What makes genetically modified organisms so distasteful?
The debate concerning genetically modified organisms goes on unabated and reflects some genuine concerns. I suggest that a significantly large number of educated people believe that moving genes around between species is intuitively wrong and that this is based on an essentialist view of the world. This essentialist view has a long history that dates back to Plato and Aristotle and was eventually overthrown by the population thinking of Charles Darwin. The essentialist, who is antipathetic to population thinking, will naturally find the transfer of a gene from one organism to another distasteful, and this, I argue, is the result of Platonic thinking, which still remains and casts its spell over us today.


Pulse-width modulation drive technique for high-resolution liquid-crystal gratings.
We report the use of a pulse-width modulation drive technique for high-resolution liquid-crystal gratings and show how the grating diffraction efficiency depends on the duty cycle of the drive signal. We identify a regime in which the diffraction efficiency is linearly proportional to the duty cycle, thereby providing a linear drive characteristic.


A comparison of electronically-delivered and face to face cognitive behavioural therapies in depressive disorders: A systematic review and meta-analysis.
Cognitive behavioural therapy (CBT) is a widely used treatment for depression. However, limited resource availability poses several barriers to patients seeking access to care, including lengthy wait times and geographical limitations. This has prompted health care services to introduce electronically delivered CBT (eCBT) to facilitate access. Although previous reviews have compared the effects of eCBT to face-to-face CBT, there is an overall lack of adequately powered and up-to-date evidence in the literature to provide a reliable comparison between the two modes of administration. The purpose of this study is to evaluate the effects of eCBT compared to face-to-face CBT through a systematic review of the literature. To be eligible for this review, studies needed to be randomized controlled trials evaluating the clinical effectiveness of any form of eCBT compared to face-to-face CBT. These encompassed studies evaluating a wide range of outcomes including severity of symptoms, adverse outcomes, clinically relevant outcomes, global functionality, participant satisfaction, quality of life, and affordability. There were no restrictions on participant age or sex.We searched MEDLINE, EMBASE, Psych Info, Cochrane CENTRAL and CINAHL databases from inception to February 20th, 2020 using a comprehensive search strategy. All stages of literature screening and data extraction were completed independently in duplicate. Data extraction and risk of bias analyses, including GRADE ratings, were conducted on studies meeting inclusion criteria. Qualitative measures are reported in a narrative summary. We pooled quantitative data in meta-analyses to provide an estimated summary effect. This review adheres to PRISMA reporting guidelines. In total, we included 17 studies in our analyses. Our results demonstrated that eCBT was more effective than face-to-face CBT at reducing depression symptom severity (Standardized mean difference [SMD]: -1.73; 95% confidence interval [CI]: -2.72, -0.74; GRADE: moderate quality of evidence). There were no significant differences between the two interventions on participant satisfaction (SMD 0.13 95%; CI -0.32, 0.59; GRADE: low quality of evidence). One RCT reported eCBT to be less costly than face-to-face CBT (GRADE: low quality of evidence). Results did not differ when stratified by subgroups such as participant age and study location. Although we found eCBT to have moderate evidence of effectiveness in reducing symptoms of depression, high heterogeneity among studies precludes definitive conclusions for all outcomes. With the current reliance and accessibility of technology to increasing number of people worldwide, serious consideration in utilizing technology should be given to maximize accessibility for depression treatments. Our results found eCBT is at least as effective as face to face CBT, thus eCBT should be offered if preferred by patients and therapists. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.


Shades of red: bird-pollinated flowers target the specific colour discrimination abilities of avian vision.
Colour signals are a major cue in putative pollination syndromes. There is evidence that the reflectance spectra of many flowers target the distinctive visual discrimination abilities of hymenopteran insects, but far less is known about bird-pollinated flowers. Birds are hypothesized to exert different selective pressures on floral colour compared with hymenopterans because of differences in their visual systems. We measured the floral reflectance spectra of 206 Australian angiosperm species whose floral visitors are known from direct observation rather than inferred from floral characteristics. We quantified the match between these spectra and the hue discrimination abilities of hymenopteran and avian vision, and analysed these metrics in a phylogenetically informed comparison of flowers in different pollination groups. We show that bird-visited flowers and insect-visited flowers differ significantly from each other in the chromatic cues they provide, and that the differences are concentrated near wavelengths of optimal colour discrimination by whichever class of pollinator visits the flowers. Our results indicate that angiosperms have evolved the spectral signals most likely to reinforce their pollinators' floral constancy (the tendency of individual pollinators to visit flowers of the same species) in communities of similarly coloured floral competitors.


A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma.
Osteoclast (OC)-mediated lytic bone disease remains a cause of major morbidity in multiple myeloma. Here we demonstrate the critical role of interleukin-17-producing marrow infiltrating lymphocytes (MILs) in OC activation and development of bone lesions in myeloma patients. Unlike MILs from normal bone marrow, myeloma MILs possess few regulatory T cells (Tregs) and demonstrate an interleukin-17 phenotype that enhances OC activation. In univariate analyses of factors mediating bone destruction, levels of cytokines that selectively induce and maintain the Th17 phenotype tightly correlated with the extent of bone disease in myeloma. In contrast, MILs activated under conditions that skew toward a Th1 phenotype significantly reduced formation of mature OC. These findings demonstrate that interleukin-17 T cells are critical to the genesis of myeloma bone disease and that immunologic manipulations shifting MILs from a Th17 to a Th1 phenotype may profoundly diminish lytic bone lesions in multiple myeloma.


Methylome analysis identifies a Wilms tumor epigenetic biomarker detectable in blood.
Wilms tumor is the most common pediatric renal malignancy and there is a clinical need for a molecular biomarker to assess treatment response and predict relapse. The known mutated genes in this tumor type show low mutation frequencies, whereas aberrant methylation at 11p15 is by far the most common aberration. We therefore analyzed the epigenome, rather than the genome, to identify ubiquitous tumor-specific biomarkers. Methylome analysis of matched normal kidney and Wilms tumor identifies 309 preliminary methylation variable positions which we translate into three differentially methylated regions (DMR) for use as tumor-specific biomarkers. Using two novel algorithms we show that these three DMRs are not confounded by cell type composition. We further show that these DMRs are not methylated in embryonic blastema but are intermediately methylated in Wilms tumor precursor lesions. We validate the biomarker DMRs using two independent sample sets of normal kidney and Wilms tumor and seven Wilms tumor histological subtypes, achieving 100% and 98% correct classification, respectively. As proof-of-principle for clinical utility, we successfully use biomarker DMR-2 in a pilot analysis of cell-free circulating DNA to monitor tumor response during treatment in ten patients. These findings define the most common methylated regions in Wilms tumor known to date which are not associated with their embryonic origin or precursor stage. We show that this tumor-specific methylated DNA is released into the blood circulation where it can be detected non-invasively showing potential for clinical utility.


Implementation of a confidential helpline for men having sex with men in India.
In India, men who have sex with men (MSM) often face physical violence and harassment from police and the general society. Many MSM may not openly disclose their sexual identity, especially if they are married to women and have families. Due to pervasive stigma and discrimination, human immunodeficiency virus (HIV) prevention programs are unable to reach many MSM effectively. The objective of this paper was to describe the design, operations, and monitoring of the Sahaay helpline, a mHealth intervention for the MSM population of India. We established the "Sahaay" mHealth intervention in 2013; a MSM-dedicated helpline whose main goal was to increase access to comprehensive, community-based HIV prevention services and improve knowledge, attitudes, and behaviors of MSM towards HIV and sexually transmitted infections (STI) in three states of India (Chhattisgarh, Delhi, and Maharashtra). The helpline provided a 24x7 confidential and easy to use interactive voice response system (IVRS) to callers. IVRS function was monitored through an online dashboard of indicators. The system also provided real-time reporting on callers and services provided. The helpline received more than 100,000 calls from 39,800 callers during the first nine months of operation. The helpline maintained an operational uptime of 99.81% (6450/6462 hours); and answered more than 81.33% (83,050/102,115) of all calls. More than three-fourths of the calls came between 9:00 am-12:00 pm. The most successful promotional activity was "interpersonal communication" (reported by 70.05%, 27,880/39,800, of the callers). Nearly three-fourths of the callers self-identified as MSM, including 17.05% (6786/39,800) as rural MSM and 5.03% (2001/39,800) as a married MSM. Most callers (93.10%, 37,055/39,800) requested information, while some (27.01%, 10,750/39,800) requested counseling on HIV/acquired immune deficiency syndrome (AIDS), STIs, and other health and nonhealth issues. There were 38.97% (15,509/39,800) of the callers that were provided contacts of different HIV/AIDS referral services. Many MSM clients reported increased self-esteem in dealing with their sexual identity and disclosing the same with their family and spouse; and an increase in HIV/AIDS risk-reduction behaviors like consistent condom use and HIV testing. National HIV/AIDS prevention interventions for MSM in India should consider scaling-up this helpline service across the country. The helpline may serve as an important mechanism for accessing hard-to-reach MSM, and thus improving HIV prevention programing.


LoRa Architecture for V2X Communication: An Experimental Evaluation with Vehicles on the Move.
The industrial development of the last few decades has prompted an increase in the number of vehicles by multiple folds. With the increased number of vehicles on the road, safety has become one of the primary concerns. Inter vehicular communication, specially Vehicle to Everything (V2X) communication can address these pressing issues including autonomous traffic systems and autonomous driving. The reliability and effectiveness of V2X communication greatly depends on communication architecture and the associated wireless technology. Addressing this challenge, a device-to-device (D2D)-based reliable, robust, and energy-efficient V2X communication architecture is proposed with LoRa wireless technology. The proposed system takes a D2D communication approach to reduce the latency by offering direct vehicle-to-vehicle (V2V) and vehicle-to-infrastructure (V2I) communication, rather than routing the data via the LoRa WAN server. Additionally, the proposed architecture offers modularity and compact design, making it ideal for legacy systems without requiring any additional hardware. Testing and analysis suggest the proposed system can communicate reliably with roadside infrastructures and other vehicles at speeds ranging from 15-50 km per hour (kmph). The data packet consists of 12 bytes of metadata and 28 bytes of payload. At 15 kmph, a vehicle sends one data packet every 25.9 m, and at 50 kmph, it sends the same data packet every 53.34 m with reliable transitions.


Cryptic lineage differentiation among Indo-Pacific bottlenose dolphins (Tursiops aduncus) in the northwest Indian Ocean.
Phylogeography can provide insight into the potential for speciation and identify geographic regions and evolutionary processes associated with species richness and evolutionary endemism. In the marine environment, highly mobile species sometimes show structured patterns of diversity, but the processes isolating populations and promoting differentiation are often unclear. The Delphinidae (oceanic dolphins) are a striking case in point and, in particular, bottlenose dolphins (Tursiops spp.). Understanding the radiation of species in this genus is likely to provide broader inference about the processes that determine patterns of biogeography and speciation, because both fine-scale structure over a range of kilometers and relative panmixia over an oceanic range are known for Tursiops populations. In our study, novel Tursiops spp. sequences from the northwest Indian Ocean (including mitogenomes and two nuDNA loci) are included in a worldwide Tursiops spp. phylogeographic analysis. We discover a new 'aduncus' type lineage in the Arabian Sea (off India, Pakistan and Oman) that diverged from the Australasian lineage ∼261 Ka. Effective management of coastal dolphins in the region will need to consider this new lineage as an evolutionarily significant unit. We propose that the establishment of this lineage could have been in response to climate change during the Pleistocene and show data supporting hypotheses for multiple divergence events, including vicariance across the Indo-Pacific barrier and in the northwest Indian Ocean. These data provide valuable transferable inference on the potential mechanisms for population and species differentiation across this geographic range.


Dimensionality control of electronic phase transitions in nickel-oxide superlattices.
The competition between collective quantum phases in materials with strongly correlated electrons depends sensitively on the dimensionality of the electron system, which is difficult to control by standard solid-state chemistry. We have fabricated superlattices of the paramagnetic metal lanthanum nickelate (LaNiO(3)) and the wide-gap insulator lanthanum aluminate (LaAlO(3)) with atomically precise layer sequences. We used optical ellipsometry and low-energy muon spin rotation to show that superlattices with LaNiO(3) as thin as two unit cells undergo a sequence of collective metal-insulator and antiferromagnetic transitions as a function of decreasing temperature, whereas samples with thicker LaNiO(3) layers remain metallic and paramagnetic at all temperatures. Metal-oxide superlattices thus allow control of the dimensionality and collective phase behavior of correlated-electron systems.


Innate immune cell-epithelial crosstalk during wound repair.
Skin and intestinal epithelial barriers play a pivotal role in protecting underlying tissues from harsh external environments. The protective role of these epithelia is, in part, dependent on a remarkable capacity to restore barrier function and tissue homeostasis after injury. In response to damage, epithelial wounds repair by a series of events that integrate epithelial responses with those of resident and infiltrating immune cells including neutrophils and monocytes/macrophages. Compromise of this complex interplay predisposes to development of chronic nonhealing wounds, contributing to morbidity and mortality of many diseases. Improved understanding of crosstalk between epithelial and immune cells during wound repair is necessary for development of better pro-resolving strategies to treat debilitating complications of disorders ranging from inflammatory bowel disease to diabetes. In this Review we focus on epithelial and innate immune cell interactions that mediate wound healing and restoration of tissue homeostasis in the skin and intestine.


Impact of the native-state stability of human lysozyme variants on protein secretion by Pichia pastoris.
We report the secreted expression by Pichia pastoris of two human lysozyme variants F57I and W64R, associated with systemic amyloid disease, and describe their characterization by biophysical methods. Both variants have a substantially decreased thermostability compared with wild-type human lysozyme, a finding that suggests an explanation for their increased propensity to form fibrillar aggregates and generate disease. The secreted yields of the F57I and W64R variants from P. pastoris are 200- and 30-fold lower, respectively, than that of wild-type human lysozyme. More comprehensive analysis of the secretion levels of 10 lysozyme variants shows that the low yields of these secreted proteins, under controlled conditions, can be directly correlated with a reduction in the thermostability of their native states. Analysis of mRNA levels in this selection of variants suggests that the lower levels of secretion are due to post-transcriptional processes, and that the reduction in secreted protein is a result of degradation of partially folded or misfolded protein via the yeast quality control system. Importantly, our results show that the human disease-associated mutations do not have levels of expression that are out of line with destabilizing mutations at other sites. These findings indicate that a complex interplay between reduced native-state stability, lower secretion levels, and protein aggregation propensity influences the types of mutation that give rise to familial forms of amyloid disease.


Host and nonhost resistance in Medicago-Colletotrichum interactions.
Medicago truncatula lines resistant (A17) or susceptible (F83005.5) to the alfalfa pathogen Colletotrichum trifolii were used to compare defense reactions induced upon inoculation with C. trifolii or with the nonadapted pathogens C. lindemuthianum and C. higginsianum. Nonadapted Colletotrichum spp. induced a hypersensitive response (HR)-like reaction similar to the one induced during the host-incompatible interaction. Molecular analyses indicated an induction of PR10 and chalcone synthase genes in host and nonhost interactions but delayed responses were observed in the F83005.5 line. The clste12 penetration-deficient C. lindemuthianum mutant induced an HR and defense gene expression, showing that perception of nonadapted strains occurs before penetration of epidermal cells. Cytological and transcriptomic analyses performed upon inoculation of near-isogenic M. truncatula lines, differing only at the C. trifolii resistance locus, Ct1, with the nonadapted Colletotrichum strain, showed that nonhost responses are similar in the two lines. These included a localized oxidative burst, accumulation of fluorescent compounds, and transient expression of a small number of genes. Host interactions were characterized by a group of defense and signaling-related genes induced at 3 days postinoculation, associated with an accumulation of salicylic acid. Together, these results show that M. truncatula displays a rapid and transient response to nonadapted Colletotrichum strains and that this response is not linked to the C. trifolii resistance locus.


Estimation of the uncertainty in a multiresidue method for the determination of pesticide residues in fruit and vegetables.
The estimation of uncertainty of an analytical result has become important in analytical chemistry. It is especially difficult to determine uncertainties for multiresidue methods, e.g. for pesticides in fruit and vegetables, as the varieties of pesticide/commodity combinations are many. In the present study, recommendations from the International Organisation for Standardisation's (ISO) Guide to the Expression of Uncertainty and the EURACHEM/CITAC guide Quantifying Uncertainty in Analytical Measurements were followed to estimate the expanded uncertainties for 153 pesticides in fruit and vegetables. Data from in-house validation were used in the estimation of the uncertainty. No significant difference in the relative standard deviation for reproducibility (RSD(R)) were found between the different concentration levels at concentration levels exceeding 2.5 times the detection limit. Therefore, it was possible to pool the RSD(R) within a single matrix. However, a difference in RSD(R) between matrices was seen, thus the poorest RSD(R) of the investigated matrices was chosen for the uncertainty estimation. The expanded uncertainties ranged from 7 to 78% with an average of 32% and median of 32%. Furthermore, only RSD(R) contributed to the uncertainty estimation.


Can a Conical Implant Successfully Address Complex Anatomy in Primary THA? Radiographs and Hip Scores at Early Followup.
Total hip arthroplasty (THA) in patients with small or abnormal proximal femoral anatomy is challenging as a result of complex anatomic deformities in the hip. It is unclear which stem is the most appropriate for these patients. One possible implant design that may help meet this need is the modified Wagner Cone prosthesis, whose design consists of monoblock cone with splines; however, to our knowledge, no clinical results have been published using this implant. We evaluated the hip scores and radiographic results (including signs of osseointegration and subsidence) of complex primary THA using the modified Wagner Cone cementless femoral component in patients with small or abnormal proximal femoral anatomic proportions. Between 2006 and 2011, we performed 59 THAs on patients whose femoral geometry precluded the use of standard-sized implants. Of these, 49 (83%) received the modified Wagner Cone prosthesis. During this time, our indications for use of the Wagner Cone implant in such patients included: femoral neck retroversion, excessive anteversion of the femoral neck, or small proximal femora not suitable for standard implants. Of those, 40 patients with 49 THAs were available for radiographic and clinical followup at a minimum of 3 years, and no patients were lost to followup. The diagnosis included developmental dysplasia of hip (22 patients, 28 hips), secondary trauma or posttuberculosis osteoarthritis (nine patients, 10 hips), and hip disease secondary to other disorders (eight patients, nine hips) and osteonecrosis (one patients, two hips). Two versions of the stem with 135° (28 hips) or 125° (21 hips) neck angle versions were used to reestablish normal hip biomechanics. Version angle was chosen based on preoperative templating. Cementless cups with screws were used for the acetabulum. Mean followup was 4 years (range, 3-7 years). Study endpoints were the Harris hip score and radiographic evaluations by a surgeon not involved in the clinical care of the patients (QZ); radiographic analysis included evaluating for the presence or absence of signs of osseointegration (including Engh's criteria) and subsidence. The Harris hip score improved from a mean of 41 ± 9 preoperatively to a mean of 85 ± 10 at last followup (p < 0.01). The mean vertical subsidence was 1.5 ± 1.1 mm. Radiographic evaluation demonstrated stability (no further subsidence) of all implants at last followup. Endosteal spot welds were found in 32 hips (65%). No progressive radiolucencies were observed. One patient (one hip) underwent revision surgery as a result of late infection; no other revisions were performed. The modified Wagner Cone femoral stem has provided improvements in hip scores and promising short-term radiographic results at short-term followup in complex cementless THA associated with abnormal or small femoral anatomical proportions in which standard implants are inappropriate. Longer followup will be needed to see if these results endure. Randomized trials are needed to determine the optimal stem design for these patients. Level IV, therapeutic study.


Co-expression of multiple transgenes in mouse CNS: a comparison of strategies.
The introduction of two transgenes into one animal is increasingly common as transgenic experiments become more sophisticated. In this study we examine two strategies for creating double transgenic founders from a single microinjection. In the first approach, two constructs, each with its own promoter element, were coinjected into the pronucleus. In the second approach, both transgenes were cloned into one vector, separated by an internal ribosomal entry site (IRES), and placed under control of a single promoter. Both strategies save time and increase the percentage of double transgenic offspring over the standard method of mating single transgenic lines. However, despite high transgene copy numbers, the bicistronic lines did not show robust expression of either protein. Copy number and protein expression correlated much better in the coinjected lines, with expression levels in one line approaching that observed in some of our best single transgenic controls. Thus we recommend coinjection of individual plasmids for the generation of multiply transgenic founders.


Subcellular fractionation by differential and zonal centrifugation of aerobically grown glucose-de-repressed Saccharomyces carlsbergensis.
1. Homogenates were prepared from sphaeroplasts of aerobically grown glucose-de-repressed Saccharomyces carlsbergensis and the distributions of marker enzymes were investigated after differential centrifugation. Cytochrome c oxidase and cytochrome c were sedimented almost completely at 10(5)g-min, and this fraction also contained 37% of the catalase, 27% of the acid p-nitrophenyl phosphatase, 53 and 54% respectively of the NADH- and NADPH-cytochrome c oxidoreductases. 2. Zonal centrifugation indicated complex density distributions of the sedimentable portions of these enzymes and of adenosine triphosphatases and suggested the presence of two mitochondrial populations, as well as a bimodal distribution of peroxisomes and heterogeneity of the acid p-nitrophenyl phosphatase-containing particles. 3. Several different adenosine triphosphatases were distinguished in a post-mitochondrial supernatant that contained no mitochondrial fragments; these enzymes varied in their sensitivities to oligomycin and ouabain and their distributions were different from those of pyrophosphatase, adenosine phosphatase and adenosine pyrophosphatase. 4. The distribution of NADPH-cytochrome c oxidoreductase demonstrated that it cannot be used in S. carlsbergensis as a specific marker enzyme for the microsomal fraction. Glucose 6-phosphatase, inosine pyrophosphatase, cytochrome P-450 and five other enzymes frequently assigned to microsomal fractions of mammalian origin were not detected in yeast under these growth conditions.


Targeting potassium channels to treat cerebellar ataxia.
Purkinje neuron dysfunction is associated with cerebellar ataxia. In a mouse model of spinocerebellar ataxia type 1 (SCA1), reduced potassium channel function contributes to altered membrane excitability resulting in impaired Purkinje neuron spiking. We sought to determine the relationship between altered membrane excitability and motor dysfunction in SCA1 mice. Patch-clamp recordings in acute cerebellar slices and motor phenotype testing were used to identify pharmacologic agents which improve Purkinje neuron physiology and motor performance in SCA1 mice. Additionally, we retrospectively reviewed records of patients with SCA1 and other autosomal-dominant SCAs with prominent Purkinje neuron involvement to determine whether currently approved potassium channel activators were tolerated. Activating calcium-activated and subthreshold-activated potassium channels improved Purkinje neuron spiking impairment in SCA1 mice (P < 0.05). Additionally, dendritic hyperexcitability was improved by activating subthreshold-activated potassium channels but not calcium-activated potassium channels (P < 0.01). Improving spiking and dendritic hyperexcitability through a combination of chlorzoxazone and baclofen produced sustained improvements in motor dysfunction in SCA1 mice (P < 0.01). Retrospective review of SCA patient records suggests that co-treatment with chlorzoxazone and baclofen is tolerated. Targeting both altered spiking and dendritic membrane excitability is associated with sustained improvements in motor performance in SCA1 mice, while targeting altered spiking alone produces only short-term improvements in motor dysfunction. Potassium channel activators currently in clinical use are well tolerated and may provide benefit in SCA patients. Future clinical trials with potassium channel activators are warranted in cerebellar ataxia.


Measuring Interoception: The CARdiac Elevation Detection Task.
Interoception has increasingly been the focus of psychiatric research, due to its hypothesized role in mental health. Existing interoceptive tasks either suffer from important methodological limitations, impacting their validity, or are burdensome and require specialized equipment, which limits their usage in vulnerable populations. We report on the development of the CARdiac Elevation Detection (CARED) task. Participants' heart rate is recorded by a wearable device connected to a mobile application. Notifications are sent to participants' mobile throughout the day over a period of 4 weeks. Participants are asked to state whether their heart rate is higher than usual, rate their confidence and describe the activity they were involved in when the notification occurred. Data (N = 30) revealed that 1/3 of the sample was classified as interoceptive and that participants presented overall good insight into their interoceptive abilities. Given its ease of administration and accessibility, the CARED task has the potential to be a significant asset for psychiatric and developmental research.


Ultrahigh 47-dB optical drop rejection multiwavelength add--drop filter using spatial filtering and dual bulk acousto-optic tunable filters.
A new high-speed, ultrahigh cross-talk-suppression multiwavelength add-drop optical filter structure is demonstrated with two bulk acousto-optic tunable filters. With simple spatial blocks, an average -47-dB optical suppression is measured for the unwanted wavelengths at the filter output ports. The filter is tested for the three standard visible wavelengths, red, green, and blue, and demonstrates a switching time of 0.65micros and an average optical loss of 5 dB. Applications for this filter include multiwavelength switching applications such as wavelength-division-multiplexed optical communications.


Urinary tract infection in diabetes.
The aim of this article is to review recent publications relevant to understanding the interaction of urinary tract infection and diabetes mellitus, including epidemiology, pathogenesis, microbiology, and treatment. The largest number of identified reports described aspects of epidemiology, including defining the incidence and outcomes of urinary infection in patients with diabetes. In several reports, mortality and risk of hospitalization for urinary infection were not increased with diabetes, although length of hospitalization may be prolonged. Other reports quantify the increased incidence of cystitis or pyelonephritis in persons with diabetes, but remain subject to potential biases which could overestimate the occurrence in diabetic relative to non-diabetic populations. Several reports suggest that resistant bacteria are more frequently isolated from diabetic outpatients with urinary infection, but it is not clear how this is directly attributable to diabetes. There are no recent clinical trials which enhance our understanding of optimal treatment of symptomatic urinary infection, although several review articles acknowledge the appropriateness of the non-treatment of asymptomatic bacteriuria in diabetic women. Recent reports exploring diabetes and urinary tract infection provide some insights, particularly for risks of infection and outcomes, but there are no recent large advances in the knowledge base. Questions related to incidence, optimal treatment, and role of metabolic control still need to be addressed to expand the knowledge base and enhance management of this common problem.


Catastrophic medical malpractice payouts in the United States.
Catastrophic medical malpractice payouts, $1 million or greater, greatly influence physicians' practice, hospital policy, and discussions of healthcare reform. However, little is known about the specific characteristics and overall cost burden of these payouts. We reviewed all paid malpractice claims nationwide using the National Practitioner Data Bank over a 7-year period (2004-2010) and used multivariate regression to identify risk factors for catastrophic and increased overall payouts. Claims with catastrophic payouts represented 7.9% (6,130/77,621) of all paid claims. Factors most associated with catastrophic payouts were patient age less than 1 year; quadriplegia, brain damage, or lifelong care; and anesthesia allegation group. Compared with court judgments, settlement was associated with decreased odds of a catastrophic payout (odds ratio, 0.31; 95% confidence interval [CI], 0.22-0.42) and lower estimated average payouts ($124,863; 95% CI, $101,509-144,992). A physician's years in practice and previous paid claims history had no effect on the odds of a catastrophic payout. Catastrophic payouts averaged $1.4 billion per year or 0.05% of the National Health Expenditures. Preventing catastrophic malpractice payouts should be only one aspect of comprehensive patient safety and quality improvement strategies. Future studies should evaluate the benefits of targeted interventions based on specific patient safety event characteristics.


Breast cancer-initiating cells: insights into novel treatment strategies.
There is accumulating evidence that breast cancer may arise from mutated mammary stem/progenitor cells which have been termed breast cancer-initiating cells (BCIC). BCIC identified in clinical specimens based on membrane phenotype (CD44+/CD24-/low and/or CD133+ expression) or enzymatic activity of aldehyde dehydrogenase 1 (ALDH1+), have been demonstrated to have stem/progenitor cell properties, and are tumorigenic when injected in immunocompromized mice at very low concentrations. BCIC have also been isolated and in vitro propagated as non-adherent spheres of undifferentiated cells, and stem cell patterns have been recognized even in cancer cell lines. Recent findings indicate that aberrant regulation of self renewal is central to cancer stem cell biology. Alterations in genes involved in self-renewal pathways, such as Wnt, Notch, sonic hedgehog, PTEN and BMI, proved to play a role in breast cancer progression. Hence, targeting key elements mediating the self renewal of BCIC represents an attractive option, with a solid rationale, clearly identifiable molecular targets, and adequate knowledge of the involved pathways. Possible concerns are related to the poor knowledge of tolerance and efficacy of inhibiting self-renewal mechanisms, because the latter are key pathways for a variety of biological functions and it is unknown whether their interference would kill BCIC or simply temporarily stop them. Thus, efforts to develop BCIC-targeted therapies should not only be focused on interfering on self-renewal, but could seek to identify additional molecular targets, like those involved in regulating EMT-related pathways, in reversing the MDR phenotype, in inducing differentiation and controlling cell survival pathways.


Reference ranges of handgrip strength from 125,462 healthy adults in 21 countries: a prospective urban rural epidemiologic (PURE) study.
The measurement of handgrip strength (HGS) has prognostic value with respect to all-cause mortality, cardiovascular mortality and cardiovascular disease, and is an important part of the evaluation of frailty. Published reference ranges for HGS are mostly derived from Caucasian populations in high-income countries. There is a paucity of information on normative HGS values in non-Caucasian populations from low- or middle-income countries. The objective of this study was to develop reference HGS ranges for healthy adults from a broad range of ethnicities and socioeconomically diverse geographic regions. HGS was measured using a Jamar dynamometer in 125,462 healthy adults aged 35-70 years from 21 countries in the Prospective Urban Rural Epidemiology (PURE) study. HGS values differed among individuals from different geographic regions. HGS values were highest among those from Europe/North America, lowest among those from South Asia, South East Asia and Africa, and intermediate among those from China, South America, and the Middle East. Reference ranges stratified by geographic region, age, and sex are presented. These ranges varied from a median (25th-75th percentile) 50 kg (43-56 kg) in men <40 years from Europe/North America to 18 kg (14-20 kg) in women >60 years from South East Asia. Reference ranges by ethnicity and body-mass index are also reported. Individual HGS measurements should be interpreted using region/ethnic-specific reference ranges.


Metagenomics unveils the attributes of the alginolytic guilds of sediments from four distant cold coastal environments.
Alginates are abundant polysaccharides in brown algae that constitute an important energy source for marine heterotrophic bacteria. Despite the key role of alginate degradation processes in the marine carbon cycle, little information is available on the bacterial populations involved in these processes. The aim of this work was to gain a better understanding of alginate utilization capabilities in cold coastal environments. Sediment metagenomes from four high-latitude regions of both Hemispheres were interrogated for alginate lyase gene homologue sequences and their genomic context. Sediments contained highly abundant and diverse bacterial assemblages with alginolytic potential, including members of Bacteroidetes and Proteobacteria, as well as several poorly characterized taxa. The microbial communities in Arctic and Antarctic sediments exhibited the most similar alginolytic profiles, whereas brackish sediments showed distinct structures with a higher proportion of novel genes. Examination of the gene neighbourhood of the alginate lyase homologues revealed distinct patterns depending on the potential lineage of the scaffolds, with evidence of evolutionary relationships among alginolytic gene clusters from Bacteroidetes and Proteobacteria. This information is relevant for understanding carbon fluxes in cold coastal environments and provides valuable information for the development of biotechnological applications from brown algae biomass.


Annexin V-containing cubosomes for targeted early detection of apoptosis in degenerative retinal tissue.
New drug delivery materials targeting damaged ocular tissues are of particular interest. In this work, we have formulated annexin/phosphatidylserine/phytantriol and annexin/phosphatidylserine/monoolein cubosomes based on incorporation of 1,2-dipalmitoyl-sn-glycero-3-phospho-l-serine (PS) lipid and annexin V (ANX) protein with phytantriol (Phy) and monoolein (MO) respectively. The incorporation of ANX is important because it can be used as a diagnostic tool for in vivo apoptosis detection due to its high affinity to phosphatidylserine in the presence of Ca2+. We have also prepared PS-Phy and PS-MO cubosomes without ANX as a comparison, and characterized them using dynamic light scattering, cryo-TEM images and small-angle X-ray scattering, showing that PS-Phy cubosomes have greater chemical stability, and that ANX-PS-Phy cubosomes have the potential for in vivo drug delivery. In addition, we have reconstituted an apoptotic biomimetic membrane on a surface to gain insights into cubosome-bilayer interactions using a quartz-crystal microbalance and neutron reflectometry. The neutron reflectivity data reveal that there is exchange of materials between the biomimetic apoptotic bilayer and ANX-PS-Phy cubosomes, with an accumulation of ANX between the membrane and cubosomes possibly being the reason for the reduced cytotoxicity of ANX-PS-Phy cubosomes. A rat model of laser-induced choroidal neovascularization showed that ANX-PS-Phy cubosomes specifically targeted apoptotic cells in vivo. We propose that ANX-PS-Phy cubosomes are a potential candidate for ocular drug delivery for eye diseases.


The DNA-dependent protein kinase catalytic subunit (p460) is cleaved during Fas-mediated apoptosis in Jurkat cells.
The DNA-dependent protein kinase (DNA-PK) is a serine/threonine kinase linked to DNA repair and V(D)J recombination. It is composed of a 460-kDa catalytic subunit (DNA-PKcs) and a 70/86-kDa heterodimeric regulatory component that is identical with the human autoantigen Ku. The regulatory subunit targets the catalytic subunit to the free ends of dsDNA breaks. Since apoptosis is associated with internucleosomal chromatin fragmentation and creation of dsDNA breaks, we examined whether the biochemical amounts of either DNA-PKcs or Ku changed during apoptosis mediated by the cell surface receptor Fas. We found that the catalytic subunit was cleaved into several smaller polypeptides early in apoptosis. In contrast to DNA-PKcs, Ku was neither cleaved nor decreased in amount during apoptosis. We then extended our in vivo results to a cellfree system. Cytosolic extracts derived from apoptotic cells were able to cleave DNA-PKcs into polypeptides of sizes identical with those seen in vivo, and this cleavage was inhibited by the cysteine protease inhibitors iodoacetamide and N-ethylmaleimide. Furthermore, DNA-PKcs was cleaved in vitro by purified apopain (CPP32), but not IL-1beta-converting enzyme. Cleavage was also inhibited by the specific tetrapeptide DEVD (amino acids 2709-2712 of the DNA-PKcs sequence), suggesting a candidate position for protease action. Finally, we found that the catalytic activity of DNA-PKcs was decreased in apoptotic cells. We conclude that DNA-PKcs is subject to selective cleavage by proteases during apoptosis. Cleavage of DNA-PKcs may represent a mechanism for regulating the function of DNA-dependent kinase during programmed cell death.


Individual foraging specialisation in a social mammal: the European badger (Meles meles).
Individual specialisation has been identified in an increasing number of animal species and populations. However, in some groups, such as terrestrial mammals, it is difficult to disentangle individual niche variation from spatial variation in resource availability. In the present study, we investigate individual variation in the foraging niche of the European badger (Meles meles), a social carnivore that lives in a shared group territory, but forages predominantly alone. Using stable isotope analysis, we distinguish the extent to which foraging variation in badgers is determined by social and spatial constraints and by individual differences within groups. We found a tendency for individual badgers within groups to differ markedly and consistently in their isotope values, suggesting that individuals living with access to the same resources occupied distinctive foraging niches. Although sex had a significant effect on isotope values, substantial variation within groups occurred independently of age and sex. Individual differences were consistent over a period of several months and in some instances were highly consistent across the two years of the study, suggesting long-term individual foraging specialisations. Individual specialisation in foraging may, therefore, persist in populations of territorial species not solely as a result of spatial variation in resources, but also arising from individuals selecting differently from the same available resources. Although the exact cause of this behaviour is unknown, we suggest that specialisation may occur due to learning trade-offs which may limit individual niche widths. However, ecological factors at the group level, such as competition, may also influence the degree of specialisation.


International Society of Sports Nutrition Position Stand: Probiotics.
Position statement: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of probiotic supplementation to optimize the health, performance, and recovery of athletes. Based on the current available literature, the conclusions of the ISSN are as follows: 1)Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (FAO/WHO).2)Probiotic administration has been linked to a multitude of health benefits, with gut and immune health being the most researched applications.3)Despite the existence of shared, core mechanisms for probiotic function, health benefits of probiotics are strain- and dose-dependent.4)Athletes have varying gut microbiota compositions that appear to reflect the activity level of the host in comparison to sedentary people, with the differences linked primarily to the volume of exercise and amount of protein consumption. Whether differences in gut microbiota composition affect probiotic efficacy is unknown.5)The main function of the gut is to digest food and absorb nutrients. In athletic populations, certain probiotics strains can increase absorption of key nutrients such as amino acids from protein, and affect the pharmacology and physiological properties of multiple food components.6)Immune depression in athletes worsens with excessive training load, psychological stress, disturbed sleep, and environmental extremes, all of which can contribute to an increased risk of respiratory tract infections. In certain situations, including exposure to crowds, foreign travel and poor hygiene at home, and training or competition venues, athletes' exposure to pathogens may be elevated leading to increased rates of infections. Approximately 70% of the immune system is located in the gut and probiotic supplementation has been shown to promote a healthy immune response. In an athletic population, specific probiotic strains can reduce the number of episodes, severity and duration of upper respiratory tract infections.7)Intense, prolonged exercise, especially in the heat, has been shown to increase gut permeability which potentially can result in systemic toxemia. Specific probiotic strains can improve the integrity of the gut-barrier function in athletes.8)Administration of selected anti-inflammatory probiotic strains have been linked to improved recovery from muscle-damaging exercise.9)The minimal effective dose and method of administration (potency per serving, single vs. split dose, delivery form) of a specific probiotic strain depends on validation studies for this particular strain. Products that contain probiotics must include the genus, species, and strain of each live microorganism on its label as well as the total estimated quantity of each probiotic strain at the end of the product's shelf life, as measured by colony forming units (CFU) or live cells.10)Preclinical and early human research has shown potential probiotic benefits relevant to an athletic population that include improved body composition and lean body mass, normalizing age-related declines in testosterone levels, reductions in cortisol levels indicating improved responses to a physical or mental stressor, reduction of exercise-induced lactate, and increased neurotransmitter synthesis, cognition and mood. However, these potential benefits require validation in more rigorous human studies and in an athletic population.


Minimum error calibration and normalization for genomic copy number analysis.
Copy number variations (CNV) are regional deviations from the normal autosomal bi-allelic DNA content. While germline CNVs are a major contributor to genomic syndromes and inherited diseases, the majority of cancers accumulate extensive "somatic" CNV (sCNV or CNA) during the process of oncogenetic transformation and progression. While specific sCNV have closely been associated with tumorigenesis, intriguingly many neoplasias exhibit recurrent sCNV patterns beyond the involvement of a few cancer driver genes. Currently, CNV profiles of tumor samples are generated using genomic micro-arrays or high-throughput DNA sequencing. Regardless of the underlying technology, genomic copy number data is derived from the relative assessment and integration of multiple signals, with the data generation process being prone to contamination from several sources. Estimated copy number values have no absolute or strictly linear correlation to their corresponding DNA levels, and the extent of deviation differs between sample profiles, which poses a great challenge for data integration and comparison in large scale genome analysis. In this study, we present a novel method named "Minimum Error Calibration and Normalization for Copy Numbers Analysis" (Mecan4CNA). It only requires CNV segmentation files as input, is platform independent, and has a high performance with limited hardware requirements. For a given multi-sample copy number dataset, Mecan4CNA can batch-normalize all samples to the corresponding true copy number levels of the main tumor clones. Experiments of Mecan4CNA on simulated data showed an overall accuracy of 93% and 91% in determining the normal level and single copy alteration (i.e. duplication or loss of one allele), respectively. Comparison of estimated normal levels and single copy alternations with existing methods and karyotyping data on the NCI-60 tumor cell line produced coherent results. To estimate the method's impact on downstream analyses, we performed GISTIC analyses on the original and Mecan4CNA normalized data from the Cancer Genome Atlas (TCGA) where the normalized data showed prominent improvements of both sensitivity and specificity in detecting focal regions. Mecan4CNA provides an advanced method for CNA data normalization, especially in meta-analyses involving large profile numbers and heterogeneous source data quality. With its informative output and visualization options, Mecan4CNA also can improve the interpretation of individual CNA profiles. Mecan4CNA is freely available as a Python package and through its code repository on Github.


Impact of CAre-related Regret Upon Sleep (ICARUS) cohort study: protocol of a 3-year multicentre, international, prospective cohort study of novice healthcare professionals.
Healthcare professionals are particularly at risk of developing numerous physical and psychological health problems. The experiences of emotional burden associated with providing healthcare, notably care-related regret, have been associated with these health problems, but only using cross-sectional data so far. Evidence of a causal impact of regret has not been assessed. The Impact of CAre-related Regret Upon Sleep (ICARUS) study is the first prospective and international cohort study established to examine how newly practising healthcare professionals adapt to their challenging job by assessing the impact of care-related regret on sleep and job quitting. The ICARUS cohort study will include newly practising healthcare professionals working in acute care hospitals and clinics recruited between May 2017 and November 2019. Data collection, which will begin as soon as the participant starts working with patients, will consist of a 1-year weekly assessment using a secure web survey. Follow-up data will be collected at 6, 12, 18 and 24 months after the end of the first year. We will collect detailed information on the experience of care-related regret (ie, highest regret intensity, accumulation of regrets and coping strategies related to regrets), sleep problems and job quitting. Moreover, quality of life, health status and burnout will be assessed during the follow-up. Several confounders factors, including sociodemographic characteristics, personality, night shifts and work environment characteristics, will be assessed. The study was approved by the Ethics Committee of Geneva Canton, Switzerland (CCER2016-02041), the Ethics Committee of London South Bank University (HSCSEP/17/06) and the University Research Ethics Committee of Bedfordshire (UREC106). Other study centres deemed local ethical approval unnecessary since the main ethics committee (Geneva) had already accepted the project. Results will be published in relevant scientific journals and be disseminated in international conferences. Fully anonymised data and questionnaires will be freely accessible to everyone (scientists and general public).


The accurate calculation of the band gap of liquid water by means of GW corrections applied to plane-wave density functional theory molecular dynamics simulations.
Knowledge about the intrinsic electronic properties of water is imperative for understanding the behaviour of aqueous solutions that are used throughout biology, chemistry, physics, and industry. The calculation of the electronic band gap of liquids is challenging, because the most accurate ab initio approaches can be applied only to small numbers of atoms, while large numbers of atoms are required for having configurations that are representative of a liquid. Here we show that a high-accuracy value for the electronic band gap of water can be obtained by combining beyond-DFT methods and statistical time-averaging. Liquid water is simulated at 300 K using a plane-wave density functional theory molecular dynamics (PW-DFT-MD) simulation and a van der Waals density functional (optB88-vdW). After applying a self-consistent GW correction the band gap of liquid water at 300 K is calculated as 7.3 eV, in good agreement with recent experimental observations in the literature (6.9 eV). For simulations of phase transformations and chemical reactions in water or aqueous solutions whereby an accurate description of the electronic structure is required, we suggest to use these advanced GW corrections in combination with the statistical analysis of quantum mechanical MD simulations.


Assessment of VAV2 Expression Refines Prognostic Prediction in Adrenocortical Carcinoma.
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with overall poor prognosis. The Ki67 labeling index (LI) has a major prognostic role in localized ACC after complete resection, but its estimates may suffer from considerable intra- and interobserver variability. VAV2 overexpression induced by increased Steroidogenic Factor-1 dosage is an essential factor driving ACC tumor cell invasion. To assess the prognostic role of VAV2 expression in ACC by investigation of a large cohort of patients. A total of 171 ACC cases (157 primary tumors, six local recurrences, eight metastases) from seven European Network for the Study of Adrenal Tumors centers were studied. H-scores were generated to quantify VAV2 expression. VAV2 expression was divided into two categories: low (H-score, <2) and high (H-score, ≥2). The Ki67 LI retrieved from patients' pathology records was also categorized into low (<20%) and high (≥20%). Clinical and immunohistochemical markers were correlated with progression-free survival (PFS) and overall survival (OS). VAV2 expression and Ki67 LI were significantly correlated with each other and with PFS and OS. Heterogeneity of VAV2 expression inside the same tumor was very low. Combined assessment of VAV2 expression and Ki67 LI improved patient stratification to low-risk and high-risk groups. Combined assessment of Ki67 LI and VAV2 expression improves prognostic prediction in ACC.


The RNA binding protein fragile X mental retardation protein promotes myelin sheath growth.
During development, oligodendrocytes in the central nervous system extend a multitude of processes that wrap axons with myelin. The highly polarized oligodendrocytes generate myelin sheaths on many different axons, which are far removed from the cell body. Neurons use RNA binding proteins to transport, stabilize, and locally translate mRNA in distal domains of neurons. Local synthesis of synaptic proteins during neurodevelopment facilitates the rapid structural and functional changes underlying neural plasticity and avoids extensive protein transport. We hypothesize that RNA binding proteins also regulate local mRNA regulation in oligodendrocytes to promote myelin sheath growth. Fragile X mental retardation protein (FMRP), an RNA binding protein that plays essential roles in the growth and maturation of neurons, is also expressed in oligodendrocytes. To determine whether oligodendrocytes require FMRP for myelin sheath development, we examined fmr1-/- mutant zebrafish and drove FMR1 expression specifically in oligodendrocytes. We found oligodendrocytes in fmr1-/- mutants developed myelin sheaths of diminished length, a phenotype that can be autonomously rescued in oligodendrocytes with FMR1 expression. Myelin basic protein (Mbp), an essential myelin protein, was reduced in myelin tracts of fmr1-/- mutants, but loss of FMRP function did not impact the localization of mbpa transcript in myelin. Finally, expression of FMR1-I304N, a missense allele that abrogates FMRP association with ribosomes, failed to rescue fmr1-/- mutant sheath growth and induced short myelin sheaths in oligodendrocytes of wild-type larvae. Taken together, these data suggest that FMRP promotes sheath growth through local regulation of translation.


Subsurface damage of fused silica lapped by fixed-abrasive diamond pellets.
Minimizing subsurface damage (SSD) is in high demand for optics during grinding, lapping, and polishing. A fixed-abrasive diamond pellet (FADP) has been validated as a potential tool in fast lapping and polishing of hard optical materials. This study inspects and measures the SSD of fused silica developed in lapping and microlapping by FADPs tool through a taper polishing method, assisted with profile measurement and microexamination. A series of experiments is conducted to reveal the influence of lapping parameters on SSD depth and surface roughness, including diamond size, lapping pressure, and velocity, as well as rubber type. Results indicate that SSD depth and surface roughness are mostly sensitive to diamond size but are generally independent of lapping pressure and velocity. Softer rubber can reduce SSD depth and improve surface roughness. The ratio of SSD depth to surface roughness (peak to valley: Rt) is confirmed to be 7.4±1.3, which can predict the SSD depth of fused silica lapped by FADPs with a rapid roughness measurement.


Performance enhancement in a-Si:H/μc-Si:H tandem solar cells with periodic microstructured surfaces.
Here we report on an efficient light-coupling scheme with a periodic microstructured surface to enhance the performance of thin film silicon solar cells. The centerpiece of the surface structure is the hemispherical pit arrays (HPAs), which are fabricated using an inexpensive and scalable process. The integration of HPAs into micromorph tandem thin film silicon solar cells leads to superior broadband reflection suppression properties. With this design, the reflection losses of the tandem cell are reduced to only 1.5%. We demonstrate an efficiency increase from 11.67% to 12.23% compared to a conventional cell with a flat surface, with a 4.6% increase in short circuit current density. The surface microstructures reported here can be applied to a variety of photovoltaic devices to further improve their performance.


Type I membranes, phase resetting curves, and synchrony.
Type I membrane oscillators such as the Connor model (Connor et al. 1977) and the Morris-Lecar model (Morris and Lecar 1981) admit very low frequency oscillations near the critical applied current. Hansel et al. (1995) have numerically shown that synchrony is difficult to achieve with these models and that the phase resetting curve is strictly positive. We use singular perturbation methods and averaging to show that this is a general property of Type I membrane models. We show in a limited sense that so called Type II resetting occurs with models that obtain rhythmicity via a Hopf bifurcation. We also show the differences between synapses that act rapidly and those that act slowly and derive a canonical form for the phase interactions.


Imatinib in the management of multiple gastrointestinal stromal tumors associated with a germline KIT K642E mutation.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gut and are distinguished by expression of CD117 (c-Kit). Oncogenic mutations in the KIT or PDGFRA gene are detected in approximately 85% of sporadic GISTs. In recent years, examples of familial GIST have been reported in which germline mutations of KIT or PDGFRA result in multiple GISTs, skin disorders, and other abnormalities. The most common germline mutations are in KIT exon 11, mutations in exons 8 and 17 have also been described, and there are 2 families with germline PDGFRA mutations. We present a case in which a germline KIT exon 13 mutation (K642E) was discovered in a patient with multiple GISTs of rectum, small intestine, and esophagus, as well as diffuse hyperplasia of the interstitial cells of Cajal. To our knowledge, this is only the second germline example of this particular mutation. The patient's esophageal tumors were stabilized with imatinib.


Growth Trajectories of Refugee and Nonrefugee Children in the United States.
Limited data examine longitudinal nutrition outcomes of refugee children after United States resettlement. Among refugee children, our aims were to (1) assess the changes in weight-based nutritional status between baseline (0-3 months) and 10-24 months after arrival and (2) compare the BMI (BMIz) or weight-for-length z score (WFLz) trajectories to nonrefugee children for up to 36 months after arrival. We conducted a retrospective study of refugees aged 0-16 years from Washington and Pennsylvania and compared them with an age and sex-matched nonrefugee low-income sample from Washington. Data included anthropometric measurements from the initial screening medical visit and subsequent primary care visits. Multilevel linear mixed-effects regression models evaluated the change in BMIz or WFLz trajectory. The study included 512 refugee and 1175 nonrefugee children. The unadjusted prevalence of overweight/obesity increased from 8.9% to 20% (P < .001) for 2- to 16-year-old refugees from baseline to 10-24 months. Refugees (2-16 years old) had a steeper increase in their BMIz per 12 months compared with nonrefugees (coefficient 0.18 vs 0.03; P < .001). Refugees <2 years old had a less steep increase in their WFLz per 12 months compared with nonrefugees (coefficient 0.12 vs 0.36, P = .002). Older refugee children exhibited a higher risk of obesity than nonrefugees, whereas refugees <2 years old exhibited a slower increase in their risk of obesity than nonrefugee children. All age groups experienced increasing obesity prevalence. Targeted and culturally tailored obesity prevention interventions may mitigate health and nutrition inequities among refugee children.


Kalman filtering of tunable diode laser spectrometer absorbance measurements.
A recursive Kalman time-series filter was applied to absorbance measurements obtained with a tunable diode laser spectrometer. The spectrometer uses frequency modulation spectroscopy and a nearinfrared diode laser operating at 1.604 µm to monitor the CO(2)-vapor concentration in a 30-cm absorption cell. The Kalman filter enhanced the signal-to-noise ratio of the spectrometer by an order of magnitude when an absorbance of 6 × 10(-5) was monitored.


pLoc_bal-mVirus: Predict Subcellular Localization of Multi-Label Virus Proteins by Chou's General PseAAC and IHTS Treatment to Balance Training Dataset.
Knowledge of protein subcellular localization is vitally important for both basic research and drug development. Facing the avalanche of protein sequences emerging in the post-genomic age, it is urgent to develop computational tools for timely and effectively identifying their subcellular localization based on the sequence information alone. Recently, a predictor called "pLoc-mVirus" was developed for identifying the subcellular localization of virus proteins. Its performance is overwhelmingly better than that of the other predictors for the same purpose, particularly in dealing with multi-label systems in which some proteins, known as "multiplex proteins", may simultaneously occur in, or move between two or more subcellular location sites. Despite the fact that it is indeed a very powerful predictor, more efforts are definitely needed to further improve it. This is because pLoc-mVirus was trained by an extremely skewed dataset in which some subset was over 10 times the size of the other subsets. Accordingly, it cannot avoid the biased consequence caused by such an uneven training dataset. Using the Chou's general PseAAC (Pseudo Amino Acid Composition) approach and the IHTS (Inserting Hypothetical Training Samples) treatment to balance out the training dataset, we have developed a new predictor called "pLoc_bal-mVirus" for predicting the subcellular localization of multi-label virus proteins. Cross-validation tests on exactly the same experiment-confirmed dataset have indicated that the proposed new predictor is remarkably superior to pLoc-mVirus, the existing state-of-theart predictor for the same purpose. Its user-friendly web-server is available at http://www.jci-bioinfo.cn/pLoc_balmVirus/, by which the majority of experimental scientists can easily get their desired results without the need to go through the detailed complicated mathematics. Accordingly, pLoc_bal-mVirus will become a very useful tool for designing multi-target drugs and in-depth understanding of the biological process in a cell.


Hip Arthroscopy for Femoroacetabular Impingement and Labral Tears in Patients Younger than 50 Years: Minimum Five-year Outcomes, Survivorship, and Risk Factors for Reoperations.
There is a paucity of literature on mid-term outcomes for hip arthroscopy for femoroacetabular impingement and labral tears. Inclusion criteria were age at surgery <50 years and documented preoperative patient-reported outcomes. Patients with a Tönnis grade >0 or previous ipsilateral hip conditions were excluded. Of 407 eligible cases, 327 hips (295 patients) had minimum 5-year follow-up. Mean age was 32.4 years. All mean patient-reported outcomes and visual analog scale improved at follow-up (P < 0.001). Mean satisfaction was 7.9. Thirty-eight hips (11.6%) required secondary arthroscopy at a mean of 25.1 months. Survivorship at minimum 5 years was 92.4%. The complication rate was 7.0%. Hip arthroscopy for management of femoroacetabular impingement and labral tears in patients aged <50 demonstrates favorable and safe mid-term outcomes. Several risk factors for conversion to total hip arthroplasty in this age group warrant cautious patient selection for arthroscopy.


Peer-to-peer interprofessional health policy education for Medicare part D.
To determine whether a peer-to-peer education program was an expedient and effective approach to improve knowledge and promote interprofessional communication and collaboration. Trained pharmacy students taught nursing students, medical students, and medical residents about the Medicare Part D prescription drug benefit (Part D), in 1- to 2-hour lectures. Learners completed a survey instrument to assess the effectiveness of the presentation and their attitudes toward the peer-to-peer instructional format. Learners strongly or somewhat agreed that the peer-to-peer format was effective in providing Part D education (99%) and promoted interprofessional collaboration (100%). Qualitative data highlighted the program's clinical relevance, value in promoting interprofessional collaboration, and influence on changing views about the roles and contributions of pharmacists. The Part D peer educator program is an innovative way to disseminate contemporary health policy information rapidly, while fostering interprofessional collaboration.


Histone tail acetylation in brain occurs in an unpredictable fashion after death.
Histone acetylation plays a role in the regulation of gene transcription. Yet it is not known whether post-mortem brain tissue is suitable for the analysis of histone acetylation. To examine this question, nucleosomes were isolated from frontal cortex of nine subjects which were obtained at short times after death and immediately frozen at -80°C or maintained at room temperature from 3 h up to 50 h after death and then frozen at -80°C to mimic variable post-mortem delay in tissue processing as currently occurs in normal practice. Chromatin immunoprecipitation assays were performed for two lysine residues, H3K9ac and H3K27ac. Four gene loci were amplified by SyBrGreen PCR: Adenosine A(2A) receptor, UCHL1, α-synuclein and β-globin. Results showed variability in the histone acetylation level along the post-mortem times and an increase in the acetylation level at an unpredictable time from one case to another and from one gene to another within the first 24 h of post-mortem delay. Similar results were found with three rat brains used to exclude the effects of agonal state and to normalize the start-point as real time zero. Therefore, the present observations show that human post-mortem brain is probably not suitable for comparative studies of histone acetylation.


Pitch adaptation patterns in bimodal cochlear implant users: over time and after experience.
Pitch plasticity has been observed in Hybrid cochlear implant (CI) users. Does pitch plasticity also occur in bimodal CI users with traditional long-electrode CIs, and is pitch adaptation pattern associated with electrode discrimination or speech recognition performance? The goals of this study were to characterize pitch adaptation patterns in long-electrode CI users, to correlate these patterns with electrode discrimination and speech perception outcomes, and to analyze which subject factors are associated with the different patterns. Electric-to-acoustic pitch matches were obtained in 19 subjects over time from CI activation to at least 12 months after activation, and in a separate group of 18 subjects in a single visit after at least 24 months of CI experience. Audiometric thresholds, electrode discrimination performance, and speech perception scores were also measured. Subjects measured over time had pitch adaptation patterns that fit one of the following categories: (1) "Pitch-adapting," that is, the mismatch between perceived electrode pitch and the corresponding frequency-to-electrode allocations decreased; (2) "Pitch-dropping," that is, the pitches of multiple electrodes dropped and converged to a similar low-pitch; and (3) "Pitch-unchanging," that is, the electrode pitches did not change. Subjects measured after CI experience had a parallel set of adaptation patterns: (1) "Matched-pitch," that is, the electrode pitch was matched to the frequency allocation; (2) "Low-pitch," that is, the pitches of multiple electrodes were all around the lowest frequency allocation; and (3) "Nonmatched-pitch," that is, the pitch patterns were compressed relative to the frequency allocations and did not fit either the matched-pitch or low-pitch categories. Unlike Hybrid CI users which were mostly in the pitch-adapting or matched-pitch category, the majority of bimodal CI users were in the latter two categories, pitch-dropping/low-pitch or pitch-unchanging/nonmatched-pitch. Subjects with pitch-adapting or matched-pitch patterns tended to have better low-frequency thresholds than subjects in the latter categories. Changes in electrode discrimination over time were not associated with changes in pitch differences between electrodes. Reductions in speech perception scores over time showed a weak but nonsignificant association with dropping-pitch patterns. Bimodal CI users with more residual hearing may have somewhat greater similarity to Hybrid CI users and be more likely to adapt pitch perception to reduce mismatch with the frequencies allocated to the electrodes and the acoustic hearing. In contrast, bimodal CI users with less residual hearing exhibit either no adaptation, or surprisingly, a third pattern in which the pitches of the basal electrodes drop to match the frequency range allocated to the most apical electrode. The lack of association of electrode discrimination changes with pitch changes suggests that electrode discrimination does not depend on perceived pitch differences between electrodes, but rather on some other characteristics such as timbre. In contrast, speech perception may depend more on pitch perception and the ability to distinguish pitch between electrodes, especially since during multielectrode stimulation, cues such as timbre may be less useful for discrimination.


Abnormalities in visually guided saccades suggest corticofugal dysregulation in never-treated schizophrenia.
Previous studies have reported intact visually guided saccades in schizophrenia, but these are limited by potential acute and long-term pharmacological treatment effects, small sample sizes, and a failure to follow patients over time. Visually guided saccades were examined in 44 antipsychotic-naive patients experiencing their first episode of schizophrenia prior to treatment and again after 6, 26, and 52 weeks of antipsychotic treatment. Thirty-nine matched healthy individuals were followed over the same period. Before treatment, patients showed faster saccade latencies to unpredictable visual targets, suggesting reduced inhibitory regulation of brainstem saccade generators by neocortical attentional systems. Risperidone treatment reduced this deficit, suggesting a facilitation of attentional function, but haloperidol treatment did not. However, there was also a modest decline in saccade accuracy after risperidone treatment. The ability to sustain fixation of static central and peripheral targets was unimpaired before and after treatment. These findings provide evidence for impairments in neocortical attentional systems that cause reduced corticofugal regulation of brainstem systems in schizophrenia. This dysfunction appears to be minimized by the atypical antipsychotic risperidone but at the cost of a subtle reduction in saccade accuracy, possibly mediated via adverse effects on cerebellar vermis function.


Graphene/Group 5 Transition Metal Dichalcogenide Composites for Electrochemical Applications.
In comparison to the extensive research and great success attained by Group 6 transition metal dichalcogenides (TMDs) as hydrogen evolution reaction (HER) electrocatalysts, there is limited research focused on metallic Group 5 TMDs for use as electrocatalysts for hydrogen evolution. Density functional theory calculations have pointed out that Group 5 TMDs are highly favorable for HER, especially vanadium disulfide. In this work, nanocomposites of graphene and Group 5 TMDs were synthesized by thermal exfoliation of graphene oxide/TMD precursors in an H2 S atmosphere or in a H2 atmosphere as a control. Graphene oxide was prepared by the Hummers method while vanadium tetrachloride, niobium pentachloride, and tantalum pentachloride were utilized as TMD precursors. Then the potential of these nanocomposites as electrocatalysts towards HER was explored. Although these nanocomposites do not have comparable HER performance to Group 6 TMDs, they exhibit higher electrocatalytic activity in comparison with thermally reduced graphene oxide (TRGO) in the absence of TMD modification. In addition, the capacitive performance of these materials was also investigated in consideration of the high capacitance of graphene. It was indicated that the presence of TMDs on graphene actually suppress the capacitance performance of graphene itself.


The taxonomic placement of three fossil Fundulus species and the timing of divergence within the North American topminnows (Teleostei: Fundulidae).
The fossils species †Fundulus detillae, †F. lariversi, and †F. nevadensis from localities in the western United States are represented by well-preserved material with date estimations. We combined morphological data for these fossil taxa with morphological and DNA-sequence data to conduct a phylogenetic analysis and a tip-based divergence-time estimation for the family Fundulidae. The resultant phylogeny is largely concordant with the prior total-evidence phylogeny. The fossil species do not form a monophyletic group, and do not represent a discrete western radiation of Fundulus as previously proposed. The genus Fundulus diverged into subgeneric clades likely in the Eocene or Oligocene (mean age 34.6 mya, 53-23 mya), and all subgeneric and most species-group clades had evolved by the middle Miocene. †Fundulus lariversi is a member of subgenus Fundulus in which all extant species are found only in eastern North America, demonstrating that fundulids had a complicated biogeographic history. We confirmed †Fundulus detillae as a member of the subgenus Plancterus. †F. nevadensis is not classified in a subgenus but likely is related to the subgenera Plancterus and Wileyichthys.


Faciotopy-A face-feature map with face-like topology in the human occipital face area.
The occipital face area (OFA) and fusiform face area (FFA) are brain regions thought to be specialized for face perception. However, their intrinsic functional organization and status as cortical areas with well-defined boundaries remains unclear. Here we test these regions for "faciotopy", a particular hypothesis about their intrinsic functional organisation. A faciotopic area would contain a face-feature map on the cortical surface, where cortical patches represent face features and neighbouring patches represent features that are physically neighbouring in a face. The faciotopy hypothesis is motivated by the idea that face regions might develop from a retinotopic protomap and acquire their selectivity for face features through natural visual experience. Faces have a prototypical configuration of features, are usually perceived in a canonical upright orientation, and are frequently fixated in particular locations. To test the faciotopy hypothesis, we presented images of isolated face features at fixation to subjects during functional magnetic resonance imaging. The responses in V1 were best explained by low-level image properties of the stimuli. OFA, and to a lesser degree FFA, showed evidence for faciotopic organization. When a single patch of cortex was estimated for each face feature, the cortical distances between the feature patches reflected the physical distance between the features in a face. Faciotopy would be the first example, to our knowledge, of a cortical map reflecting the topology, not of a part of the organism itself (its retina in retinotopy, its body in somatotopy), but of an external object of particular perceptual significance.


Role of the hypoxia sensing system, acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines.
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor implicated in many pathological processes. We investigated the regulation of 4 alternatively spliced isoforms (121, 165, 189 and 206 amino acids) by hypoxia, hypoglycemia, acidity, female reproductive hormones and vitamin D in breast carcinoma cell lines representing different tumor phenotypes. There was a 17-fold difference in total VEGF mRNA expression across the cell lines. The isoform expression, 121 > 165 > 189, was unchanged by different culture conditions. Hypoxia was the most potent stimulus, and the cell lines demonstrated a 1.4- to 6.9-fold range of VEGF induction, maintained when other hypoxically regulated genes (phosphoglycerate kinase 1 and glucose transporter 1) and a HIF-1-dependent reporter gene were examined. The relative inducibility of the genes was maintained in each cell line, but basal expression was independent of -fold induction. VEGF expression decreased under acidic conditions in 2 cell lines, but the hypoxia stimulus remained effective under acidic conditions. Hypoglycemia, female reproductive hormones and vitamin D exerted no effect on expression, nor did inhibitors of mutant ras. Our results show that VEGF expression varies widely between cell lines and that capacity to respond to hypoxia is also cell specific, relating mostly to the hypoxic sensing of the cell and the signal transduction mechanism. Such characteristics, if maintained in vivo, have implications for the angiogenic potential of different tumor cells under normal and hypoxic conditions.


Clinical microbiology of bacterial and fungal sepsis in very-low-birth-weight infants.
Twenty percent of very-low-birth-weight (<1500 g) preterm infants experience a serious systemic infection, and despite advances in neonatal intensive care and antimicrobials, mortality is as much as threefold higher for these infants who develop sepsis than their counterparts without sepsis during their hospitalization. Outcomes may be improved by preventative strategies, earlier and accurate diagnosis, and adjunct therapies to combat infection and protect the vulnerable preterm infant during an infection. Earlier diagnosis on the basis of factors such as abnormal heart rate characteristics may offer the ability to initiate treatment prior to the onset of clinical symptoms. Molecular and adjunctive diagnostics may also aid in diagnosing invasive infection when clinical symptoms indicate infection but no organisms are isolated in culture. Due to the high morbidity and mortality, preventative and adjunctive therapies are needed. Prophylaxis has been effective in preventing early-onset group B streptococcal sepsis and late-onset Candida sepsis. Future research in prophylaxis using active and passive immunization strategies offers prevention without the risk of resistance to antimicrobials. Identification of the differences in neonatal intensive care units with low and high infection rates and implementation of infection control measures remain paramount in each neonatal intensive care unit caring for preterm infants.


Assessment of indications in interventional cardiology: appropriateness and necessity of coronary angiography and revascularization.
In this study we present appropriateness and necessity assessments of coronary angiographies and revascularizations to determine adherence to Swiss guidelines by using the computerized second-opinion system (SOS) as a reference. We prospectively compared SOS ratings with ratings of treating cardiologists and surgeons for 203 coronary angiographies and 100 percutaneous transluminal coronary angioplasties. We also retrospectively assessed indications of 103 coronary artery bypass grafts. SOS ratings of appropriate, uncertain, and inappropriate indications for coronary angiography were 85.5%, 10%, and 4.5%, respectively, and 99.5%, 0.5%, and 0%, respectively, for revascularization. Corresponding clinicians' ratings were 95%, 4%, and 1% and 100%, 0%, and 0%, respectively. SOS ratings of necessary, uncertain, and unnecessary indications for angiography were 82.4%, 17.6%, and 0%, respectively, and 97%, 3%, and 0%, respectively, for revascularization. Corresponding clinicians' values were 88.2%, 10.6%, and 1.2% and 98%, 2%, and 0%, respectively. Significant statistical differences for coronary angiography were found for patients with acute myocardial infarction and for patients within 12 weeks of myocardial infarction. A high accordance between estimated SOS and clinically estimated appropriateness of procedures was found, which might suggest that the guidelines are valid. Regular validation and updating of the guidelines is highlighted. Possible overuse of angiography in patients within 12 weeks of myocardial infarction may need further investigation.


Dental and Temporomandibular Joint Pathology of the Grey Wolf (Canis lupus).
Skulls from 392 grey wolves (Canis lupus) were examined macroscopically according to predefined criteria. Two hundred and seven skulls were included in this study, comprised of 124 young adults (59.9%) and 83 adults (40.1%); of these, 65 (31.4%) specimens were from male wolves and 104 (50.3%) were from females, with 38 (18.4%) of unknown sex. Out of 8,694 possible teeth, 8,339 (95.9%) were present for evaluation. Fifty-five teeth (15.5%) were absent congenitally, 30 (8.5%) were lost during life and 270 (76.1%) were lost artefactually post mortem. Skeletal or dental malocclusion was present in 37 specimens (17.9%), with level bite being the most commonly encountered malocclusion. Enamel hypoplasia was present in five skulls (2.4%), affecting eight teeth (0.1%) in total. An abnormal number of roots was found on 23 teeth (0.3%) on 13 skulls (6.3%). Persistent deciduous teeth occurred in two (1.0%) specimens, affecting one (0.01%) tooth each. Fenestration or dehiscence was found associated with 203 teeth (2.4%) in 72 skulls (34.8%). Periodontitis was noted on 115 skulls (55.6%) and 1,000 teeth (11.5%), affecting significantly more adults (n = 63, 75.0%) than young adults (n = 52, 41.9%; P <0.0001). One hundred and sixty-one skulls (77.8%) showed signs of endodontal disease, including attrition or abrasion on 144 skulls (69.6%) and 2,522 teeth (30.2%) and 424 fractured teeth (5.1%) on 103 skulls (49.8%). Both lesions affected significantly more adults than young adults. Overt periapical disease was associated with six teeth (0.1%) distributed across five skulls (2.4%). A carious lesion was present on one tooth (0.01%) of one specimen (0.5%). Lesions consistent with temporomandibular joint (TMJ) osteoarthritis were found in 24 specimens (11.6%), affecting 38 joints (9.2%). Trauma to the skull, such as bite marks, bullet holes or blunt trauma, was noted in 44 skulls (21.2%). The grey wolf and the domestic dog (Canis lupus familiaris) share common dental diseases; however, the proportion and severity may vary. Although the clinical significance of dental and TMJ pathology in the grey wolf remains unknown, based on the impact of these disorders on the domestic dog, the occurrence and severity of these lesions are likely to play an important role in the morbidity and mortality of this wild canid species.


Flux variability scanning based on enforced objective flux for identifying gene amplification targets.
In order to reduce time and efforts to develop microbial strains with better capability of producing desired bioproducts, genome-scale metabolic simulations have proven useful in identifying gene knockout and amplification targets. Constraints-based flux analysis has successfully been employed for such simulation, but is limited in its ability to properly describe the complex nature of biological systems. Gene knockout simulations are relatively straightforward to implement, simply by constraining the flux values of the target reaction to zero, but the identification of reliable gene amplification targets is rather difficult. Here, we report a new algorithm which incorporates physiological data into a model to improve the model's prediction capabilities and to capitalize on the relationships between genes and metabolic fluxes. We developed an algorithm, flux variability scanning based on enforced objective flux (FVSEOF) with grouping reaction (GR) constraints, in an effort to identify gene amplification targets by considering reactions that co-carry flux values based on physiological omics data via "GR constraints". This method scans changes in the variabilities of metabolic fluxes in response to an artificially enforced objective flux of product formation. The gene amplification targets predicted using this method were validated by comparing the predicted effects with the previous experimental results obtained for the production of shikimic acid and putrescine in Escherichia coli. Moreover, new gene amplification targets for further enhancing putrescine production were validated through experiments involving the overexpression of each identified targeted gene under condition-controlled batch cultivation. FVSEOF with GR constraints allows identification of gene amplification targets for metabolic engineering of microbial strains in order to enhance the production of desired bioproducts. The algorithm was validated through the experiments on the enhanced production of putrescine in E. coli, in addition to the comparison with the previously reported experimental data. The FVSEOF strategy with GR constraints will be generally useful for developing industrially important microbial strains having enhanced capabilities of producing chemicals of interest.


Asynchronous respiratory activity of the diaphragm during spontaneous breathing in the lamb.
1. Direct simultaneous recordings from chronically implanted electrodes in different parts of the diaphragm were made in young lambs in which laryngeal adductor (thyroarytenoideus) and intercostal electromyograms, airflow, tracheal pressure and electrocorticogram and electro-oculograms for behavioural state were also recorded.2. An asynchrony of diaphragmatic contraction occurred which was dependent on sleep state. The vertebral portion showed maximal post-inspiratory activity while the lateral paratendinous portion usually terminated abruptly with end-inspiration, reciprocating closely with the onset of expiratory laryngeal adductor activity during quiet sleep. The contraction of the sternal portion was similar to the vertebral portion. In active (rapid eye movement) sleep there was no expiratory laryngeal constriction and post-inspiratory activity occurred in all portions of the diaphragm. During the characteristic bursts of rapid breathing in active sleep all post-inspiratory activity disappeared and the diaphragm contracted synchronously.3. General anaesthesia (Halothane/N(2)O or Nembutal) abolished expiratory laryngeal adductor activity and the discharge pattern became similar in all parts of the diaphragm.4. Intrathoracic vagotomy of Xylocaine blockade below the recurrent laryngeal nerves abolished post-inspiratory activity in all parts of the diaphragm, in contrast to the effect on expiratory laryngeal adductor activity which increased.5. Sustained ;tonic' electromyographic activity was often recorded from the costal and to a lesser extent the paratendinous portion of the diaphragm. This activity related to adjacent intercostal activity:ipsilateral intercostal blockade with local anaesthetic (Xylocaine 1%) abolished both the intercostal and the ;tonic' activity of the costal margins of the diaphragm. Conversely ipsilateral phrenic nerve blockade abolished all but the ;tonic' activity which related to intercostal activity.6. Interpretation of the respiratory activity of the diaphragm could not be made adequately from conventionally placed electrodes (i.e. costal, sternal slip or surface) during spontaneous breathing in unanaesthetized lambs. Simultaneous recordings showed that while expiratory flow and duration were actively controlled by expiratory laryngeal adductor activity and the diaphragm, the latter performed asynchronously. While both laryngeal and diaphragmatic expiratory functions were substantially under vagal control, the former increased and the latter decreased with reduced vagal input.


Radical-Induced Damage in 3'dTMP [Formula: see text] Insights into a Mechanism for DNA Strand Cleavage.
DNA strand scission and base release in 3'dTMP, induced by H and OH radical addition to thymine, is studied at the DFT B3LYP/6-31+G(d,p) level in the gas phase and in solution. In particular the mechanism of H atom transfer subsequent to radical formation, from C2' on the sugar to the C6 site on the base, is explored. Bulk solvation is found to lower the barrier by up to 5 kcal mol(-1) and the reaction energy by up to 12 kcal mol(-1) for the hydroxyl radical adducts. The strengths of the N1-C1'(N1-glycosidic bond) and C3'-O(P) bonds are calculated, showing that homolytic bond breaking processes are largely favored in both cases. The barrier for C3'-O(P) bond rupture is approximately 18.2 kcal mol(-1), and its breakage is preferred by 10-15 kcal mol(-1) over that of N1-glycosidic bond cleavage in both the gas phase and solvents, which is consistent with the changes in C3'-O(P) and N1-C1' bond lengths during the H transfer reactions. Mulliken spin densities, NPA charges, and vertical electron affinities are calculated to clarify the reactive properties of the intramolecular H-transfer radicals.


Association between maternal alcohol consumption in early pregnancy and pregnancy outcomes.
To investigate the association between alcohol consumption and binge drinking before and during early pregnancy and adverse pregnancy outcomes. We used data from 5,628 nulliparous pregnant participants recruited to the Screening for Pregnancy Endpoints (SCOPE) study, a prospective cohort study. Participants were interviewed at 15 weeks of gestation and information on alcohol intake before pregnancy and until the time of interview was obtained using a standardized questionnaire. Alcohol intake was classified as occasional (1-2 units per week), low (3-7 units per week), moderate (8-14 units per week), and heavy (greater than 14 units per week). Binge alcohol consumption was defined as consumption of 6 or more alcohol units in one session. Of the 5,628 participants, 1,090 (19%) reported occasional alcohol consumption, 1,383 (25%) low alcohol consumption, 625 (11%) moderate alcohol consumption, and 300 (5%) heavy alcohol consumption. Overall, 1,905 (34%) participants reported binge alcohol consumption in the 3 months before pregnancy, and 1,288 (23%) of these participants reported binge alcohol consumption during the first 15 weeks of pregnancy. Participants who consumed occasional to heavy amounts of alcohol in early pregnancy did not have altered odds of a small-for-gestational-age neonate, reduced birth weight, preeclampsia, or spontaneous preterm birth. Similarly, those who binge drank in early pregnancy did not have altered odds of these adverse pregnancy outcomes. Alcohol consumption in early pregnancy was prevalent in this nulliparous cohort. There was no association between alcohol consumption before 15 weeks of gestation and small for gestational age, reduced birth weight, preeclampsia, or spontaneous preterm birth. : II.


Persistent neutrophilic meningitis in an immunocompetent patient after basilar skull fracture: case report.
Persistent neutrophilic meningitis is an unusual form of chronic meningitis that is defined as clinical meningitis with a neutrophilic pleocytosis that persists for greater than 7 days despite empiric antimicrobial therapy. Although numerous disease processes can cause this syndrome, the majority of cases are due to opportunistic pathogens infecting immunocompromised hosts. A 47 year-old female presented after basilar skull fracture with persistent neutrophilic meningitis unresponsive to empiric broad-spectrum antibiotics. After more than weeks of intensive therapy, 4 hospitalizations and 3 relapses, Nocardia cyriacigeorgica was identified from cerebral spinal fluid. Induction therapy was begun with Ceftriaxone and trimethoprim-sulfamethoxazole (TMP-SMX) for 6 weeks followed by therapy with TMP-SMX and doxycycline for one year. The patient made a complete recovery without sequelae. Due to the difficulty in obtaining a microbiologic diagnosis, appropriate treatment in cases of persistent neutrophilic meningitis is often delayed leading to morbidity, This case highlights a number of the unique features of Nocardia meningitis and the importance of considering Nocardia infection as a cause of persistent neutrophilic meningitis even in immunocompetent patients.


The influence of the alpha-adducin G460W polymorphism and angiotensinogen M235T polymorphism on antihypertensive medication and blood pressure.
Despite the availability of a variety of effective antihypertensive drugs, inadequate control of blood pressure is common in hypertensive patients. The aim of this study was investigate whether the alpha-adducin G460W polymorphism or angiotensinogen M235T polymorphism has an effect on the mean difference in blood pressure in subjects using antihypertensive drugs. Data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, was used. This study started in 1990 and included 7983 subjects of 55 years and older. Data from three examination rounds were used. Subjects were included when their blood pressure was elevated at 1 or more examinations and/or a diuretic, beta-blocker, calcium antagonist, or ACE inhibitor was used. A marginal generalized linear model was used to assess the drug-gene interaction. In total, 3025 hypertensives were included. No drug-gene interaction on blood pressure levels was found. The mean difference in systolic blood pressure (SBP) between subjects with the W-allele and GG genotype of the alpha-adducin gene was for diuretic users 1.25 mmHg (95% CI:-2.86 to 5.35), for beta-blockers 0.02 mmHg (95% CI:-3.39 to 3.42), for calcium antagonists -0.70 mmHg (95% CI:-5.61 to 4.21), and for ACE inhibitors -3.50 mmHg (95% CI:-9.02 to 2.02). The mean difference in SBP between subjects with the TT and MM genotype was for diuretic users -2.33 mmHg (95% CI:-8.32 to 3.66), for beta-blocker -0.06 mmHg (95% CI:-4.91 to 4.79), for calcium antagonist 0.59 mmHg (95% CI:-5.95 to 7.13), and for ACE inhibitor -2.33 mmHg (95% CI:-9.66 to 5.01). The G460W polymorphism and the M235T polymorphism did not modify the difference in blood pressure levels among subjects who used diuretics, beta-blockers, calcium antagonists, or ACE inhibitors.