Smartphone apps for cardiopulmonary resuscitation training and real incident support: a mixed-methods evaluation study.
No systematic evaluation of smartphone/mobile apps for resuscitation training and real incident support is available to date. To provide medical, usability, and additional quality criteria for the development of apps, we conducted a mixed-methods sequential evaluation combining the perspective of medical experts and end-users. The study aims to assess the quality of current mobile apps for cardiopulmonary resuscitation (CPR) training and real incident support from expert as well as end-user perspective. Two independent medical experts evaluated the medical content of CPR apps from the Google Play store and the Apple App store. The evaluation was based on pre-defined minimum medical content requirements according to current Basic Life Support (BLS) guidelines. In a second phase, non-medical end-users tested usability and appeal of the apps that had at least met the minimum requirements. Usability was assessed with the System Usability Scale (SUS); appeal was measured with the self-developed ReactionDeck toolkit. Out of 61 apps, 46 were included in the experts' evaluation. A consolidated list of 13 apps resulted for the following layperson evaluation. The interrater reliability was substantial (kappa=.61). Layperson end-users (n=14) had a high interrater reliability (intraclass correlation 1 [ICC1]=.83, P<.001, 95% CI 0.75-0.882 and ICC2=.79, P<.001, 95% CI 0.695-0.869). Their evaluation resulted in a list of 5 recommendable apps. Although several apps for resuscitation training and real incident support are available, very few are designed according to current BLS guidelines and offer an acceptable level of usability and hedonic quality for laypersons. The results of this study are intended to optimize the development of CPR mobile apps. The app ranking supports the informed selection of mobile apps for training situations and CPR campaigns as well as for real incident support.


Current-induced thermal-lens spectrometry.
A new spectroelectrochemical method using the thermal-lens effect from electrolytes using regular joule heat generation by current focusing in a small-sized channel is proposed. The experimental dependences of the signal on the analyte concentration and applied voltage are in good concordance with the theoretical estimations. A cell design providing good reproducibility and sensitivity of measurements is proposed.


The two-pore domain potassium channel KCNK5: induction by estrogen receptor alpha and role in proliferation of breast cancer cells.
The growth of many human breast tumors requires the proliferative effect of estrogen acting via the estrogen receptor α (ERα). ERα signaling is therefore a clinically important target for breast cancer prevention and therapeutics. Although extensively studied, the mechanism by which ERα promotes proliferation remains to be fully established. We observed an up-regulation of transcript encoding the pH-sensitive two-pore domain potassium channel KCNK5 in a screen for genes stimulated by 17β-estradiol (E2) in the ERα(+) breast cancer cell lines MCF-7 and T47D. KCNK5 mRNA increased starting 1 h after the onset of E2 treatment, and protein levels followed after 12 h. Estrogen-responsive elements are found in the enhancer region of KCNK5, and chromatin immunoprecipitation assays revealed binding of ERα to the KCNK5 enhancer in E2-treated MCF-7 cells. Cells treated with E2 also showed increases in the amplitude of pH-sensitive potassium currents, as assessed by whole-cell recordings. These currents are blocked by clofilium. Although confocal microscopy suggested that most of the channels are located in intracellular compartments, the increase in macroscopic currents suggests that E2 treatment increases the number of active channels at the cell surface. Application of small interfering RNA specific for KCNK5 decreased pH-sensitive potassium currents and also reduced the estrogen-induced proliferation of T47D cells. We conclude that E2 induces the expression of KCNK5 via ERα(+) in breast cancer cells, and this channel plays a role in regulating proliferation in these cell lines. KCNK5 may therefore represent a useful target for treatment, for example, of tamoxifen-resistant breast cancer.


Ocean acidification compromises a planktic calcifier with implications for global carbon cycling.
Anthropogenically-forced changes in ocean chemistry at both the global and regional scale have the potential to negatively impact calcifying plankton, which play a key role in ecosystem functioning and marine carbon cycling. We cultured a globally important calcifying marine plankter (the foraminifer, Globigerina bulloides) under an ecologically relevant range of seawater pH (7.5 to 8.3 total scale). Multiple metrics of calcification and physiological performance varied with pH. At pH > 8.0, increased calcification occurred without a concomitant rise in respiration rates. However, as pH declined from 8.0 to 7.5, calcification and oxygen consumption both decreased, suggesting a reduced ability to precipitate shell material accompanied by metabolic depression. Repair of spines, important for both buoyancy and feeding, was also reduced at pH < 7.7. The dependence of calcification, respiration, and spine repair on seawater pH suggests that foraminifera will likely be challenged by future ocean conditions. Furthermore, the nature of these effects has the potential to actuate changes in vertical transport of organic and inorganic carbon, perturbing feedbacks to regional and global marine carbon cycling. The biological impacts of seawater pH have additional, important implications for the use of foraminifera as paleoceanographic indicators.


Exercise-related injuries among women: strategies for prevention from civilian and military studies.
The numerous health benefits of physical activity have been well documented, resulting in public health support of regular physical activity and exercise. Although beneficial, exercise also has corresponding risks, including musculoskeletal injuries. The incidence and risk factors for exercise-related injury have been poorly assessed in women. Many civilian exercise activities (e.g., jogging, walking, and erobics) have corollaries in military physical training; injury incidence and risk factors associated with military physical training have been more thoroughly studied. Injury risks increase as the amount of training increases (increased xposure). The same exercise parameters that can be modified to enhance physical fitness (i.e., frequency, duration, and intensity) also influence the risk for injury in a dose-response manner. Higher levels of current physical fitness (aerobic fitness) protect the participant against future injury. A history of previous injury is a risk factor for future injury. Smoking cigarettes has been associated with increased risk for exercise-related injury. Studies conducted in military populations suggest that the most important risk factor for injuries among persons engaged in vigorous weight-bearing aerobic physical activity might be low aerobic fitness rather than female sex. Because of the limited scientific research regarding women engaging in exercise, general recommendations are provided. Women starting exercise programs should be realistic about their goals and start slowly at frequency, duration, and intensity levels commensurate with their current physical fitness condition. Women should be informed about the early indicators of potential injury. Women who have sustained an injury should take precautions to prevent reinjury (e.g., ensuring appropriate recovery and rehabilitation). In general, a combination of factors affects the risk for exercise-related injury in women. How these factors act singly and in combination to influence injury risk is not well understood. Additional research regarding exercise-related injury in women is needed to answer many of the remaining epidemiologic questions and to help develop exercise programs that improve health while reducing the risk for injury. Exercise is an important component in improving and maintaining health; however, injury is also an accompanying risk. A review of key military and civilian research studies regarding exercise-related injuries provides some clues to reducing these injuries in women. Greater adherence to exercise guidelines can help decrease these risks.


An extremely rare manifestation of Behcet's disease: urethrovaginal fistula.
Behcet's disease (BD) is a rare chronic, relapsing, multisystemic disorder characterized by mucocutaneous, ocular, vascular and central nervous system manifestations. However, the etiopathogenesis of the disease remains unknown, and diagnosis is basically dependent on clinical manifestations. Sometimes BD may be diagnosed with rare clinical entities. Herein, we presented an extremely rare case of urethrovaginal fistula which has been diagnosed as manifestation of BD. After surgical treatment of fistula, there was no complication in 6 months following surgical repair and the follow-up period has been going on.


M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling.
Endothelial nitric oxide (NO) signaling plays a physiological role in limiting obesity-associated insulin resistance and inflammation. This study was undertaken to investigate whether this NO effect involves polarization of macrophages toward an anti-inflammatory M2 phenotype. Mice with transgenic endothelial NO synthase overexpression were protected against high-fat diet (HFD)-induced hepatic inflammation and insulin resistance, and this effect was associated with reduced proinflammatory M1 and increased anti-inflammatory M2 activation of Kupffer cells. In cell culture studies, exposure of macrophages to endothelial NO similarly reduced inflammatory (M1) and increased anti-inflammatory (M2) gene expression. Similar effects were induced by macrophage overexpression of vasodilator-stimulated phosphoprotein (VASP), a key downstream mediator of intracellular NO signaling. Conversely, VASP deficiency induced proinflammatory M1 macrophage activation, and the transplantation of bone marrow from VASP-deficient donor mice into normal recipients caused hepatic inflammation and insulin resistance resembling that induced in normal mice by consumption of an HFD. These data suggest that proinflammatory macrophage M1 activation and macrophage-mediated inflammation are tonically inhibited by NO → VASP signal transduction, and that reduced NO → VASP signaling is involved in the effect of HFD feeding to induce M1 activation of Kupffer cells and associated hepatic inflammation. Our data implicate endothelial NO → VASP signaling as a physiological determinant of macrophage polarization and show that signaling via this pathway is required to prevent hepatic inflammation and insulin resistance.


Comparative analysis of autoantibodies against a-fodrin in serum, tear fluid, and saliva from patients with Sjögren's syndrome.
To evaluate levels of IgA and IgG antibodies against a-fodrin in serum, tear fluid, and saliva and compare them with anti-Ro and anti-La antibody levels in the same samples of patients with Sjögren's syndrome (SS). Samples from 25 patients with SS (17 primary and 8 secondary), 8 patients with systemic lupus erythematosus (SLE), and 7 patients with rheumatoid arthritis (RA) as well as 20 healthy blood donor controls were collected. Antibodies were measured using ELISA. Although 40% of patients with primary SS had IgG anti-a-fodrin in their sera, it was also found in 36% and 32% of samples of their tear fluid and saliva, respectively. IgA a-fodrin antibodies were detected in 32% of SS sera, 20% of tear fluid samples, and 32% of saliva samples. Although the level of IgG anti-a-fodrin was significantly greater in serum, tear fluid, and saliva of SS patients compared to controls (p < 0.001), a significant difference was observed only in serum and saliva. While anti-Ro was detected in 48%, 56%, and 24% of serum, tear fluid, and saliva samples, respectively, anti-La was found in 40%, 44%, and 28%. Significant association was observed between serum IgG antibodies against a-fodrin and dry eye symptom score and rose bengal staining score. A negative association was also noted between tear IgA antibodies against a-fodrin and Schirmer I test. Correlation of IgG and IgA antibodies against a-fodrin with the severity of eye involvement suggests that these autoantibodies may be considered activation markers of SS.


Hydrocarbon phenotyping of algal species using pyrolysis-gas chromatography mass spectrometry.
Biofuels derived from algae biomass and algae lipids might reduce dependence on fossil fuels. Existing analytical techniques need to facilitate rapid characterization of algal species by phenotyping hydrocarbon-related constituents. In this study, we compared the hydrocarbon rich algae Botryococcus braunii against the photoautotrophic model algae Chlamydomonas reinhardtii using pyrolysis-gas chromatography quadrupole mass spectrometry (pyGC-MS). Sequences of up to 48 dried samples can be analyzed using pyGC-MS in an automated manner without any sample preparation. Chromatograms of 30-min run times are sufficient to profile pyrolysis products from C8 to C40 carbon chain length. The freely available software tools AMDIS and SpectConnect enables straightforward data processing. In Botryococcus samples, we identified fatty acids, vitamins, sterols and fatty acid esters and several long chain hydrocarbons. The algae species C. reinhardtii, B. braunii race A and B. braunii race B were readily discriminated using their hydrocarbon phenotypes. Substructure annotation and spectral clustering yielded network graphs of similar components for visual overviews of abundant and minor constituents. Pyrolysis-GC-MS facilitates large scale screening of hydrocarbon phenotypes for comparisons of strain differences in algae or impact of altered growth and nutrient conditions.


Disseminated Sporothrix brasiliensis infection with endocardial and ocular involvement in an HIV-infected patient.
Disseminated sporotrichosis occurs in individuals with impaired cellular immunity, such as in cases of neoplasia, transplantation, diabetes, and especially, acquired immunodeficiency syndrome. This report presents a 32-year-old Brazilian human immunodeficiency virus (HIV)-infected patient who developed a protracted condition of disseminated sporotrichosis with endocarditis, bilateral endophthalmitis, and lymphatic involvement. He needed cardiac surgery to replace the mitral valve. Sporothrix brasiliensis isolates were recovered from cultures of subcutaneous nodules and mitral valve fragments. Species identification was based on classical and molecular methods. The patient received amphotericin B for 52 days and subsequently, oral itraconazole. He remains asymptomatic, and he is on maintenance therapy with itraconazole. Despite his positive clinical outcome, he developed bilateral blindness. To our knowledge, this case is the first report of endocarditis and endophthalmitis caused by S. brasiliensis.


Association of adiponectin promoter variants with traits and clusters of metabolic syndrome in Arabs: family-based study.
Plasma levels of adiponectin are decreased in type 2 diabetes, obesity and hypertension. Our aim was to use a family-based analysis to identify the genetic variants of the adiponectin (ADIPOQ) gene that are associated with obesity, insulin resistance, dyslipidemia and hypertension, among Arabs. We screened 328 Arabs in one large extended family for single nucleotide polymorphisms (SNPs) in the promoter region of the ADIPOQ gene. Two common SNPs were detected: rs17300539 and rs266729. Evidences of association between traits related to the metabolic syndrome and the SNPs were studied by implementing quantitative genetic association analysis. Results showed that SNP rs266729 was significantly associated with body weight (p-value=0.001), waist circumference (p-value=0.037), BMI (p-value=0.015) and percentage of total body fat (p-value=0.003). Up to 4.1% of heritability of obesity traits was explained by the rs266729 locus. Further cross-sectional analysis showed that carriers of the G allele had significantly higher values of waist circumference, BMI and percentage of total body fat (p-values 0.014, 0.004 and 0.032, respectively). No association was detected between SNP rs266729 and other clusters of metabolic syndrome or their traits except for HOMA-IR and fasting plasma insulin levels, p-values 0.035 and 0.004, respectively. In contrast, both measured genotype and cross-sectional analysis failed to detect an association between the SNP rs17300539 with traits and clusters of metabolic syndrome. In conclusion, we showed family-based evidence of association of SNP rs266729 at ADIPOQ gene with traits defining obesity in Arab population. This is important for future prediction and prevention of obesity in population where obesity is in an increasing trend.


Guided bone regeneration with a synthetic biodegradable membrane: a comparative study in dogs.
The aim of the present study was to compare a newly developed biodegradable polylactide/polyglycolide/N-methyl-2-pyrrolidone (PLGA/NMP) membrane with a standard resorbable collagen membrane (RCM) in combination with and without the use of a bone substitute material (deproteinized bovine bone mineral [DBBM]) looking at the proposed tenting effect and bone regeneration. In five adult German sheepdogs, the mandibular premolars P2, P3, P4, and the molar M1 were bilaterally extracted creating two bony defects on each site. A total of 20 dental implants were inserted and allocated to four different treatment modalities within each dog: PLGA/NMP membrane only (Test 1), PLGA/NMP membrane with DBBM (Test 2), RCM only (negative control), and RCM with DBBM (positive control). A histomorphometric analysis was performed 12 weeks after implantation. For statistical analysis, a Friedman test and subsequently a Wilcoxon signed ranks test were applied. In four out of five PLGA/NMP membrane-treated defects, the membranes had broken into pieces without the support of DBBM. This led to a worse outcome than in the RCM group. In combination with DBBM, both membranes revealed similar amounts of area of bone regeneration and bone-to-implant contact without significant differences. On the level of the third implant thread, the PLGA/NMP membrane induced more horizontal bone formation beyond the graft than the RCM. The newly developed PLGA/NMP membrane performs equally well as the RCM when applied in combination with DBBM. Without bone substitute material, the PLGA/NMP membrane performed worse than the RCM in challenging defects, and therefore, a combination with a bone substitute material is recommended.


Configural information in gender categorisation.
The role of configural information in gender categorisation was studied by aligning the top half of one face with the bottom half of another. The two faces had the same or different genders. Experiment 1 shows that participants were slower and made more errors in categorising the gender in either half of these composite faces when the two faces had a different gender, relative to control conditions where the two faces were nonaligned or had the same gender. This result parallels the composite effect for face recognition (Young et al, 1987 Perception 16 747-759) and facial-expression recognition (Calder et al, 2000 Journal of Experimental Psychology: Human Perception and Performance 26 527-551). Similarly to responses to face identity and expression, the composite effect on gender discrimination was disrupted by inverting the faces (experiment 2). Both experiments also show that the composite paradigm is sensitive to general contextual interference in gender categorisation.


Factors Influencing Pseudo-Accommodation-The Difference between Subjectively Reported Range of Clear Focus and Objectively Measured Accommodation Range.
The key determinants of the range of clear focus in pre-presbyopes and their relative contributions to the difference between subjective range of focus and objective accommodation assessments have not been previously quantified. Fifty participants (aged 33.0 ± 6.4 years) underwent simultaneous monocular subjective (visual acuity measured with an electronic test-chart) and objective (dynamic accommodation measured with an Aston open-field aberrometer) defocus curve testing for lenses between +2.00 to -10.00 DS in +0.50 DS steps in a randomized order. Pupil diameter and ocular aberrations (converted to visual metrics normalized for pupil size) at each level of blur were measured. The difference between objective range over which the power of the crystalline lens changes and the subjective range of clear focus was quantified and the results modelled using pupil size, refractive error, tolerance to blur, and ocular aberrations. The subjective range of clear focus was principally accounted for by age (46.4%) and pupil size (19.3%). The objectively assessed accommodative range was also principally accounted for by age (27.6%) and pupil size (15.4%). Over one-quarter (26.0%) of the difference between objective accommodation and subjective range of clear focus was accounted for by age (14.0%) and spherical aberration at maximum accommodation (12.0%). There was no significant change in the objective accommodative response (F = 1.426, p = 0.229) or pupil size (F = 0.799, p = 0.554) of participants for levels of defocus above their amplitude of accommodation. Pre-presbyopes benefit from an increased subjective range of clear vision beyond their objective accommodation due in part to neural factors, resulting in a measured depth-of-focus of, on average, 1.0 D.


A designer ligand field for blue-green luminescence of organoeuropium(ii) sandwich complexes with cyclononatetraenyl ligands.
A novel η9-coordinated double-decker sandwich complex of divalent europium is synthesized. The complex exhibits blue-green photoluminescence at 516 nm, which is significantly blue-shifted from those of other organoeuropium(ii) sandwich complexes (∼630 nm). The blue-shift was quantitatively explained by the weakened electrostatic field of the expanded 10-π ring.


Membrane protein extraction and purification using styrene-maleic acid (SMA) copolymer: effect of variations in polymer structure.
The use of styrene-maleic acid (SMA) copolymers to extract and purify transmembrane proteins, while retaining their native bilayer environment, overcomes many of the disadvantages associated with conventional detergent-based procedures. This approach has huge potential for the future of membrane protein structural and functional studies. In this investigation, we have systematically tested a range of commercially available SMA polymers, varying in both the ratio of styrene and maleic acid and in total size, for the ability to extract, purify and stabilise transmembrane proteins. Three different membrane proteins (BmrA, LeuT and ZipA), which vary in size and shape, were used. Our results show that several polymers, can be used to extract membrane proteins, comparably to conventional detergents. A styrene:maleic acid ratio of either 2:1 or 3:1, combined with a relatively small average molecular mass (7.5-10 kDa), is optimal for membrane extraction, and this appears to be independent of the protein size, shape or expression system. A subset of polymers were taken forward for purification, functional and stability tests. Following a one-step affinity purification, SMA 2000 was found to be the best choice for yield, purity and function. However, the other polymers offer subtle differences in size and sensitivity to divalent cations that may be useful for a variety of downstream applications.


Neurofilament light chain level in traumatic brain injury: A system review and meta-analysis.
Neurofilament light (NfL) level was obviously increased in traumatic brain injury (TBI) individuals. But, no comprehensive meta-analysis has ever been conducted to assess the diagnostic performance of NfL. This study aims to evaluate the relationship between NfL level and TBI through a meta-analysis. Studies were selected from Pubmed, Web of science, Embase, Google Scholar, PMC and Chinese National Knowledge Infrastructure (CNKI), and the Chinese Biomedical Literature Database (CBM) through inclusion and exclusion criteria. The standard mean difference (SMD) and 95% confidence interval (CI) were calculated using the random-effect model or fixed-effect model to assess the association between NfL level and TBI. Subgroup analysis according to sample collection time, sample type and detection method was performed. The influence analysis and publication bias was also conducted. All analyses were performed using the RevMan 5.3 and Stata 12 software. A total of 9 studies were included. Results indicated that TBI individuals had a higher NfL expression level compared with the non-TBI individuals (SMD = 2.48, 95% CI = 1.52-3.43, I = 96%, P < .01). Similar NfL increasing was also observed in Caucasian population, 0-48 hour and 6-10 days sample collection time, as well as cerebrospinal fluid (CSF), serum, plasma sample subgroup analysis. Moreover, the NfL increasing still existed no matter the NfL expression level was detected by ELISA or Simoa assay. NfL expression level was increased in TBI individuals, which indicated that NfL could be a potential biomarker in the diagnosis of TBI and other neurodegenerative diseases.


Dentine oxygen isotopes (δ (18)O) as a proxy for odontocete distributions and movements.
Spatial variation in marine oxygen isotope ratios (δ (18)O) resulting from differential evaporation rates and precipitation inputs is potentially useful for characterizing marine mammal distributions and tracking movements across δ (18)O gradients. Dentine hydroxyapatite contains carbonate and phosphate that precipitate in oxygen isotopic equilibrium with body water, which in odontocetes closely tracks the isotopic composition of ambient water. To test whether dentine oxygen isotope composition reliably records that of ambient water and can therefore serve as a proxy for odontocete distribution and movement patterns, we measured δ (18)O values of dentine structural carbonate (δ (18) OSC) and phosphate (δ (18) OP) of seven odontocete species (n = 55 individuals) from regional marine water bodies spanning a surface water δ (18)O range of several per mil. Mean dentine δ (18) OSC (range +21.2 to +25.5‰ VSMOW) and δ (18) OP (+16.7 to +20.3‰) values were strongly correlated with marine surface water δ (18)O values, with lower dentine δ (18) OSC and δ (18) OP values in high-latitude regions (Arctic and Eastern North Pacific) and higher values in the Gulf of California, Gulf of Mexico, and Mediterranean Sea. Correlations between dentine δ (18) OSC and δ (18) OP values with marine surface water δ (18)O values indicate that sequential δ (18)O measurements along dentine, which grows incrementally and archives intra- and interannual isotopic composition over the lifetime of the animal, would be useful for characterizing residency within and movements among water bodies with strong δ (18)O gradients, particularly between polar and lower latitudes, or between oceans and marginal basins.


A new design for registration trials in rheumatoid arthritis allowing secondary head-to-head comparisons with standard of care treatment including biologicals.
Current drug development programs produce high quality data on the efficacy of new drugs, substantial data on safety, but little data on actual applicability of the new product compared to standard of care. After successful registration and launch, such data require years to accumulate and often remain incomplete. This viewpoint proposes a new trial design for phase 2 and 3 drug trials in rheumatoid arthritis. In this design the trial starts conventionally: patients that are inadequate responders to standard treatment (usually methotrexate) are randomised to receive the experimental drug or placebo on the background of continued (methotrexate) treatment. However, after 3 months all patients in the placebo group are additionally treated with one and the same standard of care treatment (usually an inhibitor of tumour necrosis factor) and all patients in the experimental group are additionally treated with a placebo corresponding to the chosen standard of care treatment. This design allows primary assessment of efficacy and safety of the experimental drug compared with placebo at the ethically acceptable limit of 3 months, followed by secondary assessments of efficacy (including durability) and safety compared to standard of care. The secondary assessments are observational and thus more prone to bias, but it is argued that the potential for bias is limited in this setting. Widespread adoption of the design will greatly help to determine the place of a new product in the spectrum of treatment possibilities of rheumatoid arthritis.


Noxious hot and cold stimulation produce common patterns of brain activation in humans: a functional magnetic resonance imaging study.
We used functional magnetic resonance imaging (fMRI) to determine whether similar brain regions activate during noxious hot and cold stimulation. Six male subjects underwent whole brain fMRI during phasic delivery of noxious hot (46 degrees C) and noxious cold (5 degrees C) stimulation to the dorsum of the left hand. Mid-brain regions activated included thalamus, basal ganglia and insula. Cortical areas activated included cingulate, somatosensory, premotor and motor cortices, as well as prefrontal and inferior parietal cortex. Most regions activated bilaterally but with stronger activation contralateral to the stimulus. Noxious cold stimulation produced significantly increased volumes of activation compared to noxious heat in prefrontal areas only. Our results suggest a similar network of regions activate common to the perception of pain produced by either noxious hot or cold stimulation.


Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution.
Deterioration of the thymus gland during aging is accompanied by a reduction in plasma GH. Here we report gross and microscopic results from 24-month-old Wistar-Furth rats treated with rat GH derived from syngeneic GH3 cells or with recombinant human GH. Histological evaluation of aged rats treated with either rat or human GH displayed clear morphologic evidence of thymic regeneration, reconstitution of hematopoietic cells in the bone marrow, and multiorgan extramedullary hematopoiesis. Quantitative evaluation of formalin-fixed, hematoxylin and eosin-stained sections of bone marrow from aged rats revealed at least a 50% reduction in the number hematopoietic bone marrow cells, compared with that of young 3-month-old rats. This age-associated decline in bone marrow leukocytes, as well as the increase in bone marrow adipocytes, was significantly reversed by in vivo treatment with GH. Restoration of bone marrow cellularity was caused primarily by erythrocytic and granulocytic cells, but all cell lineages were represented and their proportions were similar to those in aged control rats. On a per-cell basis, GH treatment in vivo significantly increased the number of in vitro myeloid colony forming units in both bone marrow and spleen. Morphological evidence of enhanced extramedullary hematopoiesis was observed in the spleen, liver, and adrenal glands from animals treated with GH. These results confirm that GH prevents thymic aging. Furthermore, these data significantly extend earlier findings by establishing that GH dramatically promotes reconstitution of another primary hematopoietic tissue by reversing the accumulation of bone marrow adipocytes and by restoring the number of bone marrow myeloid cells of both the erythrocytic and granulocytic lineages.


Does it matter where you live? Treatment variation for breast cancer in Yorkshire. The Yorkshire Breast Cancer Group.
Over 27,000 patients with breast cancer were identified from cancer registry data from 1978 to 1992 and differences in treatment practice across the 16 districts of Yorkshire studied. A total of 50 surgeons treated more than an average of ten cases a year. Surgeons who expressed an interest in breast cancer were more likely to treat a greater number of patients than those who had no special interest in the disease and offered patients chemotherapy, hormone therapy and radiotherapy more often. The average regional mastectomy rate fell from 70% to 44% over this period, but the rate varied between districts from 13% to 87%, with those at the extremes occupying these positions year on year. The rate of uptake of radiotherapy varied between districts from 13% to 58% over the period 1978-92. The use of adjuvant chemotherapy increased from 5% to 19% and hormone therapy from 19% to 80% over this time period. An audit of the facilities available within each district carried out in early 1994 also showed considerable variation, although all districts now have access to a nurse specialist. There were wide variations in treatment offered to patients with breast cancer. Patients in some districts were denied access to chemo- and and radiotherapy despite published guidelines showing these modalities to be useful. It is recommended that patients are referred to units with an interest in breast cancer rather than to general surgical out-patients.


Differences in forage-acquisition and fungal enzyme activity contribute to niche segregation in Panamanian leaf-cutting ants.
The genera Atta and Acromyrmex are often grouped as leaf-cutting ants for pest management assessments and ecological surveys, although their mature colony sizes and foraging niches may differ substantially. Few studies have addressed such interspecific differences at the same site, which prompted us to conduct a comparative study across six sympatric leaf-cutting ant species in Central Panama. We show that foraging rates during the transition between dry and wet season differ about 60 fold between genera, but are relatively constant across species within genera. These differences appear to match overall differences in colony size, especially when Atta workers that return to their nests without leaves are assumed to carry liquid food. We confirm that Panamanian Atta specialize primarily on tree-leaves whereas Acromyrmex focus on collecting flowers and herbal leaves and that species within genera are similar in these overall foraging strategies. Species within genera tended to be spaced out over the three habitat categories that we distinguished (forest, forest edge, open grassland), but each of these habitats normally had only a single predominant Atta and Acromyrmex species. We measured activities of twelve fungus garden decomposition enzymes, belonging to the amylases, cellulases, hemicellulases, pectinases and proteinases, and show that average enzyme activity per unit of fungal mass in Atta gardens is lower than in Acromyrmex gardens. Expression profiles of fungal enzymes in Atta also appeared to be more specialized than in Acromyrmex, possibly reflecting variation in forage material. Our results suggest that species- and genus-level identities of leaf-cutting ants and habitat-specific foraging profiles may give predictable differences in the expression of fungal genes coding for decomposition enzymes.


Toward evidence-based medical statistics. 1: The P value fallacy.
An important problem exists in the interpretation of modern medical research data: Biological understanding and previous research play little formal role in the interpretation of quantitative results. This phenomenon is manifest in the discussion sections of research articles and ultimately can affect the reliability of conclusions. The standard statistical approach has created this situation by promoting the illusion that conclusions can be produced with certain "error rates," without consideration of information from outside the experiment. This statistical approach, the key components of which are P values and hypothesis tests, is widely perceived as a mathematically coherent approach to inference. There is little appreciation in the medical community that the methodology is an amalgam of incompatible elements, whose utility for scientific inference has been the subject of intense debate among statisticians for almost 70 years. This article introduces some of the key elements of that debate and traces the appeal and adverse impact of this methodology to the P value fallacy, the mistaken idea that a single number can capture both the long-run outcomes of an experiment and the evidential meaning of a single result. This argument is made as a prelude to the suggestion that another measure of evidence should be used--the Bayes factor, which properly separates issues of long-run behavior from evidential strength and allows the integration of background knowledge with statistical findings.


Transmission disequilibrium studies of the serotonin 5-HT2A receptor gene (HTR2A) in autism.
Hyperserotonemia in autism is one of the longest-standing biochemical findings in a psychiatric disorder. This well-replicated finding and subsequent studies of platelet serotonin receptors in autism indicate that the serotonin 2A receptor gene (HTR2A) on chromosome 13q is a primary candidate gene in autism. Converging data from recent genome screens also implicates the genomic region containing HTR2A. Based on these lines of evidence, the transmission/disequilibrium test (TDT) was used to assess transmission disequilibrium between autism and haplotypes of three polymorphisms, including the promoter -1438 G/A single nucleotide polymorphism (SNP) in perfect linkage disequilibrium with the 102 T/C SNP in previous studies, a newly identified SNP in intron 1 near exon 2, and the SNP responsible for the His452Tyr amino acid change in exon 3. Because expression studies have shown HTR2A to be polymorphically imprinted in the brain, secondary analyses were split into maternal and paternal transmissions. No evidence was found for unequal transmission of haplotypes; however, power analysis reveals low power to detect a parent-of-origin effect in this sample size.


The airway epithelium undergoes metabolic reprogramming in individuals at high risk for lung cancer.
The molecular determinants of lung cancer risk remain largely unknown. Airway epithelial cells are prone to assault by risk factors and are considered to be the primary cell type involved in the field of cancerization. To investigate risk-associated changes in the bronchial epithelium proteome that may offer new insights into the molecular pathogenesis of lung cancer, proteins were identified in the airway epithelial cells of bronchial brushing specimens from risk-stratified individuals by shotgun proteomics. Differential expression of selected proteins was validated by parallel reaction monitoring mass spectrometry in an independent set of individual bronchial brushings. We identified 2,869 proteins, of which 312 proteins demonstrated a trend in expression. Pathway analysis revealed enrichment of carbohydrate metabolic enzymes in high-risk individuals. Glucose consumption and lactate production were increased in human bronchial epithelial BEAS2B cells treated with cigarette smoke condensate for 7 months. Increased lipid biosynthetic capacity and net reductive carboxylation were revealed by metabolic flux analyses of [U-13C5] glutamine in this in vitro model, suggesting profound metabolic reprogramming in the airway epithelium of high-risk individuals. These results provide a rationale for the development of potentially new chemopreventive strategies and selection of patients for surveillance programs.


Intrathecal Analgesic Drug Delivery is Effective for Analgesia in a Patient with Post-Poliomyelitis Syndrome: A Case Report.
BACKGROUND Post-poliomyelitis syndrome (PPS) is a progressive neuromuscular syndrome, with chronic pain being one of the most prevalent symptoms. We present a case report on intrathecal analgesic drug delivery to diminish chro-nic, refractory pain in a patient with PPS. CASE REPORT In a wheelchair-bound 45-year-old female patient (Caucasian, body mass index [BMI] 20.5) with severe chronic, refractory pain, a Synchromed® II pump (Medtronic, Minneapolis, Minnesota, USA) was implanted after multidisciplinary consultation and a successful trial period. After 8 months, relocation of the pump due to regional pressure problems with surrounding erythema had to occur. A second pump relocation due to pressure pro-blems and skin erosion was needed 18 months after the first relocation, moving from the abdominal wall to the sheath of the rectus abdominis muscle, resulting in resolution of the problems. CONCLUSIONS In patients with PPS, intrathecal analgesic drug delivery can be an option to treat chronic, refractory pain. Multidisciplinary consultation is necessary to deal with the wide variety of problems in these patients. Skin problems at the site of the pump reservoir can be challenging and time-consuming and, ultimately, can necessitate relocation (or removal) of the device.


Buccal misoprostol for treatment of fetal death at 14-28 weeks of pregnancy: a double-blind randomized controlled trial.
To assess whether buccal misoprostol is effective for the treatment of intrauterine fetal death. This double-blind randomized trial was conducted at five tertiary-level hospitals in the United States and Vietnam. One hundred fifty-three women with an intrauterine fetal death at 14-28 weeks of pregnancy received either 100 mcg buccal misoprostol or 200 mcg buccal misoprostol every 6 h for a maximum of 8 doses. The main outcome measure was the fetal-placental delivery rate within 48 hours of prostaglandin commencement without any additional intervention. Most of the women (140/153) were recruited at the study site in Vietnam. Expulsion of both fetus and placenta within 48 hours of prostaglandin commencement without any additional interventions occurred in 61.8% (47/76) of women receiving misoprostol 100 mcg and 77.9% (60/77) of women receiving misoprostol 200 mcg. The 200 mcg dose was significantly more effective than the 100 mcg dose at expelling the fetus and placenta within 48 h [RR 0.68 (95% CI: 0.50-0.92; p=.03)]. The mean time to expulsion was significantly shorter using the 200 mcg dose (18.5±11.9 h) than the 100 mcg dose (23.9±12.5 h) (p=.02). Most women in both groups found the procedure satisfactory or very satisfactory (100 mcg: 76.7% (56/73); 200 mcg: 89.5% (68/76) [RR 0.86 (95% CI: 0.74-1.00)]. Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. A 200 mcg dose is significantly more effective than 100 mcg for evacuating the uterus within 48h. The treatment is highly acceptable to women. Administration of 200 mcg buccal misoprostol every six hours is an effective and acceptable method to effect the delivery of a demised fetus at 14-28 weeks that can be feasibly implemented in a wide variety of settings.


Thoracic sarcomas in children.
This study reviews the experience of the Intergroup Rhabdomyosarcoma Studies (IRS) II and III with thoracic sarcomas. Thoracic sarcomas in children present special problems with histologic diagnosis, total resection of tumor, and local control. Previous studies have shown high rates of local and distant relapse. Data from evaluable patients enrolled in IRS II and IRS III were reviewed. Progression-free and overall survival were estimated by the Kaplan-Meier method and statistical differences were calculated by the log-rank test. The multivariate regression analysis of data was performed using the Cox proportional hazards model. A total of 84 patients presented with thoracic sarcomas during IRS II (51 patients) and IRS III (33 patients). Of these, 76 were chest wall tumors, 3 were lung tumors, 4 were pleural tumors, and 1 arose from the heart. The average age at diagnosis was 8.5 years (range, 1 month-20.5 years). Thirty-three patients had alveolar histology, 17 had embryonal histology, and 12 had extraosseous Ewing's sarcoma, with indeterminate, undifferentiated, and pleomorphic histologies in the remaining 22 patients. Thirteen patients presented as group I (localized disease completely resected), 18 as group II (microscopic residual or nodal disease), 31 as group III (gross residual disease or biopsy only), and 22 as group IV (distant metastatic disease). Sixty patients (71%) achieved a complete response. Thirty-nine patients had a local relapse, and 22 had a distant relapse. Thirty-five patients (42%) survived with a mean follow-up of 1.8 years (range 0.7-11.7 years); 49 (58%) have died with an average survival of 1.1 years (range 0.3-11.7 years). Four patients (5%) died of infection or treatment complications. Progression-free survival was not significantly associated with histology, site, clinical group, or IRS study. Overall survival was significantly associated with clinical group, size, and local or distant recurrence, but not with histology or IRS study by univariate analysis. In a multivariate analysis, only clinical group and local and distant recurrence showed statistical significance (p < 0.002, < 0.006, and < 0.001, respectively). As expected, outcome was better for patients with totally resected or microscopically residual tumor after resection. A higher rate of recurrence in group I versus group II,although not statistically significant, suggests that identification of margin status may be difficult, and these patients may require more intensive efforts for local control. These patients continued to have a high rate of local and distant relapse, and new strategies for preventing these are under development.


Low valent Al(ii)-Al(ii) catalysts as highly active ε-caprolactone polymerization catalysts: indication of metal cooperativity through DFT studies.
The present study first describes the reactivity of low valent Al(ii) and Ga(ii) complexes of the type (dpp-bian)M-M(dpp-bian) (1, M = Al; 2, Ga; dpp-bian2- = 1,2-bis-(2,6-iPr2-C6H3)-acenaphthenequinonediamido) with cyclic esters/carbonates such as ε-caprolactone (CL) and trimethylene carbonate (TMC). CL and TMC both readily coordinate to the Al(ii) species 1 to form the corresponding bis-adducts (dpp-bian)Al(L)-(L)Al(dpp-bian) (3, L = CL; 4, L = TMC), which were structurally characterized confirming that the Al(ii)-Al(ii) dimetallic backbone retains its integrity in the presence of such cyclic polar substrates. In contrast, the less Lewis acidic Ga(ii) analogue 2 shows no reaction in the presence of stoichiometric amounts of CL and TMC at room temperature. In combination with BnOH, the dinuclear Al(ii) species 1 revealed to be an extremely active Al(ii) initiator for the controlled ROP of CL at room temperature, outperforming all its Al(iii) congeners reported thus far. Detailed DFT studies on the ROP mechanism are consistent with a process occurring thanks to the metallic cooperativity between the two Al(ii) proximal (since directly bonded) metal centers in 1, which undoubtedly favors the ROP process through bimetallic activation and thus rationalizes the unusually high CL ROP activity at room temperature.


Multi-species prey dynamics influence local survival in resident and wintering generalist predators.
Stochasticity in food availability influences vital rates such as survival and fertility. Life-history theory predicts that in long-lived organisms, survival should be buffered against environmental stochasticity showing little temporal variability. Furthermore, to optimize survival prospects, many animal species perform migrations to wintering areas where food availability is larger. Species with large latitudinal distribution ranges may show populations that migrate and others that are resident, and they may co-occur in winter. One example of these species is the predatory raptor buzzard Buteo buteo. Here, we test whether temporal variability in the density of five small mammal species of prey inhabiting different habitats (shrubland and forests) influences local annual survival of buzzards in a wintering area depending on their age and residency status (residents versus wintering individuals). We found that prey density explained a considerable amount of annual changes in local survival, which was higher for older and resident birds. This difference in local survival likely corresponded to philopatry to the wintering area, which was larger for residents and increased when prey density was larger. The total density of prey inhabiting open shrublands was the variable explaining more variance in temporal variability of local survival, even though the study area is mostly occupied by woodlands. Temporal population dynamics of the different small mammals inhabiting shrublands were not synchronous, which suggests that buzzards preyed opportunistically on the most abundant prey each winter. Generalist predation may buffer the impact of resource unpredictability for pulsed and asynchronous prey dynamics, typical of small mammals in winter.


Use of exogenous hormones by women and lung cancer: evidence from the Royal College of General Practitioners' Oral Contraception Study.
The objective of this study was to assess the risk of lung cancer among women who have used oral contraception or hormone replacement therapy (HRT), especially those exposed to both classes of exogenous hormones. This study is a nested case-control one using prospectively collected data from the Royal College of General Practitioners' Oral Contraception Study (OCS). The 162 case patients were women with a diagnosis of lung cancer recorded on the OCS database by August 2004. Each case patient was matched with 3 control subjects who were free of the disease at the time of the case patient's diagnosis, of similar age and with similar length of follow-up in the OCS. Compared with never use, current use of oral contraception was associated with a statistically nonsignificant reduced risk of lung cancer, with an adjusted odds ratio (OR) of 0.47 and a 95% confidence interval (CI) of 0.08-2.95 (OR=0.86 and 95% CI=0.50-1.48 for former use; OR=0.84 and 95% CI=0.49-1.43 for ever use). Similar comparisons for HRT were current use (OR=1.21, 95% CI=0.23-6.37), former use (OR=0.62, 95% CI=0.23-1.68) and ever use (OR=0.71, 95% CI=0.28-1.78). The OR among women who had used both classes of hormones was 0.53 (95% CI=0.16-1.72), as compared with those who had used neither. Our results are compatible with findings from other studies that suggest that oral contraceptives may reduce the risk of lung cancer. Evidence for a beneficial effect of HRT is less convincing. Further study is needed to determine how long any benefit lasts and whether it is stronger in women exposed to both classes of exogenous hormones. The small number of events occurring in this very large cohort, however, shows that any public health benefit is likely to be marginal.


Impact of indoor environment on path loss in body area networks.
In this paper the influence of an example indoor environment on narrowband radio channel path loss for body area networks operating around 2.4 GHz is investigated using computer simulations and on-site measurements. In contrast to other similar studies, the simulation model included both a numerical human body phantom and its environment-room walls, floor and ceiling. As an example, radio signal attenuation between two different configurations of transceivers with dipole antennas placed in a direct vicinity of a human body (on-body scenario) is analyzed by computer simulations for several types of reflecting environments. In the analyzed case the propagation environments comprised a human body and office room walls. As a reference environment for comparison, free space with only a conducting ground plane, modelling a steel mesh reinforced concrete floor, was chosen. The transmitting and receiving antennas were placed in two on-body configurations chest-back and chest-arm. Path loss vs. frequency simulation results obtained using Finite Difference Time Domain (FDTD) method and a multi-tissue anthropomorphic phantom were compared to results of measurements taken with a vector network analyzer with a human subject located in an average-size empty cuboidal office room. A comparison of path loss values in different environments variants gives some qualitative and quantitative insight into the adequacy of simplified indoor environment model for the indoor body area network channel representation.


The methodological quality of 176,620 randomized controlled trials published between 1966 and 2018 reveals a positive trend but also an urgent need for improvement.
Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. There is increasing attention for responsible research practices and implementation of reporting guidelines, but whether these efforts have improved the methodological quality of RCTs (e.g., lower risk of bias) is unknown. We, therefore, mapped risk-of-bias trends over time in RCT publications in relation to journal and author characteristics. Meta-information of 176,620 RCTs published between 1966 and 2018 was extracted. The risk-of-bias probability (random sequence generation, allocation concealment, blinding of patients/personnel, and blinding of outcome assessment) was assessed using a risk-of-bias machine learning tool. This tool was simultaneously validated using 63,327 human risk-of-bias assessments obtained from 17,394 RCTs evaluated in the Cochrane Database of Systematic Reviews (CDSR). Moreover, RCT registration and CONSORT Statement reporting were assessed using automated searches. Publication characteristics included the number of authors, journal impact factor (JIF), and medical discipline. The annual number of published RCTs substantially increased over 4 decades, accompanied by increases in authors (5.2 to 7.8) and institutions (2.9 to 4.8). The risk of bias remained present in most RCTs but decreased over time for allocation concealment (63% to 51%), random sequence generation (57% to 36%), and blinding of outcome assessment (58% to 52%). Trial registration (37% to 47%) and the use of the CONSORT Statement (1% to 20%) also rapidly increased. In journals with a higher impact factor (>10), the risk of bias was consistently lower with higher levels of RCT registration and the use of the CONSORT Statement. Automated risk-of-bias predictions had accuracies above 70% for allocation concealment (70.7%), random sequence generation (72.1%), and blinding of patients/personnel (79.8%), but not for blinding of outcome assessment (62.7%). In conclusion, the likelihood of bias in RCTs has generally decreased over the last decades. This optimistic trend may be driven by increased knowledge augmented by mandatory trial registration and more stringent reporting guidelines and journal requirements. Nevertheless, relatively high probabilities of bias remain, particularly in journals with lower impact factors. This emphasizes that further improvement of RCT registration, conduct, and reporting is still urgently needed.


Redox regulation in regenerative medicine and tissue engineering: The paradox of oxygen.
One of the biggest challenges in tissue engineering and regenerative medicine is to incorporate a functioning vasculature to overcome the consequences of a lack of oxygen and nutrients in the tissue construct. Otherwise, decreased oxygen tension leads to incomplete metabolism and the formation of the so-called reactive oxygen species (ROS). Cells have many endogenous antioxidant systems to ensure a balance between ROS and antioxidants, but if this balance is disrupted by factors such as high levels of ROS due to long-term hypoxia, there will be tissue damage and dysfunction. Current attempts to solve the oxygen problem in the field rarely take into account the importance of the redox balance and are instead centred on releasing or generating oxygen. The first problem with this approach is that although oxygen is necessary for life, it is paradoxically also a highly toxic molecule. Furthermore, although some oxygen-generating biomaterials produce oxygen, they also generate hydrogen peroxide, a ROS, as an intermediate product. In this review, we discuss why it would be a superior strategy to supplement oxygen delivery with molecules to safeguard the important redox balance. Redox sensor proteins that can stimulate the anaerobic metabolism, angiogenesis, and enhancement of endogenous antioxidant systems are discussed as promising targets. We propose that redox regulating biomaterials have the potential to tackle some of the challenges related to angiogenesis and that the knowledge in this review will help scientists in tissue engineering and regenerative medicine realize this aim.


Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged ≥65 Years: Updated Recommendations of the Advisory Committee on Immunization Practices.
Two pneumococcal vaccines are currently licensed for use in adults in the United States: a 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Pfizer, Inc.]) and a 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax 23, Merck and Co., Inc.]). In 2014, the Advisory Committee on Immunization Practices (ACIP)* recommended routine use of PCV13 in series with PPSV23 for all adults aged ≥65 years based on demonstrated PCV13 safety and efficacy against PCV13-type pneumonia among adults aged ≥65 years (1). At that time, ACIP recognized that there would be a need to reevaluate this recommendation because it was anticipated that PCV13 use in children would continue to reduce disease burden among adults through reduced carriage and transmission of vaccine serotypes from vaccinated children (i.e., PCV13 indirect effects). On June 26, 2019, after having reviewed the evidence accrued during the preceding 3 years (https://www.cdc.gov/vaccines/acip/recs/grade/PCV13.html), ACIP voted to remove the recommendation for routine PCV13 use among adults aged ≥65 years and to recommend administration of PCV13 based on shared clinical decision-making for adults aged ≥65 years who do not have an immunocompromising condition,† cerebrospinal fluid (CSF) leak, or cochlear implant, and who have not previously received PCV13. ACIP recognized that some adults aged ≥65 years are potentially at increased risk for exposure to PCV13 serotypes, such as persons residing in nursing homes or other long-term care facilities and persons residing in settings with low pediatric PCV13 uptake or traveling to settings with no pediatric PCV13 program, and might attain higher than average benefit from PCV13 vaccination. When patients and vaccine providers§ engage in shared clinical decision-making for PCV13 use to determine whether PCV13 is right for a particular person, considerations might include both the person's risk for exposure to PCV13 serotypes and their risk for developing pneumococcal disease as a result of underlying medical conditions. All adults aged ≥65 years should continue to receive 1 dose of PPSV23. If the decision is made to administer PCV13, it should be given at least 1 year before PPSV23. ACIP continues to recommend PCV13 in series with PPSV23 for adults aged ≥19 years with an immunocompromising condition, CSF leak, or cochlear implant (2).


A theoretical morphological model for quantitative description of the three-dimensional floral morphology in water lily (Nymphaea).
Water lilies (Nymphaea spp.) have diverse floral morphologies. Water lilies are not only commonly used as ornamental plants, but they are also important for understanding the diversification of basal angiosperms. Although the diversity in floral morphology of water lily provides useful information for evolutionary biology, horticulture, and horticultural science, it is difficult to describe and analyze the three-dimensional morphology of flowers. In this study, we propose a method to describe the floral morphology of water lily using a three-dimensional theoretical morphological model. The theoretical model was constructed based on three components, i.e., (1) the gradual change in size of floral organs, (2) spiral phyllotaxis, and (3) the interpolation of elevation angles, which were integrated into the model. We generated three-dimensional representation of water lily flowers and visualized theoretical morphospaces by varying each morphological parameter. The theoretical morphospace is a mathematical space of morphological spectrum generated by a theoretical morphological model. These morphospaces seems to display the large part of morphological variations of water lily. We measured morphological parameters of real flowers based on our theoretical model and display the occupation pattern of morphological parameters. We also surveyed the relation between morphological parameters and flower shape descriptions found in a catalog. In some parameters, we found breeders' description can link to our morphological model. In addition, the relationship between the global features of floral morphology and the parameters of the theoretical model was calculated with flower silhouettes simulated with a range of parameter values and the global features of the silhouette. We used two simple indices to assess the global morphological features, which were calculated with the convex hull. The results indicated that our method can effectively provide an objective and quantitative overview of the diversity in the floral morphology of water lily.


The combination of a tumor necrosis factor inhibitor and antibiotic alleviates staphylococcal arthritis and sepsis in mice.
Despite advances in medical practices, in recent decades permanent reductions in joint function have not been achieved, and the high mortality rate of patients with staphylococcal septic arthritis has not substantially improved. We evaluated the effects of a combined tumor necrosis factor (TNF) inhibitor and antibiotic therapy on the course of Staphylococcus aureus arthritis and sepsis in mice. Treatment with the combination of a TNF inhibitor and an antibiotic resulted in a quicker relief of clinical arthritis in mice with septic arthritis, compared with an antibiotic monotherapy. Both histopathologically verified synovitis and the extent of joint destruction were reduced by this combined treatment. Importantly, anti-TNF treatment significantly improved the survival rate of mice with S. aureus sepsis and staphylococcal enterotoxin shock syndrome; this effect might be the result of a partial restoration of the hemostatic balance between coagulation and fibrinolysis. Finally, we demonstrated that anti-TNF treatment downregulates high-mobility group protein B1 in staphylococcal enterotoxin shock syndrome. Thus, simultaneous systemic TNF inhibition and antibiotic therapy has beneficial effects on the outcome of S. aureus arthritis and sepsis in a mouse model, suggesting that the combination of a TNF inhibitor and antibiotics represents a novel therapeutic strategy for the treatment of staphylococcal infections.


[Compliance with Physical Activity Recommendations and Associated Factors in a Cohort of Spanish Adult Workers].
Physical inactivity remains a public health problem worldwide. The purpose of this study was to determine compliance with physical activity (PA) recommendations developed by the World Health Organization (WHO) and to analyze the association with different cardiovascular risk factors (CVRF) and sociodemographic and lifestyle determinants in a sample of Spanish workers. A cross sectional analysis was carried out in a sample of 2.651 individuals (2.428 men and 133 women, aged 40-55 years old) from the Aragon Workers' Health Study (AWHS). Sample was divided into two groups depending on whether they met PA recommendations during the last year, including transportation, leisure and occupational PA. Sociodemographic, anthropometric, clinical, pharmacological and lifestyle data were collected during the years 2011-2014. Median and interquartile range for quantitative variables and frequency distribution for categorical variables were used. Crude and adjusted binary logistic regression models were carried out to study the likelihood of meeting with PA recommendations based on the number of CVRF (hypertension, dyslipidemia, diabetes, obesity and smoking) present. 47.0% of workers complied with WHO recommendations for PA. Lower prevalence of compliance was found among those participants presenting some CVRF (39.7% in hypertensive, 38.7% in dyslipidemic and 32.7% in diabetic). Of the total study sample, 51.3% reported not performing PA or practice a light PA, 20.2% moderate and 28.5% vigorous or very vigorous PA. The likelihood of compliance with PA recommendations decreased with increasing the number of CVRF: 1 CVRF (OR: 0.62; 95%IC: 0.49-0.78), 2 CVRF (OR: 0.49; 95% IC: 0.38-0.62), 3 CVRF (OR: 0.34; 95% IC: 0.25-0.46), 4 CVRF (OR: 0.19; 95% IC: 0.11-0.32). Compliance with recommendations of PA in our population remains insufficient, moreover in those with increased cardiovascular risk.


Delayed serum calcium biochemical response to successful parathyroidectomy in primary hyperparathyroidism.
Parathyroidectomy is considered the standard treatment for primary hyperparathyroidism, however, though the onset of biochemical response is variable and is different from one patient to the other. To evaluate the onset of systemic response and the biochemical normalization of serum calcium levels to a successful surgery. In a retrospective fashion, we collected clinical data from 303 patients admitted to our hospital between 2005 and 2008, with a diagnosis of primary hyperparathyroidism after sestamibi localization. The pathology reports, parathyroidectomy results, the preoperative and postoperative parathormone (PTH) and serum calcium levels were reviewed. Response of each patient to the surgery was studied and all the data were analyzed to determine how fast the serum calcium levels drop. The majority of patients (72.9%, 221/303) showed a decrease in their serum calcium levels to normal values within 48 h. While in 40 patients it took 72 hours and 42 patients (13.8%) had a delayed normalization for more than 72 h. The pathology in the PH group was predominantly of a single adenoma 80.9% vs.19.1 with hyperplasia with a P of 0.03. Preoperative parathyroid hormone PTH elevation was not significantly deferent between the two groups (PH and EN) with a mean of 7.9±5.36 vs. 7.41±14.5 pmol/L respectively with a P of 0.43. The majority of patients with primary hyperparathyroidism (PHP) respond to parathyroidectomy in the form of normalization of their serum calcium levels and PTH within 48 h; however, a certain group of patients will need more than 3 days.


Biophoton imaging: a nondestructive method for assaying R gene responses.
Plant disease resistance (R) proteins of the nucleotide binding-leucine rich repeat class are responsible for pathogen recognition and activation of defense signaling networks leading to the hypersensitive response (HR). Genetically, R-protein signaling appears to be integrated through a limited set of common downstream components. However, the timing of development of visible HR is unique to individual R proteins. By utilizing the phenomena of ultraweak photon emission from leaves undergoing an incompatible interacttion, a powerful nondestructive and facile assay is described to compare timing of defense responses elicited by different R proteins. We demonstrate that ultraweak photon emission, or "biophoton generation," is demonstrated to be associated with hypersensitive cell death. Biophoton emission requires an intact R signaling network and increases in cytosolic calcium and nitric oxide, but elevated reactive oxygen species are not necessary. Importantly, the assay is robust and applicable to a range of incompatible interactions in various plant species. The ability to assay R responses nondestructively in real time and a chosen genetic background makes this technique amenable to subtle genetic dissection of plant defense responses.


Parental and physician-related determinants of consent for neonatal autopsy.
We undertook a cross-sectional epidemiologic study of potential determinants of parental consent for neonatal autopsy at the Brigham and Women's Hospital, Boston. Data were abstracted from maternal and infant medical records in 184 cases of neonatal death occurring between January 1982 and October 1984. The overall consent rate for neonatal autopsy was 72%. Multivariate analysis by logistic regression found previous fetal loss, gestational age, and cause of death to be significantly different between the groups of consenters and nonconsenters. Parents least likely to consent to autopsy were those who had no history of previous fetal loss, who had pregnancies in which the birth weight of the infant was less than 1000 g or the gestational age was less than 28 weeks, or those who had an infant die of extreme prematurity. Factors not significantly associated with consent were maternal age, race, marital status, transfer status, type of prenatal care, the infant's sex, and the staff position of the requester. A second phase of the study surveyed physicians' attitudes regarding the importance of neonatal autopsy. The staff position and previous experience of the physician-requester, in addition to the presumed cause of the infant's death, were significantly associated with the rating assigned to the importance of the autopsy. These findings suggest that the mother's past and present obstetrical experience, the presence of extreme prematurity, and possibly the attitude and experience of the physician requesting autopsy permission may exert important influences on the likelihood of obtaining consent for a neonatal autopsy.


Risk of Stroke Among Older Medicare Antidepressant Users With Traumatic Brain Injury.
To estimate the risk of stroke associated with new antidepressant use among older adults with traumatic brain injury (TBI). A total of 64 214 Medicare beneficiaries aged 65 years or older meeting inclusion criteria and hospitalized with a TBI during 2006 to 2010. New user design. Generalized estimating equations were used to estimate the relative risks (RRs) of stroke. Primary exposure was new antidepressant use following TBI identified through Medicare part D claims. The primary outcome was stroke following TBI. Ischemic and hemorrhagic strokes were secondary outcomes. A total of 20 859 (32%) beneficiaries used an antidepressant at least once following TBI. Selective serotonin reuptake inhibitors accounted for the majority of antidepressant use. Selective serotonin reuptake inhibitor use was associated with an increased risk of hemorrhagic stroke (RR, 1.26; 95% confidence interval [CI], 1.06-1.50) but not ischemic stroke (RR, 1.04; 95% CI, 0.94-1.15). The selective serotonin reuptake inhibitors escitalopram (RR, 1.33; 95% CI, 1.02-1.74) and sertraline (RR, 1.46; 95% CI, 1.10-1.94) were associated with an increase in the risk of hemorrhagic stroke. Findings from this study will aid prescribers in choosing appropriate antidepressants to treat depression in older adults with TBI.


Exogenous CXCL4 infusion inhibits macrophage phagocytosis by limiting CD36 signalling to enhance post-myocardial infarction cardiac dilation and mortality.
Macrophage phagocytosis of dead cells is a prerequisite for inflammation resolution. Because CXCL4 induces macrophage phagocytosis in vitro, we examined the impact of exogenous CXCL4 infusion on cardiac wound healing and macrophage phagocytosis following myocardial infarction (MI). CXCL4 expression significantly increased in the infarct region beginning at Day 3 post-MI, and macrophages were the predominant source. Adult male C57BL/6J mice were subjected to coronary artery occlusion, and MI mice were randomly infused with recombinant mouse CXCL4 or saline beginning at 24 h post-MI by mini-pump infusion. Compared with saline controls, CXCL4 infusion dramatically reduced 7 day post-MI survival [10% (3/30) for CXCL4 vs. 47% (7/15) for saline, P < 0.05] as a result of acute congestive heart failure. By echocardiography, CXCL4 significantly increased left ventricular (LV) volumes and dimensions at Day 5 post-MI (all P < 0.05), despite similar infarct areas compared with saline controls. While macrophage numbers were similar at Day 5 post-MI, CXCL4 infusion increased Ccr4 and Itgb4 and decreased Adamts8 gene levels in the infarct region, all of which linked to CXCL4-mediated cardiac dilation. Isolated Day 5 post-MI macrophages exhibited comparable levels of M1 and M4 markers between saline and CXCL4 groups. Interestingly, by both ex vivo and in vitro phagocytosis assays, CXCL4 reduced macrophage phagocytic capacity, which was connected to decreased levels of the phagocytosis receptor CD36. In vitro, a CD36 neutralizing antibody (CD36Ab) significantly inhibited macrophage phagocytic capacity. The combination of CXCL4 and CD36Ab did not have an additive effect, indicating that CXCL4 regulated phagocytosis through CD36 signalling. CXCL4 infusion significantly elevated infarct matrix metalloproteinase (MMP)-9 levels at Day 5 post-MI, and MMP-9 can cleave CD36 as a down-regulation mechanism. CXCL4 infusion impaired macrophage phagocytic capacity by reducing CD36 levels through MMP-9 dependent and independent signalling, leading to higher mortality and LV dilation.


One-step large-scale synthesis of micrometer-sized silver nanosheets by a template-free electrochemical method.
We have synthesized micrometer-sized Ag nanosheets via a facile, one-step, template-free electrochemical deposition in an ultra-dilute silver nitrate aqueous electrolyte. The nanosheet growth was revealed to occur in three stages: (1) formation of polygonal Ag nuclei on a substrate, (2) growth of {112}-faceted nanowire from the nuclei, and (3) anisotropic growth of (111)-planar nanosheets, approximately 20 to 50 nm in thickness and 10 μm in width, in the <112>-direction. The vertical growth of the facet nanowire was induced by the strong interface anisotropy between the deposit and electrolyte due to the ultra-dilute concentration of electrolyte and high reduction potential. The thickness of Ag nanosheets was controllable by the adjustment of the reduction/oxidation potential and frequency of the reverse-pulse potentiodynamic mode.


In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria.
A severe mitochondrial protein synthesis defect in myoblasts from a patient with mitochondrial myopathy was transferred with myoblast mitochondria into two genetically unrelated mitochondrial DNA (mtDNA)-less human cell lines, pointing to an mtDNA alteration as being responsible and sufficient for causing the disease. The transfer of the defect correlated with marked deficiencies in respiration and cytochrome c oxidase activity of the transformants and the presence in their mitochondria of mtDNA carrying a tRNA(Lys) mutation. Furthermore, apparently complete segregation of the defective genotype and phenotype was observed in the transformants derived from the heterogeneous proband myoblast population, suggesting that the mtDNA heteroplasmy in this population was to a large extent intercellular. The present work thus establishes a direct link between mtDNA alteration and a biochemical defect.


NFKB1 polymorphism is associated with age-related gene methylation in Helicobacter pylori-infected subjects.
CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of NF-κB in the inflammatory response to H. pylori colonization has been indicated. We investigated the influence of NFKB1 polymorphisms, -94 ins/del (rs28362491) and -449 C>G (rs72696119), on the aberrant gene methylation under H. pylori infection. Gastric mucosal samples were obtained from sub-subjects without malignancies. Methylation status of genes (p14ARF, p16INK4a, DAPK and CDH1) was determined by methylation-specific PCR (MSP). The genotyping of NFKB1 was performed by PCR-SSCP. There was a strong allelic association between rs28362491 and rs72696119, and all H. pylori-infected -94 del/del homozygotes had a -449 GG genotype. The -94 del/del homozygosity was significantly associated with risk for development of CpG island high methylation (CIHM) (two or more gene methylations), especially DAPK and CDH1 methylations, and the number of methylated genes was significantly higher in -94 del/del homozygotes than in ins/del and ins/ins (ins carrier) H. pylori-infected elder subjects. In addition, this methylated gene number was significantly increased with age in H. pylori-infected del/del homozygotes, but not in infected ins carriers. Furthermore, the inflammation score was significantly higher in H. pylori-infected del/del homozygotes compared to ins carriers. NFKB1 -94 ins/del ATTG polymorphism (rs28362491) was significantly associated with the increased risk for the development of age-related gene methylation in non-cancerous gastric mucosa under H. pylori-induced inflammation.


Sources of bias in measures of allele-specific expression derived from RNA-sequence data aligned to a single reference genome.
RNA-seq can be used to measure allele-specific expression (ASE) by assigning sequence reads to individual alleles; however, relative ASE is systematically biased when sequence reads are aligned to a single reference genome. Aligning sequence reads to both parental genomes can eliminate this bias, but this approach is not always practical, especially for non-model organisms. To improve accuracy of ASE measured using a single reference genome, we identified properties of differentiating sites responsible for biased measures of relative ASE. We found that clusters of differentiating sites prevented sequence reads from an alternate allele from aligning to the reference genome, causing a bias in relative ASE favoring the reference allele. This bias increased with greater sequence divergence between alleles. Increasing the number of mismatches allowed when aligning sequence reads to the reference genome and restricting analysis to genomic regions with fewer differentiating sites than the number of mismatches allowed almost completely eliminated this systematic bias. Accuracy of allelic abundance was increased further by excluding differentiating sites within sequence reads that could not be aligned uniquely within the genome (imperfect mappability) and reads that overlapped one or more insertions or deletions (indels) between alleles. After aligning sequence reads to a single reference genome, excluding differentiating sites with at least as many neighboring differentiating sites as the number of mismatches allowed, imperfect mappability, and/or an indel(s) nearby resulted in measures of allelic abundance comparable to those derived from aligning sequence reads to both parental genomes.


Isolation of interleukin 2-induced immediate-early genes.
Clonal expansion of antigen-reactive T lymphocytes is driven by the lymphokine interleukin 2 (IL-2). To further elucidate the mechanisms of IL-2 action, we have utilized a differential hybridization procedure to clone IL-2-induced immediate-early genes from an IL-2-stimulated human T-cell cDNA library. To increase the frequency of IL-2-induced transcripts represented in the library, the protein synthesis inhibitor cycloheximide was included during the 2-hr IL-2 stimulation to superinduce gene expression, and the uridine analogue 4-thiouridine was utilized to enable selective purification of newly synthesized transcripts. From the enriched library, we have isolated eight IL-2-induced genes, six of which represent previously unrecognized human sequences. Northern blot analysis revealed that the induction of seven of the genes is specific to the IL-2-mediated G1 "progression" phase of the cell cycle, in that only one gene is also induced during the T-cell receptor-triggered G0-G1 "competence" phase. These results indicate that the effects of IL-2 are mediated by the specific induction of a number of immediate-early genes and provide a means with which to further delineate the mechanisms whereby IL-2 stimulates T-lymphocyte proliferation and differentiation. The methods described in this report should also be of general utility in the dissection of the signaling pathways activated by diverse cytokine receptors.


The relationship between demodex and ocular discomfort.
To determine the correlative relationship between the prevalence of Demodex in eyelashes and the severity of ocular discomfort, by investigating the demographic epidemiology associated with Demodex. One hundred seventy patients underwent epilation of four eyelashes of each eye, and the number of Demodex was counted. The patients answered questionnaires about ocular surface discomfort and underwent ophthalmic examinations, including slit lamp, tear film breakup time (BUT), Schirmer test, and microbial culturing. The correlative relationship between the number of Demodex and these variable data was analyzed. Demodex was found in 120 (70%) of the 170 tested patients. Of 1360 eyelashes, 740 (54%) had Demodex. There was no significant difference in the prevalence of Demodex between males and females (P = 0.35). The number of Demodex showed significant positive correlations with increased age, ocular discomfort, and 1/BUT (P < 0.001), but not with the Schirmer scores. The number of Demodex was significantly higher in patients with conjunctival papillary hypertrophy than in those without (P = 0.003). The presence or distribution of bacteria on eyelashes was similar between eyelids with and without Demodex. However, methicillin-resistant Staphylococcus aureus (MRSA) was detected more often on eyelids with Demodex, but this difference was not statistically significant. There is a strong correlation between the number of Demodex and the severity of ocular discomfort, suggesting that Demodex plays a pathogenic role in the ocular discomfort linked with aging.


Association between tea consumption and risk of cancer: a prospective cohort study of 0.5 million Chinese adults.
Current experimental and epidemiological studies provide inconsistent evidence toward the association between tea consumption and cancer incidence. We investigated whether tea consumption was associated with the incidence of all cancers and six leading types of cancer (lung cancer, stomach cancer, colorectal cancer, liver cancer, female breast cancer and cervix uteri cancer) among 455,981 participants aged 30-79 years in the prospective cohort China Kadoorie Biobank. Tea consumption was assessed at baseline (2004-2008) with an interviewer-administered questionnaire. Cancer cases were identified by linkage to the national health insurance system. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In the present population, daily tea consumers were more likely to be current smokers and daily alcohol consumers. 22,652 incident cancers occurred during 10.1 years follow-up (5.04 cases/1000 person-years). When we restricted analyses to non-smokers and non-excessive alcohol consumers to minimize confounding, tea consumption was not associated with all cancers (daily consumers who added tea leaves > 4.0 g/day vs. less-than-weekly consumers: HR, 1.03; 95%CI, 0.93-1.13), lung cancer (HR, 1.08; CI, 0.84-1.40), colorectal cancer (HR, 1.08; CI, 0.81-1.45) and liver cancer (HR, 1.08; CI, 0.75-1.55), yet might be associated with increased risk of stomach cancer (HR, 1.46; CI, 1.07-1.99). In both less-than-daily and daily tea consumers, all cancer risk increased with the amount of tobacco smoked or alcohol consumed. Our findings suggest tea consumption may not provide preventive effect against cancer incidence.


Development of mu rhythm in infants and preschool children.
Mu rhythm is an idling rhythm that originates in the sensorimotor cortex during rest. The frequency of mu rhythm, which is well established in adults, is 8-12 Hz, whereas the limited results available from children suggest a frequency as low as 5.4 Hz at 6 months of age, which gradually increases to the adult value. Understanding the normal development of mu rhythm has important theoretical and clinical implications since we still know very little about this signal in infants and how it develops with age. We measured mu rhythm over the left hemisphere using a pediatric magnetoencephalography (MEG) system in 25 infants (11-47 weeks), 18 preschool children (2-5 years) and 6 adults (20-39 years) for two 5-min sessions during two intermixed conditions: a rest condition in which the hands were at rest, and a prehension condition in which the subject squeezed a pipette with his/her right hand. In all participants, mu rhythm was present over the frontoparietal area during the rest condition, but was clearly suppressed during the prehension condition. Mu rhythm peak frequency, determined from the amplitude spectra, increased rapidly as a function of age from 2.75 Hz at 11 weeks to 8.25 Hz at 47 weeks (r2 = 0.83). It increased very slowly during the preschool period (3.1 ± 0.9 years; 8.5 ± 0.54 Hz). The frequency in these children was, however, lower than in adults (10.3 ± 1.2 Hz). Our results show a rapid maturation in spontaneous mu rhythm during the first year of life.


Cardioprotective role of β-blockers and angiotensin antagonists in early-onset anthracyclines-induced cardiotoxicity in adult patients: a systematic review and meta-analysis.
Anthracyclines are commonly used chemotherapeutic agents with proven efficacy in such malignancies as breast cancer, Hodgkin and non-Hodgkin lymphomas. These agents are associated with irreversible accumulative dose-related cardiomyopathy. Many agents have been examined to reduce cardiotoxicity risk. We performed a systematic review and meta-analysis to determine the efficacy of β-blockers and angiotensin antagonists to prevent early-onset anthracyclines-induced left ventricular dysfunction and cardiac events. Relevant articles were searched in PubMed, EMBASE and Cochrane database of systematic reviews up to July 2015. Eligible studies were limited to randomised controlled trials comparing the efficacy of cardioprotective agents (β-blocker and angiotensin antagonist) with control (either no treatment or placebo) in adult patients (age >18 years) treated with anthracyclines-based regimens. Pooled analysis showed an association of β-blockers and/or angiotensin antagonists treatment with higher post-chemotherapy left ventricular ejection fraction (LVEF) of 64.03% compared with 57.48% for control treatment. The mean difference estimate (95% CI) was 6.06% (0.54 to 11.58), p=0.03, with significant heterogeneity, I(2) (95% CI)=96% (82.7 to 109.3). Though the point estimate for the relative rate of cardiac events was lower in the experimental arm, the difference was not statistically significant. In an exploratory subgroup analysis, the benefit of experimental agents on LVEF preservation was prominent in patients treated with higher accumulative dose of anthracyclines, but not in the lower dose group. β-Blockers and angiotensin antagonists treatments were associated with better LVEF preservation, and the benefit was prominent in patients treated with higher anthracyclines accumulative dose. Unexplained heterogeneity remains, indicating the need for more controlled studies. This analysis provides some support for the routine use of β-blockers or angiotensin antagonists in patients undergoing anthracyclines treatment, especially when higher accumulative dose is expected.


Toxoplasma gondii infection in wild mustelids and cats across an urban-rural gradient.
The increase in human population and domestic pets, such as cats, are generating important consequences in terms of habitat loss and pathogen pollution of coastal ecosystems with potential to generate negative impacts in marine biodiversity. Toxoplasma gondii is the etiological agent of zoonotic disease toxoplasmosis, and is associated with cat abundance and anthropogenic disturbance. The presence of T. gondii oocysts in the ocean has negatively affected the health status of the threatened Southern sea otter (Enhydra lutris nereis) populations. The present study analyzed seroprevalence and presence of T. gondii DNA in American mink (Neovison vison), Southern river otters (Lontra provocax) and domestic cats (Felis silvestris catus) in four different areas in Southern Chile comprising studies in rivers and lakes in Andean foothills and mountains, marine habitat and island coastal ecosystems. Mean seroprevalence of T. gondii in the study was 64% of 151 total animals sampled: 59% of 73 American mink, 77% of 13 Southern river otters, 68% of 65 domestic cats and in two of two kodkods (Leopardus guigna). Toxoplasma gondii DNA was detected in tissues from one American mink and one Southern river otter. The present study confirms the widespread distribution of T. gondii in Southern Chile, and shows a high exposure of semiaquatic mustelids and domestic cats to the parasite. Cats and anthropogenic disturbance have a role in the maintenance of T. gondii infection in ecosystems of southern Chile.


Bayesian nonparametric clustering in phylogenetics: modeling antigenic evolution in influenza.
Influenza is responsible for up to 500,000 deaths every year, and antigenic variability represents much of its epidemiological burden. To visualize antigenic differences across many viral strains, antigenic cartography methods use multidimensional scaling on binding assay data to map influenza antigenicity onto a low-dimensional space. Analysis of such assay data ideally leads to natural clustering of influenza strains of similar antigenicity that correlate with sequence evolution. To understand the dynamics of these antigenic groups, we present a framework that jointly models genetic and antigenic evolution by combining multidimensional scaling of binding assay data, Bayesian phylogenetic machinery and nonparametric clustering methods. We propose a phylogenetic Chinese restaurant process that extends the current process to incorporate the phylogenetic dependency structure between strains in the modeling of antigenic clusters. With this method, we are able to use the genetic information to better understand the evolution of antigenicity throughout epidemics, as shown in applications of this model to H1N1 influenza. Copyright © 2017 John Wiley & Sons, Ltd.


Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis.
Many patients with rheumatoid arthritis are currently successfully treated with infliximab (anti-tumour necrosis factor); however, about 30% of the patients do not respond to infliximab. One of the postulated hypotheses of not responding is the fast clearance of infliximab due to the development of infliximab-anti-infliximab complexes. To investigate the in vivo mechanism of not responding and the role of human anti-chimeric antibodies (HACAs) by using radiolabelled infliximab. Two responding and two non-responding patients with rheumatoid arthritis, infused with radiolabelled infliximab, were investigated by both imaging and serum analysis. Images showed predominant presence of infliximab in blood up to 24 h, with a trend of faster blood clearance and of higher liver/spleen uptake in a non-responding patient. Clinically inflamed joints showed uptake of the drug. The HACA level in the non-responders was high (1641 and 1008 U/ml), but low or not detectable in responders. Sucrose gradients of serum showed antibody complexes in both non-responders. Various sizes of antibody complexes, including very large ones, were observed in a non-responder who developed a serious infusion reaction. Formation of infliximab-anti-infliximab complexes were found in non-responders due to the presence of large amounts of HACA. This finding, supported by both imaging and serum analysis data, may explain failure of infliximab treatment.


Divergent motor projections from the pedunculopontine nucleus are differentially regulated in Parkinsonism.
The pedunculopontine nucleus (PPN) is composed of neurons with different connectivity patterns that express different neurochemical markers, display distinct firing characteristics and are topographically organized in functional domains across its rostro-caudal axis. Previous reports have shown that the caudal region of the PPN is interconnected with motor regions of both the basal ganglia and brainstem/medulla. The co-distribution of ascending and descending motor outputs raises the question as to whether the PPN provides a coordinated or differential modulation of its targets in the basal ganglia and the medulla. To address this, we retrogradely labeled neurons in the two main PPN pathways involved in motor control and determined whether they project to one or both structures, their neurochemical phenotype, and their activity in normal and dopamine depleted rats, as indicated by Egr-1 expression. We show that ascending and descending motor pathways from the PPN arise largely from separate neurons that intermingle in the same region of the PPN, but have a distinct neurochemical composition and are differentially regulated in the Parkinsonian state. Thus, neurons projecting to the subthalamic nucleus consist of cholinergic, calbindin- and calretinin-expressing neurons, and Egr-1 is upregulated following a 6-hydroxydopamine lesion. In contrast, a larger proportion of neurons projecting to the gigantocellular nucleus are cholinergic, none express calbindin and the expression of Egr-1 is not changed by the dopamine lesion. Our results suggest that ascending and descending motor connections of the PPN are largely mediated by different sets of neurons and there are cell type-specific changes in Parkinsonian rats.


Alignment-free cancelable fingerprint templates based on local minutiae information.
To replace compromised biometric templates, cancelable biometrics has recently been introduced. The concept is to transform a biometric signal or feature into a new one for enrollment and matching. For making cancelable fingerprint templates, previous approaches used either the relative position of a minutia to a core point or the absolute position of a minutia in a given fingerprint image. Thus, a query fingerprint is required to be accurately aligned to the enrolled fingerprint in order to obtain identically transformed minutiae. In this paper, we propose a new method for making cancelable fingerprint templates that do not require alignment. For each minutia, a rotation and translation invariant value is computed from the orientation information of neighboring local regions around the minutia. The invariant value is used as the input to two changing functions that output two values for the translational and rotational movements of the original minutia, respectively, in the cancelable template. When a template is compromised, it is replaced by a new one generated by different changing functions. Our approach preserves the original geometric relationships (translation and rotation) between the enrolled and query templates after they are transformed. Therefore, the transformed templates can be used to verify a person without requiring alignment of the input fingerprint images. In our experiments, we evaluated the proposed method in terms of two criteria: performance and changeability. When evaluating the performance, we examined how verification accuracy varied as the transformed templates were used for matching. When evaluating the changeability, we measured the dissimilarities between the original and transformed templates, and between two differently transformed templates, which were obtained from the same original fingerprint. The experimental results show that the two criteria mutually affect each other and can be controlled by varying the control parameters of the changing functions.


Order and disorder in the brain function.
The interest in studying the brain electrical activity as a function of the development of intelligence has been spurred by the need to understand how the brain responds to environmental information. The description of sleep in mentally retarded children reveals deviant patterns of the EEG-spindles and of the eye movement activity (REM sleep) when compared to normal children. The patterns may be considered as a valuable index of mental function. According to experimental evidence, the distribution of the eye movements of sleep appears either as random or ordered. The latter are altered in the mentally handicapped in whom the appearance out of chaos, of the order which is needed for intelligence and memory to function, is altered. The sleep signs are redundant as from birth. Their pattern is also related to the psychomotor development of the infant. If their distribution remains random, or appears in long uninterrupted sequences of waves as in epilepsy, intelligence does not develop. A similar strategy appears to function in the foetus when nature organizes the structures that will lead to the development of intelligence. The eye movement patterns of sleep change in the pregnant women as a function of term and resemble those of premature babies of a similar gestational age. They also change as a function of the menstrual cycle and more generally as a function of age. The hypothesis that attention is the diurnal equivalent of REM sleep is discussed. Attempts at modelling the eye movement patterns of REM sleep as a function of near zero gravity environments have been made. 1) By means of a Montecarlo simulation using the semi Markov model during the Spacelab 1 flight. 2) With the method of the single and multiple g-phase transition analysis of the strange attractor dimension (d) during parabolic flights. The implication of the latter for the neural processes involved in learning is that the central nervous system can preserve intact, from input to output, over a period of several days, all the information it receives 3) The relation between spindles and eye movements has also been viewed by a quantum approach which is another medium between the information and the way of describing it.