UW Neurological Surgery Recent PubMed Publications

Type A aortic dissection secondary to a left common carotid artery dissection.

Radiol Case Rep. 2019 Jun;14(6):647-651

Authors: Doran S, Llamas Osorio Y, Murphy M, Kavanagh E, Murphy S

Abstract
Common carotid artery dissection is an unusual clinical event that most commonly occurs secondary to type A aortic dissection. We present a rare case of spontaneous common carotid artery dissection temporally preceding aortic dissection. Our case highlights the careful attention that cases of common carotid dissection should be given; our knowledge base regarding their natural history and evidence-based management is distinctly lacking compared to dissection of other cervical vessels. It also demonstrates the importance of imaging the entire aorta at the time of, a seemingly isolated, common carotid dissection to exclude other potential synchronous dissections.

PMID: 30937125 [PubMed]

Enantioselective Synthesis of 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) via Enzymatic Desymmetrization.

Org Lett. 2017 02 17;19(4):926-929

Authors: McLaughlin M, Kong J, Belyk KM, Chen B, Gibson AW, Keen SP, Lieberman DR, Milczek EM, Moore JC, Murray D, Peng F, Qi J, Reamer RA, Song ZJ, Tan L, Wang L, Williams MJ

Abstract
An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired β-anomer from the glycosylation step.

PMID: 28165251 [PubMed - indexed for MEDLINE]

Reinfection after treatment of first cerebrospinal fluid shunt infection: a prospective observational cohort study.

J Neurosurg Pediatr. 2018 04;21(4):346-358

Authors: Simon TD, Kronman MP, Whitlock KB, Gove NE, Mayer-Hamblett N, Browd SR, Cochrane DD, Holubkov R, Kulkarni AV, Langley M, Limbrick DD, Luerssen TG, Oakes WJ, Riva-Cambrin J, Rozzelle C, Shannon C, Tamber M, Wellons JC, Whitehead WE, Kestle JRW

Abstract
OBJECTIVE CSF shunt infection requires both surgical and antibiotic treatment. Surgical treatment includes either total shunt removal with external ventricular drain (EVD) placement followed by new shunt insertion, or distal shunt externalization followed by new shunt insertion once the CSF is sterile. Antibiotic treatment includes the administration of intravenous antibiotics. The Hydrocephalus Clinical Research Network (HCRN) registry provides a unique opportunity to understand reinfection following treatment for CSF shunt infection. This study examines the association of surgical and antibiotic decisions in the treatment of first CSF shunt infection with reinfection. METHODS A prospective cohort study of children undergoing treatment for first CSF infection at 7 HCRN hospitals from April 2008 to December 2012 was performed. The HCRN consensus definition was used to define CSF shunt infection and reinfection. The key surgical predictor variable was surgical approach to treatment for CSF shunt infection, and the key antibiotic treatment predictor variable was intravenous antibiotic selection and duration. Cox proportional hazards models were constructed to address the time-varying nature of the characteristics associated with shunt surgeries. RESULTS Of 233 children in the HCRN registry with an initial CSF shunt infection during the study period, 38 patients (16%) developed reinfection over a median time of 44 days (interquartile range [IQR] 19-437). The majority of initial CSF shunt infections were treated with total shunt removal and EVD placement (175 patients; 75%). The median time between infection surgeries was 15 days (IQR 10-22). For the subset of 172 infections diagnosed by CSF culture, the mean ± SD duration of antibiotic treatment was 18.7 ± 12.8 days. In all Cox proportional hazards models, neither surgical approach to infection treatment nor overall intravenous antibiotic duration was independently associated with reinfection. The only treatment decision independently associated with decreased infection risk was the use of rifampin. While this finding did not achieve statistical significance, in all 5 Cox proportional hazards models both surgical approach (other than total shunt removal at initial CSF shunt infection) and nonventriculoperitoneal shunt location were consistently associated with a higher hazard of reinfection, while the use of ultrasound was consistently associated with a lower hazard of reinfection. CONCLUSIONS Neither surgical approach to treatment nor antibiotic duration was associated with reinfection risk. While these findings did not achieve statistical significance, surgical approach other than total removal at initial CSF shunt infection was consistently associated with a higher hazard of reinfection in this study and suggests the feasibility of controlling and standardizing the surgical approach (shunt removal with EVD placement). Considerably more variation and equipoise exists in the duration and selection of intravenous antibiotic treatment. Further consideration should be given to the use of rifampin in the treatment of CSF shunt infection. High-quality studies of the optimal duration of antibiotic treatment are critical to the creation of evidence-based guidelines for CSF shunt infection treatment.

PMID: 29393813 [PubMed - indexed for MEDLINE]

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.

Am J Hum Genet. 2019 04 04;104(4):665-684

Authors: Ferreira MAR, Mathur R, Vonk JM, Szwajda A, Brumpton B, Granell R, Brew BK, Ullemar V, Lu Y, Jiang Y, 23andMe Research Team, eQTLGen Consortium, BIOS Consortium, Magnusson PKE, Karlsson R, Hinds DA, Paternoster L, Koppelman GH, Almqvist C

Abstract
The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.

PMID: 30929738 [PubMed - indexed for MEDLINE]

Frontotemporal Dermal Sinus Tract with 2 Connected Intradiploic Dermoid Cysts: A Rare Case and Review of the Literature.

World Neurosurg. 2019 Jul;127:350-353

Authors: Barkley AS, Susarla SM, Lee A

Abstract
BACKGROUND: Frontotemporal dermal sinus tracts with associated dermoid cysts are very rare, with only 1 found in the largest series to date and 10 total documented case reports.
CASE DESCRIPTION: We present the first case to our knowledge of a dermal sinus tract associated with 2 intradiploic dermoid cysts in the rare location of the pterion and sphenosquamosal suture. The patient was a 15-month-old girl presenting with periorbital cellulitis who was found to have 2 connected intradiploic cysts on radiographic imaging. The mass was excised, and pathology was consistent with a ruptured dermoid cyst.
CONCLUSIONS: We review of the literature and argue for early identification and prophylactic surgical resection to avoid complications associated with infection and to mitigate risk of subtotal resection.

PMID: 30930322 [PubMed - indexed for MEDLINE]

Enhanced perioperative care and decreased cost and length of stay after elective major spinal surgery.

Neurosurg Focus. 2019 04 01;46(4):E5

Authors: Carr DA, Saigal R, Zhang F, Bransford RJ, Bellabarba C, Dagal A

Abstract
OBJECTIVEThe purpose of this study was to compare total cost and length of stay (LOS) between spine surgery patients enrolled in an enhanced perioperative care (EPOC) pathway and patients receiving traditional perioperative care (TRDC).METHODSAll spine surgery candidates were screened for inclusion in the EPOC pathway. This cohort was compared to a retrospective cohort of patients who received TRDC and a concurrent group of patients who met inclusion criteria but did not receive the EPOC (no pathway care [NOPC] group). Direct and indirect costs as well as hospital and intensive care LOSs were analyzed between the 3 groups.RESULTSTotal costs after pathway implementation decreased by $19,344 in EPOC patients compared to a historical cohort of patients who received TRDC and $5889 in a concurrent cohort of patients who did not receive EPOC (NOPC group). Hospital and intensive care LOS were significantly lower in EPOC patients compared to TRDC and NOPC patients.CONCLUSIONSThe implementation of a multimodal EPOC pathway decreased LOS and cost in major elective spine surgeries.

PMID: 30933922 [PubMed - indexed for MEDLINE]

A spatially dynamic network underlies the generation of inspiratory behaviors.

Proc Natl Acad Sci U S A. 2019 04 09;116(15):7493-7502

Authors: Baertsch NA, Severs LJ, Anderson TM, Ramirez JM

Abstract
The ability of neuronal networks to reconfigure is a key property underlying behavioral flexibility. Networks with recurrent topology are particularly prone to reconfiguration through changes in synaptic and intrinsic properties. Here, we explore spatial reconfiguration in the reticular networks of the medulla that generate breathing. Combined results from in vitro and in vivo approaches demonstrate that the network architecture underlying generation of the inspiratory phase of breathing is not static but can be spatially redistributed by shifts in the balance of excitatory and inhibitory network influences. These shifts in excitation/inhibition allow the size of the active network to expand and contract along a rostrocaudal medullary column during behavioral or metabolic challenges to breathing, such as changes in sensory feedback, sighing, and gasping. We postulate that the ability of this rhythm-generating network to spatially reconfigure contributes to the remarkable robustness and flexibility of breathing.

PMID: 30918122 [PubMed - indexed for MEDLINE]

Targeted copy number analysis outperforms histologic grading in predicting patient survival for WHO grades II/III IDH-mutant astrocytomas.

Neuro Oncol. 2019 06 10;21(6):819-821

Authors: Cimino PJ, Holland EC

PMID: 30918961 [PubMed - indexed for MEDLINE]

Effects of intrastriatal dopamine D1 or D2 antagonists on methamphetamine-induced egocentric and allocentric learning and memory deficits in Sprague-Dawley rats.

Psychopharmacology (Berl). 2019 Jul;236(7):2243-2258

Authors: Gutierrez A, Regan SL, Hoover CS, Williams MT, Vorhees CV

Abstract
RATIONALE: Methamphetamine (MA) is an abused psychostimulant that causes cognitive deficits after chronic use. Neostriatal dopamine receptors play a role in MA monoamine neurotoxicity. Blocking dopamine receptors prior to MA exposure in adult rats attenuates monoamine reductions and reactive gliosis.
OBJECTIVES: We tested whether blocking dopamine receptors protects against cognitive deficits.
METHODS: First, we determined the effects of MA alone versus MA in combination with the dopamine receptor D1 antagonist SCH-23390 or the dopamine receptor D2 antagonist sulpiride on cFos expression and monoamines at the age when rats in the cognitive experiment were to begin testing and monoamines in rats after cognitive testing.
RESULTS: SCH-23390 infused into the neostriatum prior to systemic administration of MA attenuated MA-induced cFos activation while sulpiride induced cFos activation. Two weeks after MA, rats had dopamine and serotonin reductions that were attenuated by each antagonist. Other rats treated the same way, were tested for egocentric learning and memory in the Cincinnati water maze, for navigational strategy in a star water maze, and spatial learning and memory in a Morris water maze. Pre-treatment with SCH-23390 or sulpiride attenuated the effects of MA on egocentric and spatial learning and memory. MA-treated rats showed a shift from an egocentric to a disorganized strategy in the star maze that was less disorganized in groups receiving MA and an antagonist. Post-behavior monoamine reductions remained but were attenuated by the antagonists but not identically to what was seen in rats not behaviorally tested.
CONCLUSIONS: The results show for the first time that dopamine receptors are mediators of MA-induced cognitive deficits.

PMID: 30919007 [PubMed - indexed for MEDLINE]

High level of capture of coronary intervention and associated acute coronary syndromes in the all New Zealand acute coronary syndrome quality improvement cardiac registry and excellent agreement with national administrative datasets (ANZACS-QI 25).

N Z Med J. 2019 03 29;132(1492):19-29

Authors: Kerr AJ, Lee M, Jiang Y, Grey C, Wells S, Williams M, Jackson R, Poppe K

Abstract
BACKGROUND: The All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry was designed to collect data on all coronary angiograms and percutaneous coronary interventions (PCI) in New Zealand, and all acute coronary syndromes (ACS) associated with these procedures. This study compares the completeness of capture in ANZACS-QI of coronary procedures and ACS admissions with those recorded in the National Hospitalisation Dataset and evaluates data quality by assessing agreement in ACS diagnoses and coronary procedures between datasets.
METHODS: The national dataset, which included all New Zealand public hospital admissions in 2015 (n=962,700 episodes), was anonymously linked with the ANZACS-QI CathPCI (n=14,649 coronary angiogram episodes) and ACS cohorts (n=8,141 episodes) for 2015. Total numbers of coronary angiogram, PCI and ACS admissions were used as denominators and calculated by combining unique episodes from both data sources.
RESULTS: Of all coronary angiogram episodes (n=15,377) and all PCI episodes (n=5,711), 92% were captured in both datasets, 5% in the national dataset only and 3% in ANZACS-QI only. Overall, 95% of coronary angiogram and PCI episodes were captured in ANZACS-QI. Of ACS episodes with associated coronary angiography (n=8,237), 85% were captured. Overall, 54% of all ACS episodes (n=15,167) were captured, including 71% in <70-year-olds. Seventy-five percent of all ST-elevation myocardial infarctions (STEMI) were captured. Ninety percent of ACS diagnoses in ANZACS-QI had a matching diagnosis in the national dataset. There was excellent agreement in recorded gender, date of birth and ethnicity (>99%). Sub-type of ACS was also highly concordant for STEMI and non-STEMI diagnoses (92% and 89% agreement, respectively).
CONCLUSIONS: Consistent with its aim, the ANZACS-QI registry captured almost all New Zealand public hospital coronary angiography and PCI procedures including those associated with an ACS diagnosis. The high level of agreement between the registry and national dataset supports the use of both datasets for ongoing quality improvement reporting and research.

PMID: 30921308 [PubMed - indexed for MEDLINE]

Malaria Parasite Density in Individuals with Different Rapid Diagnostic Test Results and Concentrations of HRP2 Antigen.

Am J Trop Med Hyg. 2019 05;100(5):1202-1203

Authors: Plucinski MM, Dimbu PR, Fortes F, Murphy SC, Smith NT, Cruz KR, Seilie AM, Halsey ES, Aidoo M, Rogier E

Abstract
Low-density malaria infections are a source of human morbidity in endemic settings and potentially contribute to ongoing malaria transmission. Conventional rapid diagnostic tests (RDTs) were designed to detect clinically relevant parasite and antigen levels, but it is largely unknown what proportion of parasite (and antigen positive) infections are missed by conventional RDTs. Furthermore, RDTs can also provide false positives from lingering histidine-rich protein 2 (HRP2) antigenemia from a past infection. We analyzed 207 samples from Angolan outpatients with a bead-based HRP2 antigen assay and by qRT-PCR for the presence of parasite nucleic acids. Among patients HRP2 positive but negative by conventional RDT, the rate of quantitative reverse transcription-PCR (qRT-PCR) positivity was 45% (95% CI: 35-56%), with a median parasitemia of 3.4 parasites/µL (interquartile range: 0.14-4.8). Only 15% (7-26%) of HRP2-negative samples were found to have parasite nucleic acids. A substantial proportion of persons with blood HRP2 antigen concentrations not detected by the conventional RDT were found to have evidence of active infection, but at low parasite density levels.

PMID: 30915959 [PubMed - indexed for MEDLINE]

Divergent 6-Month Functional Recovery Trajectories and Predictors after Traumatic Brain Injury: Novel Insights from the COBRIT Study.

J Neurotrauma. 2019 Mar 26;:

Authors: Gardner RC, Cheng J, Ferguson AR, Boylan R, Boscardin WJ, Zafonte RD, Manley GT, Bagiella E, Ansel BM, Novack TA, Friedewald WT, Hesdorffer DC, Timmons S, Jallo J, Eisenberg H, Hart T, Ricker JH, Diaz-Arrastia R, Merchant R, Temkin NR, Melton S, Dikmen S, Okonkwo DO

Abstract
Cross-sectional approaches to outcome assessment may not adequately capture heterogeneity in recovery after traumatic brain injury (TBI). Using latent class mixed models (LCMM), a data-driven analytic that identifies groups of patients with similar trajectories, we identified distinct 6-month functional recovery trajectories in a large cohort (n=1,046) of adults age 18-70 years with complicated mild to severe TBI who participated in the Citicoline Brain Injury Treatment Trial (COBRIT). We used multinomial logistic fixed effect models and backward elimination, forward selection, and forward stepwise selection with several stopping rules to explore baseline predictors of functional recovery trajectory. Based on statistical and clinical considerations, the 7-class model was deemed superior. Visualization of these 7 functional recovery trajectories revealed that each trajectory class started at one of 3 recovery levels at 1-month, which, for ease of reference we labeled groups A-C: Group A. good recovery (2 classes; A1 and A2), Group B. moderate disability (2 classes; B1 and B2), Group C. severe disability (3 classes; C1, C2, and C3). By 6-months, these 3 groups experienced dramatically divergent trajectories: A experienced stable good recovery (A1, n=115) or dramatic decline (A2, n=4); B, rapid complete recovery (B1, n=71) or gradual recovery (B2, n=742); C, dramatic rapid recovery (C1, n=12), no recovery (C2, n=91), or death (C3, n=11). Trajectory class membership was not predicted by citicoline treatment (p=0.57). The models identified demographic, pre-injury, and injury-related predictors of functional recovery trajectory, including: age, race, education, pre-injury employment, pre-injury diabetes, pre-injury psychiatric disorder, site, Glasgow Coma Scale (GCS), post-traumatic amnesia, TBI mechanism, major extracranial injury, hemoglobin, and acute CT findings. GCS was the most consistently selected predictor across all models. All models also selected at least one demographic or pre-injury medical predictor. LCMM successfully identified dramatically divergent, clinically meaningful 6-month recovery trajectories with utility to inform clinical trial design.

PMID: 30909795 [PubMed - as supplied by publisher]

Brief and cost-effective tool for assessing verbal learning in multiple sclerosis: Comparison of the Rey Auditory Verbal Learning Test (RAVLT) to the California Verbal Learning Test - II (CVLT-II).

J Neurol Sci. 2019 May 15;400:104-109

Authors: Beier M, Hughes AJ, Williams MW, Gromisch ES

Abstract
BACKGROUND: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) is a common cognitive screening tool. However, administration and scoring can be time-consuming, and its use of proprietary subtests like the California Verbal Learning Test - II (CVLT-II) is financially limiting. Use of the non-proprietary Rey Auditory Verbal Learning Test (RAVLT) may be provide a valid alternative.
OBJECTIVES: To compare the RAVLT and CVLT-II in terms of diagnostic accuracy for detecting cognitive impairment, and to determine optimal cut-scores for the RAVLT.
METHODS: 100 participants with MS completed the five learning trials from the RAVLT and CVLT-II. Receiver operating characteristic analyses were used to compare the measures' sensitivities, specificities, positive predictive values (PPV) and negative predictive values (NPV), and to identify optimal cut-scores.
RESULTS: Using a criterion of 1.5 SD below the normative sample mean, the RAVLT showed fair to good (κs = 0.21-0.41) agreement with the CVLT-II. A cut-score of 12 on Trials 1 + 2 of the RAVLT showed fair sensitivity (75%) and specificity (76%) and did not differ significantly from the CVLT-II (p > .05).
CONCLUSIONS: Performance on initial learning trials of the RAVLT may provide a brief, valid, and cost-effective alternative to the CVLT-II for screening verbal learning impairments in MS.

PMID: 30913522 [PubMed - indexed for MEDLINE]

Evidence that Human Skin Microbiome Dysbiosis Promotes Atopic Dermatitis.

J Invest Dermatol. 2017 12;137(12):2460-2461

Authors: Williams MR, Gallo RL

Abstract
Patients with atopic dermatitis are frequently colonized by Staphylococcus aureus. If S. aureus is present, then the subject tends to have more severe disease. However, it is unclear if S. aureus is a cause of atopic dermatitis or a consequence of the abnormal epithelial environment. In this issue of the Journal of Investigative Dermatology, Meylan et al. present evidence from a prospective clinical trial that shows that S. aureus colonization precedes onset of atopic dermatitis in children. These observations suggest that S. aureus may cause atopic dermatitis in some individuals.

PMID: 29169458 [PubMed - indexed for MEDLINE]

Pilocytic astrocytoma with leptomeningeal spread in a patient with incontinentia pigmenti presenting with unilateral nystagmus.

Pediatr Blood Cancer. 2018 03;65(3):

Authors: Bayart CB, Ishak GE, Finn LS, Lee A, Baran F, Sun A, Gupta D, Vitanza NA

Abstract
Incontinentia pigmenti (IP) is a genetic disorder caused by mutations in IKBKG, leading to functional loss of nuclear factor kappa B (NF-ĸB). We report the case of a 6-month-old female child with IP who presented with unilateral nystagmus and was found to have a pilocytic astrocytoma with leptomeningeal spread. Enhanced understanding of the relationship between NF-ĸB, along with its upstream regulators, and tumorigenesis may shed light on whether a subset of patients with IP may be at increased risk for neoplasia.

PMID: 29171168 [PubMed - indexed for MEDLINE]

Diagnosing the GOSE: Structural and Psychometric Properties Using Item Response Theory, a TRACK-TBI Pilot Study.

J Neurotrauma. 2019 09 01;36(17):2493-2505

Authors: Ranson J, Magnus BE, Temkin N, Dikmen S, Giacino JT, Okonkwo DO, Valadka AB, Manley GT, Nelson LD, TRACK-TBI Investigators

Abstract
The Glasgow Outcome Scale-Extended (GOSE) was designed to assess global outcome after traumatic brain injury (TBI). Since its introduction, several empirically founded criticisms of the GOSE have been raised, including poor reliability; an insensitivity to small, but potentially meaningful, changes; a tendency to produce ceiling effects; inconsistent associations with neurocognitive, psychological, and quality-of-life measures; and an inability to assess the multi-dimensional nature of TBI outcome. The current project took a diagnostic approach to identifying the underlying causes of reported limitations by exploring the internal construct validity of the GOSE at 3 and 6 months post-injury using item response theory (IRT) techniques. Data were from the TRACK-TBI Pilot Study, a large (N = 586), prospective, multi-site project that included TBI cases of all injury severity levels. To assess the level of latent functional "impairment" captured by GOSE items independent of the assigned outcome category or GOSE total score, items were modified so that higher scores reflected greater impairment. Results showed that although the GOSE's items capture varying levels of impairment across a broad disability spectrum at 3 and 6 months, there was also evidence at each time point of item redundancy (multiple items capturing similar levels of impairment), item deficiency (lack of items capturing lower levels of impairment), and item inefficiency (items only capturing minimal impairment information). The findings illustrate the value of IRT to illuminate strengths and weaknesses of clinical outcome assessment measures and provide a framework for future measure refinement.

PMID: 30907261 [PubMed - indexed for MEDLINE]

Modeling breathing rhythms.

Elife. 2019 03 25;8:

Authors: Ramirez JM, Baertsch NA

Abstract
Computational models are helping researchers to understand how certain properties of neurons contribute to respiratory rhythms.

PMID: 30907725 [PubMed - indexed for MEDLINE]

Intense Focused Ultrasound Preferentially Stimulates Transected Nerves Within Residual Limbs: Pilot Study.

Pain Med. 2018 03 01;19(3):541-549

Authors: Mourad PD, Friedly JL, McClintic AM, Olmstead TA, Loeser JD

Abstract
Objective: Identifying pain generators in tissue deep in the skin can require uncomfortable, complicated, and invasive tests. We describe pilot studies testing the hypothesis that ultrasound image-guided, intense focused ultrasound (ig-iFU) can noninvasively and differentially stimulate the end of transected nerves in the residual limbs of amputee patients.
Design: We applied iFU to the transected nerve ending as individual pulses with a length of 0.1 seconds using a carrier frequency of 2.0 MHz. After targeting, we gradually increased the iFU intensity to reach consistent patient-reported stimulation of the transected nerve ending. We also stimulated the proximal nerve, tissue near the nerve ending, and the intact contralateral nerve. We described the resulting sensations and correlated the results of the study participant's pre-iFU study responses to phantom and residual limb pain questionnaires.
Results: iFU spatial and temporal average intensity values between 16 W/cm2 and 433 W/cm2 that were applied to the transected nerve ending and proximal nerve elicited sensations, including phantom limb sensations, while the same intensity applied to control tissue centimeters away from the nerve ending, or to the intact nerve on the contralateral limb, did not. Two out of 11 study participants reported only mild and transient pain created by iFU stimulation. Successful iFU intensity values correlated with neither phantom nor residual limb pain scores.
Conclusions: Transected nerves had greater sensitivity to iFU stimulation than ipsilateral and contralateral control tissue, including intact nerve. These results support the view that ig-iFU may one day help physicians identify deep, tender tissue in patients who report experiencing pain.

PMID: 29025106 [PubMed - indexed for MEDLINE]

All-Cause Mortality Following an Acute Coronary Syndrome: 12-Year Follow-Up of the Comprehensive 2002 New Zealand Acute Coronary Syndrome Audit.

Heart Lung Circ. 2019 Feb;28(2):245-256

Authors: Ellis CJ, Gamble GD, Williams MJA, Matsis P, Elliott JM, Devlin G, Mann S, French JK, White HD, Regional Cardiac Society NZ ACS Audit Group

Abstract
BACKGROUND: To describe the long-term mortality of a complete national cohort of acute coronary syndrome (ACS) patients enrolled in 2002, to compare this with a national age, sex and Māori ethnicity matched population, and to assess the influence of baseline factors on the 12-year mortality.
METHODS: We reviewed 721 patients with a discharge diagnosis of an ACS who were enrolled in the first New Zealand ACS audit group cohort over 14days in May 2002. We matched the cohort to the national mortality database using each patient's unique national identity number.
RESULTS: Over a median follow-up of 12.7 years of 721 patients discharged with an ACS, overall mortality was 52%: ST-elevation myocardial infarction (STEMI) (58%), non-ST-elevation myocardial infarction (NSTEMI) (61%) and unstable angina pectoris (UAP) (42%) patients, p<0.0001. In an age-adjusted survival model, males had a 29% increased mortality rate compared to females with a hazard ratio of 1.29 (95% CI 1.04, 1.61, p=0.019). Over 12 years there were 339 (47%) deaths, compared to 284 (39%) deaths observed in the matched population. The standardised mortality ratio for patients admitted with an ACS in New Zealand is 1.3 (95% CI 1.2, 1.5) with eight patients per 100 not surviving to 12 years compared to this matched population.
CONCLUSIONS: The high mortality rate in this ACS cohort is a stark reminder of the prognostic implications of a presentation with an ACS. It emphasises the on-going need for optimal management of these patients throughout every stage of their initial treatment and subsequent on-going care.

PMID: 29150157 [PubMed - indexed for MEDLINE]

Isoalantolactone induces apoptosis through ROS-mediated ER stress and inhibition of STAT3 in prostate cancer cells.

J Exp Clin Cancer Res. 2018 Dec 12;37(1):309

Authors: Chen W, Li P, Liu Y, Yang Y, Ye X, Zhang F, Huang H

Abstract
BACKGROUND: Prostate cancer is one of the most commonly diagnosed cancers in men worldwide. Currently available therapies for metastatic prostate cancer are only marginally effective. Therefore, new therapeutic agents are urgently needed to improve patient outcome. Isoalantolactone (IATL), an active sesquiterpene naturally present in many vegetables and medicinal plants, is known to induce cell death and apoptosis in various cancer cell lines. Nevertheless, antitumor mechanisms initiated by IATL in cancer cells have not been fully defined.
METHODS: Cell apoptosis and cellular ROS levels were analyzed by flow cytometry. Western blot and qRT-PCR were used to analyze the protein and mRNA levels of indicated molecules, respectively. Nude mice xenograft model was used to test the effects of IATL on prostate cancer cell growth in vivo.
RESULTS: In this study, we found that IATL dose-dependently inhibited cancer cell growth and induced apoptosis in PC-3 and DU145 cells. Mechanistically, our data found that IATL induced reactive oxygen species (ROS) production, resulting in the activation of endoplasmic reticulum stress pathway and eventually cell apoptosis in prostate cancer cells. IATL also decreased the protein expression levels of p-STAT3 and STAT3, and the effects of IATL were reversed by pretreatment with N-acetyl-L-cysteine (NAC). In vivo, we found that IATL inhibited the growth of prostate cancer xenografts without exhibiting toxicity. Treatment of mice bearing human prostate cancer xenografts with IATL was also associated with induction of ER stress and inhibtion of STAT3.
CONCLUSION: In summary, our results unveil a previously unrecognized mechanism underlying the biological activity of IATL, and provide a novel anti-cancer candidate for the treatment of prostate cancer.

PMID: 30541589 [PubMed - indexed for MEDLINE]