Synoptic taxonomy of Cortaderia Stapf (Danthonioideae, Poaceae).
Cortaderia (Poaceae; Danthonioideae) is a medium-sized genus of C3 tussock grasses, widespread in the temperate to tropic-alpine regions of South America. It is particularly important in the subalpine and alpine zones of the Andes. We revised the classification of the genus, and recognize 17 species grouped into five informal groups. We describe one new species, Cortaderia echinata H.P.Linder, from Peru. We provide a key to the groups and the species, complete nomenclature for each species including new lectotypes, and notes on the ecology, distribution and diagnostic morphological and anatomical characters.


Predictors of virological failure among people living with HIV receiving first line antiretroviral treatment in Myanmar: retrospective cohort analysis.
Progress toward the global target for 95% virological suppression among those on antiretroviral treatment (ART) is still suboptimal. We describe the viral load (VL) cascade, the incidence of virological failure and associated risk factors among people living with HIV receiving first-line ART in an HIV cohort in Myanmar treated by the Médecins Sans Frontières in collaboration with the Ministry of Health and Sports Myanmar. We conducted a retrospective cohort study, including adult patients with at least one HIV viral load test result and having received of at least 6 months' standard first-line ART. The incidence rate of virological failure (HIV viral load ≥ 1000 copies/mL) was calculated. Multivariable Cox's regression was performed to identify risk factors for virological failure. We included 25,260 patients with a median age of 33.1 years (interquartile range, IQR 28.0-39.1) and a median observation time of 5.4 years (IQR 3.7-7.9). Virological failure was documented in 3,579 (14.2%) participants, resulting in an overall incidence rate for failure of 2.5 per 100 person-years of follow-up. Among those who had a follow-up viral load result, 1,258 (57.1%) had confirmed virological failure, of which 836 (66.5%) were switched to second-line treatment. An increased hazard for failure was associated with age ≤ 19 years (adjusted hazard ratio, aHR 1.51; 95% confidence intervals, CI 1.20-1.89; p < 0.001), baseline tuberculosis (aHR 1.39; 95% CI 1.14-1.49; p < 0.001), a history of low-level viremia (aHR 1.60; 95% CI 1.42-1.81; p < 0.001), or a history of loss-to-follow-up (aHR 1.24; 95% CI 1.41-1.52; p = 0.041) and being on the same regimen (aHR 1.37; 95% CI 1.07-1.76; p < 0.001). Cumulative appointment delay was not significantly associated with failure after controlling for covariates. VL monitoring is an important tool to improve programme outcomes, however limited coverage of VL testing and acting on test results hampers its full potential. In our cohort children and adolescents, PLHIV with history of loss-to-follow-up or those with low-viremia are at the highest risk of virological failure and might require more frequent virological monitoring than is currently recommended.


Evaluating the protein coding potential of exonized transposable element sequences.
Transposable element (TE) sequences, once thought to be merely selfish or parasitic members of the genomic community, have been shown to contribute a wide variety of functional sequences to their host genomes. Analysis of complete genome sequences have turned up numerous cases where TE sequences have been incorporated as exons into mRNAs, and it is widely assumed that such 'exonized' TEs encode protein sequences. However, the extent to which TE-derived sequences actually encode proteins is unknown and a matter of some controversy. We have tried to address this outstanding issue from two perspectives: i-by evaluating ascertainment biases related to the search methods used to uncover TE-derived protein coding sequences (CDS) and ii-through a probabilistic codon-frequency based analysis of the protein coding potential of TE-derived exons. We compared the ability of three classes of sequence similarity search methods to detect TE-derived sequences among data sets of experimentally characterized proteins: 1-a profile-based hidden Markov model (HMM) approach, 2-BLAST methods and 3-RepeatMasker. Profile based methods are more sensitive and more selective than the other methods evaluated. However, the application of profile-based search methods to the detection of TE-derived sequences among well-curated experimentally characterized protein data sets did not turn up many more cases than had been previously detected and nowhere near as many cases as recent genome-wide searches have. We observed that the different search methods used were complementary in the sense that they yielded largely non-overlapping sets of hits and differed in their ability to recover known cases of TE-derived CDS. The probabilistic analysis of TE-derived exon sequences indicates that these sequences have low protein coding potential on average. In particular, non-autonomous TEs that do not encode protein sequences, such as Alu elements, are frequently exonized but unlikely to encode protein sequences. The exaptation of the numerous TE sequences found in exons as bona fide protein coding sequences may prove to be far less common than has been suggested by the analysis of complete genomes. We hypothesize that many exonized TE sequences actually function as post-transcriptional regulators of gene expression, rather than coding sequences, which may act through a variety of double stranded RNA related regulatory pathways. Indeed, their relatively high copy numbers and similarity to sequences dispersed throughout the genome suggests that exonized TE sequences could serve as master regulators with a wide scope of regulatory influence.


Self-assembly driven by an aromatic primary amide motif.
Primary amides are unique supramolecular synthons possessing two hydrogen donors and two hydrogen acceptors. By interacting in a complementary fashion, primary amides reliably generate two-dimensional hydrogen bonded networks that differ from conventional hydrogen bonded structures such as carboxylic acid dimers or one-dimensional secondary amide chains. This feature permits the design of sophisticated supramolecular assemblies based on primary amides (especially aromatic amides). Several interesting crystal structures have been constructed utilizing primary amides, although such structures have been applied only in the field of crystal engineering because the networks strongly favor crystallization. Expansion of the applications of primary amides to liquid crystals and self-assembly in solution requires an appropriate balance between primary amide-based hydrogen bonding and other noncovalent interactions. This perspective article reviews the key hydrogen bonding properties of primary amides determined from crystal structure studies, and a variety of supramolecular assemblies involving primary amides are discussed. A new strategy for overcoming crystallinity and solubility issues is proposed, involving introduction of a trifluoromethyl group at the ortho position of the aromatic primary amide. Such substitutions produce highly processable primary amides, while maintaining the two-dimensional hydrogen bonded network. Examples of self-assembly using 2-trifluoromethylbenzamide demonstrate its usefulness in self-assembly.


Relationship between wheat characteristics and nutrient digestibility in broilers: comparison between total collection and marker (titanium dioxide) technique.
Three wheat cultivars (Orpheus, Rustic, and Viscount) were used to formulate 3 test feeds (62.4% wheat) in a broiler digestibility trial. The diets were fed to male Ross 308 broiler chickens. The wheat cultivars mainly differed in their amount of non-starch polysaccharides ( NSP: ). The cultivar Orpheus was chosen to represent a high amount of NSP (102 g/kg DM), whereas the cultivars Rustic and Viscount represented low amounts of NSP (83.4 g/kg DM and 73.9 g/kg DM, respectively). Furthermore, the cultivars Orpheus and Viscount were feed quality wheat, whereas Rustic was a milling quality wheat. Nutrient digestibilities and AMEn contents of the diets were measured from 18 to 22-days-old by total excreta collection, or with the use of the indigestible marker titanium dioxide. In addition, the ileal viscosity was measured when the broilers were 25-days-old. Wheat cultivar affected N retention, DM digestibility, and AMEn. In general, the feed formulated with the high NSP wheat cultivar Orpheus resulted in the least favorable nutrient digestibilities and AMEn, whereas the results were better when the feed was formulated with the low NSP cultivars Viscount and Rustic. Feeding the Rustic cultivar caused the highest intestinal viscosity, although this was not reflected in the animal responses. Nutrient digestibilities and AMEn content of the diets were lower when calculated with the titanium dioxide marker than with the total excreta collection procedure. Moreover, the P-values of the effect of wheat cultivar on DM digestibility, N retention, crude fat digestibility and AMEn were lower with the use of the titanium dioxide marker. It can be concluded that wheat cultivar affected nutrient digestibility and AMEn, and that the observed differences were related to the amount of NSP. Furthermore, both the titanium dioxide marker and the total excreta collection methods showed the same trends despite the different values obtained. The titanium dioxide marker method was the simplest to use and produced valid results.


Epidemiological changes in leishmaniasis in Spain according to hospitalization-based records, 1997-2011: raising awareness towards leishmaniasis in non-HIV patients.
In Spain, Leishmania infantum is endemic, human visceral and cutaneous leishmaniasis cases occurring both in the Peninsula, as well as in the Balearic Islands. We aimed to describe the clinical characteristics of leishmaniasis patients and the changes in the disease evolution after the introduction of antiretroviral therapy in 1997. In this descriptive study, we used Spanish Centralized Hospital Discharge Database for the hospitalized leishmaniasis cases between 1997 and 2011. We included in the analysis only the records having leishmaniasis as the first registered diagnosis and calculated the hospitalization rates. Disease trend was described taking into account the HIV status. Adjusted odds-ratio was used to estimate the association between clinical and socio-demographic factors and HIV co-infection. Of the total 8010 Leishmaniasis hospitalizations records, 3442 had leishmaniasis as first diagnosis; 2545/3442 (75.6%) were males and 2240/3442 (65.1%) aged between 14-65 years. Regarding disease forms, 2844/3442 (82.6%) of hospitalizations were due to visceral leishmaniasis (VL), while 118/3442 (3.4%) hospitalizations were cutaneous leishmaniasis (CL). Overall, 1737/2844 of VL (61.1%) were HIV negatives. An overall increasing trend was observed for the records with leishmaniasis as first diagnosis (p=0.113). Non-HIV leishmaniasis increased during this time period (p=0.021) while leishmaniasis-HIV co-infection hospitalization revealed a slight descending trend (p=0.717). Leishmaniasis-HIV co-infection was significantly associated with male sex (aOR=1.6; 95% CI: 1.25-2.04), 16-64 years age group (aOR=17.4; 95%CI: 2.1-143.3), visceral leishmaniasis aOR=6.1 (95%CI: 3.27-11.28) and solid neoplasms 4.5 (95% CI: 1.65-12.04). The absence of HIV co-infection was associated with lymph/hematopoietic neoplasms (aOR=0.3; 95%CI:0.14-0.57), other immunodeficiency (aOR=0.04; 95% CI:0.01-0.32) and transplant (aOR=0.01; 95%CI:0.00-0.07). Our findings suggest a significant increase of hospitalization in the absence of HIV co-infection, with a predomination of VL. We consider that clinicians in Spain should be aware of leishmaniasis not only in the HIV population but also in non HIV patients, especially for those having immunosuppression as an associate condition.


Evolutionary rescue in a changing world.
Evolutionary rescue occurs when adaptive evolutionary change restores positive growth to declining populations and prevents extinction. Here we outline the diagnostic features of evolutionary rescue and distinguish this phenomenon from demographic and genetic rescue. We then synthesize the rapidly accumulating theoretical and experimental studies of evolutionary rescue, highlighting the demographic, genetic, and extrinsic factors that affect the probability of rescue. By doing so, we clarify the factors to target through management and conservation. Additionally, we identify several putative cases of evolutionary rescue in nature, but conclude that compelling evidence remains elusive. We conclude with a horizon scan of where the field might develop, highlighting areas of potential application, and suggest areas where experimental evaluation will help to evaluate theoretical predictions.


First Report of Bacterial Leaf Spot on Cichorium intybus Caused by Pseudomonas cichorii in Florida.
Italian dandelion (Cichorium intybus L.) is a leafy chicory plant grown as a fresh vegetable in salads. In August 2011, necrotic lesions were observed on leaves of about 20% of the Italian dandelion plants in an experimental field at the Tropical Research and Education Center (TREC) of the University of Florida in Homestead, FL. The lesions were dark brown with a yellow halo and most were irregular in shape. Some lesions formed along the leaf edge and developed into large lesions up to 20 to 30 mm long. Symptomatic leaf tissues were cut into small pieces (2 to 3 mm), sterilized in 10% Clorox (0.6% sodium hypochlorite) for 2 min following surface disinfection in 70% ethanol for 30 s, placed on nutrient agar (NA), and incubated at 28°C in the dark for 4 to 5 days. A bacterium was consistently isolated from the leaf lesions. Colonies of these bacteria were raised, opaque, and round with a slightly irregular, colorless margin while the center was light brown. The colonies were gram-negative with yellow fluorescence appearance on Pseudomonas F agar (Becton, Dickinson and Company, Sparks, MD). LOPAT tests were carried out to further identify the species of this fluorescent pseudomonad (2). The bacterium was levan negative, oxidase positive, potato rot negative, arginine dihydrolase negative, and tobacco hypersensitivity positive. Results from this test indicated that the bacterium belongs to LOPAT group III of fluorescent pseudomonads. Bacterial identity was further confirmed as Pseudomonas cichorii by amplifying the 16S rRNA gene with the universal bacterial primers 8F and 1492R (1) and sequence analysis (GenBank Accession No. KC311733). The partial 1,361-bp 16S rRNA gene sequences had 100% identity with P. cichorii (JF951725.1), which was isolated from infected soybean plants. Pathogenicity of the isolate was tested twice by spraying a suspension of the bacterium (107 CFU/ml) onto three 4-week-old plants until runoff. The control plants were sprayed with sterile distilled water. All plants were covered with plastic bags to maintain moisture for 48 h in an air-conditioned greenhouse (22 ± 1°C). Similar lesions were observed on the inoculated plant leaves 5 to 7 days after inoculation, whereas no lesions were developed on the control plants. Bacterial colonies with same morphology were recovered from the lesions, fulfilling Koch's postulates. P. cichorii is widespread worldwide with an important economic impact on celery, chrysanthemum, and lettuce. In South Florida, P. cichorii was reported as the causal agent of bacterial leaf spot on escarole (Cichorium endivia L.) (3). To our knowledge, this is the first report of bacterial leaf spot on Italian dandelion caused by P. cichorii in Florida. References: (1) J. P. Galkiewicz and C. A. Kellogg. Appl. Environ. Microbiol. 74:7828, 2008. (2) T. Goszczynska et al. Introduction to Practical Phytobacteriology. Isteg Scientific Publications, Irene, South Africa, 2000. (3) K. Pernezny and R. N. Raid. Plant Dis. 85:1208, 2001.


Alpha stimulation of the human parietal cortex attunes tactile perception to external space.
An intriguing question in neuroscience concerns how somatosensory events on the skin are represented in the human brain. Since Head and Holmes' [1] neuropsychological dissociation between localizing touch on the skin and localizing body parts in external space, touch is considered to operate in a variety of spatial reference frames [2]. At least two representations of space are in competition during orienting to touch: a somatotopic one, reflecting the organization of the somatosensory cortex (S1) [3], and a more abstract, external reference frame that factors postural changes in relation to body parts and/or external space [4, 5]. Previous transcranial magnetic stimulation (TMS) studies suggest that the posterior parietal cortex (PPC) plays a key role in supporting representations as well as orienting attention in an external reference frame [4, 6]. Here, we capitalized on the TMS entrainment approach [7, 8], targeting the intraparietal sulcus (IPS). We found that frequency-specific (10 Hz) tuning of the PPC induced spatially specific enhancement of tactile detection that was expressed in an external reference frame. This finding establishes a tight causal link between a concrete form of brain activity (10 Hz oscillation) and a specific type of spatial representation, revealing a fundamental property of how the parietal cortex encodes information.


Digit Position and Forces Covary during Anticipatory Control of Whole-Hand Manipulation.
Theoretical perspectives on anticipatory planning of object manipulation have traditionally been informed by studies that have investigated kinematics (hand shaping and digit position) and kinetics (forces) in isolation. This poses limitations on our understanding of the integration of such domains, which have recently been shown to be strongly interdependent. Specifically, recent studies revealed strong covariation of digit position and load force during the loading phase of two-digit grasping. Here, we determined whether such digit force-position covariation is a general feature of grasping. We investigated the coordination of digit position and forces during five-digit whole-hand manipulation of an object with a variable mass distribution. Subjects were instructed to prevent object roll during the lift. As found in precision grasping, there was strong trial-to-trial covariation of digit position and force. This suggests that the natural variation of digit position that is compensated for by trial-to-trial variation in digit forces is a fundamental feature of grasp control, and not only specific to precision grasp. However, a main difference with precision grasping was that modulation of digit position to the object's mass distribution was driven predominantly by the thumb, with little to no modulation of finger position. Modulation of thumb position rather than fingers is likely due to its greater range of motion and therefore adaptability to object properties. Our results underscore the flexibility of the central nervous system in implementing a range of solutions along the digit force-to-position continuum for dexterous manipulation.


Effect of the number of ball contacts within bouts of 4 vs. 4 small-sided soccer games.
The aim of this study was to examine the influence of the number of ball touches authorized per possession on the physical demands, technical performances and physiological responses throughout the bouts within 4 vs. 4 soccer small-sided games (SSGs). Twenty international soccer players (27.4 ± 1.5 y, 180.6 ± 2.3 cm, 79.2 ± 4.2 kg, body fat 12.7 ± 1.2%) performed three different 4 vs. 4 SSGs (4 × 4 min) in which the number of ball touches authorized per possession was manipulated (1 touch = 1T; 2 touches = 2T; Free Play = FP). The SSGs were divided in 4 bouts (B1, B2, B3 and B4) separated by 3 min of passive recovery. The physical performances, technical activities, heart rate responses, blood lactate and RPE were analyzed. The FP rule presented greater number of duels, induced the lowest decreases of the sprint and high-intensity performances, and affected less the technical actions (successful passes and number of ball losses) from B1 to B4 as compared with 1T and 2T forms. Moreover, the SSG played in 1T form led to reach higher solicitation of the high-intensity actions while players presented more difficulty to perform a correct technical action. The modification of the number of ball touches authorized per possession affects the soccer player activity from the first to the last bout of SSG, indicating that the determination of this rule has to be precisely planned by the coach according to the objectives of the training.


Improving protection against respirable dust at an underground crusher booth.
The U.S. National Institute for Occupational Safety and Health completed a 15-month study at an underground limestone mine crusher booth that evaluated three research parameters: (1) the effectiveness of a filtration and pressurization system for improving the air quality inside the operator booth, (2) the relative effectiveness of η > 99 and η > 95 experimental prototype filters in the system, and (3) the performance of three different cab pressure monitoring devices. The protection factor was quantified monthly using particle counters in the respirable dust range of 0.3 to 1 μm particle size, and gravimetric dust samples were gathered at the beginning and end of the overall study. Under static (closed-door) conditions, the filtration unit offered a gravimetric calculated protection factor between 10 and 31, depending on the filter type and loading condition. The monthly particle counting analysis shows that the η > 95 filter offers a protection factor nearly five times that of the η > 99 filter, where n = 15 samples. The booth pressure monitors were tested and proved to be a valid indicator of system performance over time.


Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.
We assessed effectiveness, safety, and tolerability of paclitaxel or fluorouracil when added to radiation plus cisplatin followed by adjuvant chemotherapy in a programme of selected bladder preservation for patients with muscle invasive bladder cancer. In our randomised phase 2 trial, we enrolled patients with T2-4a transitional cell carcinoma of the bladder at 24 medical centres in the USA. We randomly allocated patients to receive paclitaxel plus cisplatin (paclitaxel group) or fluorouracil plus cisplatin (fluorouracil group) with twice-daily radiation in random block sizes per site on the basis of clinical T-stage (T2 vs T3-4). Patients and physicians were aware of treatment assignment. All patients had transurethral resection of bladder tumour and twice-daily radiotherapy to 40·3 Gy, along with allocated chemotherapy, followed by cystoscopic and biopsy assessment of response. Patients who had a tumour response with downstaging to T0, Tcis, or Ta received consolidation chemoradiotherapy to 64·3 Gy, with the same chemotherapy regimen as in the induction phase. Patients received adjuvant cisplatin-gemcitabine-paclitaxel after the end of chemoradiotherapy. If, after induction, persistent disease was graded as T1 or worse, we recommended patients undergo cystectomy and adjuvant chemotherapy. We assessed the primary endpoints of rates of treatment completion and toxic effects in all randomly allocated patients. This study is registered with ClinicalTrials.gov, number NCT00055601. Between Dec 13, 2002, and Jan 11, 2008, we enrolled 97 patients, of whom 93 were eligible for analysis. Median follow-up was 5·0 years (IQR 5·0-6·2). Of 46 patients in the paclitaxel group, 45 (98%) completed induction (16 [35%] with grade 3-4 toxicity), 39 (85%) completed induction and consolidation (11 [24%] with grade 3-4 toxicity due to consolidation), and 31 (67%) completed the entire protocol with adjuvant chemotherapy. 34 (85%) of 40 assessable patients in the paclitaxel group had grade 3-4 toxicity during adjuvant chemotherapy. Of 47 patients in the fluorouracil group, 45 (96%) completed induction (nine [19%] with grade 3-4 toxicity), 39 (83%) completed induction and consolidation (12 [26%] had grade 3-4 toxicity due to consolidation), and 25 (53%) completed the entire protocol with adjuvant chemotherapy. 31 (76%) of 41 assessable patients in the fluorouracil group had grade 3-4 toxicity during adjuvant chemotherapy. Five (11%) patients treated with the paclitaxel regimen and three (6%) patients treated with the fluorouracil regimen developed late grade 3-4 radiotherapy toxicities. 11 (24%) patients treated with the paclitaxel regimen and 16 (34%) patients treated with the fluorouracil regimen developed late grade 3-4 toxicities unrelated to radiotherapy. One patient (in the fluorouracil group) died during follow-up. Six (13%) patients in the paclitaxel group and in three (6%) patients in the fluorouracil group discontinued due to treatment-related toxicity. In the absence of phase 3 data, our findings could inform selection of a bladder-sparing trimodality chemotherapy regimen for patients with muscle invasive bladder cancer. US National Cancer Institute.


Isolation of Japanese encephalitis virus from clinical specimens using a continuous mosquito cell line.
During the 1983 Japanese encephalitis (JE) epidemic in northern Thailand, we systematically attempted to isolate JE virus (JEV) from clinical specimens collected from 49 consecutive JE patients at 1 provincial hospital. Fresh acute plasma and cerebrospinal fluid (CSF) samples and postmortem brain samples were immediately inoculated onto cultured monolayers of Aedes pseudoscutellaris (LSTM-AP-61) cells which had been shipped to the epidemic site. None of 49 plasma samples yielded virus. None of 30 fresh CSF samples from nonfatal cases yielded virus, but 5 of 15 (33%) CSF samples from fatal cases did. Inoculation of fresh brain specimens obtained at autopsy yielded virus in every case attempted (7 of 7), whereas postmortem needle biopsy specimens of brain yielded virus in only 1 of 4 cases. Isolates were most frequently successful using thalamic tissue (6 of 7 cases), but isolates were also commonly obtained from frontal cortex (4/7), occipital cortex (4/7), cerebellum (4/7), medulla (4/7) and pons (2/7).


Low density lipoprotein transport across a microvascular endothelial barrier after permeability is increased.
We investigated the pathways for low density lipoprotein (LDL) transport across an endothelial barrier in individually perfused microvessels before and after an increase in permeability. The divalent cation ionophore A23187 (5 microM) was used to increase microvessel permeability. LDL permeability coefficients (PsLDL) were measured using quantitative fluorescence microscopy. In the control state, PsLDL measured after 10-23 minutes of accumulation of fluorescent-labeled LDL outside the microvessel wall was 4.8 x 10(-8) cm/sec. The transvascular vesicular exchange of approximately 50 vesicles/sec would account for the measured flux. The flux of LDL across the microvessel wall increased as much as 170-fold at the peak of the permeability increase (2-4 minutes after ionophore infusion). Permeability returned toward control values 10 minutes after ionophore infusion but remained elevated for as long as ionophore was present in the perfusate. The effective PsLDL was similar in magnitude to the Ps for fluorescent-labeled dextran (MW 20,000) when permeability was increased. To investigate the nature of pathways for LDL in the high-permeability state, PsLDL was measured at a series of microvessel pressures. LDL transport increased as microvessel pressure increased, demonstrating coupling of LDL flux to transvascular water flow. Solvent drag accounted for more than 95% of the increased flux of LDL in the period 2-10 minutes after permeability increased. Our results conform to the hypothesis that porous pathways between adjacent endothelial cells contribute to LDL transport across an endothelial barrier when permeability is increased.


A model of (often mixed) stereotype content: competence and warmth respectively follow from perceived status and competition.
Stereotype research emphasizes systematic processes over seemingly arbitrary contents, but content also may prove systematic. On the basis of stereotypes' intergroup functions, the stereotype content model hypothesizes that (a) 2 primary dimensions are competence and warmth, (b) frequent mixed clusters combine high warmth with low competence (paternalistic) or high competence with low warmth (envious), and (c) distinct emotions (pity, envy, admiration, contempt) differentiate the 4 competence-warmth combinations. Stereotypically, (d) status predicts high competence, and competition predicts low warmth. Nine varied samples rated gender, ethnicity, race, class, age, and disability out-groups. Contrary to antipathy models, 2 dimensions mattered, and many stereotypes were mixed, either pitying (low competence, high warmth subordinates) or envying (high competence, low warmth competitors). Stereotypically, status predicted competence, and competition predicted low warmth.


Social Connectedness in Family Social Support Networks: Strengthening Systems of Care for Children with Special Health Care Needs.
Current approaches to addressing the problems families face when navigating complex service systems on behalf of their children rely largely on state or nationally driven efforts around the development of systems of care (SOCs). However, operationalizing meaningful family involvement within SOCs remains a challenge, with little attention paid to the role of personal social support networks (PSSNs). Specifically, risk factors related to the variations in the social connectedness of family social support networks are difficult to identify, assess, and track over time. This paper summarizes families' descriptions of their PSSNs and describes the development of a social network analysis tool, the Person-Centered Network App (PCNA), used to measure and monitor the social connectedness of families of children with special health care and developmental needs. Twenty-nine families participated in the project and completed social network surveys, identifying a total of 38 unique types of support partners and 230 partnerships (dyadic relationships). Families identified a range of formal and informal members including primary care providers, medical specialists, family, friends, faith-based organizations, insurance providers, nurses, community organizations, early interventionists, school resources, other families, online support groups, and public resources, rating 61 percent of them as "very important." Informal network members (e.g., family, friends) provided emotional and day-to-day support. Primary care providers, medical specialists, and public resources provided health care services while early intervention and medical specialists provided therapies. PSSNs were characterized by high levels of trust but low levels of coordination. These findings inform providers and case workers that families can readily describe their social connectedness in ways that may affect health care access and utilization. Understanding how PSSNs function in the lives of families of children with complex health care needs provides opportunities for improving systems of care (e.g., medical homes) and ultimately, enhancing health and developmental outcomes.


An investigation into the use of MMCTP to tune accelerator source parameters and testing its clinical application.
This paper presents an alternative method to tune Monte Carlo electron beam parameters to match measured data using a minimal set of variables in order to reduce the model setup time prior to clinical implementation of the model. Monte Carlo calculations provide the possibility of a powerful treatment planning verification technique. The nonstandardized and nonautomated process of tuning the required accelerator model is one of the reasons for delays in the clinical implementation of Monte Carlo techniques. This work aims to establish and verify an alternative tuning method that can be carried out in a minimal amount of time, allowing it to be easily implemented in a clinical setting by personnel with minimal experience with Monte Carlo methods. This tuned model can then be incorporated into the MMCTP system to allow the system to be used as a second dose calculation check for IMRT plans. The technique proposed was used to establish the primary electron beam parameters for accelerator models for the Varian Clinac 2100 6 MV photon beam using the BEAMnrc Monte Carlo system. The method is intended to provide a clear, direct, and efficient process for tuning an accelerator model using readily available clinical quality assurance data. The tuning provides a refined model, which agrees with measured dose profile curves within 1.5% outside the penumbra or 3 mm in the penumbra, for square fields with sides of 3 cm up to 30 cm. These models can then be employed as the basis for Monte Carlo recalculations of dose distributions, using the MMCTP system, for clinical treatment plans, providing an invaluable assessment tool. This was tested on six IMRT plans and compared to the measurements performed for the pretreatment QA process. These Monte Carlo values for the average dose to the chamber volume agreed with measurements to within 0.6%.


Regulated protein aggregation: stress granules and neurodegeneration.
The protein aggregation that occurs in neurodegenerative diseases is classically thought to occur as an undesirable, nonfunctional byproduct of protein misfolding. This model contrasts with the biology of RNA binding proteins, many of which are linked to neurodegenerative diseases. RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis. The process of regulated protein aggregation is most evident in formation of stress granules. Stress granules assemble when RNA binding proteins aggregate through their glycine rich domains. Stress granules function to sequester, silence and/or degrade RNA transcripts as part of a mechanism that adapts patterns of local RNA translation to facilitate the stress response. Aggregation of RNA binding proteins is reversible and is tightly regulated through pathways, such as phosphorylation of elongation initiation factor 2α. Microtubule associated protein tau also appears to regulate stress granule formation. Conversely, stress granule formation stimulates pathological changes associated with tau. In this review, I propose that the aggregation of many pathological, intracellular proteins, including TDP-43, FUS or tau, proceeds through the stress granule pathway. Mutations in genes coding for stress granule associated proteins or prolonged physiological stress, lead to enhanced stress granule formation, which accelerates the pathophysiology of protein aggregation in neurodegenerative diseases. Over-active stress granule formation could act to sequester functional RNA binding proteins and/or interfere with mRNA transport and translation, each of which might potentiate neurodegeneration. The reversibility of the stress granule pathway also offers novel opportunities to stimulate endogenous biochemical pathways to disaggregate these pathological stress granules, and perhaps delay the progression of disease.


Managing anticoagulation for atrial fibrillation: current issues and future strategies.
Although warfarin is superior to aspirin in reducing the risk of stroke in patients with atrial fibrillation, it can increase major bleeds. Hence, physicians stratify patients according to stroke risk to ensure a net benefit. In this review, the CHA(2) DS(2) -VASc stratification scheme used in the latest European Society of Cardiology (2010/12) guidelines will be explained. The greater sensitivity of this scheme, compared to the previous CHADS(2) , more closely delineates patients for whom warfarin is appropriate. The review also anticipates that there will be a wider range of patients who may benefit from the new oral anticoagulants, which show similar or superior efficacy and/or safety to warfarin with a significant reduction in intracranial haemorrhage and do not require routine coagulation monitoring. The role of conventional and new anticoagulant options will also be discussed.


Pseudouridinylation of mRNA coding sequences alters translation.
Chemical modifications of RNAs have long been established as key modulators of nonprotein-coding RNA structure and function in cells. There is a growing appreciation that messenger RNA (mRNA) sequences responsible for directing protein synthesis can also be posttranscriptionally modified. The enzymatic incorporation of mRNA modifications has many potential outcomes, including changing mRNA stability, protein recruitment, and translation. We tested how one of the most common modifications present in mRNA coding regions, pseudouridine (Ψ), impacts protein synthesis using a fully reconstituted bacterial translation system and human cells. Our work reveals that replacing a single uridine nucleotide with Ψ in an mRNA codon impedes amino acid addition and EF-Tu GTPase activation. A crystal structure of the Thermus thermophilus 70S ribosome with a tRNAPhe bound to a ΨUU codon in the A site supports these findings. We also find that the presence of Ψ can promote the low-level synthesis of multiple peptide products from a single mRNA sequence in the reconstituted translation system as well as human cells, and increases the rate of near-cognate Val-tRNAVal reacting on a ΨUU codon. The vast majority of Ψ moieties in mRNAs are found in coding regions, and our study suggests that one consequence of the ribosome encountering Ψ can be to modestly alter both translation speed and mRNA decoding.


Long-term effects of home visitation on maternal life course and child abuse and neglect. Fifteen-year follow-up of a randomized trial.
Home-visitation services have been promoted as a means of improving maternal and child health and functioning. However, long-term effects have not been examined. To examine the long-term effects of a program of prenatal and early childhood home visitation by nurses on women's life course and child abuse and neglect. Randomized trial. Semirural community in New York. Of 400 consecutive pregnant women with no previous live births enrolled, 324 participated in a follow-up study when their children were 15 years old. Families received a mean of 9 home visits during pregnancy and 23 home visits from the child's birth through the second birthday. DATA SOURCES AND MEASURES: Women's use of welfare and number of subsequent children were based on self-report; their arrests and convictions were based on self-report and archived data from New York State. Verified reports of child abuse and neglect were abstracted from state records. During the 15-year period after the birth of their first child, in contrast to women in the comparison group, women who were visited by nurses during pregnancy and infancy were identified as perpetrators of child abuse and neglect in 0.29 vs 0.54 verified reports (P<.001). Among women who were unmarried and from households of low socioeconomic status at initial enrollment, in contrast to those in the comparison group, nurse-visited women had 1.3 vs 1.6 subsequent births (P=.02), 65 vs 37 months between the birth of the first and a second child (P=.001), 60 vs 90 months' receiving Aid to Families With Dependent Children (P=.005), 0.41 vs 0.73 behavioral impairments due to use of alcohol and other drugs (P=.03), 0.18 vs 0.58 arrests by self-report (P<.001), and 0.16 vs 0.90 arrests disclosed by New York State records (P<.001). This program of prenatal and early childhood home visitation by nurses can reduce the number of subsequent pregnancies, the use of welfare, child abuse and neglect, and criminal behavior on the part of low-income, unmarried mothers for up to 15 years after the birth of the first child.


A laser imaging and neutron reflection investigation into the monolayer behaviour of fatty acids used for taste masking microspheres.
Fatty acid microspheres have been used for taste masking purposes whereby the drug is preferentially released in the lower gastrointestinal tract, although the mechanisms involved are poorly understood. In this study, we use a combination of surface pressure measurements, Brewster angle microscopy (BAM) and neutron reflectivity measurements to study the phase miscibility and escaping tendency from mixed stearic and palmitic acid films with a view to relating this to drug dissolution behaviour. It was noted that mixed systems showed considerably greater film interaction and instability than those composed of the pure lipid, especially in alkaline media. BAM studies were able to identify a range of phase separated structures for both the pure and mixed systems. Neutron reflectivity studies indicated a marked selective dissolution of palmitic acid into the subphase as a function of time and allowed quantification of the rate of dissolution of this species. It is concluded that the fatty acids are interacting within the monolayer and in addition the palmitic acid is escaping the mixed monolayers and dissolving into the alkali subphase. These findings have strong relevance for understanding the mechanism of drug release from the associated microspheres.


First Report of Pectobacterium wasabiae Causing Soft Rot of Cabbage in Malaysia.
Soft rot of cabbage (Brassica rapa) occurs sporadically in Malaysia, causing economic damage under the hot and wet Malaysian weather conditions that are suitable for disease development. In June 2011, 27 soft rotting bacteria were isolated from cabbage plants growing in the Cameron Highlands and Johor State in Malaysia where the economic losses exceeded 50% in severely infected fields and greenhouses. Five independent strains were initially identified as Pectobacterium wasabiae based on their inability to grow at 37°C, and elicit hypersensitive reaction (HR) on Nicotiana tabaccum and their ability to utilize raffinose and lactose. These bacterial strains were gram-negative, rod-shaped, N-acetylglucosaminyl transferase, gelatin liquefaction, and OPNG-positive and positive for acid production from D-galactose, lactosemelibiose, raffinose, citrate, and trehalose. All strains were negative for indole production, phosphatase activity, reducing sucrose, and negative for acid production from maltose, sorbitol, inositol, inolin, melezitose, α-methyl-D-glucoside, and D-arabitol. All the strains exhibited pectolytic activity on potato slices. PCR assays were conducted to distinguish P. wasabiae from P. carotovorum subsp. brasiliensis, P. atrosepticum, and other Pectobacterium species using primers Br1f/L1r (2), Eca1f/Eca2r (1), and EXPCCF/EXPCCR, respectively. DNA from strains did not yield the expected amplicon with the Br1f/L1r and Eca1f/Eca2r, whereas a 550-bp amplicon typical of DNA from P. wasabiae was produced with primers EXPCCF/EXPCCR. ITS-RFLP using the restriction enzyme, Rsa I, produced similar patterns for the Malaysian strains and the P. wasabiae type strain (SCRI488), but differentiated it from P. carotovora subsp. carotovora, P. atrosepticum, P. carotovorum subsp. brasiliensis, and Dickeya chrysanthemi type strains. BLAST analysis of the 16S rRNA DNA sequence (GenBank Accession No. KC445633) showed 99% identity to the 16S rRNA of Pw WPP163. Phylogenetic reconstruction using concatenated DNA sequences of mdh and gapA from P. wasabiae Cc6 (KC484657) and other related taxa (4) clustered Malaysian P. wasabiae strains with P. wasabiae SCRI488, readily distinguishing it from other closely related species of Pectobacterium. Pathogenicity assays were conducted on leaves and stems of four mature cabbage plants for each strain (var. oleifera) by injecting 10 μl of a bacterial suspension (108 CFU/ml) into either stems or leaves, and incubating them in a moist chamber at 80 to 90% relative humidity at 30°C. Water-soaked lesions similar to those observed in the fields and greenhouses were observed 72 h after injection and bacteria with similar characteristics were consistently reisolated. Symptoms were not observed on water-inoculated controls. The pathogenicity test was repeated with similar results. P. wasabiae was previously reported to cause soft rot of horseradish in Japan (3). However, to our knowledge, this is the first report of P. wasabiae infecting cabbage in Malaysia. References: (1) S. H. De Boer and L. J. Ward. Phytopathology 85:854, 1995. (2) V. Duarte et al. J. Appl. Microbiol. 96:535, 2004. (3) M. Goto and K. Matsumoto. Int. J. Syst. Bacteriol. 37:130, 1987. (4) B. Ma et al. Phytopathology 97:1150, 2007.


Three-dimensional superresolution by three-zone complex pupil filters.
Complex pupil filters are introduced to improve the three-dimensional resolving power of an optical imaging system. Through the design of the essential parameters of such filters, the transmittance and radius of the first zone, three-dimensional superresolution is realized. The Strehl ratio and the transverse and axial gains of such filters are analyzed in detail. A series of simulation examples of such filters are also presented that prove that three-dimensional superresolution can be realized. The advantage of such filters is that it is easy to realize three-dimensional superresolution, and the disadvantage is that the sidelobes of the axial intensity distribution are too high. But this can be overcome by the application of a confocal system.


PALEOBIOLOGICAL APPLICATIONS OF THREE-DIMENSIONAL BIOMETRY ON LARGER BENTHIC FORAMINIFERA: A NEW ROUTE OF DISCOVERIES.
Four specimens of larger benthic foraminifera (the Recent Palaeonummulites venosus and Operculina ammonoides, and the phylogenetically related Paleogene Nummulites fabianii and N. fichteli) were investigated by X-ray tomography. The resulting three-dimensional measurements enabled a comprehensive, quantitative study of shell morphology to interpret cell growth without specific shell preparation and/or destruction. After segmentation and extraction of all scanned lumina, the following characters were measured on all chambers of each specimen: chamber volume, septal distance, chamber height, and chamber width. The sequence of chamber lumina follows either a logistic function (Palaeonummulites, Operculina), where the deceleration in growth rate of the latest chambers could mark the onset of reproduction, or it can be modeled by a series of stepwise functions with differing constants (Nummulites). Variations around the growth model are either periodic, following external cycles, or random as expressed by abrupt deviations. Therefore, they may reflect the response of the cell to environmental changes in terms of cyclic changes (e.g., seasonality) or single events (e.g., predator attack). Correlations between chamber volume and the other chamber parameters show that septal distance always matches the sequence in chamber volume and can therefore be used as a proxy for environmental analyses in both growth models. Chamber height and width often remain constant around their function and rarely deviate drastically to accommodate the needed lumen for retaining test size and shape. Chamber width may vary according to chamber volume in involute specimens, whereas both chamber height and width correlate with volume in those tests following an Archimedean spiral. X-ray-tomography shows particular promise in determining which parameters that can be assessed routinely in two dimensions primarily reflect environmental conditions vs. parameters best used for taxonomic identification and for systematic lineage reconstruction.


Standing time and all-cause mortality in a large cohort of Australian adults.
To determine the association between standing time and all-cause mortality. Prospective questionnaire data from 221,240 individuals from the 45 and Up Study were linked to mortality data from the New South Wales Registry of Deaths (Australia) from February 1, 2006 to June 17, 2012. Hazard ratios for all-cause mortality according to standing time at baseline were estimated in 2013 using Cox regression modelling, adjusted for sex, age, education, urban/rural residence, physical activity, sitting time, body mass index, smoking status, self-rated health and disability. During 937,411 person years (mean follow-up=4.2 yr) 8009 deaths occurred. All-cause mortality hazard ratios were 0.90 (95% CI 0.85-0.95), 0.85 (95% CI 0.80-0.95), and 0.76 (95% CI 0.69-0.95) for standing 2-≤5h/d, 5-≤8h/d, or >8h/d respectively, compared to standing two or less hours per day. Further analyses revealed no significant interactions between standing and sex (p=0.93), the presence/absence of cardiovascular disease or diabetes (p=0.22), BMI (p=0.78), physical activity (p=0.16) and sitting time (p=0.22). This study showed a dose-response association between standing time and all-cause mortality in Australian adults aged 45 years and older. Increasing standing may hold promise for alleviating the health risks of prolonged sitting.


A novel GATA6 variant in a boy with neonatal diabetes and diaphragmatic hernia: a familial case with a review of the literature.
GATA6 gene variants come along with possible features such as pancreas agenesis/hypoplasia, neonatal diabetes and congenital heart defect. Congenital hypothyroidism, and hepatobiliary and gut abnormalities are also detectable. Children with congenital heart defects and neonatal diabetes were already described in 1970. GATA6 variants can be due to de novo variants or due to inherited variants. To date, 11 cases due to an inherited variant have been described. Herein we present a novel heterozygous GATA6 variant (c.1291C > T p.[Gln431*]) in a boy with transient neonatal diabetes, diaphragmatic hernia, congenital heart defect and early-onset scoliosis. The same variant was also present in the mother. At the age of 3 years, a random evaluation revealed a hemoglobin A1c (HbA1c) level of 7.8% (62 mmol/mol) without any diabetes-related symptoms. He was started on insulin therapy and HbA1c normalized. A short review of the literature of hereditary cases of the GATA6 variant revealed the variable phenotypic spectrum and showed that patients with a mild phenotype are likely to have children with a more severe phenotype.


Determining energy expenditure from treadmill walking using hip-worn inertial sensors: an experimental study.
We describe an experimental study to estimate energy expenditure during treadmill walking using a single hip-mounted inertial sensor (triaxial accelerometer and triaxial gyroscope). Typical physical-activity characterization using commercial monitors use proprietary counts that do not have a physically interpretable meaning. This paper emphasizes the role of probabilistic techniques in conjunction with inertial data modeling to accurately predict energy expenditure for steady-state treadmill walking. We represent the cyclic nature of walking with a Fourier transform and show how to map this representation to energy expenditure (VO(2), mL/min) using three regression techniques. A comparative analysis of the accuracy of sensor streams in predicting energy expenditure reveals that using triaxial information leads to more accurate energy-expenditure prediction compared to only using one axis. Combining accelerometer and gyroscope information leads to improved accuracy compared to using either sensor alone. Nonlinear regression methods showed better prediction accuracy compared to linear methods but required an order of higher magnitude run time.


The Plastid Lipocalin LCNP Is Required for Sustained Photoprotective Energy Dissipation in Arabidopsis.
Light utilization is finely tuned in photosynthetic organisms to prevent cellular damage. The dissipation of excess absorbed light energy, a process termed nonphotochemical quenching (NPQ), plays an important role in photoprotection. Little is known about the sustained or slowly reversible form(s) of NPQ and whether they are photoprotective, in part due to the lack of mutants. The Arabidopsis thaliana suppressor of quenching1 (soq1) mutant exhibits enhanced sustained NPQ, which we term qH. To identify molecular players involved in qH, we screened for suppressors of soq1 and isolated mutants affecting either chlorophyllide a oxygenase or the chloroplastic lipocalin, now renamed plastid lipocalin (LCNP). Analysis of the mutants confirmed that qH is localized to the peripheral antenna (LHCII) of photosystem II and demonstrated that LCNP is required for qH, either directly (by forming NPQ sites) or indirectly (by modifying the LHCII membrane environment). qH operates under stress conditions such as cold and high light and is photoprotective, as it reduces lipid peroxidation levels. We propose that, under stress conditions, LCNP protects the thylakoid membrane by enabling sustained NPQ in LHCII, thereby preventing singlet oxygen stress.


Relative resistance of HIV-1 founder viruses to control by interferon-alpha.
Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed. The replication of plasma virus isolates generated from subjects acutely infected with HIV-1 and molecularly cloned founder HIV-1 strains could be reduced but not fully suppressed by type 1 IFNs in vitro. The mean IC50 value for IFNα2 (22 U/ml) was lower than that for IFNβ (346 U/ml), although at maximally-inhibitory concentrations both IFN subtypes inhibited virus replication to similar extents. Individual virus isolates exhibited differential susceptibility to inhibition by IFNα2 and IFNβ, likely reflecting variation in resistance to differentially up-regulated IFN-stimulated genes. Virus isolates from subjects acutely infected with HIV-1 were significantly more resistant to in vitro control by IFNα than virus isolates generated from the same individuals during chronic, asymptomatic infection. Viral IFN resistance declined rapidly after the acute phase of infection: in five subjects, viruses derived from six-month consensus molecular clones were significantly more sensitive to the antiviral effects of IFNs than the corresponding founder viruses. The establishment of systemic HIV-1 infection by relatively IFNα-resistant founder viruses lends strong support to the hypothesis that IFNα plays an important role in the control of HIV-1 replication during the earliest stages of infection, prior to systemic viral spread. These findings suggest that it may be possible to harness the antiviral activity of type 1 IFNs in prophylactic and potentially also therapeutic strategies to combat HIV-1 infection.


Functional role of cellular senescence in biliary injury.
Cellular senescence is a state of irreversible cell cycle arrest that has been involved in many gastrointestinal diseases, including human cholestatic liver disorders. Senescence may play a role in biliary atresia, primary sclerosing cholangitis, cellular rejection, and primary biliary cirrhosis, four liver diseases affecting cholangiocytes and the biliary system. In this review, we examine proposed mechanisms of senescence-related biliary diseases, including hypotheses associated with the senescence-associated phenotype, induction of senescence in nearby cells, and the depletion of stem cell subpopulations. Current evidence for the molecular mechanisms of senescence in the previously mentioned diseases is discussed in detail, with attention to recent advances on the role of pathways associated with senescence-associated phenotype, stress-induced senescence, telomere dysfunction, and autophagy.


Is adult neurogenesis essential for olfaction?
In mammals, new neurons are recruited into restricted brain areas throughout life. Adult-born neurons produced in the subventricular zone of the lateral ventricle migrate rostrally towards the olfactory bulb. Although thousands of neurons reach this central structure every day, the functional impact of their integration into mature circuits remains a matter of debate. Recent investigations have revealed no striking sensory deficits per se when adult bulbar neurogenesis is challenged. However, some cognitive functions, such as perceptual learning and olfactory memory, are clearly impaired. In this review we highlight the role of network activity in shaping ongoing neurogenesis and, in turn, how the integration of adult-born neurons refines pre-existing network function, and consequently olfactory behavior.


Are survivors who report cancer-related financial problems more likely to forgo or delay medical care?
Financial problems caused by cancer and its treatment can substantially affect survivors and their families and create barriers to seeking health care. The authors identified cancer survivors diagnosed as adults (n=1556) from the nationally representative 2010 National Health Interview Survey. Using multivariable logistic regression analyses, the authors report sociodemographic, clinical, and treatment-related factors associated with perceived cancer-related financial problems and the association between financial problems and forgoing or delaying health care because of cost. Adjusted percentages using the predictive marginals method are presented. Cancer-related financial problems were reported by 31.8% (95% confidence interval, 29.3%-34.5%) of survivors. Factors found to be significantly associated with cancer-related financial problems in survivors included younger age at diagnosis, minority race/ethnicity, history of chemotherapy or radiation treatment, recurrence or multiple cancers, and shorter time from diagnosis. After adjustment for covariates, respondents who reported financial problems were more likely to report delaying (18.3% vs 7.4%) or forgoing overall medical care (13.8% vs 5.0%), prescription medications (14.2% vs 7.6%), dental care (19.8% vs 8.3%), eyeglasses (13.9% vs 5.8%), and mental health care (3.9% vs 1.6%) than their counterparts without financial problems (all P<.05). Cancer-related financial problems are not only disproportionately represented in survivors who are younger, members of a minority group, and have a higher treatment burden, but may also contribute to survivors forgoing or delaying medical care after cancer.


Transverse load sensing based on a dual-frequency optoelectronic oscillator.
We propose and experimentally demonstrate a fiber-optic sensor implemented based on a dual-frequency optoelectronic oscillator (OEO) for transverse load sensing. In the OEO loop, a phase-shifted fiber Bragg grating (PS-FBG) is employed to which a transverse load is applied to introduce a birefringence to create two orthogonally polarized notches, which leads to the generation of two oscillating frequencies. The beat frequency between the two oscillating frequencies is a function of the load force applied to the PS-FBG. The proposed sensor is experimentally demonstrated. The sensitivity and the minimal detectable load are measured to be as high as ~9.73 GHz/(N/mm) and 2.06×10(-4) N/mm, respectively. The high-frequency purity and stability of the generated microwave signal by the OEO permit extremely reliable and high-accuracy measurement. The frequency interrogation allows the system to operate at an ultra-high speed. In addition, the sensing signal is insensitive to the variations of both the environmental temperature and the optical carrier wavelength.


Patterns of evolutionary change in Baikalian gammarids inferred from DNA sequences (Crustacea, Amphipoda).
The Baikalian gammarids (Crustacea, Amphipoda) are the most widely known and most spectacular example of an adaptive radiation among contemporary freshwater invertebrates. To study the phylogeny of the Baikalian gammarids we sequenced a 622-bp-long fragment of the nuclear gene coding for 18S rRNA from species of 18 endemic Baikalian genera and Gammarus pulex-a non-Baikalian taxon. Some important morphological characters appear independently in both lineages and suggest parallelism in the development of gigantism and body armament. The first lineage comprises benthic, mostly unarmed taxa. The second lineage contains predominantly armed taxa, most of which are detrivorous or carnivorous.


Transmission of HIV-1 drug resistance in Switzerland: a 10-year molecular epidemiology survey.
Representative prevalence data of transmitted drug-resistant HIV-1 are essential to establish accurate guidelines addressing resistance testing and first-line treatments. Systematic resistance testing was carried out in individuals in Switzerland with documented HIV-1 seroconversion during 1996-2005 and available samples with RNA > 1000 copies/ml obtained within 1 year of estimated seroconversion. Resistance interpretation used the Stanford list of mutations for surveillance of transmitted drug resistance and the French National Agency for AIDS Research algorithm. Viral sequences from 822 individuals were available. Risk groups were men having sex with men (42%), heterosexual contacts (32%) and intravenous drug users (20%); 30% were infected with non-B subtype viruses. Overall, prevalence of transmitted resistance was 7.7% [95% confidence interval (CI), 5.9-9.5] for any drug, 5.5% (95% CI, 3.9-7.1) for nucleoside reverse transcriptase inhibitors, 1.9% (95% CI, 1.0-2.8) for non-nucleoside reverse transcriptase inhibitors and 2.7% (95% CI, 1.6-3.8) for protease inhibitors. Dual- or triple-class resistance was observed in 2% (95% CI, 0.8-2.5). No significant trend in prevalence of transmitted resistance was observed over years. There were no differences according to ethnicity, risk groups or gender, but prevalence of transmitted resistance was highest among individuals infected with subtype B virus. The transmission rate of drug-resistant HIV-1 has been stable since 1996, with very rare transmission of dual- or triple-class resistance. These data suggest that transmission of drug resistance in the setting of easy access to antiretroviral treatment can remain stable and be kept at a low level.


The effects of cyclic tensile strain on the organisation and expression of cytoskeletal elements in bovine intervertebral disc cells: an in vitro study.
It is still relatively unclear how intervertebral disc (IVD) cells sense a mechanical stimulus and convert this signal into a biochemical response. Previous studies demonstrated that the cytoskeletal elements are mechano-responsive in many cell types and may contribute to mechano-signalling pathways. The objective of this study was to determine the response of cells from the outer annulus fibrosus (OAF) to physiological levels of cyclic tensile strain; further, cells from the nucleus pulposus (NP) were also subjected to an identical loading regime to compare biological responses across the IVD populations. We determined whether the organisation and expression of the major cytoskeletal elements and their associated accessory proteins are responsive to mechanical stimulation in these cells, and whether these changes correlated with either a catabolic or anabolic phenotype. OAF and NP cells from immature bovine IVD were seeded onto Flexcell® type I collagen coated plates. Cells were subjected to cyclic tensile strain (10 %, 1 Hz) for 60 minutes. Post-loading, cells were processed for immunofluorescence microscopy, RNA extracted for quantitative PCR and protein extracted for Western blotting analysis. F-actin reorganisation was evident in OAF and NP cells subjected to tensile strain; strain induced β-actin at the transcriptional and translational level in OAF cells. β-tubulin mRNA and protein synthesis increased in strained OAF cells, but vimentin expression was significantly inhibited. Cytoskeletal element organisation and expression were less responsive to strain in NP cells. Tensile strain increased type I collagen and differentially regulated extracellular matrix (ECM)-degrading enzymes' mRNA levels in OAF cells. Strain induced type II collagen transcription in NP cells, but had no effect on the transcription of any other genes analysed. Tensile strain induces different mechano-responses in the organisation and/or expression of cytoskeletal elements and on markers of IVD metabolism. Differential mechano-regulation of anabolic and catabolic ECM components in the OAF and NP populations reflects their respective mechanical environments in situ.


amoA Gene abundances and nitrification potential rates suggest that benthic ammonia-oxidizing bacteria and not Archaea dominate N cycling in the Colne Estuary, United Kingdom.
Nitrification, mediated by ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA), is important in global nitrogen cycling. In estuaries where gradients of salinity and ammonia concentrations occur, there may be differential selections for ammonia-oxidizer populations. The aim of this study was to examine the activity, abundance, and diversity of AOA and AOB in surface oxic sediments of a highly nutrified estuary that exhibits gradients of salinity and ammonium. AOB and AOA communities were investigated by measuring ammonia monooxygenase (amoA) gene abundance and nitrification potentials both spatially and temporally. Nitrification potentials differed along the estuary and over time, with the greatest nitrification potentials occurring mid-estuary (8.2 μmol N grams dry weight [gdw](-1) day(-1) in June, increasing to 37.4 μmol N gdw(-1) day(-1) in January). At the estuary head, the nitrification potential was 4.3 μmol N gdw(-1) day(-1) in June, increasing to 11.7 μmol N gdw(-1) day(-1) in January. At the estuary head and mouth, nitrification potentials fluctuated throughout the year. AOB amoA gene abundances were significantly greater (by 100-fold) than those of AOA both spatially and temporally. Nitrosomonas spp. were detected along the estuary by denaturing gradient gel electrophoresis (DGGE) band sequence analysis. In conclusion, AOB dominated over AOA in the estuarine sediments, with the ratio of AOB/AOA amoA gene abundance increasing from the upper (freshwater) to lower (marine) regions of the Colne estuary. These findings suggest that in this nutrified estuary, AOB (possibly Nitrosomonas spp.) were of major significance in nitrification.


Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study.
The FLT3 gene is mutated by an internal tandem duplication (ITD) in 20-25% of adults with acute myeloid leukemia (AML). We studied 82 adults <60 years of age with primary AML and normal cytogenetics, who received uniform high-dose therapy and found FLT3 ITD in 23 (28%) patients. When the 23 FLT3 ITD+ cases were compared with the 59 cases with wild-type (WT) FLT3, disease-free survival (DFS) was inferior (P = 0.03), yet overall survival (OS) was not different (P = 0.14). However, 8 (35%) of 23 FLT3 ITD/+ cases also lacked a FLT3 WT allele (FLT3(ITD-R)) as determined by PCR and loss of heterozygosity. Thus, three genotypic groups were identified: normal FLT3(WT/WT), heterozygous FLT3(ITD/WT), and hemizygous FLT3(ITD/-). DFS and OS were significantly inferior for patients with FLT3(ITD/-) (P = 0.0017 and P = 0.0014, respectively). Although DFS and OS for FLT3(WT/WT) and FLT3(ITD/WT) groups did not differ (P = 0.32 and P = 0.98, respectively), OS of the FLT3(ITD/-) group was worse than the FLT3(WT/WT) (P = 0.0005) and FLT3(ITD/WT) (P = 0.008) groups. We propose a model in which FLT3(ITD/-) represents a dominant positive, gain-of-function mutation providing AML cells with a greater growth advantage compared with cells having the FLT3(WT/WT) or FLT3(ITD/WT) genotypes. In conclusion, we have identified the FLT3(ITD/-) genotype as an adverse prognostic factor in de novo AML with normal cytogenetics. A poor prognosis of the relatively young FLT3(ITD/-) adults (median age, 37 years), despite treatment with current dose-intensive regimens, suggests that new treatment modalities, such as therapy with a FLT3 tyrosine kinase inhibitor, are clearly needed for this group of patients.


Histopathology of continuous wave neodymium: yttrium aluminum garnet and diode laser contact transscleral lesions in rabbit ciliary body. A comparative study.
Neodymium: yttrium aluminum garnet (Nd:YAG) laser transscleral cyclophotocoagulation has been shown to be an effective method of lowering intraocular pressure (IOP). Transmission and absorption features of diode laser radiation (810 nm) make these new laser sources suitable for production of transscleral thermal lesions. The transscleral effects on rabbit ciliary body of Nd:YAG and diode laser wavelengths were compared using a CW Nd:YAG laser and a CW Aluminum Gallium Arsenide diode laser. Both lasers were delivered by silica optic fibers, 600 microns in diameter. Eight rabbits were treated by applying the optic fiber 0.5 mm from limbus while increasing energy values from 0.2-2 J. The lesions produced at equal energy values underwent gross and histologic and ultrastructural comparison. Gross examination revealed threshold lesions at 1 J energy for the Nd:YAG laser and 0.8 J for the diode laser. The diode laser produced transscleral thermal lesions of the rabbit ciliary body comparable to those achieved by the Nd:YAG laser. The histologic and ultrastructural study showed that diode laser radiation produced more remarkable damage to the ciliary pigmented structures, causing deep coagulation necrosis of the pigmented epithelium, wide disorganization of the collagen in the stroma, and intravascular coagulation phenomena in the ciliary vessels. Before the introduction of these new laser sources in clinical transscleral procedures, further investigation is needed to determine optimal energy levels.


Laparoscopic cholecystectomy for elderly patients: gold standard for golden years?
Laparoscopic cholecystectomy (LC) has known physiological benefits and positive socioeconomic effects over the open procedure. Although recent studies have questioned the technique's efficacy in elderly patients (>65 years), we hypothesize that LC is safe and efficacious in that patient group. Five thousand eight hundred eighty-four consecutive patients (mean age, 40 years; 26% male) underwent an attempted LC (conversion rate, 5.2%) from 1991 to 2001 at a teaching institution. Of these, 395 patients (6.7%) were older than 65 years. Analysis included patient age, sex, American Society of Anesthesiologists classification, conversion rate, morbidity, mortality, and assessment of results over time. Elderly patients were predominantly male (64%). Septuagenarians had a 40% incidence of complicated gallstone disease, such as acute cholecystitis, choledocholithiasis, or biliary pancreatitis, and octogenarians had a 55% incidence. Overall mortality was 1.4%. The conversion rate was 17% for the first 5 years of the study period and 7% for the second half. The conversion rate was 22% for patients with complicated disease and 2.5% for patients with chronic cholecystitis. Average hospital stay decreased from 10.2 days to 4.6 days during the first and second half of the study period, respectively. The results of LC in patients aged 65 to 69 years are comparable with those previously reported in younger patients. Patients older than 70 years had a 2-fold increase in complicated biliary tract disease and conversion rates, but a low mortality rate (2%) compared with results of other authors (12%), despite an increase in American Society of Anesthesiologists classification. Increased technical experience with LC favorably affected outcomes over time. Early diagnosis and treatment prior to onset of complications are necessary for further improvement in the outcomes of elderly patients undergoing LC.


Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: a prospective double blind placebo-controlled randomized trial.
The use of peppermint oil in treating the irritable bowel syndrome has been studied with variable results probably due to the presence of patients affected by small intestinal bacterial overgrowth, lactose intolerance or celiac disease that may have symptoms similar to irritable bowel syndrome. The aim of the study was to test the effectiveness of enteric-coated peppermint oil in patients with irritable bowel syndrome in whom small intestinal bacterial overgrowth, lactose intolerance and celiac disease were excluded. Fifty-seven patients with irritable bowel syndrome according to the Rome II criteria, with normal lactose and lactulose breath tests and negative antibody screening for celiac disease, were treated with peppermint oil (two enteric-coated capsules twice per day or placebo) for 4 weeks in a double blind study. The symptoms were assessed before therapy (T(0)), after the first 4 weeks of therapy (T(4)) and 4 weeks after the end of therapy (T(8)). The symptoms evaluated were: abdominal bloating, abdominal pain or discomfort, diarrhoea, constipation, feeling of incomplete evacuation, pain at defecation, passage of gas or mucus and urgency at defecation. For each symptom intensity and frequency from 0 to 4 were scored. The total irritable bowel syndrome symptoms score was also calculated as the mean value of the sum of the average of the intensity and frequency scores of each symptom. At T(4), 75% of the patients in the peppermint oil group showed a >50% reduction of basal (T(0)) total irritable bowel syndrome symptoms score compared with 38% in the placebo group (P<0.009). With peppermint oil at T(4) and at T(8) compared with T(0) a statistically significant reduction of the total irritable bowel syndrome symptoms score was found (T(0): 2.19+/-0.13, T(4): 1.07+/-0.10*, T(8): 1.60+/-0.10*, *P<0.01 compared with T(0), mean+/-S.E.M.), while no change was found with the placebo. A 4 weeks treatment with peppermint oil improves abdominal symptoms in patients with irritable bowel syndrome.


PRESTO, the on-line photon energy spectrometer at FERMI: design, features and commissioning results.
Measurement of the emission wavelength and the spectral content of the photon radiation is essential information for both machine and experimental physicists at a free-electron laser (FEL) user facility. Knowledge of the photon beam spectral properties is needed during the machine optimization and for performing machine studies (i.e. monitoring the change of the FEL output as a function of the machine parameters). The experimentalists, on the other hand, need to know the photon beam spectral distribution of the source, shot to shot, to discriminate the acquired data. Consequently, the main requirement for the instrument, supposed to obtain this information, is the capability of working on-line and shot-to-shot, with minimal perturbation of the beam delivered to the experimental stations. Starting from the grating fundamental equations, the conceptual design of the FERMI Pulse-Resolved Energy Spectrometer: Transparent and On-line (PRESTO) is presented, explaining the optical design in detail. The performance of PRESTO, in terms of resolving power, efficiency and spectral response, is also discussed. Finally, some useful features beyond the usual measurement of the energy spectrum are reported, as they have been routinely used by both machine and experimental physicists.


An Initiative to Optimize Waste Streams in the Operating Room: RECycling in the Operating Room (RECOR) Project.
The goal of this project was to optimally sort waste material in the operating room (OR) environment and divert waste such that streams of low-cost disposal, including recyclable material, could be maximized. Using the Lean Six Sigma method, we followed 5 steps to define, measure, analyze, improve, and control. Descriptive statistics were used to describe OR characteristics during the study period. Two-sample Student t test with assumption of unequal variance was used to compare the daily weight of solid waste, regulated medical waste, and recyclable waste between the 2-week baseline period and the 2-week implementation period. The weight and number of bags of solid waste decreased by 12% and 6% per OR per day, respectively. For regulated medical waste, the weight and number of bags decreased by 59% and 61% per OR per day, respectively. Recycled-material weight and number of bags increased by 19% and 45% per OR per day, respectively. This work emphasizes the importance and feasibility of implementing a program of appropriate waste segregation in the OR not only to improve safety in disposal practices but also to minimize institutional disposal costs and reduce the environmental footprint generated by the healthcare sector.


Development of a real-time RT-PCR assay combined with ethidium monoazide treatment for RNA viruses and its application to detect viral RNA after heat exposure.
A method was developed for discriminating damaged viruses or naked viral RNA from intact viruses by ethidium monoazide (EMA) treatment before RT-PCR. The applied EMA treatment consisted of three steps: (1) EMA dose, (2) exposure to light, and (3) additional purification by spin-column gel filtration. Approximately 4-log reduction in viral RNA concentration was observed by adding a dose of 10 μg/mL-EMA with 300 s of light irradiation. Although residual EMA can be an inhibitor of RT-PCR, its effect was reduced by spin-column gel filtration or a QIAamp® Viral RNA Mini Kit. EMA-RT-PCR was applied to the thermally treated PV1. Results of EMA-RT-PCR were similar to the plaque assay when PV1 was thermally inactivated. Although this is a preliminary study investigating applicability of the EMA-RT-PCR method for RNA viruses, the results suggest that the method is potentially applicable for the selective detection of epidemiologically important enteric viruses in water such as enteroviruses and noroviruses.


ParkIndex: Validation and application of a pragmatic measure of park access and use.
Composite metrics integrating park availability, features, and quality for a given address or neighborhood are lacking. The purposes of this study were to describe the validation, application, and demonstration of ParkIndex in four diverse communities. This study occurred in Fall 2018 in 128 census block groups within Seattle(WA), Brooklyn(NY), Raleigh(NC), and Greenville County(SC). All parks within a half-mile buffer were audited to calculate a composite park quality score, and select households provided data about use of proximal parks via an online, map-based survey. For each household, the number of parks, total park acreage, and average park quality score within one half-mile were calculated using GIS. Logistic regression was used to identify a parsimonious model predicting park use. ParkIndex values (representing the probability of park use) were mapped for all study areas and after scenarios involving the addition and renovation/improvement of parks. Out of 360 participants, 23.3% reported visiting a park within the past 30 days. The number of parks (OR = 1.36, 95% CI = 1.15-1.62), total park acreage (OR = 1.13, 95% CI = 1.07-1.19), and average park quality score (OR = 1.04, 95% CI = 1.01-1.06) within one half-mile were all associated with park use. Composite ParkIndex values across the study areas ranged from 0 to 100. Hypothetical additions of or renovations to study area parks resulted in ParkIndex increases of 22.7% and 19.2%, respectively. ParkIndex has substantial value for park and urban planners, citizens, and researchers as a common metric to facilitate awareness, decision-making, and intervention planning related to park access, environmental justice, and community health.


Analysis of the phospholipase C gene of Clostridium perfringens KZ1340 isolated from Antarctic soil.
Clostridium perfringens KZ1340 isolated from Antarctic soil was first classified as Clostridium plagarum and later as a lecithinase-negative variant of C. perfringens. Although the strain produced no detectable lecithinase (phospholipase C, PLC) activity in the culture supernatant, it was shown by Southern blot hybridization to possess a PLC-encoding gene (plc). To determine the cause of the PLC deficiency, we cloned and sequenced the plc gene from KZ1340. The deduced amino acid sequence consists of 398 amino acid residues, coinciding with those of the plc genes previously determined. Tyrosine was substituted for histidine at amino acid position 148, which is thought to bind a zinc ion essential for PLC activity. Northern blot analysis revealed that KZ1340 expressed the plc gene at an extremely low level. Furthermore, the plc gene cloned from C. perfringens strain 13 into a plasmid was expressed weakly in KZ1340, compared to that in strain 13. This indicates that the former strain represses plc gene expression in trans. When a phylogenetic tree of plc genes was constructed, the KZ1340 plc gene formed a monophyletic branch along with those of various other C. perfringens strains, supporting the classification of the strain as a variant of C. perfringens.


Cell-free assembly of the herpes simplex virus capsid.
Herpes simplex virus type 1 (HSV-1) capsids were found to assemble spontaneously in a cell-free system consisting of extracts prepared from insect cells that had been infected with recombinant baculoviruses coding for HSV-1 capsid proteins. The capsids formed in this system resembled native HSV-1 capsids in morphology as judged by electron microscopy, in sedimentation rate on sucrose density gradients, in protein composition, and in their ability to react with antibodies specific for the HSV-1 major capsid protein, VP5. Optimal capsid assembly required the presence of extracts containing capsid proteins VP5, VP19, VP23, VP22a, and the maturational protease (product of the UL26 gene). Assembly was more efficient at 27 degrees C than at 4 degrees C. The availability of a cell-free assay for HSV-1 capsid formation will be of help in identifying the morphogenetic steps that occur during capsid assembly in vivo and in evaluating candidate antiherpes therapeutics directed at capsid assembly.


Cell-size confinement effect on protein diffusion in crowded poly(ethylene)glycol solution.
Micrometric membrane confinements and macromolecular crowding of cytoplasm are key factors that regulate molecular diffusion in live cells. Previous studies have shown that macromolecular crowding delays molecular diffusion. However, the effect of cell-size confinement on diffusion in the crowding environment is yet to be elucidated. Using fluorescence correlation spectroscopy (FCS), we analyzed protein diffusion in microdroplets containing polymer solution covered with lipid membranes that mimic cells. As a result, we found that a synergistic condition of crowding and micrometric confinement results in accelerated protein diffusion on a sub-millisecond time scale. This acceleration rate strongly depended on the size of the confined space and the degree of crowding. These findings indicate that cell-size confinement supports protein diffusion in highly crowded cytoplasm.


Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
Stroke is a major cause of disability and death. The Brain Attack Coalition has proposed establishment of primary and comprehensive stroke centers to provide appropriate care to stroke patients who require basic and more advanced interventions, respectively. Primary stroke centers have been designated by The Joint Commission since 2003, as well as by various states. The designation of comprehensive stroke centers (CSCs) is now being considered. To assist in this process, we propose a set of metrics and related data that CSCs should track to monitor the quality of care that they provide and to facilitate quality improvement. We analyzed available guideline statements, reviews, and other literature to identify the major features that distinguish CSCs from primary stroke centers, drafted a set of metrics and related data elements to measure the key components of these aspects of stroke care, and then revised these through an iterative process to reach a consensus. We propose a set of metrics and related data elements that cover the major aspects of specialized care for patients with ischemic cerebrovascular disease and nontraumatic subarachnoid and intracerebral hemorrhages at CSCs. The metrics that we propose are intended to provide a framework for standardized data collection at CSCs to facilitate local quality improvement efforts and to allow for analysis of pooled data from different CSCs that may lead to development of national performance standards for CSCs in the future.


Corneal collagen cross-linking as treatment for infectious and noninfectious corneal melting in cats and dogs: results of a prospective, nonrandomized, controlled trial.
UV-A/Riboflavin cross-linking of corneal collagen fibers (CXL) is a highly promising therapy for corneal melting in humans. A prospective interventional, nonrandomized, controlled study was conducted to compare the stabilizing effect of CXL treatment on melting keratitis in dogs and cats and the complication rate of CXL to those of standardized intensive medical treatment. Forty-nine eyes with melting keratitis were included in the study between October 2009 and October 2012. All eyes were treated according to the same medical treatment protocol. Nineteen eyes were CXL-treated, and 30 eyes were not. Follow-up included slit-lamp examination, fluorescein staining, ulcer size measurement, stromal stability evaluation, photographic documentation, and documentation of complications. Five of 19 eyes in the CXL group and 9/30 eyes in the control group required rescue stabilization due to continued melting. Seven of the nine control group corneas stabilized after rescue CXL treatment. At initial presentation, the ulcers in the canine CXL group were significantly deeper and larger than in the control group. Ulcer deepening during follow-up was more pronounced in the canine control group than in the canine CXL group. CXL treatment-related complications were not observed. Based on the similar failure rates in the control and CXL treatment groups despite the poorer initial situation in the CXL group, the tendency for the ulcers in the control group to deepen and the stabilization of all corneas receiving CXL rescue treatment, we believe that CXL has its place as an adjunctive therapy for melting keratitis in veterinary ophthalmology.


Differential regulation of growth-promoting signalling pathways by E-cadherin.
Despite the well-documented association between loss of E-cadherin and carcinogenesis, as well as the link between restoration of its expression and suppression of proliferation in carcinoma cells, the ability of E-cadherin to modulate growth-promoting cell signalling in normal epithelial cells is less well understood and frequently contradictory. The potential for E-cadherin to co-ordinate different proliferation-associated signalling pathways has yet to be fully explored. Using a normal human urothelial (NHU) cell culture system and following a calcium-switch approach, we demonstrate that the stability of NHU cell-cell contacts differentially regulates the Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-Regulated Kinase (ERK) and Phosphatidylinositol 3-Kinase (PI3-K)/AKT pathways. We show that stable cell contacts down-modulate the EGFR/ERK pathway, whilst inducing PI3-K/AKT activity, which transiently enhances cell growth at low density. Functional inactivation of E-cadherin interferes with the capacity of NHU cells to form stable calcium-mediated contacts, attenuates E-cadherin-mediated PI3-K/AKT induction and enhances NHU cell proliferation by allowing de-repression of the EGFR/ERK pathway and constitutive activation of β-catenin-TCF signalling. Our findings provide evidence that E-cadherin can differentially and concurrently regulate specific growth-related signalling pathways in a context-specific fashion, with direct, functional consequences for cell proliferation and population growth. Our observations not only reveal a novel, complex role for E-cadherin in normal epithelial cell homeostasis and tissue regeneration, but also provide the basis for a more complete understanding of the consequences of E-cadherin loss on malignant transformation.


The mouse alpha-globin locus regulatory element.
We have identified and cloned the major alpha globin locus regulatory element in the mouse (m alpha RE). This element shows a high level of sequence homology to its human counterpart (HS -40) and lies between the same two exons of an upstream, widely expressed gene in both species. Footprinting and band shift studies of the core element show conservation of many (but not all) of the protein binding sites identified as functionally important in HS -40. The functional equivalence of the mouse element was shown by attaching it to a human alpha globin gene and examining expression in transgenic mice. Readily detectable levels of human alpha mRNA were produced in these mice but they were lower than the endogenous gene expression and did not show copy number dependence. These results suggest that sequences additional to this major regulatory element may be necessary to obtain complete regulation of the alpha globin genes in both species.


Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q.
Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.


Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.
Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.


Recruitment to the "Breast-Activity and Healthy Eating After Diagnosis" (B-AHEAD) Randomized Controlled Trial.
Excess weight at breast cancer diagnosis and weight gain during treatment are linked to increased breast cancer specific and all-cause mortality. The Breast-Activity and Healthy Eating After Diagnosis (B-AHEAD) trial tested 2 weight loss diet and exercise programmes versus a control receiving standard written advice during adjuvant treatment. This article identifies differences in characteristics between patients recruited from the main trial site to those of the whole population from that site during the recruitment period and identifies barriers to recruitment. A total of 409 patients with operable breast cancer were recruited within 12 weeks of surgery. We compared demographic and treatment factors between women recruited from the main trial coordinating site (n = 300) to the whole breast cancer population in the center (n = 532). Uptake at the coordinating site was 42%, comparable to treatment trials in the unit (47%). Women recruited were younger (55.9 vs 61.2 years, P < .001), more likely to live in least deprived postcode areas (41.7% vs 31.6%, P = .004), and more likely to have screen-detected cancers (55.3% vs 48.7%, P = .026) than the whole breast cancer population. The good uptake highlights the interest in lifestyle change around the time of diagnosis, a challenging time in the patient pathway, and shows that recruitment at this time is feasible. Barriers to uptake among older women and women with a lower socioeconomic status should be understood and overcome in order to improve recruitment to future lifestyle intervention programs.


Alpha- and beta-adrenergic stimulation of arachidonic acid metabolism in cells in culture.
Madin-Darby canine kidney cells (MDCK) synthesize prostaglandin (PG) F(2alpha), PGI(2) (measured as 6-keto-PGE(1alpha)), PGE(2), PGD(2), and thromboxane A(2) (measured as thromboxane B(2)). When incubated in the presence of norepinephrine (6 muM), the syntheses of these arachidonic acid metabolites are stimulated 3-fold. Norepinephrine's effect can be antagonized by the addition of alpha-adrenergic receptor blocking agents (phenoxybenzamine>phentolamine>yohimbine>dibenamine>tolazoline) but not by the beta-adrenergic blocking drug propranolol. Norepinephrine's stimulation is also inhibited by low concentrations of dihydroergotamine, bromocryptine, ergocryptine, and ergotamine. The stimulation of PG synthesis by norepinephrine is reversible, continues during the 24 hr of incubation, and requires the presence of norepinephrine at the receptor site but it is not blocked by the addition of colchicine, cytochalasin B, or cycloheximide. Neither phenoxybenzamine nor ergotamine at concentrations that block norepinephrine's stimulation of PG biosynthesis suppresses the increase in PG synthesis induced by exogenous arachidonic acid, suggesting that the alpha-adrenergic regulation is not occurring primarily at the cyclooxygenase step in the metabolism of arachidonic acid. In mouse lymphoma cells (WEHI-5), low concentrations of isoproterenol or norepinephrine stimulate the synthesis of thromboxane, an effect that can be blocked by the addition of propranolol but not by relatively high concentrations of phenoxybenzamine or ergotamine. Taken together, these results suggest that alpha-adrenergic receptor stimulation promotes the deacylation of phospholipids by MDCK cells whereas beta-adrenergic mechanisms lead to activation of similar pathways in WEHI-5 cells.


Exertional desaturation as a predictor of rapid lung function decline in COPD.
To date, no clinical parameter has been associated with the decline in lung function other than emphysema severity in COPD. The main purpose of this study was to explore whether the rate of lung function decline differs between COPD patients with and without exertional desaturation. A total of 224 subjects were selected from the Korean Obstructive Lung Disease cohort. Exertional desaturation was assessed using the 6-min walk test (6MWT), and defined as a post-exercise oxygen saturation (SpO2) of < 90% or a ≥ 4% decrease. The cohort was divided into desaturator (n = 47) and non-desaturator (n = 177) groups. There was a significant difference between the desaturator and non-desaturator groups in terms of the change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) over a 3-year period of follow-up (p = 0.006). The mean rate of decline in FEV1 was greater in the desaturator group (33.8 ml/year) than in the non-desaturator group (11.6 ml/year). A statistically significant difference was also observed between the two groups in terms of the change in the St. George's Respiratory Questionnaire (SGRQ) total score over 3 years (p = 0.001). This study suggests, for the first time, that exertional desaturation may be a predictor of rapid decline in lung function in patients with COPD. The 6MWT may be a useful test to predict a rapid lung function decline in COPD.