Phenylephrine and ephedrine affect frontal lobe oxygenation ( ScO2) differently when assessed by spatially resolved near infrared spectroscopy. We evaluated the effect of phenylephrine and ephedrine ...on extra- vs intra-cerebral blood flow and on ScO2.
In 10 healthy males (age 20–54 yr), phenylephrine or ephedrine was infused for an ∼20 mm Hg increase in mean arterial pressure. Cerebral oxygenation (SavO2) was calculated from the arterial and jugular bulb oxygen saturations. Blood flow in the internal carotid artery (ICAf) and blood flow in the external carotid artery (ECAf) were assessed by duplex ultrasonography. Invos-5100c (SinvosO2) and Foresight (SforeO2) determined ScO2 while forehead skin oxygenation (SskinO2) was assessed.
Phenylephrine reduced SforeO2 by 6.9% (95% confidence interval: 4.8–9.0%; P<0.0001), SinvosO2 by 10.5 (8.2–12.9%; P<0.0001), and ECAf (6–28%; P=0.0001), but increased ICAf (5–21%; P=0.003) albeit with no consequence for SskinO2 or SavO2. In contrast, SforeO2 was maintained with administration of ephedrine while SinvosO2 and SavO2 decreased by 3.1 (0.7–4.5%; P=0.017) and 2.1 (0.5–3.3%; P=0.012) as arterial carbon dioxide pressure decreased (P=0.003). ICAf was stable and ECAf increased by 11 (4–18%; P=0.005) with administration of ephedrine while SskinO2 did not change.
The effect of phenylephrine on ScO2 is governed by a decrease in external carotid blood flow since it increases cerebral blood flow as determined by flow in the internal carotid artery. In contrast, ScO2 is largely maintained with administration of ephedrine because blood flow to extracerebral tissue increases.
Published by the American Physical Society. The C12(α,γ)O16 reaction plays a central role in astrophysics, but its cross section at energies relevant for astrophysical applications is only poorly ...constrained by laboratory data. The reduced α width, γ11, of the bound 1- level in O16 is particularly important to determine the cross section. The magnitude of γ11 is determined via sub-Coulomb α-transfer reactions or the β-delayed α decay of N16, but the latter approach is presently hampered by the lack of sufficiently precise data on the β-decay branching ratios. Here we report improved branching ratios for the bound 1- level bβ,11=(5.02±0.10)×10-2 and for β-delayed α emission bβα=(1.59±0.06)×10-5. Our value for bβα is 33% larger than previously held, leading to a substantial increase in γ11. Our revised value for γ11 is in good agreement with the value obtained in α-transfer studies and the weighted average of the two gives a robust and precise determination of γ11, which provides significantly improved constraints on the C12(α,γ) cross section in the energy range relevant to hydrostatic He burning.
Patients are not able to call for help during a generalized tonic-clonic epileptic seizure. Our objective was to develop a robust generic algorithm for automatic detection of tonic-clonic seizures, ...based on surface electromyography (sEMG) signals suitable for a portable device. Twenty-two seizures were analyzed from 11 consecutive patients. Our method is based on a high-pass filtering with a cutoff at 150 Hz, and monitoring a count of zero crossings with a hysteresis of ±50 μV . Based on data from one sEMG electrode (on the deltoid muscle), we achieved a sensitivity of 100% with a mean detection latency of 13.7 s, while the rate of false detection was limited to 1 false alarm per 24 h. The overall performance of the presented generic algorithm is adequate for clinical implementation.
Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we ...report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
Objective: An immune activation response resembling virus or type I interferon responses has been observed in untreated multiple sclerosis (MS), but its pathogenic significance is uncertain. We ...studied the relationship between a type I interferon‐like response in untreated patients with MS and disease activity.
Methods: Gene expression was analyzed by real‐time reverse transcriptase polymerase chain reaction (PCR) in whole blood samples and by microarray analysis of mononuclear cells from untreated patients with MS, patients with MS treated with IFN‐β, and patients with MS with anti‐IFN‐β neutralizing antibodies (NAb). Disease activity was assessed by gadolinium‐enhanced magnetic resonance imaging.
Results: Eight of 36 untreated patients with MS had spontaneously increased expression of the type I IFN‐induced gene MX1. Microarray gene expression analysis demonstrated that patients with increased spontaneous MX1 expression also had increased expression of other genes induced by regular IFN‐β treatment of MS. MX1 expression correlated with FOXP3 and IL10 expression, and IL10 expression correlated negatively with disease activity on magnetic resonance imaging. Further, in vivo IL10 expression was lower in NAb‐positive patients than in untreated patients with MS and healthy controls. Finally, ex vivo treatment of mononuclear blood cells with IFN‐β induced the expression of IL10, and this was blocked by the addition of serum from NAb‐positive patients with MS.
Conclusion: Our findings suggest that endogenous IFN‐β may induce the expression of immunoregulatory IL10 in MS and that this might be associated with dampening of inflammatory disease activity.
We have analyzed the chromosome 6q21 breakpoint of a non-constitutional t(6;15)(q21;q21) rearrangement in sporadic Wilms' tumor. This identified a novel gene encoding a protein with six N-terminal ...ankyrin repeats linked to a C-terminal HECT ubiquitin-protein ligase domain. We therefore designated this gene HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1). HACE1 is widely expressed in human tissues, including mature and fetal kidney. We show that Hace1 protein possesses intrinsic ubiquitin ligase activity, utilizes UbcH7 as a candidate partner E2 enzyme and localizes predominantly to the endoplasmic reticulum. Although the HACE1 locus was not directly interrupted by the translocation in the index Wilms' case, its expression was markedly lower in tumor tissue compared with adjacent normal kidney. Moreover, HACE1 expression was virtually undetectable in the SK-NEP-1 Wilms' tumor cell line and in four of five additional primary Wilms' tumor cases compared with patient-matched normal kidney. We found no evidence of HACE1 mutations or deletions, but hypermethylation of two upstream CpG islands correlates with low HACE1 expression in tumor samples. Our findings implicate Hace1 as a novel ubiquitin-protein ligase and demonstrate that its expression is very low in primary Wilms' tumors.
Congenital mesoblastic nephroma (CMN) is an infantile spindle cell tumor of the kidney that is subdivided into "classical" and "cellular" forms based on the degree of cellularity and mitotic ...activity. The histogenesis of CMN remains obscure, but relationships to other pediatric renal neoplasms have been proposed. However, cellular CMN is virtually identical histologically to congenital fibrosarcoma (CFS), a malignant tumor of fibroblasts in children of the same age group. Moreover, cytogenetic studies have reported common trisomies in CFS and cellular CMN, particularly of chromosome 11. We show here that t(12;15)(p13;q25)-associated ETV6-NTRK3 gene fusions described in CFS are also present in cellular CMN. ETV6-NTRK3 chimeric transcripts were detected in 8 of 9 cellular CMNs and 2 of 2 mixed CMNs. In contrast, all of the four classical CMNs tested were negative, as were cases of Wilms' tumor and clear cell sarcoma of the kidney. Moreover, we found trisomy 11 only in cellular or mixed CMNs with the ETV6-NTRK3 gene fusion. Our studies indicate that classical and cellular CMN have different genetic features and support the concept that cellular CMN is histogenetically related to CFS. They also provide insight into potential mechanisms involved in the transformation of the classical into the cellular form of CMN.
Abstract
Introduction:
Sleep-disordered breathing (SDB) is associated with sleepiness, high blood pressure, and cardiovascular events. Cardiovascular associations have been linked to oxygen ...desaturation. Less is known regarding SDB associations with sleepiness. Different physiologic associations (e.g. arousal vs desaturation) of SDB events may result in different pathobiologic outcomes.
Methods:
2,112 nocturnal polysomnograms (PSGs) from 1,022 subjects in the Wisconsin Sleep Cohort were analyzed with our automated algorithm, which was developed to detect breathing disturbances (decrease of 30% in nasal airflow for at least 10 seconds, without a concomitant increase in oral flow) and desaturations. Breathing disturbance events were time-locked to desaturations, resulting in 2 indices: desaturating (H-BDI) and non-desaturating (NH-BDI) events. Systolic and/or diastolic hypertension was used as a measure of cardiovascular health. Measures of subjective (Epworth Sleepiness Scale) and objective (2,981 MSLTs from a subset of 865 subjects) sleepiness were analyzed. Additional, clinically relevant variables were accounted for in modeling associations.
Results:
H-BDI, but not NH-BDI, correlated strongly with SDB severity indices that included hypoxia (r≥0.89, p≤0.001 with ODI 3% and AHI with 4%-desaturations). Each twofold increase in desaturation-associated events was associated with an increased risk of hypertension (3% ODI OR=1.06, 95% CI=1.00–1.12, p<0.05) and daytime sleepiness (β=0.20 ESS score, p<0.0001; β=-0.20 min in MSL on MSLT, p<0.01). Non-desaturating events were more strongly associated with objective sleepiness (β=-0.52 min in MSL on MSLT, p<0.001), but had less association with subjective sleepiness (β=0.12 ESS score, p=0.10). In longitudinal analyses, severity of baseline non-desaturating events was independently associated with worsening of 3% ODI over a 4-year follow up.
Conclusion:
In SDB, non-desaturating events are independently associated with objective daytime sleepiness, beyond the effect of desaturating events. The independent association of baseline non-desaturating breathing disturbances with a future worsening of desaturating suggests that non-desaturating events reflect a milder form of SDB.
Support (If Any):
Grants/gifts to the Stanford Sleep Center, Lundbeck Foundation, Technical University of Denmark, and Danish Center for Sleep Medicine. Dr. Schneider is supported by T32 HL110952. Drs. Peppard and Hagen, and Ms. Finn were supported by R01 HL062252 and UL1 RR025011.
The use of cannabis as medical therapy to treat chronic pain and spasticity in patients with multiple sclerosis (MS) is increasing. However, the evidence on safety when initiating treatment with ...medical cannabis oils is limited. The aim of this study was to investigate the safety of sublingual medical cannabis oils in patients with MS.
In this prospective observational safety study 28 patients with MS were treated with medical cannabis oils (THC-rich, CBD-rich and THC+CBD combined products) and were followed during a titration period of four weeks. Patients were evaluated at treatment start (Visit 1) and after four weeks treatment (Visit 2). At each visit neurological examination (Expanded Disability Status Scale - EDSS), ambulation (Timed 25-Foot Walk Test - T25FWT), routine blood tests, plasma cannabinoids, dexterity (9-Hole Peg Test - 9-HPT) and processing speed (Symbol Digit Modalities Test - SDMT) were tested. Adverse events (AEs) and tolerability were reported at Visit 2. Secondary, efficacy of medical cannabis on pain, spasticity and sleep disturbances were measured by numeric rating scale (NRS-11) each day during the 4-week treatment period.
During treatment with cannabis preparations containing 10-25 mg/mL THC, the most common AEs were dry mouth, drowsiness, dizziness and nausea of mild to moderate degree. Two patients experienced pronounced symptoms with excessive dreaming and drowsiness, respectively, which led to treatment stop during the titration. Three serious adverse events (SAE) were reported but were not associated with the treatment. Mean doses of THC and CBD were 4.0 mg and 7.0 mg, respectively, and primarily administered as a once-daily evening dose. Furthermore, pain decreased from a median NRS score of 7 to 4, (p = 0.01), spasticity decreased from a median NRS score of 6 to 2.5 (p = 0.01) and sleep disturbances decreased from a median NRS score of 7 to 3 (p < 0.001). No impairment in disability, ambulation, dexterity or processing speed was observed.
Treatment with medical cannabis oils was safe and well tolerated, and resulted in a reduction in pain intensity, spasticity and sleep disturbances in MS patients. This suggests that medical cannabis oils can be used safely, especially at relatively low doses and with slow titration, as an alternative to treat MS-related symptoms when conventional therapy is inadequate.
Histological diagnosis of synovial sarcoma can be difficult. Genome-wide expression profiling has identified a number of genes expressed at higher levels in synovial sarcoma than in other soft tissue ...tumors, representing excellent candidates for diagnostic immunohistochemical markers. A tissue microarray comprising 77 sarcomas, including 46 synovial sarcomas, was constructed to validate identified markers and investigate their expression in tumors in the differential diagnosis of synovial sarcoma. Immunostaining was performed for two such markers, epidermal growth factor receptor and SAL (drosophila)-like 2 (SALL2), and for fifteen established markers used in the differential diagnosis of sarcomas. As predicted by expression profiling, epidermal growth factor receptor (a potential therapeutic target) and SALL2 stained most cases of synovial sarcoma; staining was significantly less common among other tested sarcomas. Hierarchical clustering analysis applied to immunostaining results for all 18 antibodies showed that synovial sarcomas, leiomyosarcomas, hemangiopericytomas, and solitary fibrous tumors cluster distinctly, and assigned one case with indeterminate histology as a Ewing sarcoma. Digital images from over 2500 immunostained cores analyzed in this study were captured and are made accessible through the accompanying website:
http://microarray-pubs.stanford.edu/tma_portal/synsarc.
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