UW Neurological Surgery Recent PubMed Publications

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression.

Nat Commun. 2020 10 05;11(1):4997

Authors: De Boeck A, Ahn BY, D'Mello C, Lun X, Menon SV, Alshehri MM, Szulzewsky F, Shen Y, Khan L, Dang NH, Reichardt E, Goring KA, King J, Grisdale CJ, Grinshtein N, Hambardzumyan D, Reilly KM, Blough MD, Cairncross JG, Yong VW, Marra MA, Jones SJM, Kaplan DR, McCoy KD, Holland EC, Bose P, Chan JA, Robbins SM, Senger DL

Abstract
Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.

PMID: 33020472 [PubMed - indexed for MEDLINE]

Idiopathic Intracranial Hypertension in the United States: Demographic and Socioeconomic Disparities.

Front Neurol. 2020;11:869

Authors: Ghaffari-Rafi A, Mehdizadeh R, Ko AWK, Ghaffari-Rafi S, Leon-Rojas J

Abstract
Background: Obesity's risk increases for low-income, female, young, and Black patients. By extrapolation, idiopathic intracranial hypertension (IIH)-a disease associated with body mass index-would potentially display socioeconomic and demographic disparities. Methods: IIH incidence (per 100,000) was investigated with respect to sex, age, income, residence, and race/ethnicity, by querying the largest United States (US) healthcare administrative dataset (1997-2016), the National (Nationwide) Inpatient Sample. Results: Annual national incidence (with 25th and 75th quartiles) for IIH was 1.15 (0.91, 1.44). Females had an incidence of 1.97 (1.48, 2.48), larger (p = 0.0000038) than males at 0.36 (0.26, 0.38). Regarding age, largest incidence was among those 18-44 years old at 2.47 (1.84, 2.73). Low-income patients had an incidence of 1.56 (1.47, 1.82), larger (p = 0.00024) than the 1.21 (1.01, 1.36) of the middle/high. No differences (χ2 = 4.67, p = 0.097) were appreciated between urban (1.44; 1.40, 1.61), suburban (1.30; 1.09, 1.40), or rural (1.46; 1.40, 1.48) communities. For race/ethnicity (χ2 = 57, p = 2.57 × 10-12), incidence was largest for Blacks (2.05; 1.76, 2.74), followed by Whites (1.04; 0.79, 1.41), Hispanics (0.67; 0.57, 0.94), and Asian/Pacific Islanders (0.16; 0.11, 0.19). Year-to-year, incidence rose for all strata subsets except Asian/Pacific Islanders (τ = -0.84, p = 0.00000068). Conclusion: IIH demonstrates several sociodemographic disparities. Specifically, incidences are larger for those low-income, Black, 18-44 years old, or female, while annually increasing for all subsets, except Asian/Pacific Islanders. Hence, IIH differentially afflicts the US population, yielding in healthcare inequalities.

PMID: 33013623 [PubMed]

Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaque.

Circulation. 2020 Oct 02;:

Authors: Drobni ZD, Alvi RM, Taron J, Zafar A, Murphy SP, Rambarat PK, Mosarla RC, Lee C, Zlotoff DA, Raghu VK, Hartmann SE, Gilman HK, Gong J, Zubiri L, Sullivan RJ, Reynolds KL, Mayrhofer T, Zhang L, Hoffmann U, Neilan TG

Abstract
Background: Immune checkpoint inhibitors (ICI) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events. Methods: The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls, matched by age, a history of cardiovascular events and cancer type. In a second design, a case-crossover analysis was performed with an "at-risk period" defined as the two-year period after and the "control period" as the two-year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. Additionally, in an imaging sub-study (n=40), the rate of atherosclerotic plaque progression was compared from before and after starting an ICI. All study measures and outcomes were blindly adjudicated. Results: In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (HR, 3.3 [95% CI, 2.0-5.5]; P<0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at two years (adjusted HR, 4.8 [95% CI, 3.5-6.5]; P<0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/year pre-to 6.7%/year post). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids. Conclusions: Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk, prior to, during and after treatment, should be considered among patients on an ICI.

PMID: 33003973 [PubMed - as supplied by publisher]

Validation of an mRNA-based Urine Test for the Detection of Bladder Cancer in Patients with Haematuria.

Eur Urol Oncol. 2020 Sep 28;:

Authors: Valenberg FJPV, Hiar AM, Wallace E, Bridge JA, Mayne DJ, Beqaj S, Sexton WJ, Lotan Y, Weizer AZ, Jansz GK, Stenzl A, Danella JF, Cline KJ, Williams MB, Montgomery S, David RD, Harris R, Klein EW, Bradford TJ, Wolk FN, Westenfelder KR, Trainer AF, Richardson TA, Egerdie RB, Goldfarb B, Zadra JA, Lu X, Simon IM, Campbell SA, Bates MP, Higuchi RG, Witjes JA

Abstract
BACKGROUND: In patients with haematuria, a fast, noninvasive test with high sensitivity (SN) and negative predictive value (NPV), which is able to detect or exclude bladder cancer (BC), is needed. A newly developed urine assay, Xpert Bladder Cancer Detection (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC.
OBJECTIVE: To validate the performance of Xpert in patients with haematuria.
DESIGN, SETTING, AND PARTICIPANTS: Voided precystoscopy urine specimens were prospectively collected at 22 sites from patients without prior BC undergoing cystoscopy for haematuria. Xpert, cytology, and UroVysion procedures were performed. Technical validation was performed and specificity (SP) was determined in patients without BC.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion.
RESULTS AND LIMITATIONS: We included 828 patients (mean age 64.5 yr, 467 males, 401 never smoked). Xpert had an SN of 78% (95% confidence interval [CI]: 66-87) overall and 90% (95% CI: 76-96) for high-grade (HG) tumours. The NPV was 98% (95% CI: 97-99) overall. The SP was 84% (95% CI: 81-86). In patients with microhaematuria, only one HG patient was missed (NPV 99%). Xpert had higher SN and NPV than cytology and UroVysion. Cytology had the highest SP (97%). In a separate SP study, Xpert had an SP of 89% in patients with benign prostate hypertrophy and 92% in prostate cancer patients.
CONCLUSIONS: Xpert is an easy-to-use, noninvasive test with improved SN and NPV compared with cytology and UroVysion, representing a promising tool for identifying haematuric patients with a low likelihood of BC who might not need to undergo cystoscopy.
PATIENT SUMMARY: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help identify (micro)haematuria patients with a very low likelihood to have bladder cancer.

PMID: 33004290 [PubMed - as supplied by publisher]

Incorporating genomic signatures into surgical and medical decision-making for elderly glioblastoma patients.

Neurosurg Focus. 2020 Oct;49(4):E11

Authors: Ene CI, Cimino PJ, Fine HA, Holland EC

Abstract
Glioblastoma (GBM) is the most common type of malignant primary brain tumor in adults. It is a uniformly fatal disease (median overall survival 16 months) even with aggressive resection and an adjuvant temozolomide-based chemoradiation regimen. Age remains an independent risk factor for a poor prognosis. Several factors contribute to the dismal outcomes in the elderly population with GBM, including poor baseline health status, differences in underlying genomic alterations, and variability in the surgical and medical management of this subpopulation. The latter arises from a lack of adequate representation of elderly patients in clinical trials, resulting in limited data on the response of this subpopulation to standard treatment. Results from retrospective and some prospective studies have indicated that resection of only contrast-enhancing lesions and administration of hypofractionated radiotherapy in combination with temozolomide are effective strategies for optimizing survival while maintaining baseline quality of life in elderly GBM patients; however, survival remains dismal relative to that in a younger cohort. Here, the authors present historical context for the current strategies used for the multimodal management (surgical and medical) of elderly patients with GBM. Furthermore, they provide insights into elderly GBM patient-specific genomic signatures such as isocitrate dehydrogenase 1/2 (IDH1/2) wildtype status, telomerase reverse transcriptase promoter (TERTp) mutations, and somatic copy number alterations including CDK4/MDM2 coamplification, which are becoming better understood and could be utilized in a clinical trial design and patient stratification to guide the development of more effective adjuvant therapies specifically for elderly GBM patients.

PMID: 33002863 [PubMed - as supplied by publisher]

Middle meningeal artery embolization treatment of nonacute subdural hematomas in the elderly: a multiinstitutional experience of 151 cases.

Neurosurg Focus. 2020 Oct;49(4):E5

Authors: Joyce E, Bounajem MT, Scoville J, Thomas AJ, Ogilvy CS, Riina HA, Tanweer O, Levy EI, Spiotta AM, Gross BA, Jankowitz BT, Cawley CM, Khalessi AA, Pandey AS, Ringer AJ, Hanel R, Ortiz RA, Langer D, Levitt MR, Binning M, Taussky P, Kan P, Grandhi R

Abstract
OBJECTIVE: The incidence of already common chronic subdural hematomas (CSDHs) and other nonacute subdural hematomas (NASHs) in the elderly is expected to rise as the population ages over the coming decades. Surgical management is associated with recurrence and exposes elderly patients to perioperative and operative risks. Middle meningeal artery (MMA) embolization offers the potential for a minimally invasive, less morbid treatment in this age group. The clinical and radiographic outcomes after MMA embolization treatment for NASHs have not been adequately described in elderly patients. In this paper, the authors describe the clinical and radiographic outcomes after 151 cases of MMA embolization for NASHs among 121 elderly patients.
METHODS: In a retrospective review of a prospectively maintained database across 15 US academic centers, the authors identified patients aged ≥ 65 years who underwent MMA embolization for the treatment of NASHs between November 2017 and February 2020. Patient demographics, comorbidities, clinical and radiographic factors, treatment factors, and clinical outcomes were abstracted. Subgroup analysis was performed comparing elderly (age 65-79 years) and advanced elderly (age > 80 years) patients.
RESULTS: MMA embolization was successfully performed in 98% of NASHs (in 148 of 151 cases) in 121 patients. Seventy elderly patients underwent 87 embolization procedures, and 51 advanced elderly patients underwent 64 embolization procedures. Elderly and advanced elderly patients had similar rates of embolization for upfront (46% vs 61%), recurrent (39% vs 33%), and prophylactic (i.e., with concomitant surgical intervention; 15% vs 6%) NASH treatment. Transfemoral access was used in most patients, and the procedure time was approximately 1 hour in both groups. Particle embolization with supplemental coils was most common, used in 51% (44/87) and 44% (28/64) of attempts for the elderly and advanced elderly groups, respectively. NASH thickness decreased significantly from initial thickness to 6 weeks, with additional decrease in thickness observed in both groups at 90 days. At longest follow-up, the treated NASHs had stabilized or improved in 91% and 98% of the elderly and advanced elderly groups, respectively, with > 50% improvement seen in > 60% of patients for each group. Surgical rescue was necessary in 4.6% and 7.8% of cases, and the overall mortality was 8.6% and 3.9% for elderly and advanced elderly patients, respectively.
CONCLUSIONS: MMA embolization can be used safely and effectively as an alternative or adjunctive minimally invasive treatment for NASHs in elderly and advanced elderly patients.

PMID: 33002874 [PubMed - as supplied by publisher]

Validation of the 10-item Center for Epidemiologic Studies Depression Scale Post Stroke.

J Stroke Cerebrovasc Dis. 2020 Dec;29(12):105334

Authors: Williams MW, Li CY, Hay CC

Abstract
OBJECTIVE: To establish reliability and validity of the abbreviated (10-item) Center for Epidemiologic Studies Depression Scale (CESD-10) among individuals post stroke.
METHOD: The psychometric properties of the CESD-10 were evaluated in 1219 adults with stroke admitted to an eligible inpatient rehabilitation facilities (n = 11) across 9 different states post stroke during 2005 to 2006. This study was a secondary data analysis of the existing publicly available clinical trial dataset, Stroke Recovery in Underserved Populations study. Reliability, validity, factory structure and item-level psychometrics of the CESD-10 were examined. In addition, the predictive accuracy of the CESD-10 was compared against the CESD-20 (criterion).
RESULTS: The CESD-10 was highly correlated with the CESD-20 (r = 0.97). The CESD-10 had good internal reliability (Cronbach's α = 0.86). The CESD-20 and CESD-10 had similar accuracy in classifying individuals as depressed (Kappa = 0.85).
CONCLUSION: The 10-item CESD is a valid measure of depression for individuals post stroke.

PMID: 32992164 [PubMed - indexed for MEDLINE]

Quantitative Evaluation of D-Lactate Pathophysiology: New Insights into the Mechanisms Involved and the Many Areas in Need of Further Investigation.

Clin Exp Gastroenterol. 2020;13:321-337

Authors: Levitt MD, Levitt DG

Abstract
In contrast to L-lactate, D-lactate is produced in minimal quantities by human cells, and the plasma D-lactate concentration normally is maintained at a concentration of only about 0.01 mM. However, in short bowel syndrome, colonic bacterial production of D-lactate may lead to plasma concentrations >3mM with accompanying acidosis and neurological symptoms - a syndrome known as D-lactic acidosis. Minor increases in plasma D-lactate have been observed in various gastrointestinal conditions such as ischemia, appendicitis and Crohn's disease, a finding touted to have diagnostic utility. The novel aspect of this review paper is the application of numerical values to the processes involved in D-lactate homeostasis that previously have been described only in qualitative terms. This approach provides a number of new insights into normal and disordered production, catabolism and excretion of D-lactate, and identifies multiple gaps in our understanding of D-lactate physiology that should be amenable to relatively simple investigative study.

PMID: 32982363 [PubMed]

Patient-Centered Surgical Care Meets the Social Determinants of Health.

World J Surg. 2021 01;45(1):79-80

Authors: Williams M

PMID: 32975649 [PubMed - indexed for MEDLINE]

Rapid MRI of the spine in neonates with spinal dysraphism.

World Neurosurg. 2020 Sep 19;:

Authors: Khalatbari H, Perez FA, Lee A, Shaw DW

Abstract
BACKGROUND: The use of non-sedated T2-weighted Half-Fourier Acquisition Single-shot Turbo spin Echo (T2 HASTE) magnetic resonance imaging (MRI) sequences in screening for spinal cord syrinx in neonates with spinal dysraphism has not been reported in the literature.
OBJECTIVE: To review our experience using T2 HASTE imaging of the spine (i.e., rapid spine MRI) in non-sedated neonates for detecting spinal cord syrinx in neonates with spinal dysraphism.
MATERIALS AND METHODS: We performed a retrospective search of our radiology database for neonates with spinal dysraphism who had rapid spine MRIs between May 2017 to February 2020. The images were reviewed in conjunction with clinical findings and standard spine imaging, when available.
RESULTS: Thirty studies (in 29 neonates) fulfilled our inclusion criteria. Of the twenty-six neonates with myelomeningocele, 5 (19%) had spinal cord syrinx identified on neonatal rapid spine MRI. An additional two patients developed syrinx by two years of age. Potential pitfalls identified in interpreting rapid spine MRIs include motion artifacts and distinguishing a severe holocord syrinx from a truncated spinal cord.
CONCLUSION: Rapid spine MRI acquired without sedation or anesthesia may be used as a screening technique to detect spinal cord syrinx in neonates with spinal dysraphism.

PMID: 32961357 [PubMed - as supplied by publisher]

Wide Complex QRS Rhythm in a 52-Year-Old Man With Altered Mental Status.

Circulation. 2020 Sep 22;142(12):1224-1226

Authors: Krivda JS, Williams MU, Arrey-Mbi TB

PMID: 32955938 [PubMed - as supplied by publisher]

Stereotactic Brain Biopsy Hemorrhage Risk Factors and Implications for Post-Operative Care at a Single Institution: An Argument For Post Operative Imaging.

World Neurosurg. 2020 Sep 18;:

Authors: Barkley AS, Sullivan LT, Gibson AW, Camacho D, Barber JK, Ko AL, Silbergeld DL, Ravanpay AC

Abstract
OBJECTIVE: To determine pre-operative factors contributing to post-operative hemorrhage after stereotactic biopsy (STB), clinical implications of post-operative hemorrhage, and the role of post-operative imaging in clinical management.
METHODS: Retrospective review of STB (2005-2018) across 2 institutions including patients >18 years undergoing first STB. Patients with prior craniotomy, open biopsy or prior STB were excluded. Pre-operative variables included age, gender, neurosurgeon seniority, STB method. Post-operative variables included pathology, post-operative hemorrhage on CT, immediate and 30-day post-operative seizure, infection, post-operative hospital stay duration, 30-day return to OR. Analysis used Fisher's exact tests for categorical variables.
RESULTS: Overall, 410 patients were included. Average age was 56.5 (±16.5) years; 60% (n=248) were male. The majority of biopsies were performed by senior neurosurgeons (66%, n=270); frontal lobe (42%, n=182) and glioblastoma (45%, n=186) were the most common location and pathology. Post-operative hemorrhage occurred in 28% (114) of patients with 20% <0.05 cm3 and 8% >0.05 cm3. Post-operative hemorrhage of any size was associated with increased rate of post-operative deficit within both 24 hours and 30 days, post-operative seizure, and length of hospital stay when controlling for pathology. Hemorrhages >0.05cm3 had a 16% higher rate of return to the OR for evacuation, due to clinical deterioration as opposed to radiographic progression.
CONCLUSION: Post biopsy hemorrhage was associated with higher risk of immediate and delayed post-operative deficit and seizure. Post-operative CT should be used to determine whether STB patients can be discharged same day or admitted for observation; clinical evaluation should determine return to OR for evacuation.

PMID: 32956884 [PubMed - as supplied by publisher]

Seawater transmission and infection dynamics of pilchard orthomyxovirus (POMV) in Atlantic salmon (Salmo salar).

J Fish Dis. 2020 Sep 17;:

Authors: Samsing F, Rigby M, Tengesdal HK, Taylor RS, Farias D, Morrison RN, Godwin S, Giles C, Carson J, English CJ, Chong R, Wynne JW

Abstract
The Tasmanian salmon industry had remained relatively free of major viral diseases until the emergence of pilchard orthomyxovirus (POMV). Originally isolated from wild pilchards, POMV is of concern to the industry as it can cause high mortality in farmed salmon (Salmo salar). Field observations suggest the virus can spread from pen to pen and between farms, but evidence of passive transmission in sea water was unclear. Our aim was to establish whether direct contact between infected and naïve fish was required for transmission, and to examine viral infection dynamics. Atlantic salmon post-smolts were challenged with POMV by either direct exposure via cohabitation or indirect exposure via virus-contaminated sea water. POMV was transmissible in sea water and direct contact between fish was not required for infection. Head kidney and heart presented the highest viral loads in early stages of infection. POMV survivors presented low viral loads in most tissues, but these remained relatively high in gills. A consistent feature was the infiltration of viral-infected melanomacrophages in different tissues, suggesting an important role of these in the immune response to POMV. Understanding POMV transmission and host-pathogen interactions is key for the development of improved surveillance tools, transmission models and ultimately for disease prevention.

PMID: 32944982 [PubMed - as supplied by publisher]

Oncolytic HSV Vectors and Anti-Tumor Immunity.

Curr Issues Mol Biol. 2020 Sep 17;41:381-468

Authors: Glorioso JC, Cohen JB, Goins WF, Hall B, Jackson JW, Kohanbash G, Amankulor N, Kaur B, Caligiuri MA, Chiocca EA, Holland EC, Quéva C

Abstract
The therapeutic promise of oncolytic viruses (OVs) rests on their ability to both selectively kill tumor cells and induce anti-tumor immunity. The potential of tumors to be recognized and eliminated by an effective anti-tumor immune response has been spurred on by the discovery that immune checkpoint inhibition can overcome tumor-specific cytotoxic T cell (CTL) exhaustion and provide durable responses in multiple tumor indications. OV-mediated tumor destruction is now recognized as a powerful means to assist in the development of anti-tumor immunity for two important reasons: (i) OVs, through the elicitation of an anti-viral response and the production of type I interferon, are potent stimulators of inflammation and can be armed with transgenes to further enhance anti-tumor immune responses; and (ii) lytic activity can promote the release of tumor-associated antigens (TAAs) and tumor neoantigens that function as in situ tumor-specific vaccines to elicit adaptive immunity. Oncolytic herpes simplex viruses (oHSVs) are among the most widely studied OVs for the treatment of solid malignancies, and Amgen's oHSV Imlygic® for the treatment of melanoma is the only OV approved in major markets. Here we describe important biological features of HSV that make it an attractive OV, clinical experience with HSV-based vectors, and strategies to increase applicability to cancer treatment.

PMID: 32938804 [PubMed - as supplied by publisher]

Daily Generation of a Footward Fluid Shift Attenuates Ocular Changes Associated with Head-Down Tilt Bedrest.

J Appl Physiol (1985). 2020 Sep 17;:

Authors: Lawley JS, Babu G, Janssen SLJE, Petersen LG, Hearon CM, Dias KA, Sarma S, Williams MA, Whitworth LA, Levine BD

Abstract
Astronauts have presented with a constellation of visual changes referred to as spaceflight-associated neuro-ocular syndrome (SANS). However, early markers of microgravity-induced optic remodeling have not been fully identified nor have countermeasures been developed. In order to identify early markers of SANS, we studied 10 subjects with optical coherence tomography and ultrasound when upright and supine, and again after 24 hours of 6-degree head down tilt (HDT) bedrest. Upon acute transition from upright to supine, choroid area (2.24±0.53 to 2.28±0.52 mm2, p=0.001) and volume (9.51±2.08 to 9.73±2.08 mm3, p=0.002) increased. After 24 hours of HDT bedrest, subfoveal choroidal thickness (372±93 to 381±95 µm, p=0.02) , choroid area (2.25±0.52 to 2.33±0.54 mm2, p=0.08) and volume (9.64±2.03 to 9.82±2.08 mm3, p=0.08) increased relative to the supine position. Subsequently, 7 subjects spent 3 days in -6 deg HDT bedrest to assess whether low-level lower body negative pressure (LBNP) could prevent the observed choroidal engorgement during bedrest. Maintaining the -6 deg HDT position for 3 days caused choroid area (Δ0.11 mm2, p=0.05) and volume (Δ0.45 mm3, p=0.003) to increase. When participants also spent 8 hours daily under -20mmHg LBNP, choroid volume still increased, but substantially (40%) less than in the control trial (Δ0.27 mm3, p=0.05). Moreover, the increase in choroid area was diminished (Δ0.03 mm2, p=0.13), indicating that low-level LBNP attenuates the choroid expansion associated with 3 days of -6 deg HDT bedrest. These data suggest that low-level LBNP may be an effective countermeasure for SANS.

PMID: 32940563 [PubMed - as supplied by publisher]

A dual role for Cav1.4 Ca2+ channels in the molecular and structural organization of the rod photoreceptor synapse.

Elife. 2020 09 17;9:

Authors: Maddox JW, Randall KL, Yadav RP, Williams B, Hagen J, Derr PJ, Kerov V, Della Santina L, Baker SA, Artemyev N, Hoon M, Lee A

Abstract
Synapses are fundamental information processing units that rely on voltage-gated Ca2+ (Cav) channels to trigger Ca2+-dependent neurotransmitter release. Cav channels also play Ca2+-independent roles in other biological contexts, but whether they do so in axon terminals is unknown. Here, we addressed this unknown with respect to the requirement for Cav1.4 L-type channels for the formation of rod photoreceptor synapses in the retina. Using a mouse strain expressing a non-conducting mutant form of Cav1.4, we report that the Cav1.4 protein, but not its Ca2+ conductance, is required for the molecular assembly of rod synapses; however, Cav1.4 Ca2+ signals are needed for the appropriate recruitment of postsynaptic partners. Our results support a model in which presynaptic Cav channels serve both as organizers of synaptic building blocks and as sources of Ca2+ ions in building the first synapse of the visual pathway and perhaps more broadly in the nervous system.

PMID: 32940604 [PubMed - indexed for MEDLINE]

Investigating effects of soil chemicals on density of small mammal bioindicators using spatial capture-recapture models.

PLoS One. 2020;15(9):e0238870

Authors: Gaukler SM, Murphy SM, Berryhill JT, Thompson BE, Sutter BJ, Hathcock CD

Abstract
Monitoring the ecological impacts of environmental pollution and the effectiveness of remediation efforts requires identifying relationships between contaminants and the disruption of biological processes in populations, communities, or ecosystems. Wildlife are useful bioindicators, but traditional comparative experimental approaches rely on a staunch and typically unverifiable assumption that, in the absence of contaminants, reference and contaminated sites would support the same densities of bioindicators, thereby inferring direct causation from indirect data. We demonstrate the utility of spatial capture-recapture (SCR) models for overcoming these issues, testing if community density of common small mammal bioindicators was directly influenced by soil chemical concentrations. By modeling density as an inhomogeneous Poisson point process, we found evidence for an inverse spatial relationship between Peromyscus density and soil mercury concentrations, but not other chemicals, such as polychlorinated biphenyls, at a site formerly occupied by a nuclear reactor. Although the coefficient point estimate supported Peromyscus density being lower where mercury concentrations were higher (β = -0.44), the 95% confidence interval overlapped zero, suggesting no effect was also compatible with our data. Estimated density from the most parsimonious model (2.88 mice/ha; 95% CI = 1.63-5.08), which did not support a density-chemical relationship, was within the range of reported densities for Peromyscus that did not inhabit contaminated sites elsewhere. Environmental pollution remains a global threat to biodiversity and ecosystem and human health, and our study provides an illustrative example of the utility of SCR models for investigating the effects that chemicals may have on wildlife bioindicator populations and communities.

PMID: 32941472 [PubMed - indexed for MEDLINE]

Interactions between genetics and environment shape Camelina seed oil composition.

BMC Plant Biol. 2020 Sep 14;20(1):423

Authors: Brock JR, Scott T, Lee AY, Mosyakin SL, Olsen KM

Abstract
BACKGROUND: Camelina sativa (gold-of-pleasure) is a traditional European oilseed crop and emerging biofuel source with high levels of desirable fatty acids. A twentieth century germplasm bottleneck depleted genetic diversity in the crop, leading to recent interest in using wild relatives for crop improvement. However, little is known about seed oil content and genetic diversity in wild Camelina species.
RESULTS: We used gas chromatography, environmental niche assessment, and genotyping-by-sequencing to assess seed fatty acid composition, environmental distributions, and population structure in C. sativa and four congeners, with a primary focus on the crop's wild progenitor, C. microcarpa. Fatty acid composition differed significantly between Camelina species, which occur in largely non-overlapping environments. The crop progenitor comprises three genetic subpopulations with discrete fatty acid compositions. Environment, subpopulation, and population-by-environment interactions were all important predictors for seed oil in these wild populations. A complementary growth chamber experiment using C. sativa confirmed that growing conditions can dramatically affect both oil quantity and fatty acid composition in Camelina.
CONCLUSIONS: Genetics, environmental conditions, and genotype-by-environment interactions all contribute to fatty acid variation in Camelina species. These insights suggest careful breeding may overcome the unfavorable FA compositions in oilseed crops that are predicted with warming climates.

PMID: 32928104 [PubMed - in process]

UQCRH downregulation promotes Warburg effect in renal cell carcinoma cells.

Sci Rep. 2020 09 14;10(1):15021

Authors: Luo Y, Medina Bengtsson L, Wang X, Huang T, Liu G, Murphy S, Wang C, Koren J, Schafer Z, Lu X

Abstract
Ubiquinol-cytochrome c reductase hinge protein (UQCRH) is the hinge protein for the multi-subunit complex III of the mitochondrial electron transport chain and is involved in the electron transfer reaction between cytochrome c1 and c. Recent genome-wide transcriptomic and epigenomic profiling of clear cell renal cell carcinoma (ccRCC) by The Cancer Genome Atlas (TCGA) identified UQCRH as the top-ranked gene showing inverse correlation between DNA hypermethylation and mRNA downregulation. The function and underlying mechanism of UQCRH in the Warburg effect metabolism of ccRCC have not been characterized. Here, we verified the clinical association of low UQCRH expression and shorter survival of ccRCC patients through in silico analysis and identified KMRC2 as a highly relevant ccRCC cell line that displays hypermethylation-induced UQCRH extinction. Ectopic overexpression of UQCRH in KMRC2 restored mitochondrial membrane potential, increased oxygen consumption, and attenuated the Warburg effect at the cellular level. UQCRH overexpression in KMRC2 induced higher apoptosis and slowed down in vitro and in vivo tumor growth. UQCRH knockout by CRISPR/Cas9 had little impact on the metabolism and proliferation of 786O ccRCC cell line, suggesting the dispensable role of UQCRH in cells that have entered a Warburg-like state through other mechanisms. Together, our study suggests that loss of UQCRH expression by hypermethylation may promote kidney carcinogenesis through exacerbating the functional decline of mitochondria thus reinforcing the Warburg effect.

PMID: 32929120 [PubMed - indexed for MEDLINE]

A Retrospective Evaluation of Airway Anatomy in Young Children and Implications for One-Lung Ventilation.

J Cardiothorac Vasc Anesth. 2020 Aug 12;:

Authors: Downard MG, Lee AJ, Heald CJ, Anthony EY, Singh J, Templeton TW

Abstract
OBJECTIVE: One-lung ventilation (OLV) in children remains a niche practice with few studies to guide best practices. The objective of this study was to describe lower airway anatomy relevant to establishment of OLV in young children.
DESIGN: Retrospective, observational study using pre-existing studies in the electronic health record.
SETTING: Single institution, academic medical center, tertiary-care hospital.
PARTICIPANTS: Pediatric patients <8 years old.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Chest computed tomographic scans of 111 children 4 days to 8 years of age were reviewed. Measurements were taken from the thyroid isthmus to the carina, carina to first lobar branch on the left and right, diameter of the trachea at the carina, and diameter of the left and right mainstem bronchi. Dimensions were correlated with the outer diameter of endotracheal tubes and bronchial blockers. The left mainstem bronchus is consistently smaller than the right. Lung isolation using a mainstem technique on the left should use an endotracheal tube a half size smaller than would be used for tracheal intubation. The length from the carina to the first lobar branch on the left is consistently 3 times longer than on the right. Further, age-delineated bronchial diameters suggest that the clinician should transition from a 5F to a 7F Arndt bronchial blocker at 3-to-4 years of age.
CONCLUSION: A more detailed and accurate understanding of pediatric lower airway anatomy may assist the clinician in successfully performing OLV in young children.

PMID: 32921610 [PubMed - as supplied by publisher]