative stress that evolve over time, expanding the brain injury, but also clearing cellular debris and establishing homeostasis in the region of damage. Accumulating evidence suggests that oxidative stress and neuroinflammatory sequelae of TBI contribute to posttraumatic epileptogenesis. This review will focus on possible roles of reactive oxygen species (ROS), their interactions with neuroinflammation in posttraumatic epileptogenesis, and emerging therapeutic strategies after TBI. We propose that inhibitors of the professional ROS-generating enzymes, the NADPH oxygenases and myeloperoxidase alone, or combined with selective inhibition of cyclooxygenase mediated signaling may have promise for the treatment or prevention of PTE and other sequelae of TBI.

PMID: 31837825 [PubMed - as supplied by publisher]

A Multi-Criteria Decision-Making Model for Evaluating Senior Daycare Center Locations.

Int J Environ Res Public Health. 2019 12 10;16(24):

Authors: Lee AHI, Kang HY

Abstract
Many developed and developing countries are facing an imminent population aging and rapid demographics changing problem. The need of various kinds of eldercare is increasing tremendously. A senior daycare center, very similar to a daycare center for toddlers and preschoolers, can provide the elderly a place to go during daytime and have a more diversified social life. In this research, a senior daycare center location evaluation problem is studied, and a model for facilitating the decision-making of the senior daycare center location is constructed by considering the benefits, opportunities, costs, and risks (BOCR) of the locations. Senior daycare center location evaluation factors are listed first through literature review and interview with experts. These factors are used to construct a network, which is applied to prepare a questionnaire to ask about the influences of a criterion to other criteria. The interrelationships among the criteria are calculated by adopting fuzzy interpretative structural modeling (FISM). Based on the results from the FISM, a fuzzy analytic network process (FANP) questionnaire is given out, and the results are used to determine the priorities of the criteria. In addition, the final ranking of the senior daycare center locations can be obtained. The research results can provide references for prospective senior daycare center providers for making relevant decisions.

PMID: 31835613 [PubMed - indexed for MEDLINE]

Endovascular management of iatrogenic dissection into the petrous segment of the internal carotid artery during mechanical thrombectomy for acute stroke.

J Clin Neurosci. 2020 Jan;71:273-274

Authors: Bass DI, Walker M, Kim LJ, Levitt MR

Abstract
Iatrogenic dissection of the internal carotid artery is a well-known complication that can occur during mechanical thrombectomy for acute stroke. The vast majority of these injuries are limited to the cervical segment, and only in exceptional circumstances do they require surgical intervention. In the present case, extension of the lesion into the petrous segment of the carotid artery resulted in an acute neurologic decline necessitating emergent endovascular repair. We discuss the nuances of managing an exceptionally rare presentation of this complication.

PMID: 31836382 [PubMed - indexed for MEDLINE]

Editorial.

Curr Opin Pharmacol. 2019 Dec 10;:

Authors: Williams M, Trist D

PMID: 31836467 [PubMed - as supplied by publisher]

Litter effects: Comments on Golub and Sobin's "Statistical modeling of litter as a random effect in mixed models to manage "intralitter likeness"".

Neurotoxicol Teratol. 2020 Jan - Feb;77:106852

Authors: Vorhees CV, Williams MT

Abstract
The importance of litter effects (clustering of variance among offspring in rodents) has been known for decades. The standard approach was to treat the entire litter as a unit or to select one male and one female from each litter to prevent oversampling. These methods work but are imperfect. Treating the litter as a whole fails to use valuable interindividual differences among offspring, and selecting representative pups fails to use all the data available. Golub and Sobin [https://doi.org/10.1016/j.ntt.2019.106841] address this using a better method. They show that using litter as a random factor in mixed linear models resolves this conundrum. As they demonstrate, such models control for litter clustering by partitioning litter variance from error variance. This reduces error variance and increases the power of F-tests of the independent variable(s). In our experience, this is the optimal solution. But as good as mixed linear models are when used with litter as a random factor, if other aspects of the experimental design are not appropriate, this cannot compensate for threats to validity from small sample sizes, dams not strictly randomly assigned to groups, repeated measure covariance structures not appropriately modeled, interactions not properly sliced, or a posteriori group comparisons not controlled for multiple comparisons. Appropriate handling of litter is only one consideration of experimental design and statistical analysis that when used in combination lead to valid, reproducible data.

PMID: 31837394 [PubMed - indexed for MEDLINE]

Relationship between epicardial adipose tissue thickness and epicardial adipocyte size with increasing body mass index.

Adipocyte. 2019 12;8(1):412-420

Authors: Aitken-Buck HM, Moharram M, Babakr AA, Reijers R, Van Hout I, Fomison-Nurse IC, Sugunesegran R, Bhagwat K, Davis PJ, Bunton RW, Williams MJA, Stiles MK, Jones PP, Coffey S, Lamberts RR

Abstract
Macroscopic deposition of epicardial adipose tissue (EAT) has been strongly associated with numerous indices of obesity and cardiovascular disease risk. In contrast, the morphology of EAT adipocytes has rarely been investigated. We aimed to determine whether obesity-driven adipocyte hypertrophy, which is characteristic of other visceral fat depots, is found within EAT adipocytes. EAT samples were collected from cardiac surgery patients (n = 49), stained with haematoxylin & eosin, and analysed for mean adipocyte size and non-adipocyte area. EAT thickness was measured using echocardiography. A significant positive relationship was found between EAT thickness and body mass index (BMI). When stratified into standardized BMI categories, EAT thickness was 58.7% greater (p = 0.003) in patients from the obese (7.3 ± 1.8 mm) compared to normal (4.6 ± 0.9 mm) category. BMI as a continuous variable significantly correlated with EAT thickness (r = 0.56, p < 0.0001). Conversely, no correlation was observed between adipocyte size and either BMI or EAT thickness. No difference in the non-adipocyte area was found between BMI groups. Our results suggest that the increased macroscopic EAT deposition associated with obesity is not caused by adipocyte hypertrophy. Rather, alternative remodelling via adipocyte proliferation might be responsible for the observed EAT expansion.

PMID: 31829077 [PubMed - indexed for MEDLINE]

Presynaptic Mechanisms and KCNQ Potassium Channels Modulate Opioid Depression of Respiratory Drive.

Front Physiol. 2019;10:1407

Authors: Wei AD, Ramirez JM

Abstract
Opioid-induced respiratory depression (OIRD) is the major cause of death associated with opioid analgesics and drugs of abuse, but the underlying cellular and molecular mechanisms remain poorly understood. We investigated opioid action in vivo in unanesthetized mice and in in vitro medullary slices containing the preBötzinger Complex (preBötC), a locus critical for breathing and inspiratory rhythm generation. Although hypothesized as a primary mechanism, we found that mu-opioid receptor (MOR1)-mediated GIRK activation contributed only modestly to OIRD. Instead, mEPSC recordings from genetically identified Dbx1-derived interneurons, essential for rhythmogenesis, revealed a prevalent presynaptic mode of action for OIRD. Consistent with MOR1-mediated suppression of presynaptic release as a major component of OIRD, Cacna1a KO slices lacking P/Q-type Ca2+ channels enhanced OIRD. Furthermore, OIRD was mimicked and reversed by KCNQ potassium channel activators and blockers, respectively. In vivo whole-body plethysmography combined with systemic delivery of GIRK- and KCNQ-specific potassium channel drugs largely recapitulated these in vitro results, and revealed state-dependent modulation of OIRD. We propose that respiratory failure from OIRD results from a general reduction of synaptic efficacy, leading to a state-dependent collapse of rhythmic network activity.

PMID: 31824331 [PubMed]

Biocompatibility of Root Canal Sealers: A Systematic Review of In Vitro and In Vivo Studies.

Materials (Basel). 2019 Dec 09;12(24):

Authors: Fonseca DA, Paula AB, Marto CM, Coelho A, Paulo S, Martinho JP, Carrilho E, Ferreira MM

Abstract
(1) Aim: To perform a systematic review of the literature on the biocompatibility of root canal sealers that encompasses the various types of sealers that are commercially available as well as both in vitro and in vivo evidence. (2) Methods: This systematic review has been registered in PROSPERO (ID 140445) and was carried out according to PRISMA guidelines using the following databases: PubMed, Cochrane Library, ClinicalTrials.gov, Science Direct, and Web of Science Core Collection. Studies published between 2000 and 11 June 2019 that evaluated cytotoxicity (cell viability/proliferation) and biocompatibility (tissue response) of root canal sealers were included. (3) Results: From a total of 1249 studies, 73 in vitro and 21 in vivo studies were included. In general, studies suggest that root canal sealers elicit mild to severe toxic effects and that several factors may influence biocompatibility, e.g., material setting condition and time, material concentration, and type of exposure. Bioactive endodontic sealers seem to exhibit a lower toxic potential in vitro. (4) Conclusions: The available evidence shows that root canal sealers exhibit variable toxic potential at the cellular and tissue level. However, the methodological heterogeneity among studies included in this systematic review and the somewhat conflicting results do not allow a conclusion on which type of sealer presents higher biocompatibility. Further research is crucial to achieve a better understanding of the biological effects of root canal sealers.

PMID: 31818038 [PubMed]

Distinct Populations of Sudden Unexpected Infant Death Based on Age.

Pediatrics. 2020 01;145(1):

Authors: Lavista Ferres JM, Anderson TM, Johnston R, Ramirez JM, Mitchell EA

Abstract
OBJECTIVES: In most recent studies, authors combine all cases of sudden infant death syndrome, other deaths from ill-defined or unknown causes, and accidental suffocation and strangulation in bed as a single population to analyze sudden unexpected infant death (SUID). Our aim with this study is to determine if there are statistically different subcategories of SUID that are based on the age of death of an infant.
METHODS: In this retrospective, cross-sectional analysis, we analyzed the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set (2003-2013: 41 125 233 births and 37 624 SUIDs). Logistic regression models were developed to identify subpopulations of SUID cases by age of death, and we subsequently analyzed the effects of a set of covariates on each group.
RESULTS: Two groups were identified: sudden unexpected early neonatal deaths (SUENDs; days 0-6) and postperinatal SUIDs (days 7-364). These groups significantly differed in the distributions of assigned International Classification of Diseases, 10th Revision code, live birth order, marital status, age of mother, birth weight, and gestational length compared to postperinatal SUIDs (days 7-364). Maternal smoking during pregnancy was not a significant risk factor for deaths that occurred in the first 48 hours.
CONCLUSIONS: SUEND should be considered as a discrete entity from postperinatal SUID in future studies. These data could help improve the epidemiological understanding of SUEND and SUID and provide clues to a mechanistic understanding underlying the causes of death.

PMID: 31818863 [PubMed - indexed for MEDLINE]

Acute interaction between human epicardial adipose tissue and human atrial myocardium induces arrhythmic susceptibility.

Am J Physiol Endocrinol Metab. 2020 02 01;318(2):E164-E172

Authors: Babakr AA, Fomison-Nurse IC, van Hout I, Aitken-Buck HM, Sugunesegran R, Davis PJ, Bunton RW, Williams MJA, Coffey S, Stiles MK, Jones PP, Lamberts RR

Abstract
Epicardial adipose tissue (EAT) deposition has a strong clinical association with atrial arrhythmias; however, whether a direct functional interaction exists between EAT and the myocardium to induce atrial arrhythmias is unknown. Therefore, we aimed to determine whether human EAT can be an acute trigger for arrhythmias in human atrial myocardium. Human trabeculae were obtained from right atrial appendages of patients who have had cardiac surgery (n = 89). The propensity of spontaneous contractions (SCs) in the trabeculae (proxy for arrhythmias) was determined under physiological conditions and during known triggers of SCs (high Ca2+, β-adrenergic stimulation). To determine whether EAT could trigger SCs, trabeculae were exposed to superfusate of fresh human EAT, and medium of 24 h-cultured human EAT treated with β1/2 (isoproterenol) or β3 (BRL37344) adrenergic agonists. Without exposure to EAT, high Ca2+ and β1/2-adrenergic stimulation acutely triggered SCs in, respectively, 47% and 55% of the trabeculae that previously were not spontaneously active. Acute β3-adrenergic stimulation did not trigger SCs. Exposure of trabeculae to either superfusate of fresh human EAT or untreated medium of 24 h-cultured human EAT did not induce SCs; however, specific β3-adrenergic stimulation of EAT did trigger SCs in the trabeculae, either when applied to fresh (31%) or cultured (50%) EAT. Additionally, fresh EAT increased trabecular contraction and relaxation, whereas media of cultured EAT only increased function when treated with the β3-adrenergic agonist. An acute functional interaction between human EAT and human atrial myocardium exists that increases the propensity for atrial arrhythmias, which depends on β3-adrenergic rather than β1/2-adrenergic stimulation of EAT.

PMID: 31821041 [PubMed - indexed for MEDLINE]

Localization and Microsurgical Resection of Left Postcentral Gyrus Spetzler-Martin Grade 3 Arteriovenous Malformation by Intraoperative Neuronavigation and Tracing of Subcortical Draining Vein: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2019 Dec 07;:

Authors: Zeeshan Q, Carrasco Hernandez JP, Sekhar LN

Abstract
This 42-yr-old man presented with a history of sudden right-sided facial and right arm weakness and dysarthria. Head computed tomography showed a left frontal-parietal blood clot. An intra-arterial digital subtraction angiography demonstrated a left subcortical postcentral, Spetzler-Martin Grade 3 arteriovenous malformation (AVM) with a diffuse nidus, measuring 2.1 × 1.5 cm, supplied by branches of the left MCA, and draining into a cortical vein and a deep vein, which was going toward the ventricle. Preoperative embolization was not possible.  The patient underwent left frontal-parietal craniotomy with intraoperative motor and sensory mapping. No arterialized veins were visible on the cortical surface. Neuronavigation localized the AVM in the subcortical postcentral gyrus. Through an incision in the postcentral sulcus, microdissection led to a yellowish gliotic plane. The large cortical vein was in the gliotic area and traced to the AVM. Circumferential microdissection was performed around the AVM. It had a very diffuse nidus; the arterial feeders were cauterized and divided, and the superior superficial and inferior deep draining veins were finally occluded, and AVM was removed.  Postoperative angiogram showed total removal of the AVM. At discharge, his right arm weakness had improved (power 5/5), and facial weakness and dysarthria were improving (modified Rankin Scale (mRS) 2). At 1-yr follow-up, facial weakness and dysarthria had improved considerably, and patient returned to work (mRS 1).  This video shows microsurgical resection of an AVM by neuronavigation and tracing of the subcortical draining vein. The technique of cauterizing the perforating arteries after temporary clipping with flow arrest is shown in the video. Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 31811300 [PubMed - as supplied by publisher]

Nonsynonymous SNPs in LPA homologous to plasminogen deficiency mutants represent novel null apo(a) alleles.

J Lipid Res. 2019 Dec 05;:

Authors: Morgan BM, Brown AN, Deo N, Harrop TWR, Taiaroa G, Mace PD, Wilbanks SM, Merriman TR, Williams MJ, McCormick SPA

Abstract
Plasma lipoprotein(a) [Lp(a)] levels are largely determined by variation in the LPA gene which codes for apolipoprotein(a) [apo(a)]. Genome-wide association studies (GWAS) have identified nonsynonymous variants in LPA that associate with low Lp(a) levels although their effect on apo(a) function is unknown. We investigated two such variants, R990Q and R1771C, which were present in four null Lp(a) individuals, for structural and functional effects. Sequence alignments showed the R990 and R1771 residues to be highly conserved and homologous to each other and to residues associated with plasminogen deficiency. Structural modelling showed both residues to make several polar contacts with neighboring residues that would be ablated on substitution. Recombinant expression of the wildtype (WT) and R1771C apo(a) in liver and kidney cells showed an abundance of an immature form for both apo(a) proteins. A mature form of apo(a) was only seen with the WT protein. Imaging of the recombinant apo(a) proteins in conjunction with markers of the secretory pathway indicated a poor transit of R1771C into the Golgi. Furthermore, the R1771C mutant displayed a glycosylation pattern consistent with ER, but not Golgi, glycosylation. We conclude that R1771, and the equivalent R990 residue, facilitate correct folding of the apo(a) kringle structure and mutations at these positions prevent the proper folding required for full maturation and secretion. To our knowledge, this is the first example of nonsynonymous variants in LPA being causative of a null Lp(a) phenotype.

PMID: 31806727 [PubMed - as supplied by publisher]

Review of clinical trials in intraoperative molecular imaging during cancer surgery.

J Biomed Opt. 2019 12;24(12):1-8

Authors: Lee JYK, Cho SS, Stummer W, Tanyi JL, Vahrmeijer AL, Rosenthal E, Smith B, Henderson E, Roberts DW, Lee A, Hadjipanayis CG, Bruce JN, Newman JG, Singhal S

Abstract
Most solid cancers are treated by surgical resections to reduce the burden of disease. Surgeons often face the challenge of detecting small areas of residual neoplasm after resection or finding small primary tumors for the initial resection. Intraoperative molecular imaging (IMI) is an emerging technology with the potential to dramatically improve cancer surgery operations by allowing surgeons to better visualize areas of neoplasm using fluorescence imaging. Over the last two years, two molecular optical contrast agents received U.S. Food and Drug Administration approval, and several more drugs are now on the horizon. Thus a conference was organized at the University of Pennsylvania to bring together oncologic surgeons from different specialties to discuss the current clinical status of IMI trials with a specific focus on phase 2 and phase 3 studies. In addition, phase 1 and experimental trials were also discussed briefly, to highlight other novel techniques. Our review summarizes the discussions from the conference and delves into the types of cancers discussed, different contrast agents in human trials, and the clinical value being studied.

PMID: 31808327 [PubMed - indexed for MEDLINE]