Stenting versus endarterectomy for treatment of carotid-artery stenosis.
Carotid-artery stenting and carotid endarterectomy are both options for treating carotid-artery stenosis, an important cause of stroke. We randomly assigned patients with symptomatic or asymptomatic carotid stenosis to undergo carotid-artery stenting or carotid endarterectomy. The primary composite end point was stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization. For 2502 patients over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy group (7.2% and 6.8%, respectively; hazard ratio with stenting, 1.11; 95% confidence interval, 0.81 to 1.51; P=0.51). There was no differential treatment effect with regard to the primary end point according to symptomatic status (P=0.84) or sex (P=0.34). The 4-year rate of stroke or death was 6.4% with stenting and 4.7% with endarterectomy (hazard ratio, 1.50; P=0.03); the rates among symptomatic patients were 8.0% and 6.4% (hazard ratio, 1.37; P=0.14), and the rates among asymptomatic patients were 4.5% and 2.7% (hazard ratio, 1.86; P=0.07), respectively. Periprocedural rates of individual components of the end points differed between the stenting group and the endarterectomy group: for death (0.7% vs. 0.3%, P=0.18), for stroke (4.1% vs. 2.3%, P=0.01), and for myocardial infarction (1.1% vs. 2.3%, P=0.03). After this period, the incidences of ipsilateral stroke with stenting and with endarterectomy were similarly low (2.0% and 2.4%, respectively; P=0.85). Among patients with symptomatic or asymptomatic carotid stenosis, the risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly in the group undergoing carotid-artery stenting and the group undergoing carotid endarterectomy. During the periprocedural period, there was a higher risk of stroke with stenting and a higher risk of myocardial infarction with endarterectomy. (ClinicalTrials.gov number, NCT00004732.)


Positive correlation between estradiol and vascular endothelial growth factor but not fibroblast growth factor-2 in normal human breast tissue in vivo.
Angiogenesis is crucial in tumor development and progression. Ovarian hormones regulate angiogenesis in the reproductive tract but very little is known about its regulation in the normal breast. Sex steroids play an important role in breast cancer development by poorly understood mechanisms. Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) are potent stimulators of angiogenesis. Both VEGF and FGF-2 function in autocrine/paracrine pathways and there is a major contribution of bioactive proteins by a posttranslational activation of sequestered molecules in the extracellular space. A direct measurement of these molecules in the extracellular compartment is, therefore, needed. In this study, microdialysis was used to measure extracellular VEGF and FGF-2 in normal human breast tissue in situ in 11 premenopausal and 5 postmenopausal women. Significantly higher level of VEGF in breast tissue of premenopausal women was found. Plasma as well as local estradiol and breast tissue VEGF exhibited significant correlations, whereas progesterone had no correlation with breast VEGF. FGF-2 did not correlate with either estradiol or progesterone. The result suggests that estradiol is a more potent regulator of free VEGF levels than progesterone in the normal breast. The control of free FGF-2 seems to be independent of sex steroids in the breast. Estrogen induction of free extracellular VEGF may be one mechanism involved in sex steroid-dependent breast carcinogenesis.


The effect of melanin on the bystander effect in human keratinocytes.
The influence of melanin on radiation-induced bystander effects has been studied. Melanin is known to be a natural substance with proved radioprotective properties in different organisms and cell lines. It is non-toxic and is effective against acute and chronic irradiation. The lower the radiation dose, the higher the relative impact of melanin protection. In this study influence of melanin on human keratinocytes (HPV-G cells) has been studied using the colony-forming assay. We have shown that bystander donor medium from 0.5 Gy irradiated cells when transferred to unirradiated cells, caused almost the same effect as direct irradiation. Melanin increased the colony-forming ability of bystander recipient cells when it was added into culture medium before irradiation. The effect of melanin added after irradiation was to produce less protection in both the directly irradiated and bystander medium treated groups. The absorption spectrum of the filtered medium is identical to one of the intact culture medium showing that melanin was not present in filtered medium. Thus, it cannot protect recipient cells but reduces the amount of the bystander effect. It is concluded that melanin added before irradiation effectively decreased the radiation dose. The reduction of the impact of the bystander signal on recipient cells when melanin was added to the donor medium after harvest but before filtration, may mean that the bystander signal has a physical component as melanin can absorb all types of physical energy.


E×B Flux Driven Detachment Bifurcation in the DIII-D Tokamak.
A bifurcative step transition from low-density, high-temperature, attached divertor conditions to high-density, low-temperature, detached divertor conditions is experimentally observed in DIII-D tokamak plasmas as density is increased. The step transition is only observed in the high confinement mode and only when the B×∇B drift is directed towards the divertor. This work reports for the first time a theoretical explanation and numerical simulations that qualitatively reproduce this bifurcation and its dependence on the toroidal field direction. According to the model, the bifurcation is primarily driven by the interdependence of the E×B-drift fluxes, divertor electric potential structure, and divertor conditions. In the attached conditions, strong potential gradients in the low field side (LFS) divertor drive E×B-drift flux towards the high field side divertor, reinforcing low density, high temperature conditions in the LFS divertor leg. At the onset of detachment, reduction in the potential gradients in the LFS divertor leg reduce the E×B-drift flux as well, such that the divertor plasma evolves nonlinearly to high density, strongly detached conditions. Experimental estimates of the E×B-drift fluxes, based on divertor Thomson scattering measurements, and their dependence on the divertor conditions are qualitatively consistent with the numerical predictions. The implications for divertor power exhaust and detachment control in the next step fusion devices are discussed.


High-efficiency near-degenerate PPMgLN optical parametric oscillator with a volume Bragg grating.
We demonstrate a high-efficiency near-degenerate periodically poled MgO:LiNbO(3) (PPMgLN) optical parametric oscillator (OPO) using a volume Bragg grating (VBG) output coupler (OC) pumped by a multilongitudinal Q-switched Nd:YVO(4) laser at 20 kHz repetition rate. A total parametric power of 4.3 W with a conversion efficiency of 60% is achieved in a double-pass pump configuration. The output power improvement over the case of a single-pass pump is nearly 60%. Both the signal and the idler bandwidths are less than 40 GHz and are confined within 170 GHz bandwidth at 2128.8 nm. Such efficiency is, to our knowledge, the highest ever achieved from a degenerate OPO using a VBG OC.


Kinematic, kinetic, and blood lactate profiles of continuous and intraset rest loading schemes.
The purpose of this study was to investigate and compare the acute kinematic, kinetic, and blood lactate responses to continuous and intraset rest loading schemes that differed in terms of rest frequency but not total rest duration. Nine male subjects performed an isoinertial bench press task (6 repetition maximum load) with a continuous, an intraset rest equated by total rest time, volume, and load (ISRV), and an intraset rest equated by total rest time and load (ISRR) loading scheme. The scheme order was assigned in a block-randomized order with a minimum of 48 hours of recovery between testing sessions. Attached to the bar of the Smith machine was a linear position transducer that measured vertical displacement with an accuracy of 0.01 cm. Displacement data was sampled at 1,000 Hz and collected by a laptop computer running custom-built data acquisition software. Finger prick blood lactate samples were taken from the nondominant hand before exercise, immediately after exercise, and 5, 15 and 30 minutes after exercise. Blood glucose samples were taken before exercise only. It was observed that manipulating the rest period, by increasing the frequency but decreasing the length of each rest period, did not significantly influence the kinematics and kinetics associated with resistance training, but did have an effect on the postexercise blood lactate response when the load, rest duration, and training volume were equated (ISRV). This finding may be of practical significance if fatigue is important in strength development or conversely if power training requires minimal fatigue. It was also observed that increasing the frequency of the rest period enabled the subjects to perform a greater number of repetitions (ISRR), resulting in significantly greater kinematics, kinetics, and blood lactate accumulation.


Moyamoya disease: case report and literature review.
Moyamoya disease is a chronic, progressive occlusion of the circle of Willis arteries that leads to the development of characteristic collateral vessels seen on imaging, particularly cerebral angiography. The disease may develop in children and adults, but the clinical features differ. Moyamoya disease occurs predominantly in Japanese individuals but has been found in all races with varying age distributions and clinical manifestations. As a result, moyamoya disease has been underrecognized as a cause of ischemic and hemorrhagic strokes in Western countries. At this time, there is no known cure, and existing treatment options are controversial. The authors describe the case of a 44-year-old African American woman with a history of hypertension, cervical cancer, breast cancer, and stroke who was diagnosed as having moyamoya disease. A review of the literature for the various facets of this condition is also provided.


Selective killing of candidate AML stem cells by antibody targeting of IL1RAP.
IL1RAP, a co-receptor for interleukin (IL)-1 and IL-33 receptors, was previously found to be highly upregulated on candidate chronic myeloid leukemia stem cells, allowing for leukemia-selective killing using IL1RAP-targeting antibodies. We analyzed IL1RAP expression in a consecutive series of 29 patients with acute myeloid leukemia (AML) and, based on the level of expression in mononuclear cells (MNCs), we divided the samples into 3 groups: IL1RAP low (n = 6), IL1RAP intermediate (n = 11), and IL1RAP high (n = 12). Within the CD34+CD38- population, the intermediate and high groups expressed higher levels of IL1RAP than did corresponding normal cells. With the aim to target AML stem cells, an anti-IL1RAP monoclonal antibody was generated followed by isotype switching for improved antibody-dependent, cell-mediated cytotoxicity activity. Using this antibody, we achieved selective killing of AML MNC, CD34+CD38+, and CD34+CD38- cells. Our findings demonstrate that IL1RAP is a promising new therapeutic target in AML.


Evolution of the structure of ferredoxin based on living relics of primitive amino Acid sequences.
The structure of present-day ferredoxin, with its simple, inorganic active site and its functions basic to photon-energy utilization, suggests the incorporation of its prototype into metabolism very early during biochemical evolution, even before complex proteins and the complete modern genetic code existed. The information in the amino acid sequence of ferredoxin enables us to propose a detailed reconstruction of its evolutionary history. Ferredoxin has evolved by doubling a shorter protein, which may have contained only eight of the simplest amino acids. This shorter ancestor in turn developed from a repeating sequence of the amino acids alanine, aspartic acid or proline, serine, and glycine. We explain the persistence of living relics of this primordial structure by invoking a conservative principle in evolutionary biochemistry: The processes of natural selection severely inhibit any change a well-adapted system on which several other essential components depend.


Differential meta-analysis of RNA-seq data from multiple studies.
High-throughput sequencing is now regularly used for studies of the transcriptome (RNA-seq), particularly for comparisons among experimental conditions. For the time being, a limited number of biological replicates are typically considered in such experiments, leading to low detection power for differential expression. As their cost continues to decrease, it is likely that additional follow-up studies will be conducted to re-address the same biological question. We demonstrate how p-value combination techniques previously used for microarray meta-analyses can be used for the differential analysis of RNA-seq data from multiple related studies. These techniques are compared to a negative binomial generalized linear model (GLM) including a fixed study effect on simulated data and real data on human melanoma cell lines. The GLM with fixed study effect performed well for low inter-study variation and small numbers of studies, but was outperformed by the meta-analysis methods for moderate to large inter-study variability and larger numbers of studies. The p-value combination techniques illustrated here are a valuable tool to perform differential meta-analyses of RNA-seq data by appropriately accounting for biological and technical variability within studies as well as additional study-specific effects. An R package metaRNASeq is available on the CRAN (http://cran.r-project.org/web/packages/metaRNASeq).


Comparison of the magnetoencephalogram and electroencephalogram.
The spatial response of the magnetoencephalogram (MEG) to sources in the brain's cortex is compared with that of the electroencephalogram (EEG). This is done using computer modeling of the head which is approximated by 4 concentric spherical regions that represent the brain and surrounding bone and tissue. Lead fields are calculated at points on the cortex for unipolar, bipolar and quadrupolar MEG and EEG measurements. Since lead fields are patterns of the sensitivity of these measurements to a source at various locations and orientations, they provide a convenient means for comparison. It is found that a unipolar MEG has a very different lead field than a unipolar EEG. Hence, this type of MEG detects sources at different locations and orientations than this EEG. Although bipolar MEG and EEG lead fields are found to have similar patterns, the MEG lead field is narrower than that of the EEG and hence 'sees' a smaller area on the cortex than the EEG. This is because the potentials measured by the EEG are 'smeared' by the low-conductivity skull; the magnetic fields measured by the MEG are not smeared. Quadrupolar MEG and EEG lead fields are found to be about the same. The responses of bipolar MEGs and EEGs to distributed sources, which are composed of aligned and randomly oriented dipoles, are compared. It is found that for both types of sources, the MEG 'sees' an area on the cortex which is approximately 0.3 times that for the EEG. Hence, the MEG appears to be useful for detecting a more restricted group of sources than the EEG.


Remission and low disease activity (LDA) prevent damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.
To determine the independent impact of different definitions of remission and low disease activity (LDA) on damage accrual. Patients with ≥2 annual assessments from a longitudinal multinational inception lupus cohort were studied. Five mutually exclusive disease activity states were defined: remission off-treatment: clinical Systemic Lupus Erythematosus Disease Activity Index (cSLEDAI)-2K=0, without prednisone or immunosuppressants; remission on-treatment: cSLEDAI-2K score=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; low disease activity Toronto cohort (LDA-TC): cSLEDAI-2K score of ≤2, without prednisone or immunosuppressants; modified lupus low disease activity (mLLDAS): Systemic Lupus Erythematosus Disease Activity Index-2K score of 4 with no activity in major organ/systems, no new disease activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants; active: all remaining visits. Only the most stringent definition was used per visit. Antimalarials were allowed in all. The proportion of time that patients were in a specific state at each visit since cohort entry was determined. Damage accrual was ascertained with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Univariable and multivariable generalised estimated equation negative binomial regression models were used. Time-dependent covariates were determined at the same annual visit as the disease activity state but the SDI at the subsequent visit. There were 1652 patients, 1464 (88.6%) female, mean age at diagnosis 34.2 (SD 13.4) years and mean follow-up time of 7.7 (SD 4.8) years. Being in remission off-treatment, remission on-treatment, LDA-TC and mLLDAS (per 25% increase) were each associated with a lower probability of damage accrual (remission off-treatment: incidence rate ratio (IRR)=0.75, 95% CI 0.70 to 0.81; remission on-treatment: IRR=0.68, 95% CI 0.62 to 0.75; LDA: IRR=0.79, 95% CI 0.68 to 0.92; and mLLDAS: IRR=0.76, 95% CI 0.65 to 0.89)). Remission on-treatment and off-treatment, LDA-TC and mLLDAS were associated with less damage accrual, even adjusting for possible confounders and effect modifiers.