An assessment of nutritional information in oral health education leaflets.
Dental caries prevalence in UK children remains high and obesity, closely linked to Type 2 diabetes, is rising. Literature suggests that dentists may not give dietary advice due to a lack of clear and consistent guidelines. The aim of the study was to determine whether oral health education leaflets with a food and nutritional focus conform to existing UK national nutritional guidelines from the Department of Health (DoH), the Food Standards Agency (FSA) and the Committee on Medical Aspects of Food and Nutrition Policy (COMA). A sample of 30 information leaflets, aimed at parents and children aged 3-16 years, was sourced during the winter of 2005-2006. A qualitative content analysis was carried out to identify key recommendations on type, frequency and quantity of food and drink and general diet-related health advice. Most leaflets (21) promoted milk and water in agreement with nutritional guidelines. Timing of sugary food and drink to mealtimes (25) and decreasing frequency of 'sugary' e.g. non-milk extrinsic (NME) sugar containing foods (22) and drinks (25) reflected guidelines. Inconsistencies were, however, recorded in the leaflets. Five leaflets advised that frequency of consumption rather than the amount of sugary food or drink was important for oral health. This conflicts with nutritional guidelines, aimed at tackling obesity, to decrease both amount and frequency. There was conflicting advice on healthy snacks. Crisps were presented as 'healthy' by two leaflets; another two advised against snacking on dried fruit, conflicting with FSA guidelines that dried fruit contributes to "5 a day". Sixteen leaflets promoted cheese as 'healthy' with no limits on portion size; this could conflict with nutritional guidelines associated with percentage energy contribution of saturated fat to the diet. While there was agreement between leaflet content and nutritional guidelines, there were inconsistencies. Dental professionals should acknowledge these when selecting leaflets for lay dissemination.


Cancer Stem Cells, EMT, and Developmental Pathway Activation in Pancreatic Tumors.
Pancreatic cancer is a disease with remarkably poor patient survival rates. The frequent presence of metastases and profound chemoresistance pose a severe problem for the treatment of these tumors. Moreover, cross-talk between the tumor and the local micro-environment contributes to tumorigenicity, metastasis and chemoresistance. Compared to bulk tumor cells, cancer stem cells (CSC) have reduced sensitivity to chemotherapy. CSC are tumor cells with stem-like features that possess the ability to self-renew, but can also give rise to more differentiated progeny. CSC can be identified based on increased in vitro spheroid- or colony formation, enhanced in vivo tumor initiating potential, or expression of cell surface markers. Since CSC are thought to be required for the maintenance of a tumor cell population, these cells could possibly serve as a therapeutic target. There appears to be a causal relationship between CSC and epithelial-to-mesenchymal transition (EMT) in pancreatic tumors. The occurrence of EMT in pancreatic cancer cells is often accompanied by re-activation of developmental pathways, such as the Hedgehog, WNT, NOTCH, and Nodal/Activin pathways. Therapeutics based on CSC markers, EMT, developmental pathways, or tumor micro-environment could potentially be used to target pancreatic CSC. This may lead to a reduction of tumor growth, metastatic events, and chemoresistance in pancreatic cancer.


What young people want from a sexual health website: design and development of Sexunzipped.
Sexual health education in the United Kingdom is of variable quality, typically focusing on the biological aspects of sex rather than on communication, relationships, and sexual pleasure. The Internet offers a unique opportunity to provide sexual health education to young people, since they can be difficult to engage but frequently use the Internet as a health information resource. To explore through qualitative research young people's views on what elements of a sexual health website would be appealing and engaging, and their views on the content, design, and interactive features of the Sexunzipped intervention website. We recruited 67 young people aged 16-22 years in London, UK. We held 21 focus groups and 6 one-to-one interviews to establish sexual health priorities, views on website look and feel, and what features of a sexual heath website would attract and engage them. Two researchers facilitated the focus groups, using a semistructured topic guide to lead the discussions and asking open questions to elicit a range of views. The discussions and interviews were audio recorded and detailed notes were made on key topics from the audio recording. Young people's views influenced design templates for the content and interactive features of Sexunzipped. Young people particularly wanted straightforward information on sexual pleasure, sexually transmitted infections and pregnancy, how to communicate with partners, how to develop skills in giving pleasure, and emotions involved in sex and relationships. Focus group participants wanted social interaction with other young people online and wanted to see themselves reflected in some way such as through images or videos. While it is challenging to meet all of young people's technological and design requirements, consultation with the target audience is valuable and necessary in developing an online sexual health intervention. Young people are willing to talk about sensitive issues, enjoy the discussions, and can offer key insights that influence intervention development.


E-cigarettes and cigarettes worsen peripheral and central hemodynamics as well as arterial stiffness: A randomized, double-blinded pilot study.
The introduction of electronic cigarettes has led to widespread discussion on the cardiovascular risks compared to conventional smoking. We therefore conducted a randomized cross-over study of the acute use of three tobacco products, including a control group using a nicotine-free liquid. Fifteen active smokers were studied during and after smoking either a cigarette or an electronic cigarette with or without nicotine (eGo-T CE4 vaporizer). Subjects were blinded to the nicotine content of the electronic cigarette and were followed up for 2 hours after smoking a cigarette or vaping an electronic cigarette. Peripheral and central blood pressures as well as parameters of arterial stiffness were measured by a Mobil-O-Graph® device. The peripheral systolic blood pressure rose significantly for approximately 45 minutes after vaping nicotine-containing liquid ( p<0.05) and for approximately 15 minutes after smoking a conventional cigarette ( p<0.01), whereas nicotine-free liquids did not lead to significant changes during the first hour of follow-up. Likewise, heart rate remained elevated approximately 45 minutes after vaping an electronic cigarette with nicotine-containing liquid and over the first 30 minutes after smoking a cigarette in contrast to controls. Elevation of pulse wave velocity was independent from mean arterial pressure as well as heart rate in the electronic cigarette and cigarette groups. In this first of its kind trial, we observed changes in peripheral and central blood pressure and also in pulse wave velocity after smoking a cigarette as well as after vaping a nicotine-containing electronic cigarette. These findings may be associated with an increased long-term cardiovascular risk.


Sex and menopausal status influence human dietary requirements for the nutrient choline.
Although humans require dietary choline for methyl donation, membrane function, and neurotransmission, choline can also be derived from the de novo synthesis of phosphatidylcholine, which is up-regulated by estrogen. A recommended Adequate Intake (AI) exists for choline; however, an Estimated Average Requirement has not been set because of a lack of sufficient human data. The objective of the study was to evaluate the dietary requirements for choline in healthy men and women and to investigate the clinical sequelae of choline deficiency. Fifty-seven adult subjects (26 men, 16 premenopausal women, 15 postmenopausal women) were fed a diet containing 550 mg choline x 70 kg(-1) x d(-1) for 10 d followed by <50 mg choline x 70 kg(-1) x d(-1) with or without a folic acid supplement (400 microg/d per randomization) for up to 42 d. Subjects who developed organ dysfunction during this diet had normal organ function restored after incremental amounts of choline were added back to the diet. Blood and urine were monitored for signs of toxicity and metabolite concentrations, and liver fat was assessed by using magnetic resonance imaging. When deprived of dietary choline, 77% of men and 80% of postmenopausal women developed fatty liver or muscle damage, whereas only 44% of premenopausal women developed such signs of organ dysfunction. Moreover, 6 men developed these signs while consuming 550 mg choline x 70 kg(-1) x d(-1), the AI for choline. Folic acid supplementation did not alter the subjects' response. Subject characteristics (eg, menopausal status) modulated the dietary requirement for choline, and a daily intake at the current AI was not sufficient to prevent organ dysfunction in 19 of the subjects.


DNA mismatch synthesis complexes provide insights into base selectivity of a B family DNA polymerase.
Current hypotheses that attempt to rationalize the high degree of base selectivity exhibited by replicative DNA polymerases (pols) concur that ternary complexes formed with incorrect dNTPs are destabilized. Knowing what accounts for this destabilization is likely to be the key to understanding base discrimination. To address this issue, we have determined crystal structures of ternary complexes with all 12 mismatches using an engineered RB69 pol quadruple mutant (qm, L415A/L561A/S565G/Y567A) that enabled us to capture nascent mispaired dNTPs. These structures show that mismatches in the nascent base-pair binding pocket (NBP) of the qm pol differ markedly from mismatches embedded in binary pol-DNA complexes. Surprisingly, only 3 of 12 mismatches clash with the NBP when they are modeled into the wild-type (wt) pol. The remaining can fit into a wt pol ternary complex but deviate from normal Watson-Crick base-pairs. Repositioning of the templating nucleotide residue and the enlarged NBP in qm ternary complex play important roles in accommodating incorrect incoming dNTPs. From these structures, we propose additional reasons as to why incorrect dNTPs are incorporated so inefficiently by wt RB69 pol: (i) steric clashes with side chains in the NBP after Fingers closing; (ii) weak interactions or large gaps between the incoming dNTP and the templating base; and (iii) burying a protonated base in the hydrophobic environment of the NBP. All of these possibilities would be expected to destabilize the closed ternary complex so that incorporation of incorrect dNTP would be a rare event.


Comparing perceptual signals of single V5/MT neurons in two binocular depth tasks.
Neurons in the extrastriate visual area V5/MT show perceptually relevant signals in binocular depth tasks, which can be measured as a choice probability (CP) for the neuron. The presence of a CP in a particular paradigm may be an indicator that the neuron is generally part of the substrate for the perception of binocular depth. We compared the responses of those single neurons that show CPs in one stereoscopic depth task with their responses in another stereo task. Each neuron was tested for the presence of 1) CPs during a task in which macaques responded to the sign of binocular depth in a structure-from-motion stimulus, to judge its direction of three-dimensional rotation and 2) a consistent response to the stereo disparity of binocularly anti-correlated stimuli. Previous work, confirmed here, shows that changing the disparity of these binocularly anti-correlated stimuli often fails to yield a coherent change in the depth percept. For each test alone, there are V5/MT neurons that carry signals that are congruent with the perceptual effects. However, on comparing tests, there is no fixed pool of neurons that can account for the binocular depth percept. Excitation of neurons with a measurable CP does not necessarily lead to a change in perception. The cortical circuitry must be able to make dynamic changes in the pools of neurons that underlie perceptual judgments according to the demands of the task.


Incidence of Head and Neck Lymphoma in Guilan Province, Iran.
The aim of this research was to describe the incidence and histopathological subtypes of head and neck lymphoma in Guilan province, Iran. In this retrospective study, all cases of head and neck cancers registered in Iranian Cancer Registry Program in Guilan province of Iran from 2004 to 2009 were obtained and included in the analysis. Out of 1,510 cases, 169 (11.2%) were reported as lymphomas (87 cases of non-Hodgkin, 67 cases of Hodgkin, and 13 cases of unknown type). The mean ages of males and females diagnosed with Hodgkin's lymphoma were 30.4 and 28.7 years, re-spectively. For non-Hodgkin's lymphoma the respective figures were 50.5 and 49.3 years old. Among various histological subtypes of non-Hodgkin's lymphoma, the diffuse large B-cell type (74.2%) was the most frequent while immunoblastic lymphoma (1.1%) was the least frequent. Nodular sclerosis (58.2%) and mixed cellularity (18.0%) types were most frequent among Hodgkin's lymphomas.


Biomechanical evaluation of simulated feline patellar fracture repairs.
To investigate four techniques for stabilization of feline patellar fracture. Feline cadaveric stifles with simulated patellar fracture were stabilized with one of four techniques: Group A - circumferential wire, group B - figure-of-eight wire, group C - combined figure-of-eight and circumferential wire, group D - pin and tension band wire. All repairs were subjected to a period of cyclic loading prior to load to failure testing. Experiments were recorded by video capture to determine load at failure and failure mode. Failure was defined as an opening of the fracture gap of 3 mm. Mean fracture gap opening (±SD) during peak loading after 1000 cycles was: group A with 1.66 mm (± 0.69), group B with 1.01 mm (± 0.45), group C with 0.81 mm (± 0.58), and group D with 0.65 mm (± 0.54). Groups C and D had significantly lower mean fracture gap opening after 1000 cycles when compared to group A (p <0.05). Mean loads (± SD) at failure were: group A with 171.4 N (± 62.2), group B with 208.7 N (± 20.7), group C with 288.2 N (± 62.5), and group D with 219.5 N (± 48.0). Group C had significantly higher mean load to failure than all other groups (p <0.05). There was no difference between other groups. In groups A, B and C the principle mode of failure was wire elongation and tearing of sutures through the retinaculae and periarticular soft tissues. In group D, the principle mode of failure was the pin pulling through the bone of the distal fragment. Combined figure-of-eight and circumferential wires may be useful for treatment of transverse feline patellar fracture.


Flytrap, a database documenting a GFP protein-trap insertion screen in Drosophila melanogaster.
Flytrap is a web-enabled relational database of transposable element insertions in Drosophila melanogaster. A green fluorescent protein (GFP) artificial exon carried by a transposable P-element is mobilized and inserted into a host gene intron creating a GFP fusion protein. The sequence of the tagged gene is determined by sequencing inverse-PCR products derived from genomic DNA. Flytrap contains two principle data types: micrographs of protein localization and a cellular component ontology, based on rules derived from the Gene Ontology consortium (http://www.geneontology.org), describing protein localization. Flytrap also has links to gene information contained in Flybase (http:// flybase.bio.indiana.edu). The system is designed to accept submissions of micrographs and descriptions from any type of tissue (e.g. wing imaginal disk, ovary) and at any stage of development. Insertion lines can be searched using a number of queries, including Berkeley Drosophila Genome Project (BDGP) numbers and protein localization. In addition, Flytrap provides online order forms linked to each insertion line so that users may request any line generated from this project. Flytrap may be accessed from the homepage at http://flytrap.med. yale.edu.


Frank-ter Haar syndrome associated with sagittal craniosynostosis and raised intracranial pressure.
Frank-ter Haar syndrome is a rare disorder associated with skeletal, cardiac, ocular and craniofacial features including hypertelorism and brachycephaly. The most common underlying genetic defect in Frank-ter Haar syndrome appears to be a mutation in the SH3PXD2B gene on chromosome 5q35.1. Craniosynostosis, or premature fusion of the calvarial sutures, has not previously been described in Frank-ter Haar syndrome. We present a family of three affected siblings born to consanguineous parents with clinical features in keeping with a diagnosis of Frank-ter Haar syndrome. All three siblings have a novel mutation caused by the deletion of exon 13 of the SH3PXD2B gene. Two of the three siblings also have non-scaphocephalic sagittal synostosis associated with raised intracranial pressure. The clinical features of craniosynostosis and raised intracranial pressure in this family with a confirmed diagnosis of Frank-ter Haar syndrome expand the clinical spectrum of the disease. The abnormal cranial proportions in a mouse model of the disease suggests that the association is not coincidental. The possibility of craniosynostosis should be considered in individuals with a suspected diagnosis of Frank-ter Haar syndrome.


Gender difference in the prognostic role of interleukin 6 in oral squamous cell carcinoma.
Interleukin 6 (IL6) plays an important role in immunoregulation and tumorigenesis in human cancers. Oral squamous cell carcinoma (OSCC) is a malignant tumor of the oral cavity with a male predominant tendency and a poor clinical prognosis. Due to the relatively few cases in females, the gender difference of prognostic markers for OSCC is seldom discussed. In this study, we used immunohistochemical staining methods to investigate the associations between IL6 expression and the clinicopathological characteristics of OSCC. In addition, we collected 74 female and 263 male OSCC patients for evaluation. High IL6 expression in tumor cells was significantly associated OSCC patient characteristics including female gender (P<0.001), high lymph node metastatic rate (P = 0.007), and poor tumor differentiation (P = 0.008). Tumor-expressed IL6 had prognostic role in male OSCC patients as defined by the log-rank test (P = 0.014), but not in female patients (P = 0.959). In male OSCC patients, high IL6 expression in tumor cells was associated with poor prognosis (P = 0.025) and a 1.454-fold higher death risk, as determined by Cox regression. High IL6 expression in tumor cells was therefore significantly associated with aggressive clinical manifestations and might be an independent survival predictor, particularly in male OSCC patients.


A mechanistic assessment of the relationship between gut morphology and endozoochorous seed dispersal by waterfowl.
Many plants and invertebrates rely on internal transport by animals for long-distance dispersal. Their dispersal capacity is greatly influenced by interactions with the animal's digestive tract. Omnivorous birds adjust their digestive tract morphology to seasonally variable diets. We performed feeding trials in waterfowl to unravel how changing organ size, in combination with seed size, affects dispersal potential. We subjected captive mallards to mimics of summer (animal-based), winter (plant-based), and intermediate diets, and analyzed gut passage of seeds before and after the treatment (trials 1 and 2). To test the effect of gut morphology on seed digestion, we measured digestive organ size after euthanasia. Three hours before euthanasia, differently sized seeds were fed to test how seed size affects gut passage by determining their relative position in the digestive tract (trial 3). Trials 1 and 2 showed that intact seed passage was lower in the plant-based than in the animal-based diet group. Retention time changed only within groups, decreasing in the animal-based, and increasing in the plant-based diet group. No post-diet differences in organ size were detected, probably due to large between-individual variation within groups. Digestive tract measures did not explain variation in seed survival or retention time. Trial 3 revealed that small seeds pass the digestive tract rapidly, while large seeds are retained longer, particularly in the gizzard. Differential retention in the gizzard, the section where seeds can be destroyed, is likely why larger seeds have a lower probability to pass the digestive tract intact. Our results confirm that rapid, flexible adaptation to diet shifts affects seed digestion in waterfowl, although we could not conclusively relate this to organ size. Large interindividual variation in digestive efficiency between mallards feeding on the same diet may provide opportunities for seed dispersal in the field throughout the annual cycle.


Frog nest foams exhibit pharmaceutical foam-like properties.
Foams have frequently been used as systems for the delivery of cosmetic and therapeutic molecules; however, there is high variability in the foamability and long-term stability of synthetic foams. The development of pharmaceutical foams that exhibit desirable foaming properties, delivering appropriate amounts of the active pharmaceutical ingredient (API) and that have excellent biocompatibility is of great interest. The production of stable foams is rare in the natural world; however, certain species of frogs have adopted foam production as a means of providing a protective environment for their eggs and larvae from predators and parasites, to prevent desiccation, to control gaseous exchange, to buffer temperature extremes, and to reduce UV damage. These foams show great stability (up to 10 days in tropical environments) and are highly biocompatible due to the sensitive nature of amphibian skin. This work demonstrates for the first time that nests of the túngara frog (Engystomops pustulosus) are stable ex situ with useful physiochemical and biocompatible properties and are capable of encapsulating a range of compounds, including antibiotics. These protein foam mixtures share some properties with pharmaceutical foams and may find utility in a range of pharmaceutical applications such as topical drug delivery systems.


Reverse genetics provides direct evidence for a correlation of hemagglutinin cleavability and virulence of an avian influenza A virus.
To obtain direct evidence for a relationship between hemagglutinin (HA) cleavability and the virulence of avian influenza A viruses, we generated a series of HA cleavage mutants from a virulent virus, A/turkey/Ontario/7732/66 (H5N9), by reverse genetics. A transfectant virus containing the wild-type HA with R-R-R-K-K-R at the cleavage site, which was readily cleaved by endogenous proteases in chicken embryo fibroblasts (CEF), was highly virulent in intramuscularly or intranasally/orally inoculated chickens. By contrast, a mutant containing the HA with an avirulent-like sequence (R-E-T-R) at the cleavage site, which was not cleaved by the proteases in CEF, was avirulent in chickens, indicating that a genetic alteration confined to the HA cleavage site can affect cleavability and virulence. Mutant viruses with HA cleavage site sequences of T-R-R-K-K-R or T-T-R-K-K-R were as virulent as viruses with the wild-type HA, whereas a mutant with a two-amino-acid deletion but retention of four consecutive basic residues (R-K-K-R) was as avirulent as a virus with the avirulent-type HA. Interestingly, although a mutant containing an HA with R-R-R-K-T-R, which has reduced cleavability in CEF, was as virulent as viruses with high HA cleavability when given intramuscularly, it was less virulent when given intranasally/orally. We conclude that the degree of HA cleavability in CEF predicts the virulence of avian influenza viruses.


Comparison of ArcGIS and SAS Geostatistical Analyst to Estimate Population-Weighted Monthly Temperature for US Counties.
Temperature changes are known to have significant impacts on human health. Accurate estimates of population-weighted average monthly air temperature for US counties are needed to evaluate temperature's association with health behaviours and disease, which are sampled or reported at the county level and measured on a monthly-or 30-day-basis. Most reported temperature estimates were calculated using ArcGIS, relatively few used SAS. We compared the performance of geostatistical models to estimate population-weighted average temperature in each month for counties in 48 states using ArcGIS v9.3 and SAS v 9.2 on a CITGO platform. Monthly average temperature for Jan-Dec 2007 and elevation from 5435 weather stations were used to estimate the temperature at county population centroids. County estimates were produced with elevation as a covariate. Performance of models was assessed by comparing adjusted R2, mean squared error, root mean squared error, and processing time. Prediction accuracy for split validation was above 90% for 11 months in ArcGIS and all 12 months in SAS. Cokriging in SAS achieved higher prediction accuracy and lower estimation bias as compared to cokriging in ArcGIS. County-level estimates produced by both packages were positively correlated (adjusted R2 range=0.95 to 0.99); accuracy and precision improved with elevation as a covariate. Both methods from ArcGIS and SAS are reliable for U.S. county-level temperature estimates; However, ArcGIS's merits in spatial data pre-processing and processing time may be important considerations for software selection, especially for multi-year or multi-state projects.


A Standardized Framework for Fluorescence-Guided Margin Assessment for Head and Neck Cancer Using a Tumor Acidosis Sensitive Optical Imaging Agent.
Intra-operative management of the surgical margin in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) remains challenging as surgeons still have to rely on visual and tactile information. Fluorescence-guided surgery using tumor-specific imaging agents can assist in clinical decision-making. However, a standardized imaging methodology is lacking. In this study, we determined whether a standardized, specimen-driven, fluorescence imaging framework using ONM-100 could assist in clinical decision-making during surgery. Thirteen patients with histologically proven HNSCC were included in this clinical study and received ONM-100 24 ± 8 h before surgery. Fluorescence images of the excised surgical specimen and of the surgical cavity were analyzed. A fluorescent lesion with a tumor-to-background ratio (TBR) > 1.5 was considered fluorescence-positive and correlated to standard of care (SOC) histopathology. All six tumor-positive surgical margins were detected immediately after excision using fluorescence-guided intra-operative imaging. Postoperative analysis showed a median TBR (±IQR) of the fluorescent lesions on the resection margin of 3.36 ± 1.62. Three fluorescence-positive lesions in the surgical cavity were biopsied and showed occult carcinoma and severe dysplasia, and a false-positive fluorescence lesion. Our specimen-driven fluorescence framework using a novel, pH-activatable, fluorescent imaging agent could assist in reliable and real-time adequate clinical decision-making showing that a fluorescent lesion on the surgical specimen with a TBR of 1.5 is correlated to a tumor-positive resection margin. The binary mechanism of ONM-100 allows for a sharp tumor delineation in all patients, giving the surgeon a clinical tool for real-time margin assessment, with a high sensitivity.


Single-walled carbon nanotube-based polymer monoliths for the enantioselective nano-liquid chromatographic separation of racemic pharmaceuticals.
Single-walled carbon nanotubes were encapsulated into different polymer-based monolithic backbones. The polymer monoliths were prepared via the copolymerization of 20% monomers, glycidyl methacrylate, 20% ethylene glycol dimethacrylate and 60% porogens (36% 1-propanol, 18% 1,4-butanediol) or 16.4% monomers (16% butyl methacrylate, 0.4% sulfopropyl methacrylate), 23.6% ethylene glycol dimethacrylate and 60% porogens (36% 1-propanol, 18% 1,4-butanediol) along with 6% single-walled carbon nanotubes aqueous suspension. The effect of single-walled carbon nanotubes on the chiral separation of twelve classes of pharmaceutical racemates namely; α- and β-blockers, antiinflammatory drugs, antifungal drugs, dopamine antagonists, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, diuretics, antihistaminics, anticancer drugs and antiarrhythmic drugs was investigated. The enantioselective separation was carried out under multimodal elution to explore the chiral recognition capabilities of single-walled carbon nanotubes using reversed phase, polar organic and normal phase chromatographic conditions using nano-liquid chromatography. Baseline separation was achieved for celiprolol, chlorpheniramine, etozoline, nomifensine and sulconazole under multimodal elution conditions. Satisfactory repeatability was achieved through run-to-run, column-to-column and batch-to-batch investigations. Our findings demonstrate that single-walled carbon nanotubes represent a promising stationary phase for the chiral separation and may open the field for a new class of chiral selectors.


The role of impaction grafting: the when and how.
The challenges of acetabular revision include bone loss and poor bone biology. Favorable 10-year reports exist of uncemented acetabular revision using hemispherical uncemented sockets. In the presence of bone stock deficiency, adjunctive morsellized impaction bone grafting is a recognized means of restoring bone stock. We attempt to restore bone stock with impaction grafting beneath a cementless cup for contained defects, defects that can be rendered contained, and whenever there is capacity for rim fixation. The technique of bone graft preparation is important. We use a mixture of bone milling and bone chips of various sizes. Morsellized allograft is inserted, packed, and/or reverse reamed into any defects. The reconstruction relies on the ability to gain biological fixation of the component to the underlying host bone. This requires intimate host bone contact and rigid implant stability. The fixation is therefore augmented with screws in all cases. It is important to achieve host bone contact in a least part of the dome and posterior column. When this is possible, and particularly when there is a good rim fit, we have not found it absolutely necessary to have contact with host bone over >50% of the surface. Stability of primary fixation is a better predictor of outcome than volume of graft or percentage of host bone contact. The advantages of bone grafting in acetabular reconstruction include the ability to restore bone stock, rebuild a normal hip center and hip biomechanics, and increase bone stock for future revisions.


Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study.
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77,469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)-proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.


Cost-effectiveness analysis of adjunct VSL#3 therapy versus standard medical therapy in pediatric ulcerative colitis.
Inflammatory bowel diseases (IBDs) are costly chronic gastrointestinal diseases, with pediatric IBD representing increased costs per patient compared to adult disease. Health care expenditures for ulcerative colitis (UC) are >$2 billion annually. It is not clear whether the addition of VSL#3 to standard medical therapy in UC induction and maintenance of remission is a cost-effective strategy. We performed a systematic review of the literature and created a Markov model simulating a cohort of 10-year-old patients with severe UC, studying them until 100 years of age or death. We compared 2 strategies: standard medical therapy versus medical therapy + VSL#3. For both strategies, we assumed that patients progressed through escalating therapies--mesalamine, azathioprine, and infliximab--before receiving a colectomy + ileal pouch anal anastamosis (IPAA) if the 3 medical therapy options were exhausted. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), defined as the difference of costs between strategies for each quality-adjusted life-year (QALY) gained. One-way sensitivity analyses were performed on variables to determine the key variables affecting cost-effectiveness. Standard medical care accrued a lifetime cost of $203,317 per patient, compared to $212,582 per patient for medical therapy + VSL#3. Lifetime QALYs gained was comparable for standard medical therapy and medical therapy + VSL#3 at 24.93 versus 25.05, respectively. Using the definition of ICER <50,000/QALY as a cost-effective intervention, medical therapy + VSL#3 produced an ICER of $79,910 per QALY gained, making this strategy cost-ineffective. Sensitivity analyses showed that 4 key parameters could affect the cost-effectiveness of the 2 strategies: cost of colectomy + IPAA, maintenance cost after surgery, probability of developing pouchitis after surgery, and the quality of life after a colectomy + IPAA. High surgical and postsurgical costs, a high probability of developing pouchitis, and a low quality of life after a colectomy + IPAA could make adjunct VSL#3 use a cost-effective strategy. Given present data, adjunct VSL#3 use for pediatric UC induction and maintenance of remission is not cost-effective, although several key parameters could make this strategy cost-effective. The quality of life after an IPAA is the single most important variable predicting whether this procedure benefits patients over escalating standard medical therapy.


Value of pulse oximetry in screening for long-term oxygen therapy requirement.
Pulse oximetry, combined with spirometry, was evaluated as a method of selecting chronic obstructive pulmonary disease (COPD) out-patients requiring definitive arterial blood gas analysis for long-term oxygen therapy (LTOT) assessment. A relatively high screening arterial oxygen saturation by pulse oximetry (SaO2) level was set, in order to maximize sensitivity. All 113 COPD out-patients attending the hospital clinic over a 6 month period were screened. Sixty had a forced expiratory volume in one second < 1.5 l and 26 had an SaO2 < or = 92%. These 26 underwent arterial blood gas analysis. Nine had an arterial oxygen tension < 7.3 kPa all with an arterial carbon dioxide tension (PaCO2) > 6 kPa. A further eight had a PaO2 < 8 kPa. This produced a sensitivity of 100% and specificity of 69% for oximetry in the detection of PaO2 < 7.3 kPa determined by direct arterial puncture and 100% and 86% respectively for detecting a PaO2 < 8 kPa. Although the poor specificity of oximetry in the crucial PaO2 range makes it unsuitable, when used alone, for prescription of LTOT, it may prove valuable in selecting patients who require further definitive arterial blood gas analysis.


Post-immunisation fever and the antibody response to measles-containing vaccines.
Fever is a common adverse event following measles vaccination, more frequent among older children and those receiving Measles-Mumps-Rubella-Varicella vaccine vs. Measles-Mumps-Rubella vaccine, two factors associated with a better antibody response. However, the role of fever in the immunogenicity of measles-containing vaccines (MCV) is unclear. We performed a post-hoc pooled analysis of data of 5 216 11 to 22 month-old children receiving MCV from 2004 to 2012 in Europe and USA to evaluate the association between post-immunisation fever and antibody response, measured by geometric mean concentrations (GMCs). We further evaluated fever as an effect modifier or a mediator in the associations between the type of MCV or the age at first vaccination and vaccine immunogenicity. After the first dose, fever was associated with 60% higher GMCs (95% CI 1.51-1.68). For children vaccinated at ⩾12 months, the fever did not modify and minimally mediated (2% to 3%) the association between age and antibody response. Fever mediated 18% of the association between type of MCV and GMCs. In a model including fever, age and type of vaccine, fever was the strongest predictor of GMCs. These results suggest that fever is associated with a stronger measles antibody response independently of age and type of MCV.


Structural analysis of the activation of ribavirin analogs by NDP kinase: comparison with other ribavirin targets.
Ribavirin used in therapies against hepatitis C virus (HCV) is potentially efficient against other viruses but presents a high cytotoxicity. Several ribavirin triphosphate analogs modified on the ribose moiety were synthesized and tested in vitro on the RNA polymerases of HCV, phage T7, and HIV-1 reverse transcriptase. Modified nucleotides with 2'-deoxy, 3'-deoxy, 2',3'-dideoxy, 2',3'-dideoxy-2',3'-dehydro, and 2',3'-epoxy-ribose inhibited the HCV enzyme but not the other two polymerases. They were also analyzed as substrates for nucleoside diphosphate (NDP) kinase, the enzyme responsible for the last step of the cellular activation of antiviral nucleoside analogs. An X-ray structure of NDP kinase complexed with ribavirin triphosphate was determined. It demonstrates that the analog binds as a normal substrate despite the modified base and confirms the crucial role of the 3'-hydroxyl group in the phosphorylation reaction. The 3'-hydroxyl is required for inhibition of the initiation step of RNA synthesis by HCV polymerase, and both sugar hydroxyls must be present to inhibit elongation. The 2'deoxyribavirin is the only derivative efficient in vitro against HCV polymerase and properly activated by NDP kinase.


Overview: The Design, Adoption, and Analysis of a Visual Document Mining Tool for Investigative Journalists.
For an investigative journalist, a large collection of documents obtained from a Freedom of Information Act request or a leak is both a blessing and a curse: such material may contain multiple newsworthy stories, but it can be difficult and time consuming to find relevant documents. Standard text search is useful, but even if the search target is known it may not be possible to formulate an effective query. In addition, summarization is an important non-search task. We present Overview, an application for the systematic analysis of large document collections based on document clustering, visualization, and tagging. This work contributes to the small set of design studies which evaluate a visualization system "in the wild", and we report on six case studies where Overview was voluntarily used by self-initiated journalists to produce published stories. We find that the frequently-used language of "exploring" a document collection is both too vague and too narrow to capture how journalists actually used our application. Our iterative process, including multiple rounds of deployment and observations of real world usage, led to a much more specific characterization of tasks. We analyze and justify the visual encoding and interaction techniques used in Overview's design with respect to our final task abstractions, and propose generalizable lessons for visualization design methodology.


Muramyl peptides. Variation of somnogenic activity with structure.
Sleep-promoting activities of muramyl dipeptide (MDP) (NAc-Mur-L-ala-D-isogln) and the naturally occurring muramyl peptide(s), factor S, have recently been demonstrated. We now have amplified our understanding of structural requirements for somnogenic activity. The effects of several analogs of MDP on rabbit slow-wave sleep are presented and these results are compared to the dose-response relationship for MDP. Some tentative conclusions as to structural requirements for somnogenic activity are presented; most notably, amidation of the free gamma-carboxyl of MDP and several of its analogs resulted in the loss of somnogenic activity. MDP also can induce febrile and immunostimulatory responses. In the present paper, we show that some analogs possess immunostimulatory and pyrogenic activity but not somnogenic activity, thus suggesting that these biological activities of muramyl peptides may, in part, be mediated by separate mechanisms.


Biotechnology, physiology and genetics of the yeast Pichia anomala.
The ascomycetous yeast Pichia anomala is frequently associated with food and feed products, either as a production organism or as a spoilage yeast. It belongs to the nonSaccharomyces wine yeasts and contributes to the wine aroma by the production of volatile compounds. The ability to grow in preserved food and feed environments is due to its capacity to grow under low pH, high osmotic pressure and low oxygen tension. A new application of P. anomala is its use as a biocontrol agent, which is based on the potential to inhibit a variety of moulds in different environments. Although classified as a biosafety class-1 organism, cases of P. anomala infections have been reported in immunocompromised patients. On the other hand, P. anomala killer toxins have a potential as antimicrobial agents. The yeast can use a broad range of nitrogen and phosphor sources, which makes it a potential agent to decrease environmental pollution by organic residues from agriculture. However, present knowledge of the physiological basis of its performance is limited. Recently, the first studies have been published dealing with the global regulation of the metabolism of P. anomala under different conditions of oxygenation.


Behavioral and olfactory responses of female Salaria pavo (Pisces: Blenniidae) to a putative multi-component male pheromone.
The peacock blenny, Salaria pavo (Risso 1810), typically breeds in rocky shores of the Mediterranean and adjacent Atlantic coast. Males defend a territory around a hole or cavity wherein females deposit eggs that the male guards until hatching. A pair of exocrine glands on the anal fin (anal glands) of males produces a putative pheromone involved in attraction of reproductively competent females to the nest. We used behavioral assays to assess species-specific attraction of reproductively competent females to putative male pheromones, including the anal gland pheromone. Additionally, chromatographic fractions of anal glands and male-conditioned water were tested for olfactory potency in females by electro-olfactogram analysis (EOG). In a flow-through tank or fluviarium, reproductive females were attracted to male-conditioned water and to the anal gland macerate from conspecifics but not to those of a closely related heterospecific. In addition, attraction of reproductive females to conspecific anal gland macerate occurred only during their initial upstream movement in the fluviarium; this was an ephemeral response when compared with the response to male-conditioned water that attracted females throughout the entire period of observation (5 min). Reproductive females also were attracted during the entire period of observation to water-conditioned by conspecific males whose anal glands had been removed. However, the attraction was more variable than that to water conditioned by intact males. Moreover, females were not attracted to male (without anal glands) odor during their initial upstream movement in the fluviarium. Finally, non-reproductive females were not attracted to the conspecific anal gland macerate. The EOG responses of females to molecular weight fractions and solid-phase extraction and high-performance liquid chromatography fractions of anal gland macerates and male-conditioned water (with and without anal glands) suggest that the anal glands release hydrophilic odorants that consist mainly of molecules smaller than 500 Da. Furthermore, males released potent odorants that do not originate from the anal glands. We hypothesize that females respond to a multi-component male pheromone to find mates. The putative anal gland pheromone is possibly comprised of hydrophilic odorants, whereas the other component(s), presumably of gonadal origin, may be less water-soluble.


Synaptophysin: a substrate for the protein tyrosine kinase pp60c-src in intact synaptic vesicles.
Expression of pp60c-src, the first well defined proto-oncogene product, is developmentally regulated and tissue-specific, with neuronal tissues displaying high amounts of the c-src encoded pp60c-src kinase activity. In the central nervous system pp60c-src is preferentially expressed in regions characterized by a high content of grey matter and elevated density of nerve terminals. In this study we show for the first time a direct interaction between pp60c-src and synaptophysin as a physiological target protein in neurons by demonstrating that endogenous pp60c-src is able to phosphorylate synaptophysin (p38). p38 is a major constituent of the synaptic vesicle membrane protein and is thought to play a key role in the exocytosis of small synaptic vesicles and possibly small clear vesicles in neuroendocrine cells.


Ribose-protonated DNA base excision repair: a combined theoretical and experimental study.
Living organisms protect the genome against external influences by recognizing and repairing damaged DNA. A common source of gene mutation is the oxidized guanine, which undergoes base excision repair through cleavage of the glycosidic bond between the ribose and the nucleobase of the lesion. We unravel the repair mechanism utilized by bacterial glycosylase, MutM, using quantum-chemical calculations involving more than 1000 atoms of the catalytic site. In contrast to the base-protonated pathway currently favored in the literature, we show that the initial protonation of the lesion's ribose paves the way for an almost barrier-free glycosidic cleavage. The combination of theoretical and experimental data provides further insight into the selectivity and discrimination of MutM's binding site toward various substrates.


Mechanism of cell cycle arrest and apoptosis induction by conjugated eicosapentaenoic acid, which is a mammalian DNA polymerase and topoisomerase inhibitor.
Conjugated eicosapentaenoic acid (cEPA) selectively inhibited the activities of mammalian DNA polymerases (pols) and human DNA topoisomerases (topos). cEPA inhibited the cell growth of two human leukemia cell lines, NALM-6, which is a p53-wild type, and HL-60, which is a p53-null mutant, with LD50 values of 37.5 and 12.5 microM, respectively. In both cell lines, cEPA arrested in the G1 phase, and increased cyclin E protein levels, indicating that it blocks the primary step of in vivo DNA replication by inhibiting the activity of replicative pols rather than topos. DNA replication-related proteins such as RPA70, ATR and phosphorylated-Chk1/2 were increased by cEPA treatment in the cell lines, suggesting that cEPA led to DNA replication fork stress inhibiting the activities of pols and topos, and the ATR-dependent DNA damage response pathway could respond to the inhibitor of DNA replication. The compound induced cell apoptosis through both p53-dependent and p53-independent pathways in cell lines NALM-6 and HL-60, respectively. These results suggested the therapeutic potential of cEPA as a leading anti-cancer compound that inhibited activities of pols and topos.


Feasibility of Delaying Removal of Row Covers to Suppress Bacterial Wilt of Muskmelon (Cucumis melo).
Bacterial wilt, caused by Erwinia tracheiphila, is a major disease of cucurbit crops in the United States. Management of the disease relies on controlling two vector species, striped (Acalymma vittatum) and spotted (Diabrotica undecimpunctata) cucumber beetles. Six field trials were conducted at Iowa State University research farms during 2007, 2008, and 2009 to assess the efficacy of delayed removal of spunbond polypropylene row covers to control bacterial wilt on muskmelon (Cucumis melo). Treatments were (i) row cover removed at anthesis (conventional timing of removal), (ii) covers removed 10 days after row cover ends were opened at anthesis, (iii) covers removed 10 days after bumble bee hives were inserted under row covers at anthesis, and (iv) a noncovered control. In two field trials during 2007 and 2008, the delayed-removal row-cover treatments significantly suppressed bacterial wilt throughout the growing season and enhanced yield compared with the noncovered and removal-at-anthesis controls. In Gilbert in 2008, however, bacterial wilt suppression was equivalent among all three row-cover treatments. No bacterial wilt was observed during three trials in 2009, and there was minimal difference in marketable yield among treatments. Net returns were compared using partial budget and sensitivity analyses. Melon prices and occurrence of bacterial wilt had a strong impact on net returns. Using row covers increased production costs by 45%. In site years in which bacterial wilt occurred, delaying removal of row covers resulted in the highest returns. When bacterial wilt was absent, however, the delayed-removal row-cover treatments had the lowest returns. Results of the sensitivity analysis indicated that delaying removal of row covers for 10 days could be a cost-effective component of an integrated bacterial wilt suppression strategy for muskmelon where bacterial wilt occurs ≥50% of production seasons.


Ecology and epidemiology of rabies in humans, domestic animals and wildlife in Namibia, 2011-2017.
Rabies is a fatal zoonotic disease that causes a heavy burden on societies. Namibia, a country in southern Africa, is aiming at controlling the disease in its main reservoir, the domestic dog. To facilitate the implementation comprehensive information on the ecology and epidemiology of the disease and surveillance is of utmost importance. The study presented assesses the baseline data for both human and animal rabies surveillance in Namibia in recent times and establishes correlations with ecological and socio-economic data in order to provide an up-to-date picture on the epidemiology of rabies in Namibia. For instance, it was important to identify the main drivers in the epidemiology, and whether the control strategy by mass vaccination of dogs is undermined by cycles of rabies in wildlife. Rabies in humans was reported mainly from the Northern Communal Areas (NCAs), with a total of 113 cases from 2011 to 2017, representing an incidence of between 1.0 and 2.4 annual human rabies deaths per 100,000 inhabitants. Kavango, the region with the highest human rabies incidence was also the region with the lowest animal rabies surveillance intensity. Generally, the vast majority (77%) of dog samples originated from communal farm land, followed by urban areas (17%), while only a small fraction (3%) was submitted from freehold farm areas. In contrast, kudu and eland submissions were almost exclusively from freehold farmland (76%) and urban areas (19%), whereas the submission of cattle samples was evenly distributed among freehold farms (46%) and communal farm land (46%). The likelihood of sample submission decreased exponentially with distance to one of the two laboratories. Overall, 67% (N = 1,907) of all samples submitted tested rabies-positive, with the highest positivity rate observed in kudus (89%) and jackals (87%). The transmission cycle of rabies in dogs appears restricted to the northern communal areas of Namibia, whilst rabies in wildlife species is predominately reported from farmland in central Namibia, mostly affecting kudu (Tragelaphus strepsiceros) and livestock with a likely reservoir in wildlife canids such as jackals or bat-eared foxes. The analysis confirms the presence of two independent transmission cycles in Namibia with little geographic overlap, thus allowing for a sustainable control of rabies in dogs in the NCAs.


Further additions to MolScript version 1.4, including reading and contouring of electron-density maps.
MolScript is one of the most popular programs for the generation of publication-quality figures and the recent re-working of the program should ensure its continued popularity. However, some functionality of particular interest to crystallographers is not part of the standard program. A modified MolScript version 1.4 has been described previously, with more flexible colouring schemes among its new features. This report describes further enhancements to MolScript version 1.4, including facilities for drawing rods for helices and ribbons for oligonucleotides and allowing several formats of electron-density maps to be read and contoured using either lines or smoothed triangulated surfaces.


Vascular lesion of the masseter presenting with phlebolith.
When evaluating an intramuscular soft tissue mass, a large differential diagnosis including both benign and malignant lesions must be considered. Because the treatment of these masses can range from simple observation to radical surgical excision, a minimally invasive but accurate method of diagnosis is desired. The workup should include radiographic imaging. MRI is the modality of choice for differentiating soft tissue lesions, although CT may be helpful in identifying calcifications such as a phlebolith. Although usually unnecessary, a sialogram can verify that a calcification lies within or outside the salivary ductal system. In most cases a biopsy specimen is required to confirm the diagnosis. However, if the imaging studies show characteristics consistent with a vascular soft tissue mass, the finding of a phlebolith is pathognomonic for a benign vascular lesion. If such a lesion is not causing significant cosmetic or functional disability, it can be observed without the need for invasive biopsy or treatment.


Bromoanisoles and methoxylated bromodiphenyl ethers in macroalgae from Nordic coastal regions.
Marine macroalgae are used worldwide for human consumption, animal feed, cosmetics and agriculture. In addition to beneficial nutrients, macroalgae contain halogenated natural products (HNPs), some of which have toxic properties similar to those of well-known anthropogenic contaminants. Sixteen species of red, green and brown macroalgae were collected in 2017-2018 from coastal waters of the northern Baltic Sea, Sweden Atlantic and Norway Atlantic, and analyzed for bromoanisoles (BAs) and methoxylated bromodiphenyl ethers (MeO-BDEs). Target compounds were quantified by gas chromatography-low resolution mass spectrometry (GC-LRMS), with qualitative confirmation in selected species by GC-high resolution mass spectrometry (GC-HRMS). Quantified compounds were 2,4-diBA, 2,4,6-triBA, 2'-MeO-BDE68, 6-MeO-BDE47, and two tribromo-MeO-BDEs and one tetrabromo-MeO-BDE with unknown bromine substituent positions. Semiquantitative results for pentabromo-MeO-BDEs were also obtained for a few species by GC-HRMS. Three extraction methods were compared; soaking in methanol, soaking in methanol-dichloromethane, and blending with mixed solvents. Extraction yields of BAs did not differ significantly (p > 0.05) with the three methods and the two soaking methods gave equivalent yields of MeO-BDEs. Extraction efficiencies of MeO-BDEs were significantly lower using the blend method (p < 0.05). For reasons of simplicity and efficiency, the soaking methods are preferred. Concentrations varied by orders of magnitude among species: ∑2BAs 57 to 57 700 and ∑5MeO-BDEs < 10 to 476 pg g-1 wet weight (ww). Macroalgae standing out with ∑2BAs >1000 pg g-1 ww were Ascophyllum nodosum, Ceramium tenuicorne, Ceramium virgatum, Fucus radicans, Fucus serratus, Fucus vesiculosus, Saccharina latissima, Laminaria digitata, and Acrosiphonia/Spongomorpha sp. Species A. nodosum, C. tenuicorne, Chara virgata, F. radicans and F. vesiculosus (Sweden Atlantic only) had ∑5MeO-BDEs >100 pg g-1 ww. Profiles of individual compounds showed distinct differences among species and locations.


Position document: IgE-mediated cow's milk allergy.
The present document offers an update on the recommendations for managing patients with cow's milk allergy - a disorder that manifests in the first year of life, with an estimated prevalence of 1.6-3% in this paediatric age group. The main causal allergens are the caseins and proteins in lactoserum (beta-lactoglobulin, alpha-lactoalbumin), and the clinical manifestations are highly variable in terms of their presentation and severity. Most allergic reactions affect the skin, followed by the gastrointestinal and respiratory systems, and severe anaphylaxis may occur. The diagnosis of cow's milk allergy is based on the existence of a suggestive clinical history, a positive allergy study and the subsequent application of controlled exposure testing, which constitutes the gold standard for confirming the diagnosis. The most efficient treatment for cow's milk allergy is an elimination diet and the use of adequate substitution formulas. The elimination diet must include milk from other mammals (e.g., sheep, goat, etc.) due to the risk of cross-reactivity with the proteins of cow's milk. Most infants with IgE-mediated cow's milk allergy become tolerant in the first few years of life. In those cases where cow's milk allergy persists, novel treatment options may include oral immunotherapy, although most authors do not currently recommend this technique in routine clinical practice. Enough evidence is not there to confirm the efficacy of elimination diets in the mother and infant for preventing the appearance of cow's milk allergy. Likewise, no benefits have been observed with prebiotic and probiotic dietetic supplements in infants for preventing food allergy.


Diffractive m-bonacci lenses.
Fibonacci zone plates are proving to be promising candidates in image forming devices. In this letter we show that the set of Fibonacci zone plates are a particular member of a new family of diffractive lenses which can be designed on the basis of a given m-bonacci sequence. These lenses produce twin axial foci whose separation depends on the m-golden mean. Therefore, with this generalization, bifocal systems can be freely designed under the requirement at particular focal planes. Experimental results support our proposal.


Contrasting localizations of MALS/LIN-7 PDZ proteins in brain and molecular compensation in knockout mice.
Proteins containing PDZ (postsynaptic density-95, discs large, zonula occludens) domains play a general role in recruiting receptors and enzymes to specific synaptic sites. In Caenorhabditis elegans, a complex of three PDZ proteins, LIN-2/7/10, mediates basolateral targeting of a receptor tyrosine kinase. Homologs of these LIN proteins have also been identified in higher organisms, and here we analyze the MALS/Veli (mammalian LIN-7/vertebrate homolog of LIN-7) proteins in brain. Immunohistochemical staining and in situ hybridization show that MALS occur differentially in discrete populations of neurons throughout the brain. Most neurons express only one MALS protein, although some cells contain two or even all three MALS isoforms. At the subcellular level, MALS proteins are found in both dendritic and axonal locations, suggesting that they may regulate processes at both pre- and postsynaptic sites. Targeted disruption of MALS-1 and MALS-2 does not yield a detectable phenotype, and hippocampal synaptic function and plasticity are intact in the MALS-1/2 double knockouts. Interestingly, MALS-3 protein is dramatically induced in the MALS-1/2 double knockouts, implying that dynamic changes in protein expression may play an important regulatory role for this family of synaptic PDZ proteins.


A penalized likelihood approach for an illness-death model with interval-censored data: application to age-specific incidence of dementia.
We consider the problem of estimating the intensity functions for a continuous time 'illness-death' model with intermittently observed data. In such a case, it may happen that a subject becomes diseased between two visits and dies without being observed. Consequently, there is an uncertainty about the precise number of transitions. Estimating the intensity of transition from health to illness by survival analysis (treating death as censoring) is biased downwards. Furthermore, the dates of transitions between states are not known exactly. We propose to estimate the intensity functions by maximizing a penalized likelihood. The method yields smooth estimates without parametric assumptions. This is illustrated using data from a large cohort study on cerebral ageing. The age-specific incidence of dementia is estimated using an illness-death approach and a survival approach.


Prevalence, Diagnosis, and Treatment Rates of Mood Disorders among Opioid Users under Criminal Justice Supervision.
Individuals involved in the criminal justice system have disproportionately high rates of psychiatric disorders when compared to the general U.S. If left untreated, the likelihood of subsequent arrest increases and risk for adverse health consequences is great, particularly among opioid users. To explore the prevalence, characteristics, and treatment of mood disorders among justice involved opioid-dependent populations. The current study enrolled 258 treatment-seeking opioid-dependent individuals under community-based criminal justice supervision (e.g., probation, parole) screened from the larger parent study, Project STRIDE, a seek/test/treat randomized control trial (RCT) examining HIV and opioid use treatment. During baseline, individuals were screened for depression using the Patient Health Questionnaire-9 (PHQ-9) and screened for bipolar disorder using the Mood Disorder Questionnaire (MDQ) tool. Overall, 78 (30%) participants screened positive for moderate to severe depression and 54 (21%) screened positive for bipolar disorder. Participants self-reported mood disorders at higher rates than they screened positive for these conditions. Participants screening positive for these conditions experienced significantly greater family, legal, and medical problems on the Addiction Severity Index-Lite (ASI-Lite) than those who did not screen positive. Incidence of a lifetime suicide attempt was found to be associated with a positive screen for both mood disorders. Prescribed psychotropic treatment utilization was similar among those who screened positive for depression or bipolar disorder with approximately 38% reporting taking medication. Findings suggest universal mood disorder screening to improve comprehensive psychiatric care and treatment of opioid-dependent justice-involved individuals.


Accuracy of clinical neurological examination in diagnosing lumbo-sacral radiculopathy: a systematic literature review.
Lumbar radiculopathy remains a clinical challenge among primary care clinicians in both assessment and diagnosis. This often leads to misdiagnosis and inappropriate treatment of patients resulting in poor health outcomes, exacerbating this already debilitating condition. This review evaluated 12 primary diagnostic accuracy studies that specifically assessed the performance of various individual and grouped clinical neurological tests in detecting nerve root impingement, as established in the current literature. Eight electronic data bases were searched for relevant articles from inception until July 2016. All primary diagnostic studies which investigated the accuracy of clinical neurological test (s) in diagnosing lumbar radiculopathy among patients with low back and referred leg symptoms were screened for inclusion. Qualifying studies were retrieved and independently assessed for methodological quality using the 'Quality Assessment of Diagnostic tests Accuracy Studies' criteria. A total of 12 studies which investigated standard components of clinical neurological examination of (sensory, motor, tendon reflex and neuro-dynamics) of the lumbo-sacral spine were included. The mean inter-observer agreement on quality assessment by two independent reviewers was fair (k = 0.3 - 0.7). The diagnostic performance of sensory testing using MR imaging as a reference standard demonstrated a sensitivity (confidence interval 95%) 0.61 (0.47-0.73) and a specificity of 0.63 (0.38-0.84). Motor tests sensitivity was poor to moderate, ranging from 0.13 (0.04-0.31) to 0.61 (0.36-0.83). Generally, the diagnostic performance of reflex testing was notably good with specificity ranging from (confidence interval 95%) 0.60 (0.51-0.69) to 0.93 (0.87-0.97) and sensitivity ranging from 0.14 (0.09-0.21) to 0.67 (0.21-0.94). Femoral nerve stretch test had a high sensitivity of (confidence interval 95%) 1.00 (0.40-1.00) and specificity of 0.83 (0.52-0.98) while SLR test recorded a mean sensitivity of 0.84 (0.72-0.92) and specificity of 0.78 (0.67-0.87). There is a scarcity of studies on the diagnostic accuracy of clinical neurological examination testing. Furthermore there seem to be a disconnect among researchers regarding the diagnostic utility of lower limb neuro-dynamic tests which include the Straight Leg Raise and Femoral Nerve tests for sciatic and femoral nerve respectively. Whether these tests are able to detect the presence of disc herniation and subsequent nerve root compression or hyper-sensitivity of the sacral and femoral plexus due to mechanical irritation still remains debatable.


Mobile phones improve antenatal care attendance in Zanzibar: a cluster randomized controlled trial.
Applying mobile phones in healthcare is increasingly prioritized to strengthen healthcare systems. Antenatal care has the potential to reduce maternal morbidity and improve newborns' survival but this benefit may not be realized in sub-Saharan Africa where the attendance and quality of care is declining. We evaluated the association between a mobile phone intervention and antenatal care in a resource-limited setting. We aimed to assess antenatal care in a comprehensive way taking into consideration utilisation of antenatal care as well as content and timing of interventions during pregnancy. This study was an open label pragmatic cluster-randomised controlled trial with primary healthcare facilities in Zanzibar as the unit of randomisation. 2550 pregnant women (1311 interventions and 1239 controls) who attended antenatal care at selected primary healthcare facilities were included at their first antenatal care visit and followed until 42 days after delivery. 24 primary health care facilities in six districts were randomized to either mobile phone intervention or standard care. The intervention consisted of a mobile phone text-message and voucher component. Primary outcome measure was four or more antenatal care visits during pregnancy. Secondary outcome measures were tetanus vaccination, preventive treatment for malaria, gestational age at last antenatal care visit, and antepartum referral. The mobile phone intervention was associated with an increase in antenatal care attendance. In the intervention group 44% of the women received four or more antenatal care visits versus 31% in the control group (OR, 2.39; 95% CI, 1.03-5.55). There was a trend towards improved timing and quality of antenatal care services across all secondary outcome measures although not statistically significant. The wired mothers' mobile phone intervention significantly increased the proportion of women receiving the recommended four antenatal care visits during pregnancy and there was a trend towards improved quality of care with more women receiving preventive health services, more women attending antenatal care late in pregnancy and more women with antepartum complications identified and referred. Mobile phone applications may contribute towards improved maternal and newborn health and should be considered by policy makers in resource-limited settings.


Evidence that thyroid hormone induces olfactory cellular proliferation in salmon during a sensitive period for imprinting.
Salmon have long been known to imprint and home to natal stream odors, yet the mechanisms driving olfactory imprinting remain obscure. The timing of imprinting is associated with elevations in plasma thyroid hormone levels, with possible effects on growth and proliferation of the peripheral olfactory system. Here, we begin to test this idea by determining whether experimentally elevated plasma levels of 3,5,3'-triiodothyronine (T(3)) influence cell proliferation as detected by the 5-bromo-2'-deoxyuridine (BrdU) cell birth-dating technique in the olfactory epithelium of juvenile coho salmon (Oncorhynchus kisutch). We also explore how natural fluctuations in thyroxine (T(4)) relate to proliferation in the epithelium during the parr-smolt transformation. In both studies, we found that BrdU labeled both single and clusters of mitotic cells. The total number of BrdU-labeled cells in the olfactory epithelium was significantly greater in fish with artificially elevated T(3) compared with placebo controls. This difference in proliferation was restricted to the basal region of the olfactory epithelium, where multipotent progenitor cells differentiate into olfactory receptor neurons. The distributions of mitotic cluster sizes differed significantly from a Poisson distribution for both T(3) and placebo treatments, suggesting that proliferation tends to be non-random. Over the course of the parr-smolt transformation, changes in the density of BrdU cells showed a positive relationship with natural fluctuations in plasma T(4). This relationship suggests that even small changes in thyroid activity can stimulate the proliferation of neural progenitor cells in the salmon epithelium. Taken together, our results establish a link between the thyroid hormone axis and measurable anatomical changes in the peripheral olfactory system.


Extracellular dGMP enhances Deinococcus radiodurans tolerance to oxidative stress.
Free extracellular DNA provides nutrition to bacteria and promotes bacterial evolution by inducing excessive mutagenesis of the genome. To understand the influence of extracellular DNA fragments on D. radiodurans, we investigated cell growth and survival after extracellular DNA or dNMPs treatment. The results showed that the extracellular DNA fragments inhibited the growth of D. radiodurans. Interestingly, dGMP, a DNA component, enhanced D. radiodurans tolerance to H(2)O(2) and gamma-radiation significantly. Further experiments indicated that extracellular dGMP stimulated the activity of one catalase (KatA, DR1998), and induced gene transcription including the extracellular nuclease (drb0067). When this only extracellular nuclease gene (drb0067) in D. radiodurans was deleted, the mutant strain showed more sensitive to H(2)O(2) and gamma-radiation than the wild type strain. These results suggest that DRB0067 plays an important role in oxidative stress resistance. Taken together, we proposed a new anti-oxidation mechanism in D. radiodurans. This mechanism acts to increase expression levels of DRB0067 which then secretes active nuclease to degrade extracellular DNA fragments. The extracellular nuclease has a two-fold benefit, creating more free dNTPs for further cell protection and the removal of extracellular DNA fragments.


The effects of the transition from home-based childcare to childcare centers on children's health and development in Colombia.
Colombia's national early childhood strategy launched in 2011 aimed at improving the quality of childcare services offered to socio-economically vulnerable children, and included the possibility that children and their childcare providers could transfer from non-parental family daycare units to large childcare centers in urban areas. This study seeks to understand whether the offer to transfer and the actual transfer from one program to the other had an impact on child cognitive and socioemotional development, and nutrition, using a cluster-randomized control trial with a sample of 2767 children between the ages of 6 and 60 months located in 14 cities in Colombia. The results indicate a negative effect of this initiative on cognitive development, a positive effect on nutrition, and no statistically significant effect of the intervention on socioemotional development. We also explored the extent to which these impacts might be explained by differences in the quality of both services during the transition, and report that quality indicators are low in both programs but are significantly worse in centers compared to community nurseries.


segment_liftover : a Python tool to convert segments between genome assemblies.
The process of assembling a species' reference genome may be performed in a number of iterations, with subsequent genome assemblies differing in the coordinates of mapped elements. The conversion of genome coordinates between different assemblies is required for many integrative and comparative studies. While currently a number of bioinformatics tools are available to accomplish this task, most of them are tailored towards the conversion of single genome coordinates. When converting the boundary positions of segments spanning larger genome regions, segments may be mapped into smaller sub-segments if the original segment's continuity is disrupted in the target assembly. Such a conversion may lead to a relevant degree of data loss in some circumstances such as copy number variation (CNV) analysis, where the quantitative representation of a genomic region takes precedence over base-specific accuracy. segment_liftover aims at continuity-preserving remapping of genome segments between assemblies and provides features such as approximate locus conversion, automated batch processing and comprehensive logging to facilitate processing of datasets containing large numbers of structural genome variation data.


Self in motion: sensorimotor and cognitive mechanisms in gait agency.
Acting in our environment and experiencing ourselves as conscious agents are fundamental aspects of human selfhood. While large advances have been made with respect to understanding human sensorimotor control from an engineering approach, knowledge about its interaction with cognition and the conscious experience of movement (agency) is still sparse, especially for locomotion. We investigated these relationships by using life-size visual feedback of participants' ongoing locomotion, thereby extending agency research previously limited to goal-directed upper limb movements to continuous movements of the entire body. By introducing temporal delays and cognitive loading we were able to demonstrate distinct effects of bottom-up visuomotor conflicts as well as top-down cognitive loading on the conscious experience of locomotion (gait agency) and gait movements. While gait agency depended on the spatial and temporal congruency of the avatar feedback, gait movements were solely driven by its temporal characteristics as participants nonconsciously attempted to synchronize their gait with their avatar's gait. Furthermore, gait synchronization was suppressed by cognitive loading across all tested delays, whereas gait agency was only affected for selective temporal delays that depended on the participant's step cycle. Extending data from upper limb agency and auditory gait agency, our results are compatible with effector-independent and supramodal control of agency; they show that both mechanisms are dissociated from automated sensorimotor control and that cognitive loading further enhances this dissociation.


Epigenome-wide DNA methylation study of IgE concentration in relation to self-reported allergies.
Epigenetic mechanisms are critical for normal immune development and epigenetic alterations might therefore be possible contributors to immune diseases. To investigate if DNA methylation in whole blood is associated with total and allergen-specific IgE levels. We performed an epigenome-wide association study to investigate the association between DNA methylation and IgE level, allergen-specific IgE and self-reported immune diseases and allergies in 728 individuals. We identified and replicated 15 CpG sites associated with IgE, mapping to biologically relevant genes, including ACOT7, ILR5A, KCNH2, PRG2 and EPX. A total of 331 loci were associated with allergen-specific IgE, but none of these CpG sites were associated with self-reported allergies and immune diseases. This study shows that IgE levels are associated with DNA methylation levels at numerous CpG sites, which might provide new leads for investigating the links between IgE and allergic inflammation.


A quantitative study of the in vitro binding of the C-terminal domain of p21 to PCNA: affinity, stoichiometry, and thermodynamics.
Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication, repair, and control of cell proliferation, and its activity can be modulated by interaction with p21(Waf1/Cip1) [Cox, L. S., (1997) Trends Cell Biol. 7, 493-497]. This protein-protein interaction provides a particularly good model target for designing therapeutic agents to treat proliferative disorders such as cancer. In this study, the formation of complexes between PCNA and peptides derived from the C-terminus of p21 has been investigated at the molecular level and quantified using a competitive PCNA binding assay and isothermal titration calorimetry (ITC). The affinity constant for the interaction between p21 (141-160) peptide and PCNA has been determined to be 1.14 x 10(7) M(-)(1), corresponding to a K(d) of 87.7 nM. Measurement of the interaction of truncation and substitution analogues based on the p21 (141-160) sequence with PCNA revealed that the N-terminal part (residues 141-152) of the above peptide is the minimum recognition motif, required for PCNA binding. Truncation of the C-terminal region p21 (153-160), though, inhibited significantly the ability of the peptides to compete with the full-length p21 (141-160) for binding to PCNA. Alanine mutation of Met 147 or Asp 149 completely abolished or significantly decreased, respectively, the level of the PCNA binding and the inhibition of SV40 DNA replication. Comparison of the data obtained by the competitive PCNA binding assay and the ITC measurements demonstrated the usefulness of this assay for screening for compounds that could modulate the PCNA-p21 interaction. Using this assay, we have screened rationally designed peptides for binding to PCNA and interruption of the PCNA-p21 (141-160) complex. As a result of this screening, we have identified a 16-residue peptide (consensus motif 1 peptide) with the following sequence: SAVLQKKITDYFHPKK. Consensus motif 1 peptide and p21 (141-160) have similar affinities for binding PCNA and abilities to inhibit in vitro replication of DNA originated from SV40. Such peptides could prove useful in assessing p21-mimetic strategies for cancer treatment.


Plant cell wall biosynthesis: genetic, biochemical and functional genomics approaches to the identification of key genes.
Cell walls are dynamic structures that represent key determinants of overall plant form, plant growth and development, and the responses of plants to environmental and pathogen-induced stresses. Walls play centrally important roles in the quality and processing of plant-based foods for both human and animal consumption, and in the production of fibres during pulp and paper manufacture. In the future, wall material that constitutes the major proportion of cereal straws and other crop residues will find increasing application as a source of renewable fuel and composite manufacture. Although the chemical structures of most wall constituents have been defined in detail, the enzymes involved in their synthesis and remodelling remain largely undefined, particularly those involved in polysaccharide biosynthesis. There have been real recent advances in our understanding of cellulose biosynthesis in plants, but, with few exceptions, the identities and modes of action of polysaccharide synthases and other glycosyltransferases that mediate the biosynthesis of the major non-cellulosic wall polysaccharides are not known. Nevertheless, emerging functional genomics and molecular genetics technologies are now allowing us to re-examine the central questions related to wall biosynthesis. The availability of the rice, Populus trichocarpa and Arabidopsis genome sequences, a variety of mutant populations, high-density genetic maps for cereals and other industrially important plants, high-throughput genome and transcript analysis systems, extensive publicly available genomics resources and an increasing armoury of analysis systems for the definition of candidate gene function will together allow us to take a systems approach to the description of wall biosynthesis in plants.


Skeletal muscle alkaline Pi pool is decreased in overweight-to-obese sedentary subjects and relates to mitochondrial capacity and phosphodiester content.
Defects in skeletal muscle energy metabolism are indicative of systemic disorders such as obesity or type 2 diabetes. Phosphorus magnetic resonance spectroscopy ((31)P-MRS), in particularly dynamic (31)P-MRS, provides a powerful tool for the non-invasive investigation of muscular oxidative metabolism. The increase in spectral and temporal resolution of (31)P-MRS at ultra high fields (i.e., 7T) uncovers new potential for previously implemented techniques, e.g., saturation transfer (ST) or highly resolved static spectra. In this study, we aimed to investigate the differences in muscle metabolism between overweight-to-obese sedentary (Ob/Sed) and lean active (L/Ac) individuals through dynamic, static, and ST (31)P-MRS at 7T. In addition, as the dynamic (31)P-MRS requires a complex setup and patient exercise, our aim was to identify an alternative technique that might provide a biomarker of oxidative metabolism. The Ob/Sed group exhibited lower mitochondrial capacity, and, in addition, static (31)P-MRS also revealed differences in the Pi-to-ATP exchange flux, the alkaline Pi-pool, and glycero-phosphocholine concentrations between the groups. In addition to these differences, we have identified correlations between dynamically measured oxidative flux and static concentrations of the alkaline Pi-pool and glycero-phosphocholine, suggesting the possibility of using high spectral resolution (31)P-MRS data, acquired at rest, as a marker of oxidative metabolism.


Ganymede: observations by radar.
Radar cross-section measurements indicate that Ganymede scatters to Earth 12 percent of the power expected from a conducting sphere of the same size and distance. This compares with 8 percent for Mars, 12 percent for Venus, 6 percent for Mercury, and about 8 percent for the asteroid Toro. Furthermore, Ganymede is considerably rougher (to the scale of the wavelength used, 12.6 centimeters) than Mars, Venus, or Mercury. Roughness is made evident in this experiment by the presence of echoes away from the center of the disk. A perfectly smooth target would reflect only a glint from the center, whereas a very rough target would reflect power from over the entire disk.


Temperature-dependent interconversion of phosphoramidite-Cu complexes detected by combined diffusion studies, 31P NMR, and low-temperature NMR spectroscopy.
For copper-catalyzed enantioselective conjugate additions, knowledge about the precatalytic and catalytic complexes has not yet been sufficiently developed to understand the strong influence of different temperatures on these famous reactions. Therefore, NMR experiments with four Cu(I) salts and two phosphoramidite ligands have been performed to elucidate the temperature dependence and the low-temperature structures of these copper complexes. The existence of the precatalytic binuclear complex with a mixed trigonal/tetrahedral coordination on copper is for the first time proven with direct NMR spectroscopic methods. Below 200 K, intermolecular interactions between free ligands and [Cu2X2L3] complexes induce binuclear [Cu2X2L4] complexes similar to the crystal structures. By combining diffusion experiments and (31)P integrals at different temperatures, it is for the first time possible to follow the formation of stoichiometrically different complexes, even under experimental conditions in which the (31)P signals of the complexes are spectroscopically not resolved due to exchange processes. This allows a first correlation between the complex species observed and the synthetic conditions reported. Furthermore, different preferences to build homo- or heterochiral complexes are detected for binaphthol and biphenol phosphoramidite complexes.


Antimicrobial activity of heat-treated Polish honeys.
Bactericidal properties of honey depend on botanical and geographical origin, where thermal treatment can have a significant affect. The aim of this study was to investigate the effect of temperature on minimum bactericidal concentration (MBC), vitamin C content, total polyphenols content and antioxidant capacity of ferric reducing antioxidant potential (FRAP) of several nectar honey varieties from northern Poland (lime, rapeseed, multifloral and buckwheat). The honeys were subjected to thermal treatment at 22 °C, 42 °C, 62 °C, 82 °C and 100 °C for two exposure times. The results showed a significant reduction of antimicrobial properties (MBC ⩾50%) at 82 °C and 62 °C after 15 and 120 min exposure time for most samples. Short time exposure reduced vitamin C content (⩽50 %) but increased total polyphenols content (⩾27%) and FRAP value (⩾106%).


Feasibility of using maternal cancer screening visits to identify adolescent girls eligible for human papillomavirus vaccination.
Breast or cervical cancer screening visits may present an opportunity to motivate mothers to have their daughters vaccinated against human papillomavirus (HPV). In preparation for a future intervention study, we sought to establish the feasibility of using these visits to identify women with at least one daughter in the appropriate age range for adolescent HPV vaccination. We conducted a cross-sectional mailed survey of women who had received breast or cervical cancer screening within the 6-18 months before the survey. The study was conducted at two diverse institutions: one serving a mostly black (54.1%) urban inner-city population and another serving a mostly white (87.5%) suburban population. Our overall response rate was 28% (n = 556) in the urban site and 38% (n = 381) in the suburban site. In the urban site, the proportions of mothers completing mammography or Pap smear visits with HPV vaccine-eligible daughters were 23% and 24%, respectively. In the suburban site, the proportions of mothers completing mammography or Pap smear with at least one vaccine-eligible daughter were 41% and 26%, respectively. Women who undergo breast or cervical cancer screening in the two different demographic groups evaluated have at least one adolescent daughter at the appropriate age for HPV vaccination. An important implication of this finding in adolescent daughters of urban mothers is the potential use of maternal breast or cervical cancer screening encounters to target a potentially undervaccinated group.


T lymphocytes in the murine vaginal mucosa are phenotypically distinct from those in the periphery.
The results from both clinical studies of women with recurrent vulvovaginal candidiasis and a murine model of experimental vaginitis indicate that systemic cell-mediated immunity may not represent a dominant host defense mechanism against vaginal infections by Candida albicans. Recent experimental evidence indicates the presence of local vaginal immune reactivity against C. albicans. The present study was designed to examine T-lymphocyte subpopulations in the vaginal mucosae of naive CBA/J mice. Vaginal lymphocytes (VL) were isolated by collagenase digestion of whole vaginal tissues. Cell populations were identified by flow cytometry, and the results were compared with those for both lymph node cells (LNC) and peripheral blood lymphocytes (PBL). The results of flow cytometry showed that 45% +/- 10% of lymphocytes in the vaginal mucosa are CD3+ compared with 75% +/- 5% in LNC and 50% +/- 5% in PBL. The majority (85%) of CD3+ VL are CD4+ and express the alpha/beta T-cell receptor (TCR), similar to the results for LNC and PBL. In contrast to LNC and PBL, VL contain a significantly higher percentage (15 to 20%) of gamma/delta TCR+ cells, 80% or more of which appear to express CD4. In addition, while CD4-CD8 cell ratios in LNC and PBL were 3:1 and 6:1, respectively, only 1% of VL expressed CD8, resulting in a CD4-CD8 cell ratio of > 100:1. Finally, while LNC and PBL recognized two epitope-distinct (GK 1.5 and 2B6) anti-CD4 antibodies, VL recognized only 2B6 anti-CD4 antibodies. Further analysis of VL showed that Thy-1 cells, but not CD4 cells, were reduced after intravaginal injection of complement-fixing anti-Thy-1.2 and GK 1.5 anti-CD4 antibodies, respectively. Taken together, these data suggest that T lymphocytes in the vaginal mucosae of mice are phenotypically distinct from those in the periphery and that CD4+ VL have an uncharacteristic or atypical expression of the CD4 receptor.


Perturbed rhythmic activation of signaling pathways in mice deficient for Sterol Carrier Protein 2-dependent diurnal lipid transport and metabolism.
Through evolution, most of the living species have acquired a time keeping system to anticipate daily changes caused by the rotation of the Earth. In all of the systems this pacemaker is based on a molecular transcriptional/translational negative feedback loop able to generate rhythmic gene expression with a period close to 24 hours. Recent evidences suggest that post-transcriptional regulations activated mostly by systemic cues play a fundamental role in the process, fine tuning the time keeping system and linking it to animal physiology. Among these signals, we consider the role of lipid transport and metabolism regulated by SCP2. Mice harboring a deletion of the Scp2 locus present a modulated diurnal accumulation of lipids in the liver and a perturbed activation of several signaling pathways including PPARα, SREBP, LRH-1, TORC1 and its upstream regulators. This defect in signaling pathways activation feedbacks upon the clock by lengthening the circadian period of animals through post-translational regulation of core clock regulators, showing that rhythmic lipid transport is a major player in the establishment of rhythmic mRNA and protein expression landscape.


Beyond "safe and effective": the role of the federal government in supporting and disseminating comparative-effectiveness research.
Over the past century, medical advancements have resulted in tremendous health gains for Americans. Although the federal government has played a prominent role in ensuring that new treatments are safe and effective, questions about which medical treatments work best under which circumstances have largely remained unanswered. Thus, the federal government's recent major investments in comparative-effectiveness research have potential to play a significant role in helping both patients and health care providers navigate the vast array of available treatment options, as well as in improving the quality, efficiency, and delivery of health care system-wide. Yet, the controversial nature of the government's foray into comparative-effectiveness research also suggests that the path toward realizing these goals may be treacherous. This Article describes the rationales for federal support of comparative-effectiveness research and potential models for that involvement, analyzes the federal government's recent investments in the research, and concludes with predictions about the probable outcomes of these investments. While increased federal support for comparative-effectiveness research is unlikely to achieve all of the benefits anticipated by its supporters, it is a crucial step toward ensuring that Americans are able to take full advantage of the benefits of medical innovation


Nitrogen and carbon contents and δ(15) N and δ(13) C signatures in six bryophyte species: assessment of long-term deposition changes (1980-2010) in Spanish beech forests.
In this study we used recent (2010) and herbarium material (1980) of six bryophyte species to assess long-term atmospheric deposition in natural forested areas in northern Spain. For this purpose, tissue nitrogen and carbon content, as well as δ(13) C and δ(15) N signatures of samples of Hypnum cupressiforme, Polytrichastrum formosum, Leucobryum juniperoideum, Rhytidiadelphus loreus, Homalothecium lutescens and Diplophyllum albicans were analysed and comparisons made between years and species. In addition, the usefulness of each of the six species was evaluated. The range of values observed was similar to that in other studies carried out in rural areas. Significantly lower values were found in 2010 for N (H. cupressiforme), δ(15) N (R. loreus and D. albicans), C (R. loreus) and δ(13) C (all except L. juniperoideum). Our natural areas are thus now less influenced by atmospheric pollutants than they were, most probably due to changes in some traditional local activities. Differences were observed between species for all the four parameters studied, so different species must not be analysed together. Finally, R. loreus and H. lutescens seem to be good bioindicators, sensitive even with a few samples, although further studies are needed to corroborate their usefulness.


Frequent occurrence of deletions in primary mediastinal B-cell lymphoma.
Primary mediastinal B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma. PMBCL has been previously studied with a variety of genomic techniques resulting in frequent detection of chromosomal gains; however, chromosomal losses have been rarely reported. This finding contrasts many other types of lymphoma, in which deletions are common. We hypothesize that segmental losses do exist but may have escaped detection by methods used in the previous studies. Using array comparative genomic hybridization to a tiling-resolution microarray encompassing the entire human genome, PMBCL samples were analyzed for genomic copy number alterations. An almost equal number of gains and losses of chromosomal material were detected throughout the genome (216 vs. 193, respectively). A selection of these DNA copy number alterations were confirmed by quantitative real-time PCR. Recurrent gains were detected at all previously reported regions of gain, including 9p seen in approximately 70% of cases. Recurrent chromosomal losses were observed at 1p, 3p, 4q, 6q, 7p, and 17p, with a novel event at 1p13.1-p13.2 representing the most frequent at 42% of cases analyzed. We conclude that consistent losses are present in the PMBCL genome. Given the similar frequency of losses to that of segmental gains of DNA, they are likely to play an important role in the pathogenesis of PMBCL.


Evaluation of a 23S rDNA polymerase chain reaction assay for identification of Serpulina intermedia, and strain typing using pulsed-field gel electrophoresis.
A polymerase chain reaction assay, amplifying a 1027 base pair portion of the 23S rDNA gene, was evaluated for identification of the intestinal spirochaete Serpulina intermedia. A total of 34 strains of S. intermedia isolated from pigs and chickens and 195 strains of other related species were tested. The optimised assay correctly identified all the S. intermedia strains, but generated 11 false positive reactions, giving a test sensitivity of 100% and a test specificity of 94.3%. The false positive reactions were generated from strains of four different species of intestinal spirochaetes, and the product was of the original predicted size. This suggests that the primer sites selected on the 23S rRNA gene were not completely specific for S. intermedia. Pulsed-field gel electrophoresis was then developed to investigate diversity amongst the S. intermedia strains. All strains tested had distinct DNA banding patterns using Mlu1, although three isolates from chickens on the same farm appeared closely related. The collection exhibited considerable genetic diversity, and strains from pigs and chickens were distributed in clusters throughout the dendrogram produced. The most closely related porcine and avian strains shared only 62% similarity.


Low sexual desire: sex therapy results and prognostic factors.
In a prospective study of 60 couples who entered sex therapy because of the female partners' low sexual desire, 38 (63.3%) completed treatment and 34 (56.7%) had a positive outcome. The principal predictor of completion of treatment was the male partners' apparent motivation at the outset. Poorer outcome was associated with younger age of the couple (especially the male partner) and a shorter duration of the sexual problem. Surprisingly, few aspects of the couples' general relationships prior to treatment were related to outcome, except for poorer outcome being associated with a history of previous separations. The apparent lack of significant contribution of general relationship factors and psychopathology to outcome probably reflects the stringency of the initial selection process. Eventual outcome was also related to couples' progress by the third treatment session. The modest outcome of treatment for low sexual desire in this and other studies emphasises the need for further understanding of factors which contribute to this problem and for the development of novel treatment strategies.