Mode resolved bend loss in few-mode optical fibers.
We present a novel approach to directly measure the bend loss of individual modes in few-mode fibers based on the correlation filter technique. This technique benefits from a computer-generated hologram performing a modal decomposition, yielding the optical power of all propagating modes in the bent fiber. Results are compared with rigorous loss simulations and with common loss formulas for step-index fibers revealing high measurement fidelity. To the best of our knowledge, we demonstrate for the first time an experimental loss discrimination between index-degenerated modes.


Rapid electrokinetic isolation of cancer-related circulating cell-free DNA directly from blood.
Circulating cell-free DNA (ccf-DNA) is becoming an important biomarker for cancer diagnostics and therapy monitoring. The isolation of ccf-DNA from plasma as a "liquid biopsy" may begin to replace more invasive tissue biopsies for the detection and analysis of cancer-related mutations. Conventional methods for the isolation of ccf-DNA from plasma are costly, time-consuming, and complex, preventing the use of ccf-DNA biomarkers for point-of-care diagnostics and limiting other biomedical research applications. We used an AC electrokinetic device to rapidly isolate ccf-DNA from 25 μL unprocessed blood. ccf-DNA from 15 chronic lymphocytic leukemia (CLL) patients and 3 healthy individuals was separated into dielectrophoretic (DEP) high-field regions, after which other blood components were removed by a fluidic wash. Concentrated ccf-DNA was detected by fluorescence and eluted for quantification, PCR, and DNA sequencing. The complete process, blood to PCR, required <10 min. ccf-DNA was amplified by PCR with immunoglobulin heavy chain variable region (IGHV)-specific primers to identify the unique IGHV gene expressed by the leukemic B-cell clone, and then sequenced. PCR and DNA sequencing results obtained by DEP from 25 μL CLL blood matched results obtained by use of conventional methods for ccf-DNA isolation from 1 mL plasma and for genomic DNA isolation from CLL patient leukemic B cells isolated from 15-20 mL blood. Rapid isolation of ccf-DNA directly from a drop of blood will advance disease-related biomarker research, accelerate the transition from tissue to liquid biopsies, and enable point-of-care diagnostic systems for patient monitoring.


Protective effects of hydrogen gas in a rat model of branch retinal vein occlusion via decreasing VEGF-α expression.
Oxidative stress (OS) is an essential factor in the pathogenesis of branch retinal vein occlusion (BRVO). Studies have demonstrated the role of hydrogen gas in the regulation of OS. This study was designed to evaluate the efficacy of hydrogen gas on the BRVO rat model. Twenty-four BRVO rats were randomly divided into two groups: the hydrogen gas (H) group (42% H2, 21% O2, 37% N2) and the model (M) group (21% O2, 79% N2). Rats in the H group inhaled hydrogen gas for 8 h every day up to 30 d post-occlusion. Twelve age-matched healthy rats served as the control (C) group. Retinal function and morphology were detected at 1, 7, 14 and 30 d post-occlusion. Furthermore, the expression of vascular endothelial growth factor (VEGF-α) was detected by immunofluorescent staining. Full-field electroretinography (ffERG) revealed that the amplitude of the b-wave (dark-adaptation 3.0 response), the amplitude of the OPs2 wave and the light-adapted flicker response in the H group were all higher than those in the M group at 7 d post-occlusion (all p < 0.05). The reopen time of occlusive retinal vessels in the H group was 2.235 ± 1.128 d, which was shorter than that in the M group (4.234 ± 2.236 d, p < 0.05). The rats in the H group had a thinner IPL + GCL + NFL and an increased total retina compared with those in the M group at 3 d post-occlusion (p < 0.05), while the rats in the H group had a thicker INL, IPL + GCL + NFL and total retina compared with those at 7, 14 and 30 d post-occlusion (p < 0.05). Moreover, the flow velocity of ear vein blood was increased in the H group compared with that in the M group (p < 0.05). The expression of VEGF-α in the H group was dramatically decreased compared with that in the M group at 1, 7 and 14 d post-occlusion (p < 0.05), while the expression kept in similar level at 30 d post-occlusion (p > 0.05). Our findings demonstrate that inhalation of hydrogen gas could alleviate retinal oedema, shorten reopen time and improve retinal function, and the potential mechanism might be related to a decrease in VEGF-α expression.


A meta-analysis of voice outcome comparing calcium hydroxylapatite injection laryngoplasty to silicone thyroplasty.
To compare the voice outcome of calcium hydroxylapatite (CaHA) injection laryngoplasty (IL) vs silicone medialization thyroplasty (MT) in the treatment of unilateral vocal fold paralysis (UVFP). Systematic review of English literature from MEDLINE, Google Scholar, Web of Science, Scopus, and the Cochrane library from January 1, 1980, to December 31, 2010. Included studies reporting voice-related quality of life (Voice Handicap Inventory [VHI]) following IL with CaHA or MT with silicone. The primary outcome measure was the improvement in VHI. The secondary outcome was improvement in maximum phonatory time (MPT). Of the 742 abstracts screened for relevancy, 24 studies qualified for analysis. The mean (SD) VHI scores were 72.22 (11.06) before MT and 34.02 (6.48) after MT. The mean (SD) VHI scores were 68.36 (6.88) before IL and 32.24 (7.33) after IL. The paired difference mean of VHI improvement was 38.20 (95% confidence interval [CI], 17.05-59.32; P = .007) for MT and 36.11 (95% CI, 29.65-42.57; P = .001) for IL. The mean (SD) MPT scores were 7.40 (3.14) before IL and 13.00 (1.75) after IL. The mean (SD) MPT scores were 6.16 (1.90) before MT and 12.40 (2.72) after MT. The paired difference mean of MPT improvement was 6.23 (95% CI, 4.74-7.73; P < .001) for MT and 5.60 (95% CI, 2.95-8.25; P = .006) for IL. Injection laryngoplasty with CaHA and MT with silicone appear to achieve comparable voice improvement within 1 year, but a definitive conclusion is limited by a lack of standardized outcome measures.


Glibenclamide, but not acarbose, increases leptin concentrations parallel to changes in insulin in subjects with NIDDM.
To hypothesize if glibenclamide, which increases insulin levels, also increases leptin concentrations. Leptin is a hormone that regulates weight in mice. In obese humans, leptin concentrations are increased, suggesting resistance to the effects of this hormone. Although short-term infusion of insulin during the hyperinsulinemiceuglycemic clamp does not increase leptin concentration, the effect of oral antidiabetic agents on leptin concentration is unknown. Differing effects can be expected, since glibenclamide acts via stimulation of insulin secretion, whereas acarbose inhibits alpha-glucosidases of the small intestine and has no direct effect on insulin levels. We examined the effect of acarbose (n = 4), glibenclamide (n = 6), and placebo (n = 6) on insulin and leptin levels during 24-h periods before and after 16 weeks of therapy. We observed a significant diurnal variation in leptin concentrations. This was inversely related to insulin levels during the 24-h follow-up with usual diet. Neither the placebo nor acarbose altered leptin concentrations. However, glibenclamide increased leptin concentrations parallel to insulin levels. There were only minor changes in body weight during the l6-week follow-up: decrease in the placebo group (change -0.5 kg/m2, P = 0.07) and acarbose (change -0.7 kg/m2, P = 0.046) and increase in the glibenclamide group (change 0.8 kg/m2, P = 0.27). However, individual subjects who gained weight had increases in their leptin concentrations. The diurnal variation in leptin concentrations was preserved after glibenclamide. Glibenclamide increases circadian leptin and insulin concentrations, whereas acarbose does not. This observation may help to explain weight gain in subjects treated with glibenclamide and stable weight in those treated with acarbose in the long run.


Prevalence and Impact of Long-term Use of Nicotine Replacement Therapy in UK Stop-Smoking Services: Findings From the ELONS Study.
Nicotine replacement therapy (NRT) was licensed for harm reduction in the United Kingdom in 2005, and guidance to UK Stop-Smoking Services (SSS) to include long-term partial or complete substitution of cigarettes with NRT was issued in 2013. Yet, NRT prevalence data and data on changes in biomarkers associated with long-term NRT use among SSS clients are scarce. SSS clients abstinent 4 weeks postquit date were followed up at 12 months. At baseline standard sociodemographic, smoking and SSS use characteristics were collected and of those eligible, 60.6% (1047/1728) provided data on smoking status and NRT use at follow-up. A subsample also provided saliva samples at baseline and of those eligible, 36.2% (258/712) provided follow-up samples. Saliva was analyzed for cotinine (a metabolite of nicotine) and alpha-amylase (a stress biomarker). Among those who had used NRT during their initial quit attempt (61.5%, 95% CI 58.4%-64.6%), 6.0% (95% CI 4.3%-8.3%) were still using NRT at 1 year, significantly more ex-smokers than relapsed smokers (9.5% vs. 3.7%; p = .005). In adjusted analysis, NRT use interacted with smoking status to determine change in cotinine, but not alpha-amylase, levels (Wald χ2 (1) = 13.0, p < .001): cotinine levels remained unchanged in relapsed smokers and ex-smokers with long-term NRT use but decreased in ex-smokers without long-term NRT use. Long-term NRT use is uncommon in SSS clients, particularly among relapsed smokers. Its use is associated with continued high intake of nicotine among ex-smokers but does not increase nicotine intake in smokers. It does not appear to affect stress response. Little is known about the long-term effects of NRT. Given an increasing shift towards harm reduction in tobacco control, reducing the harm from combustible products by partial or complete substitution with noncombustible products, more data on long-term use are needed. This study shows that in the context of SSS, clients rarely use products for up to a year and that NRT use does not affect users' stress response. Ex-smokers using NRT long-term can completely replace nicotine from cigarettes with nicotine from NRT; long-term NRT use by continuing smokers does not increase nicotine intake. Long-term NRT appears to be a safe and effective way to reduce exposure to combustible nicotine.


A timescale and phylogeny for "bandicoots" (Peramelemorphia: Marsupialia) based on sequences for five nuclear genes.
Relationships among the living and recently extinct genera of bandicoots (Marsupialia: Peramelemorphia) have proven difficult to discern. Previous phylogenetic studies have used only morphology or mitochondrial DNA and have reported conflicting results in regards to their relationships. Most phylogenetic reconstructions recognize a basal split between the bilby Macrotis (Thylacomyidae) and the Peramelidae. The Peramelidae is composed of the Peramelinae (Isoodon and Perameles), Echymiperinae (Echymipera and Microperoryctes), and Peroryctinae (Peroryctes). Within Peramelidae, Echymipera and Microperoryctes usually group together to the exclusion of Peroryctes. This clade is sister to the Peramelinae. Placement of the recently extinct pig-footed bandicoot (Chaeropus: Chaeropodidae) has been ambiguous. We address the interrelationships and estimate times of divergence for the living bandicoot genera using a 6 kilobase concatenation consisting of protein-coding regions of five nuclear genes (ApoB, BRCA1, IRBP, Rag1, and vWF). We analyzed this concatenation using maximum parsimony, maximum likelihood, and Bayesian methods and estimated times of divergence using two Bayesian relaxed molecular clock methods. In all concatenated analyses, all nodes associated with the Peramelemorphia were robustly supported (bootstrap support percentages=100; posterior probabilities=1.00). Macrotis was recovered as basal to the remaining living bandicoots. Within the Peramelidae, Echymipera and Microperoryctes grouped to the exclusion of Peroryctes and this clade was sister to the Peramelinae. Only Rag1 amplified for Chaeropus; analyses based on this gene provide moderate support for an association of Chaeropus plus Peramelidae to the exclusion of Macrotis. Both relaxed clock Bayesian methods suggest that the living bandicoots are a relatively recent radiation originating sometime in the late Oligocene or early Miocene with subsequent radiations in the late Miocene to early Pliocene.


Role of astrocytes in cerebrovascular regulation.
Astrocytes send processes to synapses and blood vessels, communicate with other astrocytes through gap junctions and by release of ATP, and thus are an integral component of the neurovascular unit. Electrical field stimulations in brain slices demonstrate an increase in intracellular calcium in astrocyte cell bodies transmitted to perivascular end-feet, followed by a decrease in vascular smooth muscle calcium oscillations and arteriolar dilation. The increase in astrocyte calcium after neuronal activation is mediated, in part, by activation of metabotropic glutamate receptors. Calcium signaling in vitro can also be influenced by adenosine acting on A2B receptors and by epoxyeicosatrienoic acids (EETs) shown to be synthesized in astrocytes. Prostaglandins, EETs, arachidonic acid, and potassium ions are candidate mediators of communication between astrocyte end-feet and vascular smooth muscle. In vivo evidence supports a role for cyclooxygenase-2 metabolites, EETs, adenosine, and neuronally derived nitric oxide in the coupling of increased blood flow to increased neuronal activity. Combined inhibition of the EETs, nitric oxide, and adenosine pathways indicates that signaling is not by parallel, independent pathways. Indirect pharmacological results are consistent with astrocytes acting as intermediaries in neurovascular signaling within the neurovascular unit. For specific stimuli, astrocytes are also capable of transmitting signals to pial arterioles on the brain surface for ensuring adequate inflow pressure to parenchymal feeding arterioles. Therefore, evidence from brain slices and indirect evidence in vivo with pharmacological approaches suggest that astrocytes play a pivotal role in regulating the fundamental physiological response coupling dynamic changes in cerebral blood flow to neuronal synaptic activity. Future work using in vivo imaging and genetic manipulation will be required to provide more direct evidence for a role of astrocytes in neurovascular coupling.


Design of an internet-based health economic evaluation of a preventive group-intervention for children of parents with mental illness or substance use disorders.
Preventive interventions are developed for children of parents with mental and substance use disorders (COPMI), because these children have a higher risk of developing a psychological or behavioral disorder in the future. Mental health and substance use disorders contribute significantly to the global burden of disease. Although the exact number of parents with a mental illness is unclear, the subject of mentally ill parents is gaining attention. Moreover there is a lack of interventions for COPMI-children, as well of (cost-) effectiveness studies evaluating COPMI interventions. Innovative interventions such as e-health provide a new field for exploration. There is no knowledge about the opportunities for using the internet to prevent problems in children at risk. In the current study we will focus on the (cost-) effectiveness of an online health prevention program for COPMI-children. We designed a randomized controlled trial to examine the (cost-) effectiveness of the Kopstoring intervention. Kopstoring is an online intervention for COPMI-children to strengthen their coping skills and prevent behavioral and psychological problems. We will compare the Kopstoring intervention with (waiting list) care as usual. This trial will be conducted entirely over the internet. An economic evaluation, from a societal perspective will be conducted, to examine the trial's cost-effectiveness. Power calculations show that 214 participants are needed, aged 16-25. Possible participants will be recruited via media announcements and banners on the internet. After screening and completing informed consent procedures, participants will be randomized. The main outcome is internalizing and externalizing symptoms as measured by the Youth Self Report. For the economic evaluation, healthcare costs and costs outside the healthcare sector will be measured at the same time as the clinical measures, at baseline, 3, 6 and 9 months. An extended measure for the intervention group will be provided at 12 months, to examine the long-term effects. In addition, a process evaluation will be conducted. Recent developments, such as international conferences and policy discussions, show the pressing need to study the (cost-) effectiveness of interventions for vulnerable groups of children. This study will shed light on the (cost-) effectiveness of an online preventive intervention. NTR1982.


Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.


Comparative assessment of pedicle morphology of the lumbar spine in various degenerative diseases.
Measurement of the morphological dimensions of the pedicles of the lumbar spine was conducted using computed tomography (CT) to clarify the difference in pedicle morphology among different lumbar degenerative diseases. The subjects were 136 patients with lumbar spinal disorders who underwent myelography followed by CT scans. They were divided into four groups, that is a group of 25 patients with degenerative spondylolisthesis (DS group), a group of 54 patients with lumbar canal stenosis (LCS group), a group of 42 patients with lumbar disc herniation (LDH group), and a control group of 15 patients with spinal cord tumor in cervicothoracic region but without lumbar diseases (control group). Measurements of the transverse diameter, axial length, and axial angle of the pedicles were performed on CT slices obtained at the middle of the pedicle. The transverse diameter was the width of the isthmus, the axial length was the distance between the anterior of the vertebral body and the posterior of the vertebral arch on a line perpendicular to the line bisecting the isthmus, and the axial angle was the angle between the line perpendicular to the line bisecting the isthmus and the midline of the vertebral body. While there were no significant differences in the mean transverse diameter or axial length among the four groups, the mean axial angle was significantly smaller in the DS and LCS groups when compared to that in the LDH and control groups. In the DS and LCS groups, the pedicles were more sagitally oriented than in the LDH and control groups. Such difference in the axial angle of the pedicles in different lumbar diseases should be taken into consideration when placing at the insertion of pedicle screws, because precise orientation of screw insertion would scarcely allow penetration of the pedicle wall.


Family Caregiver Factors Associated With Emergency Department Utilization Among Community-Living Older Adults With Disabilities.
Background: Older adults with disability are frequent users of the emergency department (ED) and often rely on family caregiver support. We identify whether and which caregiver characteristics are associated with older adults' ED use. Methods: We use Cox proportional hazards regression to model the likelihood of all-cause ED use (defined as 1 or more visits within 12 months of survey) as a function of caregiver characteristics after adjusting for older adult sociodemographic and health characteristics. We draw from linked older adult and caregiver surveys and administrative claims, creating a sample of 2521 community-living older adults with mobility/self-care disability receiving care from a family or unpaid caregiver. Results: About half (52.5%) of older adults receiving mobility or self-care help incurred 1 or more ED visits within 12 months of interview. Adjusting for year of data collection, sociodemographic characteristics, and health status, these older adults were at greater risk of all-cause ED use if their primary caregiver provided greater than 40 hours of care per week (hazard ratio [HR] 1.22, 95% CI 1.04-1.43; P = .02), helped with health care tasks (HR 1.26; 95% CI 1.08-1.46; P < .01), or experienced physical strain (HR 1.18; 95% CI 1.03-1.36; P = .02). Conclusion: Caregiver strain, helping with health care tasks, and greater hours of help per week are associated with heightened risk of ED use among older adults receiving mobility or self-care help. Study findings suggest the potential benefit of caregiver assessment and support.


Clinical, CSF, and MRI findings in Devic's neuromyelitis optica.
Since Devic's original description of neuromyelitis optica in 1894 there has been much debate regarding its aetiology. A specific cause has been identified in a minority of cases but in most the question has arisen whether or not Devic's neuromyelitis optica is a variant of multiple sclerosis. This study was undertaken to help clarify this issue. Neuromyelitis optica was defined as (1) a severe transverse myelitis; (2) an acute unilateral or bilateral optic neuropathy; (3) no clinical involvement beyond the spinal cord or optic nerves, and (4) a monophasic or multiphasic illness. The clinical and autoantibody status was documented. Patients underwent CSF examination and MRI of brain and spinal cord. Twelve patients, with a mean age of presentation of 35.1 years, were seen. Eleven were women; vision was reduced to counting fingers or worse in 10 patients and seven became confined to a wheelchair. Examination of CSF showed local synthesis of oligoclonal bands in only two patients and a neutrophil pleocytosis in two. A possible aetiology was identified in five: a specific connective tissue disorder (two), pulmonary tuberculosis (one), and possible acute disseminated encephalomyelitis (two). Six had non-specific increases in various autoantibodies. Eleven patients underwent MRI of the brain and spinal cord. In 10 there were diffuse abnormalities involving cervical and thoracic cords with extensive swelling in the acute phase. Brain MRI was normal in five; in five there were multiple deep white matter lesions, and one patient had minor age related changes. It is proposed that Devic's neuromyelitis optica is a distinctive disorder with some clinical, CSF, and MRI features different from those found in classic multiple sclerosis. In most cases a specific aetiology is not identified, but an immunological mechanism of tissue damage seems likely.


Effusion-synovitis and infrapatellar fat pad signal intensity alteration differentiate accelerated knee osteoarthritis.
To determine whether greater effusion-synovitis volume and infrapatellar fat pad (IFP) signal intensity alteration differentiate incident accelerated knee OA (KOA) from a gradual onset of KOA or no KOA. We classified three sex-matched groups of participants in the Osteoarthritis Initiative who had a knee with no radiographic KOA at baseline (recruited 2004-06; Kellgren-Lawrence <2; n = 125/group): accelerated KOA: ⩾1 knee progressed to Kellgren-Lawrence grade ⩾3 within 48 months; common KOA: ⩾1 knee increased in radiographic scoring within 48 months; and no KOA: both knees had the same Kellgren-Lawrence grade at baseline and 48 months. The observation period included up to 2 years before and after when the group criteria were met. Two musculoskeletal radiologists reported presence of IFP signal intensity alteration and independent readers used a semi-automated method to segment effusion-synovitis volume. We used generalized linear mixed models with group and time as independent variables, as well as testing a group-by-time interaction. Starting at 2 years before disease onset, adults who developed accelerated KOA had greater effusion-synovitis volume than their peers (accelerated KOA: 11.94 ± 0.90 cm3, KOA: 8.29 ± 1.19 cm3, no KOA: 8.14 ± 0.90 cm3) and have greater odds of having IFP signal intensity alteration than those with no KOA (odds ratio = 2.07, 95% CI = 1.14-3.78). Starting at 1 year prior to disease onset, those with accelerated KOA have greater than twice the odds of having IFP signal intensity alteration than those with common KOA. People with IFP signal intensity alteration and/or greater effusion-synovitis volume in the absence of radiographic KOA may be at high risk for accelerated KOA, which may be characterized by local inflammation.


Fuerstia marisgermanicae gen. nov., sp. nov., an Unusual Member of the Phylum Planctomycetes from the German Wadden Sea.
Members of the phylum Planctomycetes are ubiquitous bacteria that dwell in aquatic and terrestrial habitats. While planctomycetal species are important players in the global carbon and nitrogen cycle, this phylum is still undersampled and only few genome sequences are available. Here we describe strain NH11T, a novel planctomycete obtained from a crustacean shell (Wadden Sea, Germany). The phylogenetically closest related cultivated species is Gimesia maris, sharing only 87% 16S rRNA sequence identity. Previous isolation attempts have mostly yielded members of the genus Rhodopirellula from water of the German North Sea. On the other hand, only one axenic culture of the genus Pirellula was obtained from a crustacean thus far. However, the 16S rRNA gene sequence of strain NH11T shares only 80% sequence identity with the closest relative of both genera, Rhodopirellula and Pirellula. Thus, strain NH11T is unique in terms of origin and phylogeny. While the pear to ovoid shaped cells of strain NH11T are typical planctomycetal, light-, and electron microscopic observations point toward an unusual variation of cell division through budding: during the division process daughter- and mother cells are connected by an unseen thin tubular-like structure. Furthermore, the periplasmic space of strain NH11T was unusually enlarged and differed from previously known planctomycetes. The complete genome of strain NH11T, with almost 9 Mb in size, is among the largest planctomycetal genomes sequenced thus far, but harbors only 6645 protein-coding genes. The acquisition of genomic components by horizontal gene transfer is indicated by the presence of numerous putative genomic islands. Strikingly, 45 "giant genes" were found within the genome of NH11T. Subsequent analysis of all available planctomycetal genomes revealed that Planctomycetes as such are especially rich in "giant genes". Furthermore, Multilocus Sequence Analysis (MLSA) tree reconstruction support the phylogenetic distance of strain NH11T from other cultivated Planctomycetes of the same phylogenetic cluster. Thus, based on our findings, we propose to classify strain NH11T as Fuerstia marisgermanicae gen. nov., sp. nov., with the type strain NH11T, within the phylum Planctomycetes.


Assessing clarity of message communication for mandated USEPA drinking water quality reports.
The United States Environmental Protection Agency mandates that community water systems (CWSs), or drinking water utilities, provide annual consumer confidence reports (CCRs) reporting on water quality, compliance with regulations, source water, and consumer education. While certain report formats are prescribed, there are no criteria ensuring that consumers understand messages in these reports. To assess clarity of message, trained raters evaluated a national sample of 30 CCRs using the Centers for Disease Control Clear Communication Index (Index) indices: (1) Main Message/Call to Action; (2) Language; (3) Information Design; (4) State of the Science; (5) Behavioral Recommendations; (6) Numbers; and (7) Risk. Communication materials are considered qualifying if they achieve a 90% Index score. Overall mean score across CCRs was 50 ± 14% and none scored 90% or higher. CCRs did not differ significantly by water system size. State of the Science (3 ± 15%) and Behavioral Recommendations (77 ± 36%) indices were the lowest and highest, respectively. Only 63% of CCRs explicitly stated if the water was safe to drink according to federal and state standards and regulations. None of the CCRs had passing Index scores, signaling that CWSs are not effectively communicating with their consumers; thus, the Index can serve as an evaluation tool for CCR effectiveness and a guide to improve water quality communications.


Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation.
Mitotane inhibits steroid synthesis by an action on steroidogenic enzymes, as 11beta-hydroxylase and cholesterol side chain cleavage. It also has a cytotoxic effect on the adrenocortical cells and represents a primary drug used in the adrenocortical carcinoma (ACC). H295R and SW13 cell lines were treated with mitotane 10(-5) M and ionizing radiations (IR) in combination therapy, inducing an irreversible inhibition of cell growth in both adrenocortical cancer cells. As shown in a previous report, mitotane/IR combination treatment induced a cell accumulation in the G2 phase. Here, we report the radiosensitizing properties of mitotane in two different ACC cell lines. The drug reveals the effectiveness to enhance the cytotoxic effects of IR by attenuating DNA repair and interfering on the activation of mitosis promoting factor (MPF), mainly regulated by the degradation of cyclin B1 in the mitotic process. These events may explain the inappropriate activation of cdc2, implicated in G2/M phase arrest and probably induced by the mitotane and IR in the combined treatment. Indeed, treatment with purvalanol, a cdc2-inhibitor prevents cell cycle arrest, triggering the G2/M transition. The observation that mitotane and IR in combination treatment amplifies the activation level of cyclin B/cdc2 complexes contributing to cell cycle arrest, suggests that the MPF could function as a master signal for controlling the temporal order of different mitotic events. Moreover, we report that mitotane interferes in modulation of mismatch repair (MMR) enzymes, revealing radiosensitizing drug ability.


Caveolin-associated filamentous actin (Cav-actin) defines a novel F-actin structure in adipocytes.
Dynamic actin remodeling has been implicated in the translocation of the insulin-responsive glucose transporter 4 (GLUT4) to the plasma membrane in adipocytes. Here we show that fully differentiated 3T3L1 adipocytes have unique cortical filamentous actin structure, designated Cav-actin (caveolae-associated F-actin). During 3T3L1 adipocyte differentiation, rhodamine-phalloidin staining demonstrated the formation of a cortical actin cytoskeleton that is composed of small dot-like F-actin spikes lining the inside of the plasma membrane. Double labeling with a caveolin antibody indicated that these F-actin spikes emanate from organized rosette-like clusters of caveolae/lipid raft microdomains. In contrast, there was no obvious relationship between F-actin and caveolin localization and/or organization in 3T3L1 preadipocytes (fibroblasts). Treatments of differentiated adipocytes with latrunculin B, Clostridium difficile toxin B or a dominant-interfering TC10 mutant (TC10/T31N) disrupted the Cav-actin structure without significantly affecting the organization of clustered caveolae. Similarly, disruption of the clustered caveolae with methyl-beta-cyclodextrin also dispersed the Cav-actin structure. These data demonstrate that this novel Cav-actin structure is organized through clustered caveolae but that the formation of caveolae-rosettes are not dependent upon F-actin.


Surgical-orthodontic treatment for skeletal class II malocclusion with vertical maxillary excess, anterior open bite, and transverse maxillary deficiency.
Nongrowing adult patients with skeletal open bite have been considered among the most difficult to treat. This case report describes the surgical-orthodontic treatment of a blind 20-year-old woman who presented with skeletal class II malocclusion with vertical maxillary excess, anterior open bite, and transverse maxillary deficiency.After the transverse maxillary deficiency was corrected with miniscrew-assisted rapid palatal expansion, Le Fort I osteotomy with anterior segmental osteotomy and bilateral sagittal split ramus osteotomy with advancement genioplasty were used to correct the vertical maxillary excess and the anterior open bite. The patient's facial appearance was markedly improved, and she achieved a functional and stable occlusion after these treatments.This case report demonstrates the efficiency of miniscrew-assisted rapid palatal expansion for a patient with transverse maxillary deficiency and the benefit of a team approach using effective orthodontic mechanics in orthognathic surgery to correct a severe dentofacial deformity.


A detailed canine brain label map for neuroimaging analysis.
Dogs have recently become an important model species for comparative social and cognitive neuroscience. Brain template-related label maps are essential for functional magnetic resonance imaging (fMRI) data analysis, to localize neural responses. In this study, we present a detailed, individual-based, T1-weighted MRI-based brain label map used in dog neuroimaging analysis. A typical, medium-headed dog (a 7.5-year-old male Golden Retriever) was selected from a cohort of 22 dogs, based on brain morphology (shape, size, and gyral pattern), to serve as the template for a label map. Eighty-six 3-dimensional labels were created to highlight the main cortical (cerebral gyri on the lateral and medial side) and subcortical (thalamus, caudate nucleus, amygdala, and hippocampus) structures of the prosencephalon and diencephalon, and further main parts of brainstem (mesencephalon and rhombencephalon). Importantly, this label map is (a) considerably more detailed than any available dog brain template; (b) it is easy to use with freeware and commercial neuroimaging software for MRI and fMRI analysis; and (c) it can be registered to other existing templates, including a recent average-based dog brain template. Using the coordinate system and label map proposed here can enhance precision and standard localization during future canine neuroimaging studies.


Analysis of ectatomin action on cell membranes.
Ectatomin (m = 7928 Da) is a toxic component from the Ectatomma tuberculatum ant venom containing two homologous polypeptide chains (37 and 34 residues) linked to each other by a disulfide bond. In aqueous solution it forms a four alpha-helix bundle. At concentrations of 0.05-0.1 microm, ectatomin forms channels in cellular and artificial bilayer membranes. Immunochemical analysis of the intracellular distribution of ectatomin showed that the toxin gets efficiently inserted into the plasma membrane at a concentration of 5 x 10-7 m and does not penetrate inside the cell. The effect of ectatomin on cardiac L-type calcium current was studied. Calcium currents (ICa) in isolated rat cardiac ventricular myocytes were measured using the whole-cell perforated patch-clamp technique. It was shown that ectatomin at concentrations of 0.01-10 nm inhibited ICa after a latency of few seconds. ICa was decreased twofold by 10 nm ectatomin. However, the most prominent effect of ectatomin was observed after stimulation of ICa by isoproterenol, an agonist of beta-adrenoreceptors, or forskolin, a stimulator of adenylate cyclase. At a concentration of 1 nm, ectatomin abolished the isoproterenol- and forskolin-sensitive components of ICa. The inhibitory effect of ectatomin was partially reversed by subsequent application of 2 microm of forskolin, whereas subsequent isoproterenol application did not produce the same effect.


Evidence-Informed Planning for Healthy Liveable Cities: How Can Policy Frameworks Be Used to Strengthen Research Translation?
A compelling body of research demonstrates associations between urban design and health, but this research is often not reflected in urban policies. This article reviews the literature on the science and practice of translating health research into urban policy and planning. Two Australian case studies demonstrate how policy frameworks can help guide evidence-based planning for healthy urban environments. To influence city planning, health researchers need to undertake policy-relevant research and understand policymaking processes. Policy frameworks can assist researchers to tailor research evidence and research translation strategies to the political and policymaking context. Strong links between urban policymakers and health researchers can help bridge the knowledge-policy divide. Policy frameworks can help researchers to identify and capitalise on windows of opportunity for evidence-based policy change. Doing so increases the likelihood of public health evidence informing urban policies that will create healthy liveable cities.


Characteristic sonographic pattern of schistosomal hepatic fibrosis.
The hepatic sonographic patterns from 50 patients undergoing operations for bleeding esophageal varices were compared with the interpretation of the histological findings in a hepatic wedge biopsy obtained during surgery. The sonographic pattern for schistosomiasis periportal fibrosis is characteristic and is not mimicked by other hepatic diseases we have studied. Sonography agreed with pathology in 44 out of 50 patients. Schistosomiasis could be separated from cirrhosis, as well as from combined lesions. Where there was a discordance, we believe that sonography gave a more accurate diagnosis.


Structural changes accompanying phosphorylation of tarantula muscle myosin filaments.
Electron microscopy has been used to study the structural changes that occur in the myosin filaments of tarantula striated muscle when they are phosphorylated. Myosin filaments in muscle homogenates maintained in relaxing conditions (ATP, EGTA) are found to have nonphosphorylated regulatory light chains as shown by urea/glycerol gel electrophoresis and [32P]phosphate autoradiography. Negative staining reveals an ordered, helical arrangement of crossbridges in these filaments, in which the heads from axially neighboring myosin molecules appear to interact with each other. When the free Ca2+ concentration in a homogenate is raised to 10(-4) M, or when a Ca2+-insensitive myosin light chain kinase is added at low Ca2+ (10(-8) M), the regulatory light chains of myosin become rapidly phosphorylated. Phosphorylation is accompanied by potentiation of the actin activation of the myosin Mg-ATPase activity and by loss of order of the helical crossbridge arrangement characteristic of the relaxed filament. We suggest that in the relaxed state, when the regulatory light chains are not phosphorylated, the myosin heads are held down on the filament backbone by head-head interactions or by interactions of the heads with the filament backbone. Phosphorylation of the light chains may alter these interactions so that the crossbridges become more loosely associated with the filament backbone giving rise to the observed changes and facilitating crossbridge interaction with actin.


Mechanoadaptation: articular cartilage through thick and thin.
The articular cartilage is exquisitely sensitive to mechanical load. Its structure is largely defined by the mechanical environment and destruction in osteoarthritis is the pathophysiological consequence of abnormal mechanics. It is often overlooked that disuse of joints causes profound loss of volume in the articular cartilage, a clinical observation first described in polio patients and stroke victims. Through the 1980s, the results of studies exploiting experimental joint immobilisation supported this. Importantly, this substantial body of work was also the first to describe metabolic changes that resulted in decreased synthesis of matrix molecules, especially sulfated proteoglycans. The molecular mechanisms that underlie disuse atrophy are poorly understood despite the identification of multiple mechanosensing mechanisms in cartilage. Moreover, there has been a tendency to equate cartilage loss with osteoarthritic degeneration. Here, we review the historic literature and clarify the structural, metabolic and clinical features that clearly distinguish cartilage loss due to disuse atrophy and those due to osteoarthritis. We speculate on the molecular sensing pathways in cartilage that may be responsible for cartilage mechanoadaptation.


Coherent and collimated blue light generated by four-wave mixing in Rb vapour.
We investigate frequency up-conversion of low power cw resonant radiation in Rb vapour as a function of various experimental parameters. We present evidence that the process of four wave mixing is responsible for unidirectional blue light generation and that the phase matching conditions along a light-induced waveguide determine the direction and divergence of the blue light. Velocity-selective excitation to the 5D level via step-wise and two-photon processes results in a Doppler-free dependence on the frequency detuning of the applied laser fields from the respective dipole-allowed transitions. Possible schemes for ultraviolet generation are discussed.


Yawning throughout life.
Yawning is a behavior that begins in the first stages of life. It has not only been observed in infants and in newborns, but also in fetuses of 12-14 weeks' gestational age. Yawning frequency changes over the life span. In preterm infants, the number of yawns decreases between 31 and 40 weeks' postconceptional age, mainly during the day. In this period of life, yawning is an isolated behavior rarely occurring in bursts, and its frequency is quite low with respect to adults. The incidence of yawning seems to increase when children attend elementary school, whereas this is reduced in the elderly. Aged people yawn less than younger ones, mainly during morning and mid-afternoon. In adults, the time course of yawning is associated with the time course of sleepiness, except upon awakening when the high frequency of yawns is not associated with high sleepiness. In adults, yawning frequency increases in the early morning and in the late evening, whereas at the earliest stages of development (fetuses and preterm infants) yawning does not show diurnal variations. Yawning seems to be involved in the modulation of arousal process across the whole life span. In preterm infants, yawning is often followed by motor activation and it is more common during waking than sleep; in adults, yawning occurs mainly at sleep onset and upon awakening.


What goes up must come down: biomarkers and novel biologicals in severe asthma.
Asthma is a heterogeneous airway disease characterized by typical symptoms in combination with variable airway obstruction. Most patients with asthma have well controlled symptoms and a low risk of asthma attacks with inhaled corticosteroid (ICS) treatment. However, a clinically important subgroup (~ 10%) remains symptomatic and/or at risk of asthma attacks despite maximum inhaled therapy. Patients with severe asthma are responsible for a significant proportion of healthcare costs attributable to asthma and have a large unmet need for better treatments. An important advance in recent years has been the recognition that severe asthma is heterogeneous with respect to clinical problems and the pattern of lower airway inflammation. Identification of eosinophilic inflammation in the airways has become an important priority as novel biologicals that target Th2 cytokines, such as anti-IL5, anti-IL-13 and combined anti-IL-4/13 are showing considerable promise as treatments for this subgroup. It has also become clear that anti-IgE (Omalizumab), the first monoclonal antibody registered for treatment of severe asthma, is only active in patients with active eosinophilic airway inflammation. The future will be identification of potentially responsive patients on the basis of raised biomarkers and, as suggested by the title of this review, targeted treatment with specific cytokine blockade that has a direct effect on the biomarkers. In this review, we outline an approach to the clinical assessment of patients potentially suitable for biological treatment and describe in detail the likely clinical impact of established and new biological treatments.


Face processing occurs outside the fusiform 'face area' in autism: evidence from functional MRI.
Processing the human face is at the focal point of most social interactions, yet this simple perceptual task is difficult for individuals with autism, a population that spends limited amounts of time engaged in face-to-face eye contact or social interactions in general. Thus, the study of face processing in autism is not only important because it may be integral to understanding the social deficits of this disorder, but also, because it provides a unique opportunity to study experiential factors related to the functional specialization of normal face processing. In short, autism may be one of the only disorders where affected individuals spend reduced amounts of time engaged in face processing from birth. Using functional MRI, haemodynamic responses during a face perception task were compared between adults with autism and normal control subjects. Four regions of interest (ROIs), the fusiform gyrus (FG), inferior temporal gyrus, middle temporal gyrus and amygdala were manually traced on non-spatially normalized images and the percentage ROI active was calculated for each subject. Analyses in Talairach space were also performed. Overall results revealed either abnormally weak or no activation in FG in autistic patients, as well as significantly reduced activation in the inferior occipital gyrus, superior temporal sulcus and amygdala. Anatomical abnormalities, in contrast, were present only in the amygdala in autistic patients, whose mean volume was significantly reduced as compared with normals. Reaction time and accuracy measures were not different between groups. Thus, while autistic subjects could perform the face perception task, none of the regions supporting face processing in normals were found to be significantly active in the autistic subjects. Instead, in every autistic patient, faces maximally activated aberrant and individual-specific neural sites (e.g. frontal cortex, primary visual cortex, etc.), which was in contrast to the 100% consistency of maximal activation within the traditional fusiform face area (FFA) for every normal subject. It appears that, as compared with normal individuals, autistic individuals 'see' faces utilizing different neural systems, with each patient doing so via a unique neural circuitry. Such a pattern of individual-specific, scattered activation seen in autistic patients in contrast to the highly consistent FG activation seen in normals, suggests that experiential factors do indeed play a role in the normal development of the FFA.


Podocyte injury damages other podocytes.
Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis.


Whole-Genome Sequences of Burkholderia pseudomallei Isolates Exhibiting Decreased Meropenem Susceptibility.
We report here paired isogenic Burkholderia pseudomallei genomes obtained from three patients receiving intravenous meropenem for melioidosis treatment, with post-meropenem isolates developing decreased susceptibility. Two genomes were finished, and four were drafted to improved high-quality standard. These genomes will be used to identify meropenem resistance mechanisms in B. pseudomallei.


Global biodiversity conservation priorities.
The location of and threats to biodiversity are distributed unevenly, so prioritization is essential to minimize biodiversity loss. To address this need, biodiversity conservation organizations have proposed nine templates of global priorities over the past decade. Here, we review the concepts, methods, results, impacts, and challenges of these prioritizations of conservation practice within the theoretical irreplaceability/vulnerability framework of systematic conservation planning. Most of the templates prioritize highly irreplaceable regions; some are reactive (prioritizing high vulnerability), and others are proactive (prioritizing low vulnerability). We hope this synthesis improves understanding of these prioritization approaches and that it results in more efficient allocation of geographically flexible conservation funding.


Viral hepatitis B and hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world, some 630,000 new cases being diagnosed each year. 82% of cases are related to viral hepatitis, 55% to hepatitis B virus (HBV), 89% of those in regions where HBV is endemic. There is a striking parallel between the geographical distribution of the rates of chronic HBV infection and that of HCC. In the majority of HCC cases (70-90%) there is underlying liver cirrhosis. However, because HBV is an oncogenic virus, it can cause HCC in the absence of cirrhosis. The annual risk of HBV-induced HCC varies according to the presence or absence of concomitant cirrhosis. In HBV carriers without cirrhosis, the risk is 0.02-03% in Caucasians and 0.4-0.6% per year in Asians. In those with cirrhosis, the risk is 2.2% and 3.7% respectively in Caucasians and Asians. HBV likely causes HCC via both indirect (necro-inflammation and regeneration injury) and direct (by integration of its DNA in the host genome) pathways. During recent years it has become evident that HBV viral load >2000 IU/mL is associated with a high risk of malignant transformation. The most effective measure of prevention of HBV-related HCC is prevention of HBV infection by vaccination. A universal vaccination program in Taiwan was shown to be effective in reducing the rate of childhood and early adulthood HCC. In patients already infected with HBV, antiviral therapy remains the best strategy. Interferon-alfa therapy appears to be effective in preventing HCC in cirrhosis in Asia but not in Europe. Medium-term nucleos/tide-analogue therapy significantly reduces but does not eliminate the risk of HCC, especially in patients with pre-existing cirrhosis. Maintenance of virological remission is important for the reduction of HCC risk. With more potent antiviral drugs currently available (entecavir, tenofovir), long-term HBV DNA suppression is now possible with very low risk of drug resistance.


Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus.
Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers. Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice. These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus.


Proliferating larval cestode in a man in Paraguay. A case report and review.
Large tumors removed from the lower abdomen and pleural cavity of a 24-year-old male Amerindian in Paraguay consisted mainly of multitudes of minute, proliferating, acephalic cestode larvae embedded in fibrous tissue. The parasite resembled Sparganum proliferum Stiles 1908 but was markedly less differentiated. From a review of the literature and examination of available reference material, it is concluded that in addition to the present one there are eight well documented cases of proliferating acephalic larval cestode infection in man: five in Japan and one in Florida (USA) that were S. proliferum, one in Pennsylvania (USA) that was an undifferentiated cysticercus or cysticercoid, and one in Taiwan that probably was an undifferentiated tetrathyridium. In four other cases the parasites are reclassified as being of doubtful nature in three and a racemose cysticercus in one. Review of the known species of proliferating cestode larvae naturally occurring in animals failed to identify possible sources of the acephalic forms observed in man.


The Magnaporthe oryzae effector AvrPiz-t targets the RING E3 ubiquitin ligase APIP6 to suppress pathogen-associated molecular pattern-triggered immunity in rice.
Although the functions of a few effector proteins produced by bacterial and oomycete plant pathogens have been elucidated in recent years, information for the vast majority of pathogen effectors is still lacking, particularly for those of plant-pathogenic fungi. Here, we show that the avirulence effector AvrPiz-t from the rice blast fungus Magnaporthe oryzae preferentially accumulates in the specialized structure called the biotrophic interfacial complex and is then translocated into rice (Oryza sativa) cells. Ectopic expression of AvrPiz-t in transgenic rice suppresses the flg22- and chitin-induced generation of reactive oxygen species (ROS) and enhances susceptibility to M. oryzae, indicating that AvrPiz-t functions to suppress pathogen-associated molecular pattern (PAMP)-triggered immunity in rice. Interaction assays show that AvrPiz-t suppresses the ubiquitin ligase activity of the rice RING E3 ubiquitin ligase APIP6 and that, in return, APIP6 ubiquitinates AvrPiz-t in vitro. Interestingly, agroinfection assays reveal that AvrPiz-t and AvrPiz-t Interacting Protein 6 (APIP6) are both degraded when coexpressed in Nicotiana benthamiana. Silencing of APIP6 in transgenic rice leads to a significant reduction of flg22-induced ROS generation, suppression of defense-related gene expression, and enhanced susceptibility of rice plants to M. oryzae. Taken together, our results reveal a mechanism in which a fungal effector targets the host ubiquitin proteasome system for the suppression of PAMP-triggered immunity in plants.


Automated Segmentation of Optical Coherence Tomography Angiography Images: Benchmark Data and Clinically Relevant Metrics.
To generate the first open dataset of retinal parafoveal optical coherence tomography angiography (OCTA) images with associated ground truth manual segmentations, and to establish a standard for OCTA image segmentation by surveying a broad range of state-of-the-art vessel enhancement and binarization procedures. Handcrafted filters and neural network architectures were used to perform vessel enhancement. Thresholding methods and machine learning approaches were applied to obtain the final binarization. Evaluation was performed by using pixelwise metrics and newly proposed topological metrics. Finally, we compare the error in the computation of clinically relevant vascular network metrics (e.g., foveal avascular zone area and vessel density) across segmentation methods. Our results show that, for the set of images considered, deep learning architectures (U-Net and CS-Net) achieve the best performance (Dice = 0.89). For applications where manually segmented data are not available to retrain these approaches, our findings suggest that optimally oriented flux (OOF) is the best handcrafted filter (Dice = 0.86). Moreover, our results show up to 25% differences in vessel density accuracy depending on the segmentation method used. In this study, we derive and validate the first open dataset of retinal parafoveal OCTA images with associated ground truth manual segmentations. Our findings should be taken into account when comparing the results of clinical studies and performing meta-analyses. Finally, we release our data and source code to support standardization efforts in OCTA image segmentation. This work establishes a standard for OCTA retinal image segmentation and introduces the importance of evaluating segmentation performance in terms of clinically relevant metrics.


Recanalization and reuse of early occluded radial artery within 6 days after previous transradial diagnostic procedure.
Late radial artery (RA) thrombosis occurs in 3-9% after transradial interventions. RA occlusion has made this approach unsuitable for repeat interventions and obviated the need for alternative vascular access for catheterization, e.g., left RA (with certain risk of bilateral RA occlusion) or femoral artery with its shortcomings and, sometimes, life-threatening complications requiring surgical treatment (large groin hematoma, arterio-venous fistula or false aneurysm, retroperitoneal hemorrhage). We demonstrate the possibility of retrograde RA recanalization, dilatation, and restoration of the RA patency within 6 days after first transradial coronary diagnostic catheterization complicated with acute RA occlusion. Thus we were able to recanalize previously occluded RA and reuse it for repeat transradial coronary interventions.


Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer.
Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. F-box/WD repeat-containing protein 7 (FBXW7) is a ubiquitin ligase that regulates quiescence by targeting the c-MYC protein for ubiquitination. We previously reported that gefitinib-resistant persisters (GRPs) in EGFR-mutant non-small cell lung cancer (NSCLC) cells highly expressed octamer-binding transcription factor 4 (Oct-4) as well as the lung CSC marker CD133, and they exhibited distinctive features of the CSC phenotype. However, the role of FBXW7 in lung CSCs and their resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in NSCLC is not fully understood. In this study, we developed GRPs from the two NSCLC cell lines PC9 and HCC827, which express an EGFR exon 19 deletion mutation, by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high levels of CD133 and FBXW7, but low levels of c-MYC. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the FBXW7 gene significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. We also found that FBXW7 expression in CD133-positive cells was increased and c-MYC expression was decreased in gefitinib-resistant tumors of PC9 cells in mice and in 9 out of 14 tumor specimens from EGFR-mutant NSCLC patients with acquired resistance to gefitinib. These findings suggest that FBXW7 plays a pivotal role in the maintenance of quiescence in gefitinib-resistant lung CSCs in EGFR mutation-positive NSCLC.


Cloning and characterization of a novel Drosophila stress induced DNase.
Drosophila melanogaster flies mount an impressive immune response to a variety of pathogens with an efficient system comprised of both humoral and cellular responses. The fat body is the main producer of the anti-microbial peptides (AMPs) with anti-pathogen activity. During bacterial infection, an array of secreted peptidases, proteases and other enzymes are involved in the dissolution of debris generated by pathogen clearance. Although pathogen destruction should result in the release a large amount of nucleic acids, the mechanisms for its removal are still not known. In this report, we present the characterization of a nuclease gene that is induced not only by bacterial infection but also by oxidative stress. Expression of the identified protein has revealed that it encodes a potent nuclease that has been named Stress Induced DNase (SID). SID belongs to a family of evolutionarily conserved cation-dependent nucleases that degrade both single and double-stranded nucleic acids. Down-regulation of sid expression via RNA interference leads to significant reduction of fly viability after bacterial infection and oxidative stress. Our results indicate that SID protects flies from the toxic effects of excess DNA/RNA released by pathogen destruction and from oxidative damage.


No effect of inoculation site and injection device on the skin test response of red deer to the intradermal injection of Mycobacterium avium-derived purified protein derivative (PPD).
Mycobacterial diseases are important health issues in farmed deer. The single intradermal tuberculin test is the standard test for tuberculosis testing in deer. We studied two factors which might influence the response of deer to skin testing: the inoculation site and the injection device. Deer included in this study were 2.5 years old farmed red deer (Cervus elaphus) hinds (n = 80). Two areas of 3 cm × 3 cm were shaved at the left side of the neck. Site A (SA) was situated about 10 cm caudal to the head, while site B (SB) was 10 cm caudal to SA. All hinds received at the same time two 0.1 ml inoculations of Mycobacterium avium derived purified protein derivative (aPPD). One inoculation was made by syringe and the other one with the needle-free syringe Dermojet. To test the inoculation site effect, half of the animals were inoculated by Dermojet in SA and by syringe in SB to compare with the inoculation in SA by syringe and Dermojet in SB in the other half. No differences were recorded for the injection device nor for the inoculation site. Ten hinds had a skinfold increase larger than 30 tenths of mm by any injection device and inoculation site. Seven (9%) and 6 (8%) hinds were classified as positive by syringe and Dermojet, and at the anterior or posterior inoculation site, respectively. The distribution of skinfold thickness increases did not differ by injection device. Our findings support the needle-free Dermojet syringe as a suitable tool for skin-testing in red deer and suggest no relevant effect of the position of the inoculation site along the neck in red deer.


A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma.
We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.


A computational study of the role of the aortic arch in idiopathic unilateral vocal-fold paralysis.
Unilateral vocal-fold paralysis (UVP) occurs when one of the vocal folds becomes paralyzed due to damage to the recurrent laryngeal nerve (RLN). Individuals with UVP experience problems with speaking, swallowing, and breathing. Nearly two-thirds of all cases of UVP is associated with impaired function of the left RLN, which branches from the vagus nerve within the thoracic cavity and loops around the aorta before ascending to the larynx within the neck. We hypothesize that this path predisposes the left RLN to a supraphysiological, biomechanical environment, contributing to onset of UVP. Specifically, this research focuses on the identification of the contribution of the aorta to onset of left-sided UVP. Important to this goal is determining the relative influence of the material properties of the RLN and the aorta in controlling the biomechanical environment of the RLN. Finite element analysis was used to estimate the stress and strain imposed on the left RLN as a function of the material properties and loading conditions. The peak stress and strain in the RLN were quantified as a function of RLN and aortic material properties and aortic blood pressure using Spearman rank correlation coefficients. The material properties of the aortic arch showed the strongest correlation with peak stress [ρ = -0.63, 95% confidence interval (CI), -1.00 to -0.25] and strain (ρ = -0.62, 95% CI, -0.99 to -0.24) in the RLN. Our results suggest an important role for the aorta in controlling the biomechanical environment of the RLN and potentially in the onset of left-sided UVP that is idiopathic.


Suppression of endothelial PGC-1α is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension.
Endothelial dysfunction plays a principal role in the pathogenesis of pulmonary arterial hypertension (PAH), which is a fatal disease with limited effective clinical treatments. Mitochondrial dysregulation and oxidative stress are involved in endothelial dysfunction. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key regulator of cellular energy metabolism and a master regulator of mitochondrial biogenesis. However, the roles of PGC-1α in hypoxia-induced endothelial dysfunction are not completely understood. We hypothesized that hypoxia reduces PGC-1α expression and leads to endothelial dysfunction in hypoxia-induced PAH. We confirmed that hypoxia has a negative impact on endothelial PGC-1α in experimental PAH in vitro and in vivo. Hypoxia-induced PGC-1α inhibited the oxidative metabolism and mitochondrial function, whereas sustained PGC-1α decreased reactive oxygen species (ROS) formation, mitochondrial swelling, and NF-κB activation and increased ATP formation and endothelial nitric oxide synthase (eNOS) phosphorylation. Furthermore, hypoxia-induced changes in the mean pulmonary arterial pressure and right heart hypertrophy were nearly normal after intervention. These results suggest that PGC-1α is associated with endothelial function in hypoxia-induced PAH and that improved endothelial function is associated with improved cellular mitochondrial respiration, reduced inflammation and oxygen stress, and increased PGC-1α expression. Taken together, these findings indicate that PGC-1α may be a new therapeutic target in PAH.


Population and demographic structure of Ixodes scapularis Say in the eastern United States.
The most significant vector of tick-borne pathogens in the United States is Ixodes scapularis Say (the blacklegged tick). Previous studies have identified significant genetic, behavioral and morphological differences between northern vs. southern populations of this tick. Because tick-borne pathogens are dependent on their vectors for transmission, a baseline understanding of the vector population structure is crucial to determining the risks and epidemiology of pathogen transmission. We investigated population genetic variation of I. scapularis populations in the eastern United States using a multilocus approach. We sequenced and analyzed the mitochondrial COI and 16S genes and three nuclear genes (serpin2, ixoderin B and lysozyme) from wild specimens. We identified a deep divergence (3-7%) in I. scapularis COI gene sequences from some southern specimens, suggesting we had sampled a different Ixodes species. Analysis of mitochondrial 16S rRNA sequences did not support this hypothesis and indicated that all specimens were I. scapularis. Phylogenetic analysis and analysis of molecular variance (AMOVA) supported significant differences between northern vs. southern populations. Demographic analysis suggested that northern populations had experienced a bottleneck/expansion event sometime in the past, possibly associated with Pleistocene glaciation events. Similar to other studies, our data support the division of northern vs. southern I. scapularis genetic lineages, likely due to differences in the demographic histories between these geographic regions. The deep divergence identified in some COI gene sequences highlights a potential hazard of relying solely on COI for species identification ("barcoding") and population genetics in this important vector arthropod.


A signaling mucin at the head of the Cdc42- and MAPK-dependent filamentous growth pathway in yeast.
Signaling molecules such as Cdc42 and mitogen-activated protein kinases (MAPKs) can function in multiple pathways in the same cell. Here, we propose one mechanism by which such factors may be directed to function in a particular pathway such that a specific response is elicited. Using genomic approaches, we identify a new component of the Cdc42- and MAPK-dependent signaling pathway that regulates filamentous growth (FG) in yeast. This factor, called Msb2, is a FG-pathway-specific factor that promotes differential activation of the MAPK for the FG pathway, Kss1. Msb2 is localized to polarized sites on the cell surface and interacts with Cdc42 and with the osmosensor for the high osmolarity glycerol response (HOG) pathway, Sho1. Msb2 is glycosylated and is a member of the mucin family, proteins that in mammalian cells promote disease resistance and contribute to metastasis in cancer cells. Remarkably, loss of the mucin domain of Msb2 causes hyperactivity of the FG pathway, demonstrating an inhibitory role for mucin domains in MAPK pathway activation. Taken together, our data suggest that Msb2 is a signaling mucin that interacts with general components, such as Cdc42 and Sho1, to promote their function in the FG pathway.


Xeno III self-etching adhesive in orthodontic bonding: the next generation.
The newer single-step self-etching adhesives that etch, prime, and apply the resin bonding agent simultaneously without rinsing have been increasing in popularity in orthodontic bonding. The purpose of this study was to compare the bond strengths and to evaluate the debonding site (with the adhesive remnant index), when a conventional acid-etch conditioner and a self-etching adhesive system (Xeno III, Dentsply DeTrey GmbH, Konstanz, Germany) were used with either a composite resin adhesive (Transbond XT, 3M Unitek, Monrovia, Calif) or a resin-modified glass ionomer cement (Fuji Ortho LC, GC Corp, Tokyo, Japan). One hundred twenty extracted human premolars were mounted in acrylic resin and randomly assigned to 6 groups of 20 teeth each. Shear-peel bond strength testing was performed after thermocycling (5 degrees C-55 degrees C for 500 times) with a Zwick 1440 compression machine (Zwick, Ulm, Germany). The results showed that the bond strengths achieved with Xeno III were comparable with the traditional methods of either 37% phosphoric acid or 10% polyacrylic acid for both Transbond XT and Fuji Ortho LC. Adhesive remnant index scores showed less adhesive remaining on the tooth surface in the Xeno III/Transbond XT adhesive only (no primer) group. Xeno III can be used to bond orthodontic brackets with the adhesives in this study.


Surface modification for enhanced silanation of zirconia ceramics.
The overall goal of this research was to develop a practical method to chemically modify the surface of high strength dental ceramics (i.e. zirconia) to facilitate viable, robust adhesive bonding using commercially available silanes and resin cements. Investigation focused on a novel approach to surface functionalize zirconia with a Si(x)O(y) "seed" layer that would promote chemical bonding with traditional silanes. ProCAD and ZirCAD blocks were bonded to a dimensionally similar composite block using standard techniques designed for silica-containing materials (silane and resin cement). ZirCAD blocks were treated with SiCl4 by vapor deposition under two different conditions prior to bonding. Microtensile bars were prepared and subjected to tensile forces at a crosshead speed of 1 mm/min scanning electron microscopy was used to analyze fracture surfaces and determine failure mode; either composite cohesive failure (partial or complete cohesive failure within composite) or adhesive failure (partial or complete adhesive failure). Peak stress values were analyzed using single-factor ANOVA (p<0.05). Microtensile testing results revealed that zirconia with a surface treatment of 2.6 nm Si(x)O(y) thick "seed" layer was similar in strength to the porcelain group (control). Analysis of failure modes indicated the above groups displayed higher percentages of in-composite failures. Other groups tested had lower strength values and displayed adhesive failure characteristics. Mechanical data support that utilizing a gas-phase chloro-silane pretreatment to deposit ultra-thin silica-like seed layers can improve adhesion to zirconia using traditional silanation and bonding techniques. This technology could have clinical impact on how high strength dental materials are used today.


Current perspectives on control of equine influenza.
Influenza A viruses of the H3N8 subtype are a major cause of respiratory disease in horses. Subclinical infection with virus shedding can occur in vaccinated horses, particularly where there is a mismatch between the vaccine strains and the virus strains circulating in the field. Such infections contribute to the spread of the disease. Rapid diagnostic techniques are available for detection of virus antigen and can be used as an aid in control programmes. Improvements have been made to methods of standardising inactivated virus vaccines, and a direct relationship between vaccine potency measured by single radial diffusion and vaccine-induced antibody measured by single radial haemolysis has been demonstrated. Improved adjuvants and antigenic presentation systems extend the duration of immunity induced by inactivated virus vaccines, but high levels of antibody are required for protection against field infection. In addition to circulating antibody, infection with influenza virus stimulates mucosal and cellular immunity; unlike immunity to inactivated virus vaccines, infection-induced immunity is not dependent on the presence of circulating antibody to HA. Live attenuated or vectored equine influenza vaccines, which may better mimic the immunity generated by influenza infection than inactivated virus vaccines, are now available. Mathematical modelling based upon experimental and field data has been applied to examine issues relating to vaccine efficacy at the population level. A vaccine strain selection system has been implemented and a more global approach to the surveillance of equine influenza is being developed.


Radiation doses from global fallout and cancer incidence among reindeer herders and Sami in Northern Finland.
People in the Arctic regions are one of the most heavily exposed population from the global fallout from atmospheric atomic bomb testing of the 1950s and 1960s due to their diet rich in reindeer meat in which radionuclides accumulate. We estimated the effect of the radioactive fallout and ethnicity on the cancer incidence in Northern Finland. A cohort of the Arctic population in Finland (n=34,653) was identified through the Population Register Centre with grouping by reindeer herding status, ethnicity and radiation exposure. Annual average radiation doses, based on (137)Cs whole-body measurements, were assigned by birth year, gender and reindeer herder status. Incident cancer cases of a priori selected cancer types in the study cohort during 1971-2005 were identified from the Finnish Cancer Registry. A total of 2630 cancer cases were observed versus 3073 expected on the basis of incidence rates in Northern Finland (standardised incidence ratio (SIR) was 0.86 with 95% CI of 0.82 to 0.89). For the indigenous Sami people SIR was even lower, 0.60 (95% CI 0.50 to 0.71). None of the cancer sites was significantly associated with the lifetime cumulative radiation dose. The SIR for the combined group of radiation-related cancer sites increased with the cumulative radiation dose received before 15 years of age (p=0.004). Despite the low overall cancer incidence in the Arctic population and ethnic Sami people in Finland and lack of association between the lifetime cumulative radiation exposure from global radioactive fallout and cancer incidence, we found some indication of an increased cancer risk associated with radiation exposure received during childhood. Potential underestimation and misclassification of the radiation dose may affect the results and the findings should be interpreted with caution.


Life Partner Influence on Uptake of Preventive Services: Evidence From Flu Vaccine Adoption Among the Aging Population.
Objectives: This study examines how the patterns of life partner concordance on preventive health service uptake vary by a partner's previous behavioral history and between genders. Method: This study uses 2008 and 2012 waves of Health and Retirement Study (HRS), a nationally representative sample of U.S. aging population, to examine one's decision to receive a preventive service as a function of the partner's decision changes over time (N = 2,680). Results: Life partner concordance on preventive service use is different by the partner's previous use history and gender. Positive partner preventive engagement showed greater association than negative ones. Women are more responsive to the positive health behaviors (of their partners), and men are more sensitive to the negative partner health behaviors. Conclusion: The asymmetric partner concordance by gender and the partner's previous usage experience provide implications to develop efficient and culturally acceptable interventions to increase the uptake of preventive health services.


Protein phosphatase inhibitor okadaic acid enhances transmitter release at neuromuscular junctions.
To test the hypothesis that continual phosphorylation and dephosphorylation of protein components of nerve terminals might be important determinants of synaptic efficacy, the effect of okadaic acid, a potent natural inhibitor of two serine threonine protein phosphatases (phosphatase 1 and phosphatase 2A), was examined on synaptic transmission at frog (cholinergic) and lobster (glutamatergic and GABAergic) neuromuscular junctions. At frog junctions, the addition of 1 microM okadaic acid to the extracellular fluid caused almost a doubling of the amplitude of the end-plate potential. The effect of okadaic acid was reversible. Quantal analysis showed that the augmenting effect was presynaptic, resulting from an increase in the number of quanta of transmitter released by a nerve impulse. Where was no significant change in the amplitude of spontaneously liberated miniature end-plate potentials, but their frequency of release increased in parallel with the increase in amplitude of the nerve-evoked synaptic potential. Similar studies with lobster neuromuscular junctions showed increases in the size of both excitatory and inhibitory synaptic responses that were similar in magnitude to the effects seen in the frog junctions. No significant changes in membrane potential or in input resistance accompanied the increased response size. These results suggest that transmitter release at a variety of junctions using different transmitters is constantly modulated by phosphorylation and dephosphorylation of important protein components within nerve terminals.


Systematically generated antibodies against human gene products: high throughput screening on sections from the rat nervous system.
Completion of the Human Genome Project and recent developments in proteomics make it possible to systematically generate affinity reagents to a large portion of the proteome. Recently an antibody-based human protein atlas covering many organs including four areas of the brain has been released (www.proteinatlas.org). Due to the heterogeneity, size, and availability of tissue a more thorough analysis of the human brain is associated with considerable difficulties. Here we applied 120 antibodies raised against 112 human gene products to the smaller rat brain, a rodent animal model, where a single section represents a 'superarray' including many brain areas, and consequently allowing analysis of a huge number of cell types and their neurochemicals. Immunoreactive structures were seen in the investigated brain tissue after incubation with 56 antibodies (46.6%), of which 25 (20.8%) showed a clearly discrete staining pattern that was limited to certain areas, or subsets of brain cells. Bioinformatics, pre-adsorption tests and Western blot analysis were applied to identify non-specific antibodies. Eleven antibodies, including such raised against four 'ambiguous' proteins, passed all validation criteria, and the expression pattern and subcellular distribution of these proteins were studied in detail. To further explore the potential of the systematically generated antibodies, all 11 antibodies that passed validation were used to analyze the spinal cord and lumbar dorsal root ganglia after unilateral transection of the sciatic nerve. Discrete staining patterns were observed for four of the proteins, and injury-induced regulation was found for one of them. In conclusion, the study presented here suggests that a significant portion (10%) of the antibodies generated to a human protein can be used to analyze orthologues present in the rodent brain and to produce a protein-based atlas of the rodent brain. It is hoped that this type of antibody-based, high throughput screening of brain tissue from various rodent disease models will provide new information on the brain chemical neuroanatomy and insights in processes underlying neurological pathologies.


Dopamine-Decorated TiO2 Nanoparticles in Water: A QM/MM vs an MM Description.
Nanoparticle functionalization is a modern strategy in nanotechnology to build up devices for several applications. Modeling fully decorated metal oxide nanoparticles of realistic size (few nanometers) in an aqueous environment is a challenging task. In this work, we present a case study relevant for solar-light exploitation and for biomedical applications, i.e., a dopamine-functionalized TiO2 nanoparticle (1700 atoms) in bulk water, for which we have performed an extensive comparative investigation with both MM and QM/MM approaches of the structural properties and of the conformational dynamics. We have used a combined multiscale protocol for a more efficient exploration of the complex conformational space. On the basis of the results of this study and of some QM and experimental data, we have defined strengths and limitations of the existing force field parameters. Our findings will be useful for an improved modeling and simulation of many other similar hybrid bioinorganic nanosystems in an aqueous environment that are pivotal in a broad range of nanotechnological applications.


Molecular study of parental origin of extra chromosome 21 in regular and de novo translocation trisomies.
The parental origin of the extra chromosome 21 (or extra 21q) was determined in seven informative families with a Down syndrome (DS) child by using molecular polymorphisms. Five DS patients had regular trisomy, one a de novo 14/21 translocation and another a de novo 21/21 translocation or isochromosome 21q. In four families with regular trisomy, the extra chromosome was of maternal origin, and in one family it was paternally derived. In the two families with a de novo aberration, both the 14/21 translocation and 21/21 rearrangement originated during maternal meiosis. For a better evaluation of the stage of meiotic error and the occurrence of crossovers between nondisjoined chromosomes, the regional map position of four of the nine informative DNA markers, used in this study, was refined, leading to useful localizations in both centromeric and distal regions. Recombination events were found in two families with regular trisomy, one occurring between chromosomes 21 that failed to disjoin at maternal meiosis I, the other prior to a paternal meiosis II nondisjunction.


Data imputation through the identification of local anomalies.
We introduce a comprehensive and statistical framework in a model free setting for a complete treatment of localized data corruptions due to severe noise sources, e.g., an occluder in the case of a visual recording. Within this framework, we propose: 1) a novel algorithm to efficiently separate, i.e., detect and localize, possible corruptions from a given suspicious data instance and 2) a maximum a posteriori estimator to impute the corrupted data. As a generalization to Euclidean distance, we also propose a novel distance measure, which is based on the ranked deviations among the data attributes and empirically shown to be superior in separating the corruptions. Our algorithm first splits the suspicious instance into parts through a binary partitioning tree in the space of data attributes and iteratively tests those parts to detect local anomalies using the nominal statistics extracted from an uncorrupted (clean) reference data set. Once each part is labeled as anomalous versus normal, the corresponding binary patterns over this tree that characterize corruptions are identified and the affected attributes are imputed. Under a certain conditional independency structure assumed for the binary patterns, we analytically show that the false alarm rate of the introduced algorithm in detecting the corruptions is independent of the data and can be directly set without any parameter tuning. The proposed framework is tested over several well-known machine learning data sets with synthetically generated corruptions and experimentally shown to produce remarkable improvements in terms of classification purposes with strong corruption separation capabilities. Our experiments also indicate that the proposed algorithms outperform the typical approaches and are robust to varying training phase conditions.


Evaluating Atmospheric pressure Solids Analysis Probe (ASAP) mass spectrometry for the analysis of low molecular weight synthetic polymers.
Atmospheric pressure Solids Analysis Probe (ASAP) mass spectrometry has facilitated the ionisation of oligomers from low molecular weight synthetic polymers, poly(ethylene glycol) (PEG: M(n) = 1430) and poly(styrene) (PS: M(n) = 1770), directly from solids, providing a fast and efficient method of identification. Ion source conditions were evaluated and it was found that the key instrument parameter was the ion source desolvation temperature which, when set to 600 °C was sufficient to vapourise the heavier oligomers for ionisation. PS, a non-polar polymer that is very challenging to analyse by MALDI or ESI without the aid of metal salts to promote cationisation, was ionised promptly by ASAP resulting in the production of radical cations. A small degree of in-source dissociation could be eliminated by control of the instrument ion source voltages. The fragmentation observed through in-source dissociation could be duplicated in a controlled manner through Collision-Induced Dissociation (CID) of the radical cations. PEG, which preferentially ionises through adduction with alkali metal cations in MALDI and ESI, was observed as a protonated molecular ion by ASAP. In-source dissociation could not be eliminated entirely and the fragmentation observed resulted from cleavage of the C-C and C-O backbone bonds, as opposed to only C-O bond cleavage observed from tandem mass spectrometry.


Barriers to immunization among children of migrant workers from Myanmar living in Tak province, Thailand.
Immunization is a cost-effective means of improving child survival but implementation of programmes in low- and middle-income countries is variable. Children of migrants are less likely to be immunized. The qualitative study aimed to identify barriers to the successful implementation of migrant immunization programmes in Tak province, Thailand. We ran a total of 53 focus groups involving 371 participants in three sites. Tak province in Thailand borders Myanmar and has an estimated 200,000 migrants from Myanmar. Vaccine-preventable diseases are a documented cause of morbidity in this population but there is no systematic or coordinated immunization programme in the area. As a result of the findings, the subsequent immunization campaign targeted children in school to overcome those barriers of distance to immunization services, fear of arrest, not remembering immunization appointments, and the disruption of parental work. The campaigns also included immunization education for both parents and teachers. Migrant parents identified similar barriers to accessing childhood immunization programmes as migrant populations elsewhere in the world, although a unique barrier identified by parents from Myanmar was "fear of arrest". The subsequent school-based strategy to overcome these barriers appears to be effective.


[Associations between sleep status and risk for kidney stones in Chinese adults: a prospective cohort study].
Objective: To analyze the associations between sleep status and the risk for kidney stone in Chinese adults. Methods: This study used baseline and long-term follow-up data of China Kadoorie Biobank. After excluding those with self-reporting of diagnosed chronic kidney disease and cancer and those with extreme values of sleep duration at baseline survey, 501 701 participants were included in this study. The information about their sleep status were collected, including insomnia symptoms, daytime sleepiness, nap habit, snoring and sleep duration. The sleep score was constructed based on insomnia symptoms, daytime sleepiness, and sleep duration, ranging from 0 to 3. Cox proportional hazards regression models were used to evaluate the association of sleep status with the risk for kidney stone, including individual sleep factors and combined sleep score. Results: During the follow-up for average (10.7±2.2) years, 12 381 cases of kidney stone were recorded for the first time. Compared with participants without insomnia symptoms, the multivariable-adjusted HR of kidney stone in those with difficulty falling asleep and waking up early were 1.12 (95%CI: 1.06-1.18) and 1.06 (95%CI: 1.00-1.12), respectively. There was no statistically significant association of kidney stone risk with sleeping pill use, daytime sleepiness, nap habit, or snoring. Compared with participants with sleep duration ≥7 hours per day, the HR of kidney stone in those with sleep duration <7 hours per day was 1.13 (95%CI: 1.08-1.18). Compared with participants with sleep score of 3 (highest sleep quality), the HR of kidney stone in those with sleep score of 2, 1, and 0 were 1.08 (95%CI: 1.03-1.13), 1.16 (95%CI: 1.10-1.23), and 1.19 (95%CI: 1.03-1.37), respectively. Conclusion: In China, adults with insomnia symptoms or short sleep duration have increased risk for kidney stone.


Measles-mumps-rubella vaccination induced thrombocytopenia: a case report and review of the literature.
Immune thrombocytopenia (ITP) is a disease with autoimmune destruction of platelets. ITP among children has been associated with viral infections and some vaccinations. We report a case of ITP after measles-mumps-rubella (MMR) vaccination in a 10-month-old male infant who presented with purpura and acute gastrointestinal bleeding. This case was successfully treated with corticosteroids and intravenous immunoglobulin. ITP is a rare complication of the MMR vaccine that physicians should be aware of.


An evolutionary consequence of dosage compensation on Drosophila melanogaster female X-chromatin structure?
X chromosomes are subject to dosage compensation in Drosophila males. Dosage compensation requires cis sequence features of the X chromosome that are present in both sexes by definition and trans acting factors that target chromatin modifying machinery to the X specifically in males. The evolution of this system could result in neutral X chromatin changes that will be apparent in females. We find that the general chromatin structure of female X chromosomes is distinct from autosomes. Additionally, specific histone marks associated with dosage compensation and active chromatin marks on the male X chromosome are also enriched on the X chromosomes of females, albeit to a lesser degree. Our data indicate that X chromatin structure is fundamentally different from autosome structure in both sexes. We suggest that the differences between the X chromosomes and autosomes in females are a consequence of mechanisms that have evolved to ensure sufficient X chromosome expression in the soma of males.


Tuberculosis in asylum seekers in Belgium. VRGT (Flemish Lung and Tuberculosis Association).
Countries with a low incidence of tuberculosis have recently been faced with the problem of tuberculosis (TB) in asylum seekers from countries with a high TB prevalence. We report on the tuberculosis case notification rate (TBCNR) in Belgium in 1993, and on the results of active screening in a group of asylum seekers. The TBCNR in Belgium in 1993 increased slightly to 14.9 per 100,000, mainly due to the nonindigenous population. The highest TBCNR (312 per 100,000) was reported among the 26,882 asylum seekers staying in Belgium in 1993. Of all new asylum seekers admitted in 1993, 4,794 agreed to undergo radiographic screening for TB at entry, of whom 123 had a chest radiograph which was suspect. Among the 123, 67 could be further investigated, and, of these, 19 cases (28%) of active TB were detected; this represents a TBCNR of 396 per 100,000 when referred to the 4,794 asylum seekers screened. In addition, 56 asylum seekers with suspect chest radiograph were lost to further investigation. From the present results it appears that: 1) in Belgium, asylum seekers constitute an important risk group for TB, with a TBCNR after screening which is approximately 30 times that in the indigenous population; and 2) there is a deficient follow-up after first screening, generating the risk of transmission of TB within the community. Our recommendations are, therefore, that in all asylum seekers screening for tuberculosis should be mandatory and follow-up of active tuberculosis should be regulated.