UW Neurological Surgery Recent PubMed Publications

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]

WSES consensus conference guidelines: monitoring and management of severe adult traumatic brain injury patients with polytrauma in the first 24 hours.

World J Emerg Surg. 2019;14:53

Authors: Picetti E, Rossi S, Abu-Zidan FM, Ansaloni L, Armonda R, Baiocchi GL, Bala M, Balogh ZJ, Berardino M, Biffl WL, Bouzat P, Buki A, Ceresoli M, Chesnut RM, Chiara O, Citerio G, Coccolini F, Coimbra R, Di Saverio S, Fraga GP, Gupta D, Helbok R, Hutchinson PJ, Kirkpatrick AW, Kinoshita T, Kluger Y, Leppaniemi A, Maas AIR, Maier RV, Minardi F, Moore EE, Myburgh JA, Okonkwo DO, Otomo Y, Rizoli S, Rubiano AM, Sahuquillo J, Sartelli M, Scalea TM, Servadei F, Stahel PF, Stocchetti N, Taccone FS, Tonetti T, Velmahos G, Weber D, Catena F

Abstract
The acute phase management of patients with severe traumatic brain injury (TBI) and polytrauma represents a major challenge. Guidelines for the care of these complex patients are lacking, and worldwide variability in clinical practice has been documented in recent studies. Consequently, the World Society of Emergency Surgery (WSES) decided to organize an international consensus conference regarding the monitoring and management of severe adult TBI polytrauma patients during the first 24 hours after injury. A modified Delphi approach was adopted, with an agreement cut-off of 70%. Forty experts in this field (emergency surgeons, neurosurgeons, and intensivists) participated in the online consensus process. Sixteen recommendations were generated, with the aim of promoting rational care in this difficult setting.

PMID: 31798673 [PubMed - indexed for MEDLINE]

Insights into the dynamic control of breathing revealed through cell-type-specific responses to substance P.

Elife. 2019 12 05;8:

Authors: Baertsch NA, Ramirez JM

Abstract
The rhythm generating network for breathing must continuously adjust to changing metabolic and behavioral demands. Here, we examined network-based mechanisms in the mouse preBötzinger complex using substance P, a potent excitatory modulator of breathing frequency and stability, as a tool to dissect network properties that underlie dynamic breathing. We find that substance P does not alter the balance of excitation and inhibition during breaths or the duration of the resulting refractory period. Instead, mechanisms of recurrent excitation between breaths are enhanced such that the rate that excitation percolates through the network is increased. We propose a conceptual framework in which three distinct phases of inspiration, the burst phase, refractory phase, and percolation phase, can be differentially modulated to control breathing dynamics and stability. Unraveling mechanisms that support this dynamic control may improve our understanding of nervous system disorders that destabilize breathing, many of which involve changes in brainstem neuromodulatory systems.

PMID: 31804180 [PubMed - indexed for MEDLINE]

Prescribing Trends of Topical Glaucoma Medications in Australia From 2001 to 2017.

J Glaucoma. 2020 03;29(3):175-183

Authors: Perera N, Pinnuck BC, Jamieson MPH, Ling D, Williams M, Chen O

Abstract
PRECIS: As new glaucoma treatments arise, including minimally invasive glaucoma surgeries and new classes of glaucoma medications, it is important to examine the prescription trends of current topical glaucoma medications and how they may change.
PURPOSE: To determine the prescribing trends of topical glaucoma medications in Australia from 2001 to 2017.
METHODS AND ANALYSIS: Pharmaceutical Benefits Scheme (PBS) item numbers were used to determine glaucoma medication prescribing rates from 2001 to 2017. All data were adjusted for population (/100,000) as per the Australian Bureau of Statistics (ABS) population data.
RESULTS: Overall prescription rates for glaucoma medications ranged between 67,904 and 86,936 per 100,000 from 2001 to 2017. An upward trend was noted from 2001 to 2015, with the exception of a notable decline in 2013 by 14.7%, before then increasing by 13.7% in 2014. After 2015, prescribing rates were seen to decrease over the subsequent years in the study period. Latanoprost remained the most prescribed medication and prostaglandin the most prescribed class. Prescribing rates of single-agent beta-blockers were noted to decrease during the 17-year period, particularly with the introduction of combination agents, which note an upward trend. Brinzolamide/brimonidine has increased by 50.0% from 2016 to 2017.
CONCLUSIONS: Total rates of prescriptions have remained relatively stable from 2001 to 2017. The number of medications prescribed when considering combination agents separately was seen to be increasing from 2001 to 2015. From 2015 to 2017, a downward trend was noted in the number of medications prescribed. Prostaglandins remain the most prescribed class throughout the study period.

PMID: 31790066 [PubMed - indexed for MEDLINE]

Enhancing Concussion Management in the National Football League: Evolution and Initial Results of the Unaffiliated Neurotrauma Consultants Program, 2012-2017.

Neurosurgery. 2020 08 01;87(2):312-319

Authors: Mack C, Sendor RR, Solomon G, Ellenbogen RG, Myers E, Berger M, Sills A

Abstract
BACKGROUND: The real-time detection of concussive injury in professional sports can be challenging for the healthcare provider on the sideline. It can be difficult to monitor all on-field players during active game play and diagnose complex injuries such as concussion during a fast-paced athletic event.
OBJECTIVE: To enhance the in-game identification of potentially concussed professional athletes, the National Football League (NFL) initiated an Unaffiliated Neurotrauma Consultants (UNC) program in 2013, which, in tandem with other in-arena spotters and live video review systems, is designed to improve the safety of the players through enhanced concussion detection efforts.
METHODS: This paper reports on the evolution of the UNC program, describes its participants and training requirements, details the role of UNC involvement, and delineates the systematic revisions and enhancements completed each year in the program.
RESULTS: UNC reporting compliance has increased from 56% in 2014 to 100% in 2017. During the 2016 and 2017 seasons, (1) UNCs submitted an average of 1.9 evaluations per game, and (2) the UNC concussion assessments yielded sensitivity (93.4%-97.4%) and specificity (81.0%-88.3%) values.
CONCLUSION: The UNC program has enhanced the detection of concussion in NFL players. Directions for research and future program improvements are addressed.

PMID: 31792503 [PubMed - indexed for MEDLINE]

Current Update on Treatment Strategies for Idiopathic Normal Pressure Hydrocephalus.

Curr Treat Options Neurol. 2019 Dec 03;21(12):65

Authors: Isaacs AM, Williams MA, Hamilton MG

Abstract
PURPOSE OF REVIEW: Idiopathic normal pressure hydrocephalus (iNPH) is a surgically treatable neurological disorder of the elderly population that is characterized by abnormal ventricular enlargement due to cerebrospinal fluid (CSF) accumulation and gait disturbance, cognitive impairment, or urinary incontinence. The objective of this review is to present the current diagnostic and treatment approaches for iNPH and to discuss some of the postoperative modalities that complement positive surgical outcomes.
RECENT FINDINGS: Although historically reported patient outcomes following iNPH surgery were dismal and highly variable, recent advances in terms of better understanding of the iNPH disease process, better standardization of iNPH diagnostic and treatment processes arising from the adoption of clinical guidelines for diagnosis, treatment and in research methodologies, and availability of long-term follow-up data, have helped reduce the variations to a much improved 73 to 96% reported good outcomes. With careful evaluation, good patient selection, and advanced surgical techniques, iNPH can be surgically treated to return patients close to their pre-iNPH functional status. Institution of an interdisciplinary effort to rehabilitate patients following surgery may help augment their recovery.

PMID: 31792620 [PubMed]

Anti-PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma.

Neuro Oncol. 2019 Dec 03;:

Authors: Ene CI, Kreuser SA, Jung M, Zhang H, Arora S, White Moyes K, Szulzewsky F, Barber J, Cimino PJ, Wirsching HG, Patel A, Kong P, Woodiwiss TR, Durfy SJ, Houghton AM, Pierce RH, Parney IF, Crane CA, Holland EC

Abstract
BACKGROUND: Most glioblastoma recurrences occur near prior radiation treatment sites. Future clinical success will require achieving and optimizing an 'abscopal effect', whereby un-irradiated neoplastic cells outside treatment sites are recognized and attacked by the immune system. Radiation combined with anti-PD-L1 demonstrated modest efficacy in phase II human glioblastoma clinical trials, but the mechanism and relevance of the abscopal effect during this response remains unknown.
METHODS: We modified an immune-competent, genetically-driven mouse glioma model (forced PDGF expression + PTEN loss) where a portion of the tumor burden is irradiated (PDGF) and another un-irradiated luciferase expressing tumor (PDGF+Luciferase) is used as a readout of the abscopal effect following systemic anti-PD-L1 immunotherapy. We assessed relevance of tumor neoepitope during the abscopal response by inducing expression of EGFRvIII (PDGF+EGFRvIII). Statistical tests were two-sided.
RESULTS: Following radiation of one lesion, anti-PD-L1 immunotherapy enhanced the abscopal response to the un-irradiated lesion. In PDGF-driven gliomas without tumor neoepitope (PDGF+Luciferase, n=8), the abscopal response occurred via anti-PD-L1-driven, ERK-mediated, bone marrow-derived macrophage phagocytosis of adjacent un-irradiated tumor cells, with modest survival implications (median survival 41 days vs. radiation alone 37.5 days, P=.03). In PDGF-driven gliomas with tumor neoepitope (PDGF+EGFRvIII, n=8), anti-PD-L1-enhanced abscopal response was associated with macrophage and T-cell infiltration and increased survival benefit (median survival 36 days vs. radiation alone 28 days, P=.001).
CONCLUSION: Our results indicate that anti-PD-L1 immunotherapy enhances a radiation induced abscopal response via canonical T-cell activation and direct macrophage activation in glioblastoma.

PMID: 31793634 [PubMed - as supplied by publisher]

Transcranial Doppler ultrasonography in neurological surgery and neurocritical care.

Neurosurg Focus. 2019 12 01;47(6):E2

Authors: Bonow RH, Young CC, Bass DI, Moore A, Levitt MR

Abstract
Transcranial Doppler (TCD) ultrasonography is an inexpensive, noninvasive means of measuring blood flow within the arteries of the brain. In this review, the authors outline the technology underlying TCD ultrasonography and describe its uses in patients with neurosurgical diseases. One of the most common uses of TCD ultrasonography is monitoring for vasospasm following subarachnoid hemorrhage. In this setting, elevated blood flow velocities serve as a proxy for vasospasm and can herald the onset of ischemia. TCD ultrasonography is also useful in the evaluation and management of occlusive cerebrovascular disease. Monitoring for microembolic signals enables stratification of stroke risk due to carotid stenosis and can also be used to clarify stroke etiology. TCD ultrasonography can identify patients with exhausted cerebrovascular reserve, and after extracranial-intracranial bypass procedures it can be used to assess adequacy of flow through the graft. Finally, assessment of cerebral autoregulation can be performed using TCD ultrasonography, providing data important to the management of patients with severe traumatic brain injury. As the clinical applications of TCD ultrasonography have expanded over time, so has their importance in the management of neurosurgical patients. Familiarity with this diagnostic tool is crucial for the modern neurological surgeon.

PMID: 31786564 [PubMed - indexed for MEDLINE]

Therapies for White Spot Lesions-A Systematic Review.

J Evid Based Dent Pract. 2017 Mar;17(1):23-38

Authors: Paula AB, Fernandes AR, Coelho AS, Marto CM, Ferreira MM, Caramelo F, do Vale F, Carrilho E

Abstract
INTRODUCTION: The first sign of dental caries is denoted by white spot lesions (WSLs) which can be defined as a demineralization of the enamel surface and subsurface, although these lesions can be reversed and do not form cavities. The aim of this systematic review was investigate which remineralization agents are effective for the treatment of WSLs.
MATERIALS AND METHODS: For this systematic review a literature search was conducted on Pubmed, Cochrane Library and ScienceDirect.
RESULTS: The initial search resulted in 273 references. After elimination of duplicate articles, 236 references remained. After reading titles and abstracts, all non-relevant results were excluded, resulting in 45 potentially relevant studies. After reading the full text, 13 references were included.
CONCLUSION: More studies are required for scientific evidence in order to reach a conclusion of the most suitable therapeutic method for the treatment of surface and subsurface demineralization of the enamel.

PMID: 28259311 [PubMed - indexed for MEDLINE]

Alpha Omega Alpha Honor Medical Society: A Commitment to Inclusion, Diversity, Equity, and Service in the Profession of Medicine.

Acad Med. 2020 05;95(5):670-673

Authors: Byyny RL, Martinez D, Cleary L, Ballard B, Barth BE, Christensen S, Eidson-Ton W, Estevez-Ordonez D, Fuhrer J, Kinzie JM, Lee AL, Lynch C, Pfeil S, Schoenbaum E

Abstract
With a motto of "Be Worthy to Serve the Suffering," Alpha Omega Alpha Honor Medical Society (AΩA) supports the importance, inclusion, and development of a culturally and ethnically diverse medical profession with equitable access for all. The underrepresentation of minorities in medical schools and medicine continues to be a challenge for the medical profession, medical education, and AΩA. AΩA has worked, and continues to work, to ensure the development of diverse leaders, fostering within them the objectivity and equity to be inclusive servant leaders who understand and embrace diversity in all its forms.Inclusion of talented individuals from different backgrounds benefits patient care, population health, education, and scientific discovery. AΩA values an inclusive, diverse, fair, and equitable work and learning environment for all and supports the medical profession in its work to achieve a welcoming, inclusive environment in teaching, learning, caring for patients, and collaboration.The diversity of medical schools is changing and will continue to change. AΩA is committed to continuing to work with its members, medical school deans, and AΩA chapters to assure that AΩA elections are unbiased and based on the values of AΩA and the profession of medicine in service to patients and the profession.Progress toward diversity, inclusion, and equity is more than simply checking off a box or responding to criticism-it is about being and developing diverse excellent physicians. AΩA and all those in the medical profession must continue to guide medicine to be unbiased, open, accepting, inclusive, and culturally aware in order to "Be Worthy to Serve the Suffering."

PMID: 31764080 [PubMed - indexed for MEDLINE]

Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI.

Transl Psychiatry. 2019 11 21;9(1):315

Authors: Pisanu C, Williams MJ, Ciuculete DM, Olivo G, Del Zompo M, Squassina A, Schiöth HB

Abstract
Patients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E-04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E-05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E-24), five were located in the ETV5 gene (best SNP: rs1516725, p = 1E-24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E-09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E-08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.

PMID: 31754094 [PubMed - indexed for MEDLINE]