Adipokines and genetic factors in overweight or obese but metabolically healthy Polish women.
Obesity may be accompanied by enhanced metabolic disturbances but not all obese patients suffer from metabolic syndrome. Since metabolic homeostasis is under control of genetic factors underlying expression of adipokines, we aimed to compare the serum concentrations of adiponectin and resistin, and polymorphism in their genes, in overweight or obese Polish women. The study included 265 women with BMI above 25 kg/m2 (140 metabolically healthy and 125 with metabolic syndrome) and 104 non-obese women as a control group. Anthropometric parameters (BMI, BIA, WHR), blood pressure, lipid, glucose and HOMA-IR profiles as well as serum concentrations of adiponectin, HMW adiponectin and resistin were evaluated. Gene polymorphisms of adiponectin gene (276G/T; 11377C/G; 11391G/A) and resistin gene (420C/G; 62G/A; 537A/C) were analyzed using TaqMan SNP genotyping assays. Higher serum concentrations of total adiponectin and lower levels of resistin were found in metabolically healthy patients when compared to those diagnosed with metabolic syndrome. No differences of serum HMW and resistin concentrations were observed between overweight or obese but metabolically healthy subjects and normal weight controls. No associations of investigated polymorphisms and the presence of metabolic syndrome were noticed in overweight/obese women with metabolic syndrome. The assessment of total adiponectin in sera seems to be promising target in distinguishing subjects with obesity who undergo a diagnostic procedure for metabolic syndrome. Moreover, the evaluation of adipokine array may help to select patients with higher risk of metabolic disturbances that are associated with severe diseases.


Replication timing of genes and middle repetitive sequences.
DNA replication in mammals is temporally bimodal. "Housekeeping" genes, which are active in all cells, replicate during the first half of the S phase of cell growth. Tissue-specific genes replicate early in those cells in which they are potentially expressed, and they usually replicate late in tissues in which they are not expressed. Replication during the first half of the S phase is, therefore, a necessary but not sufficient condition for gene transcription. A change in the replication timing of a tissue-specific gene appears to reflect the commitment of that gene to transcriptional competence or to quiescence during ontogeny. Most families of middle repetitive sequences replicate either early or late. These data are consistent with a model in which two functionally distinct genomes coexist in the nucleus.


High-ranked social science journal articles can be identified from early citation information.
Do citations accumulate too slowly in the social sciences to be used to assess the quality of recent articles? I investigate whether this is the case using citation data for all articles in economics and political science published in 2006 and indexed in the Web of Science. I find that citations in the first two years after publication explain more than half of the variation in cumulative citations received over a longer period. Journal impact factors improve the correlation between the predicted and actual future ranks of journal articles when using citation data from 2006 alone but the effect declines sharply thereafter. Finally, more than half of the papers in the top 20% in 2012 were already in the top 20% in the year of publication (2006).


Questionnaire on the perceptions of patients about shoulder surgery.
We developed a 12-item questionnaire for completion by patients having shoulder operations other than stabilisation. A prospective study of 111 patients was undertaken before operation and at follow-up six months later. Each patient completed the new questionnaire and the SF36 form. Some filled in the Stanford Health Assessment Questionnaire (HAQ). An orthopaedic surgeon assessed the Constant shoulder score. The single score derived from the questionnaire had a high internal consistency. Reproducibility, examined by test-retest reliability, was found to be satisfactory. The validity of the questionnaire was established by obtaining significant correlations in the expected direction with the Constant score and the relevant scales of the SF36 and the HAQ. Sensitivity to change was assessed by analysing the differences between the preoperative scores and those at follow-up. Changes in scores were compared with the patients' responses to postoperative questions about their condition. The standardised effect size for the new questionnaire compared favourably with that for the SF36 and the HAQ. The new questionnaire was the most efficient in distinguishing patients who said that their shoulder was much better from all other patients. The shoulder questionnaire provides a measure of outcome for shoulder operations which is short, practical, reliable, valid and sensitive to clinically important changes.


Theoretical versus Ex Vivo Assessment of Radiation Damage Repair: An Investigation in Normal Breast Tissue.
In vivo validation of models of DNA damage repair will enable their use for optimizing clinical radiotherapy. In this study, a theoretical assessment was made of DNA double-strand break (DSB) induction in normal breast tissue after intraoperative radiation therapy (IORT), which is now an accepted form of adjuvant radiotherapy for selected patients with early breast cancer. DSB rates and relative biological effectiveness (RBE) were calculated as a function of dose, radiation quality and dose rate, each varying based on the applicator size used during IORT. The spectra of primary electrons in breast tissue adjacent to each applicator were calculated using measured X-ray spectra and Monte Carlo methods, and were used to inform a Monte Carlo damage simulation code. In the absence of repair, asymptotic RBE values (relative to (60)Co) were approximately 1.5. Beam-quality changes led to only minor variations in RBE among applicators, though differences in dose rate and overall dose delivery time led to larger variations and a rapid decrease in RBE. An experimental assessment of DSB induction was performed ex vivo using pre- and postirradiation tissue samples from patients receiving breast intraoperative radiation therapy. Relative DSB rates were assessed via γ-H2AX immunohistochemistry using proportional staining. Maximum-likelihood parameter estimation yielded a DSB repair halftime of 25.9 min (95% CI, 21.5-30.4 min), although the resulting model was not statistically distinguishable from one where there was no change in DSB yield among patients. Although the model yielded an in vivo repair halftime of the order of previous estimates for in vitro repair halftimes, we cannot conclude that it is valid in this context. This study highlights some of the uncertainties inherent in population analysis of ex vivo samples, and of the quantitative limitations of immunohistochemistry for assessment of DSB repair.


Type 5 adenylyl cyclase disruption leads to enhanced exercise performance.
The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β-AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac- and skeletal muscle-specific AC5 KO's, where exercise performance was no longer improved by the cardiac-specific AC5 KO, but was by the skeletal muscle-specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti-oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy-3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.


Albumin for Prehospital Fluid Resuscitation of Hemorrhagic Shock in Tactical Combat Casualty Care.
Optimal fluid resuscitation on the battlefield in the absence of blood products remains unclear. Contemporary Combat medics are generally limited to hydroxyethyl starch or crystalloid solutions, both of which present significant drawbacks. Obtaining US Food and Drug Administration (FDA)-approved freeze-dried plasma (FDP) is a top casualty care research priority for the US Military. Interest in this agent reflects a desire to simultaneously expand intravascular volume and address coagulopathy. The history of FDP dates to the Second World War, when American expeditionary forces used this agent frequently. Also fielded was 25% albumin, an agent that lacks coagulation factors but offers impressive volume expansion with minimal weight to carry and requires no reconstitution in the field. The current potential value of 25% albumin is largely overlooked. Although FDP presents an attractive future option for battlefield prehospital fluid resuscitation once FDA approved, this article argues that in the interim, 25% albumin, augmented with fibrinogen concentrate and tranexamic acid to mitigate hemodilution effects on coagulation capacity, offers an effective volume resuscitation alternative that could save lives on the battlefield immediately.


Silencing IL-13Rα2 promotes glioblastoma cell death via endogenous signaling.
Glioblastoma multiforme (GBM) is one of the most lethal forms of cancer, with a survival rate of only 13% to 27% within 2 years of diagnosis despite optimal medical treatment. We hypothesize that the presence of a unique IL-13Rα2 decoy receptor prevents GBM apoptosis. This receptor has a high affinity for interleukin-13 (IL-13), binds the cytokine, and competitively inhibits the intracellular signaling cascade initiated by IL-13. In cells lacking the IL-13Rα2 decoy receptor, IL-13 initiates the production of 15-lipoxygenase-1 (15-LOX-1), which has been implicated in cellular apoptosis. Our group and others have shown that induction of 15-LOX-1 correlates with tumor cell death in colorectal, pancreatic, and prostate cancer. How 15-LOX-1 induces apoptosis remains unclear. Preliminary evidence in GBM cells implicates an apoptotic process mediated by PPARγ. 15-LOX-1 metabolites can modulate PPARγ and activation of PPARγ can suppress tumor growth. We hypothesize that in GBM, IL-13 can induce 15-LOX-1, which regulates cell apoptosis via signaling through PPARγ and that expression of IL-13Rα2 prevents apoptosis and contributes to tumor growth. Our in vitro and in vivo data support this. Knocking down IL-13Rα2 with short interfering RNA dramatically induces 15-LOX-1 expression, promotes apoptosis, and reduces GBM tumor growth in vivo. These findings identify a mechanism for eliminating the blockade of endogenous IL-13 signaling and for promotion of apoptosis, and characterize a role for 15-LOX-1 in GBM apoptosis. Identifying a mechanistic pathway that can be targeted for pharmacologic intervention will have applied implications to developing novel and effective treatments of GBM.


Action-potential broadening and endogenously sustained bursting are substrates of command ability in a feeding neuron of Pleurobranchaea.
1. The ventral white cells (VWC's) of the buccal ganglion of Pleurobranchaea, so named for their position and color, are a bilateral pair of neuron somata. Each sends a single axon out its contralateral stomatogastric nerve and has a dendritic field originating close to the soma. 2. The vwcs exhibit spontaneous episodes of prolonged depolarization (duration 1--4 min) accompanied by repetitive action-potential activity and separated by regular intervals of 3--30 min. Such prolonged burst episodes can be triggered by short pulses of depolarizing current. During the repetitive activity of the spontaneous bursts or that driven by imposed depolarization, the action potentials progressively broaden to 5--16 times their initial duration. 3. During spontaneous bursting or activity driven by imposed depolarization, the cyclic motor output of the feeding network is initiated or accelerated with a latency corresponding with the development of appreciable VWC spike broadening. When broadening of antidromic VWC spikes is suppressed by imposed hyperpolarization of the soma, the frequency of feeding cycles is significantly lower than when broadened spikes are allowed to develop. When trains of spikes are driven by depolarizing current, the motor output of the feeding network is not initiated until the VWC spikes have broadened to a repeatable "threshold" duration, regardless of the intensity of the depolarizing current. 4. The endogenous production of prolonged burst episodes, triggered by depolarizing current pulses, and progressive spike broadening can be demonstrated in the surgically isolated VWC soma. 5. The paired VWCs are strongly electrically coupled and display highly synchronous activity. They receive synaptic inputs from many previously identified interneurons of the feeding network and are thus reciprocally coupled within the network. 6. These results demonstrate that the capacity of this neuron to generate broadened action potentials during repetitive activity confers the ability to command coordinated motor-network output. The appropriate repetitive activity can be produced endogenously in the form of prolonged bursts of spikes.


Responses of an African tall-grass (Hyparrhenia filipendula stapf.) to defoliation and limitations of water and nitrogen.
Hyparrhenia filipendula stapf., a tall (1-1.5 m) perennial grass common in dry-subhumid African savannas, was collected from Serengeti National Park in Tanzania, propagated vegetatively, and grown in controlled environments simulating conditions in nature. Plants were subjected to a factorial experiment with combinations of watering frequency, nitrogen supply, clipping height (10 and 15 cm) and clipping frequency (7 and 14 d). Biomass yield and allocation to various tissue types, morphometric traits, and growth processes were measured.Watering frequency affected leaf elongation rate while nitrogen affected tiller number. Clipped yield was strongly correlated with leaf elongation rate but not tiller number, therefore it was primarily controlled by the activities of intercalary rather than apical meristems. There was a negative exponential relationship between tillering and clipped yield per tiller. Plants that received both high nitrogen and high water closely followed a-3/2 power law in this tradeoff. The fraction of total net photosynthate allocated to roots was not significantly related to any environmental treatment. Root and crown growths were not affected by defoliation treatment; leaf blade and stem growths were inhibited; and sheaths were inhibited only under low water.Despite a tall stature, H. filipendula tolerated herbivory by increased photosynthetic rate (Wallace et al. 1984), through continued production of young tissues by intercalary meristems balanced against tiller number, and by a statistically constant proportional allocation to roots. Clipped yield increased only when both nitrogen and water were abundant, and then, proportional clipped yield did not surpass an upper asymptotic limit.


Cardiac troponin I concentrations in horses with colic.
To determine prevalence of myocardial injury in horses with colic on the basis of high concentrations of cardiac troponin I (cTnI), frequency of cardiac arrhythmias within the first 24 to 48 hours after hospital admission or surgery because of colic, and associations between high cTnI concentrations and cardiac arrhythmias, clinical course, and outcome (survival to discharge from hospital vs nonsurvival [death or euthanasia]). Prospective observational study. 111 horses with colic. Blood was drawn at admission and 12 and 24 hours after admission if horses were treated medically or 12 and 24 hours after surgery if treated surgically. A 24-hour ambulatory ECG was recorded beginning the morning after admission in medically treated cases or after surgery and evaluated for arrhythmias. Clinical and clinicopathologic data and outcome were obtained. Associations between cTnI concentrations and other variables were determined. An abnormal cTnI concentration (≥ 0.10 ng/mL) at admission was significantly associated with the occurrence of ventricular arrhythmias, outcome, and surgical treatment. The data suggested that horses with colic and high cTnI concentrations at admission were more likely to have ventricular arrhythmias and have a less favorable prognosis for recovery. High cTnI concentrations in horses with colic were suggestive of myocardial damage.


Reconsideration of laparoscopic cholecystectomy.
We describe the surgical method of cases showing a distended gallbladder. Because the most important thing does not cause biliary tract injury, it is to find orientation carefully. The frequency of incidental gallbladder cancer was in 7 (0.7%) of the 983. Only cholecystectomy is necessary to be performed for Tis or T1 cancer, and surgery has to be changed to radical surgery for T2 cancer or deeper invasion. Laparoscopic cholecystectomy is already an established standard operation. In the presence of acute or severe chronic inflammation, special attention should be paid to these points.


Localization--the revolution in consumer markets.
Standardization has been a powerful strategy in consumer markets, but it's reached the point of diminishing returns. And diversity is not the only chink in standardization's armor: Attempts to build stores in the remaining attractive locations often meet fierce resistance from community activists. From California to Florida to New Jersey, neighborhoods are passing ordinances that dictate the sizes and even architectural styles of new shops. Building more of the same--long the cornerstone of retailer growth--seems to be tapped out as a strategy. Of course, a company can't customize every element of its business in every location. Strategists have begun to use clustering techniques to simplify and smooth out decision making and to focus their efforts on the relatively small number of variables that usually drive the bulk of consumer purchases. The customization-by-clusters approach, which began as a strategy for grocery stores in 1995, has since proven effective in drugstores, department stores, mass merchants, big-box retailers, restaurants, apparel companies, and a variety of consumer goods manufacturers. Clustering sorts things into groups, so that the associations are strong between members of the same cluster and weak between members of different clusters. In fact, by centralizing data-intensive and scale-sensitive functions (such as store design, merchandise assortment, buying, and supply chain management), localization liberates store personnel to do what they do best: Test innovative solutions to local challenges and forge strong bonds with communities. Ultimately, all companies serving consumers will face the challenge of local customization. We are advancing to a world where the strategies of the most successful businesses will be as diverse as the communities they serve.


The effects of stereotype activation on behavior: a review of possible mechanisms.
Considerable recent research has examined the effects that activated stereotypes have on behavior. Research on both self-stereotype activation and other-stereotype activation has tended to show that people behave in ways consistent with the stereotype (e.g., walking more slowly if the elderly stereotype is activated). Interestingly, however, the dominant account for the behavioral effects of self-stereotype activation involves a hot motivational factor (i.e., stereotype threat), whereas the dominant account for the behavioral effects of other-stereotype activation focuses on a rather cold cognitive explanation (i.e., ideomotor processes). The current review compares and contrasts the behavioral research on self- and other-stereotype activation and concludes that both motivational and cognitive explanations might account for effects in each domain.


Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia.
Classic galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research, the mechanisms that underlie pathophysiology in classic galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we describe application of our fly genetic model of galactosemia to the question of whether oxidative stress contributes to the acute galactose sensitivity of GALT-null animals. Our first approach tested the impact of pro- and antioxidant food supplements on the survival of GALT-null and control larvae. We observed a clear pattern: the oxidants paraquat and DMSO each had a negative impact on the survival of mutant but not control animals exposed to galactose, and the antioxidants vitamin C and α-mangostin each had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested but, interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose sensitivity of GALT-null Drosophila and, by extension, suggest that reactive oxygen species might also contribute to the acute pathophysiology in classic galactosemia.


Minor impact of multiple psychiatric symptoms on quality of life (EQ5D) in psychogeriatric patients: a clinical-empirical structural modeling approach.
The relationship of clinical variables for cognitive functioning and other variables such as multiple neuropsychiatric symptoms and quality of life are usually analyzed bivariately and multivariately. In randomized controlled trials analyses are mostly performed on individual outcome variables. To unravel interdependencies of determinants and outcome variables, Structural Equation Modeling (SEM) was applied. Using SEM, we explored interdependencies of clinical determinants (MMSE, BI, and NPI-sum severity) and quality of life (EQ5D) in psychogeriatric patients (including dementia) suffering from cognitive problems and multiple neuropsychiatric symptoms. MMSE and BI showed direct and indirect impact on EQ5D, but the association with NPI-sum severity was minor. The identified model showed that R(2) of EQ5D varied from 0.21 to 0.48. This clinical-empirical study showed that SEM could be utilized to unravel and identify a model of complex direct and indirect effects of MMSE and BI on EQ5D. In relation to NPI-sum severity, however, the validity of EQ5D seemed insufficient in psychogeriatric patients. Consequently, the cost-benefit analyses and cost-effectiveness analyses using quality-adjusted life-year measures of an intervention in psychogeriatric patients with multiple neuropsychiatric symptoms, based on EQ5D, are considered questionable. Construction of a quality of life instrument that is more sensitive with regard to multiple neuropsychiatric symptoms in psychogeriatric patients is highly recommended.


Modified two-flux approximation for identification of radiative properties of absorbing and scattering media from directional-hemispherical measurements.
A modified two-flux approximation is suggested for calculating the hemispherical transmittance and reflectance of a refracting, absorbing, and scattering medium in the case of collimated irradiation of the sample along the normal to the interface. The Fresnel reflection is taken into account in this approach. It is shown that the new approximation is rather accurate for the model transport scattering function. For an arbitrary scattering medium, the error of the modified two-flux approximation is estimated by comparison with the exact numerical calculations for the Henyey-Greenstein scattering function in a wide range of albedos and optical thicknesses. Possible applications of the derived analytical solution to identification problems are discussed.


From trochophore to pilidium and back again - a larva's journey.
Nemerteans, a phylum of marine lophotrochozoan worms, have a biphasic life history with benthic adults and planktonic larvae. Nemertean larval development is traditionally categorized into direct and indirect. Indirect development via a long-lived planktotrophic pilidium larva is thought to have evolved in one clade of nemerteans, the Pilidiophora, from an ancestor with a uniformly ciliated planuliform larva. Planuliform larvae in a member of a basal nemertean group, the Palaeonemertea, have been previously shown to possess a vestigial prototroch, homologous to the primary larval ciliated band in the trochophores of other spiralian phyla, such as annelids and mollusks. We review literature on nemertean larval development, and include our own unpublished observations. We highlight recent discoveries of numerous pilidiophoran species with lecithotrophic larvae. Some of these larvae superficially resemble uniformly ciliated planuliform larvae of other nemerteans. Others possess one or two transverse ciliary bands, which superficially resemble the prototroch and telotroch of some spiralian trochophores. We also summarize accumulating evidence for planktotrophic feeding by larvae of the order Hoplonemertea, which until now were considered to be lecithotrophic. We suggest that 1) non-feeding pilidiophoran larval forms are derived from a feeding pilidium; 2) such forms have likely evolved many times independently within the Pilidiophora; 3) any resemblance of such larvae to the trochophores of other spiralians is a result of convergence and that 4) the possibility of planktotrophy in hoplonemertean larvae may influence estimates of pelagic larval duration, dispersal, and population connectivity in this group.


Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma.
Alveolar rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a. We investigated the complementary role of Rb1 loss in aRMS tumor initiation and progression using conditional mouse models. Rb1 loss was not a necessary and sufficient mutational event for rhabdomyosarcomagenesis, nor a strong cooperative initiating mutation. Instead, Rb1 loss was a modifier of progression and increased anaplasia and pleomorphism. Whereas Pax3:Foxo1a expression was unaltered, biomarkers of aRMS versus embryonal rhabdomyosarcoma were both increased, questioning whether these diagnostic markers are reliable in the context of Rb1 loss. Genome-wide gene expression in Pax3:Foxo1a,Rb1 tumors more closely approximated aRMS than embryonal rhabdomyosarcoma. Intrinsic loss of pRb function in aRMS was evidenced by insensitivity to a Cdk4/6 inhibitor regardless of whether Rb1 was intact or null. This loss of function could be attributed to low baseline Rb1, pRb and phospho-pRb expression in aRMS tumors for which the Rb1 locus was intact. Pax3:Foxo1a RNA interference did not increase pRb or improve Cdk inhibitor sensitivity. Human aRMS shared the feature of low and/or heterogeneous tumor cell pRb expression. Rb1 loss from an already low pRb baseline is a significant disease modifier, raising the possibility that some cases of pleomorphic rhabdomyosarcoma may in fact be Pax3:Foxo1a-expressing aRMS with Rb1 or pRb loss of function.


A specific inhibitor of calcium/calmodulin-dependent protein kinase-II provides neuroprotection against NMDA- and hypoxia/hypoglycemia-induced cell death.
Calcium/calmodulin-dependent protein kinase-II (CamK-II) is a major neuronal protein which plays a significant role in the cellular process of long-term potentiation (LTP), and vesicular release of neurotransmitters. Here, we show that KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine, a specific cell-permeable inhibitor of CamK-II substantially protected neurons from (1) acute NMDA toxicity and (2) hypoxia/hypoglycemia-induced neuronal injury in fetal rat cortical cultures. KN-62 did not directly inhibit glutamate, kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), glycine, or [piperidyl-3,4-(N)]-(N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine) (TCP) binding to rat brain membranes. Finally, KN-62 significantly reduced cellular calcium accumulation following either NMDA challenge or hypoxia/hypoglycemia insult. Our results show that CamK-II plays a key role in mediating some of the biochemical events leading to cell death following an acute excitotoxic insult.


Status and the evaluation of workplace deviance.
Bias in the evaluation of workplace misbehavior is hotly debated in courts and corporations, but it has received little empirical attention. Classic sociological literature suggests that deviance by lower-status actors will be evaluated more harshly than deviance by higher-status actors. However, more recent psychological literature suggests that discrimination in the evaluation of misbehavior may be moderated by the relative status of the evaluator because status influences both rule observance and attitudes toward social hierarchy. In Study 1, the psychological experience of higher status decreased rule observance and increased preferences for social hierarchy, as we theorized. In three subsequent experiments, we tested the hypothesis that higher-status evaluators would be more discriminating in their evaluations of workplace misbehavior, evaluating fellow higher-status deviants more leniently than lower-status deviants. Results supported the hypothesized interactive effect of evaluator status and target status on the evaluation of workplace deviance, when both achieved status characteristics (Studies 2a and 2b) and ascribed status characteristics (i.e., race and gender in Study 3) were manipulated.


Serological response to in vitro-shed antigen(s) of Tritrichomonas foetus in cattle.
We developed a serological assay for detection of (l) an erythrocyte-adhering molecule(s) shed by the bovine venereal pathogen Tritrichomonas foetus and (II) serum antibodies to this antigen(s) in exposed cattle. Sera from exposed and unexposed cattle were tested for their ability to induce complement-mediated lysis of bovine erythrocytes that had been previously incubated overnight at room temperature in pH-adjusted supernatants of T. foetus culture media. Eight of 180 serum specimens from six groups of presumably unexposed cows or heifers showed a positive (> or = 1:2) hemolytic titer (specificity = 95.6%). Thirteen of 14 females in two experimentally infected groups showed a positive hemolytic titer following infection (sensitivity = 94%). In experimentally infected heifers, there was little correlation (r2 = 0.33) between serum hemolytic titers with respect to shed antigen and titers obtained in serum enzyme-linked immunosorbent assays in which whole T. foetus served as the antigen. Serum hemolytic titers rose 3 to 4 weeks sooner than did previously described vaginal mucus immunoglobulin G1 or immunoglobulin A titers with respect to whole-cell antigen or TF1.17 subunit antigen, respectively. Among 14 chronically infected bulls, only 6 (43%) showed a positive hemolytic titer. This study is the first, to our knowledge, to show a specific serological response in the host to an in vitro-shed antigen(s) of T. foetus and suggests a useful diagnostic test for potentially exposed herds.


Recent advances in incretin-based therapies.
The global burden of type 2 diabetes is growing. Traditional therapies are suboptimal and there is a clear unmet need for treatments that offer effective glucose control while addressing the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease, without the fear of hypoglycaemia. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors offer a novel way of reducing hyperglycaemia by targeting the incretin system. This review provides an overview of the development of incretin-based therapies and explains their differing modes of action compared with traditional interventions. A comparison of the clinical profiles of current glucagon-like peptide-1 receptor agonists [liraglutide and exenatide (twice-daily and once-weekly)] and dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, vildagliptin and linagliptin) is performed alongside a discussion of the placement of incretin-based therapies in treatment guidelines. Further improvements in this class are expected, and we will examine some of the novel glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors currently under development.


Genetic polymorphisms in the cyclooxygenase-2 gene, use of nonsteroidal anti-inflammatory drugs, and breast cancer risk.
The association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer risk remains unclear. Inconsistencies in previously reported findings may be partly due to differences in expression of cyclooxygenase (COX)-2. We hypothesized that genetic polymorphisms (COX-2 .926, COX-2 .5209, and COX-2 .8473) may reduce overall breast cancer risk or risk for subtypes of breast cancer by modulating the inflammatory response and may interact with aspirin or any NSAID use. We conducted a population-based, case-control study in which we genotyped 1,067 breast cancer cases and 1,110 control individuals included in the Long Island Breast Cancer Study Project. No major effects of the three COX-2 variant alleles on breast cancer risk were found. A total of eight distinct haplotypes and 18 diplotypes were observed in the population. Overall, no significant associations between COX-2 haplotypes/diplotypes and breast cancer risk were observed. Among women who used aspirin or any NSAID there was little evidence for an interaction with the at-risk COX-2 genotypes, with one exception. Among women with hormone receptor positive breast cancer, the reduced risk for any NSAID use was only evident among those who had at least one variant C allele of COX-2 .8473 (odds ratio = 0.7, 95% confidence interval = 0.5 to 1.0; P for the interaction = 0.02). There was no corresponding interaction for aspirin use, possibly because of limited power. These data provide modest evidence that the C allele of COX-2 .8473 may interact with NSAIDs to reduce risk for hormone receptor positive breast cancer.


Aluminum Nitride Hydrolysis Enabled by Hydroxyl-Mediated Surface Proton Hopping.
Aluminum nitride (AlN) is used extensively in the semiconductor industry as a high-thermal-conductivity insulator, but its manufacture is encumbered by a tendency to degrade in the presence of water. The propensity for AlN to hydrolyze has led to its consideration as a redox material for solar thermochemical ammonia (NH3) synthesis applications where AlN would be intentionally hydrolyzed to produce NH3 and aluminum oxide (Al2O3), which could be subsequently reduced in nitrogen (N2) to reform AlN and reinitiate the NH3 synthesis cycle. No quantitative, atomistic mechanism by which AlN, and more generally, metal nitrides react with water to become oxidized and generate NH3 yet exists. In this work, we used density-functional theory (DFT) to examine the reaction mechanisms of the initial stages of AlN hydrolysis, which include: water adsorption, hydroxyl-mediated proton diffusion to form NH3, and NH3 desorption. We found activation barriers (Ea) for hydrolysis of 330 and 359 kJ/mol for the cases of minimal adsorbed water and additional adsorbed water, respectively, corroborating the high observed temperatures for the onset of steam AlN hydrolysis. We predict AlN hydrolysis to be kinetically limited by the dissociation of strong Al-N bonds required to accumulate protons on surface N atoms to form NH3. The hydrolysis mechanism we elucidate is enabled by the diffusion of protons across the AlN surface by a hydroxyl-mediated Grotthuss mechanism. A comparison between intrinsic (Ea = 331 kJ/mol) and mediated proton diffusion (Ea = 89 kJ/mol) shows that hydroxyl-mediated proton diffusion is the predominant mechanism in AlN hydrolysis. The large activation barrier for NH3 generation from AlN (Ea = 330 or 359 kJ/mol, depending on water coverage) suggests that in the design of materials for solar thermochemical ammonia synthesis, emphasis should be placed on metal nitrides with less covalent metal-nitrogen bonds and, thus, more-facile NH3 liberation.


Quality of end-of-life care between medical oncologists and other physician specialists for Taiwanese cancer decedents, 2001-2006.
Oncologists play a significant role in cancer care throughout the cancer trajectory and have traditionally emphasized underuse of procedures/treatments with well-established effectiveness as the source of poor care quality with little attention to overusing end-of-life (EOL) care. The purpose of this population-based study was to compare the quality of EOL care between medical oncologists and other physician specialists. This retrospective cohort study compared indicators of poor quality EOL care by examining administrative data for 204,850 Taiwanese cancer decedents in 2001-2006. Taiwanese cancer patients whose primary physician was a medical oncologist were significantly more likely than patients of other physician specialists to receive chemotherapy and to spend >14 days in a hospital in the last month of life. However, they were significantly less likely than patients of other physician specialists to visit the emergency room (ER) more than once and to use intensive care unit (ICU) care, cardiopulmonary resuscitation (CPR), intubation, and mechanical ventilation in the last month of life. The quality of EOL cancer care in Taiwan varied significantly by physician specialty. Cancer decedents cared for by medical oncologists were more likely to receive chemotherapy and prolonged hospitalization but less likely to have multiple ER visits, ICU care, or undergo CPR, intubation, or mechanical ventilation in the last month of life than patients of other physician specialists.


Supplementing a home exercise programme with a class-based exercise programme is more effective than home exercise alone in the treatment of knee osteoarthritis.
The study aimed to compare the relative effectiveness of providing a home-based exercise programme versus home-based exercise supplemented with an 8-week class-based exercise programme in reducing pain and improving function in patients with knee osteoarthritis. Patients (n = 214) with radiologically confirmed knee osteoarthritis were selected. Patients were randomly allocated to either home or home supplemented with class-based exercise programmes. Both groups were given a home exercise programme whilst the supplemented group also attended for 8 weeks of twice weekly knee classes. Assessments of locomotor function, walking pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were made. Assessments were made pre- and post-treatment and also at 6- and 12-month follow-ups. Statistical analysis involved the use of a longitudinal linear model ANCOVA with baseline values entered as a covariate. Patients from the class-based group demonstrated significantly greater improvement in locomotor function (-3.7 seconds; 95% C.I. -4.9 to -2.5) and decrease in walking pain (-15 mm; 95% C.I. -20 to -11) than the home-based group, at 12-months follow-up. The supplementation of a home based exercise programme with a class-based exercise programme led to clinically significant superior improvement. These improvements were still evident at 12-month review. This is the first trial to evaluate this common physiotherapeutic practice, and based on this evidence, supplementation of home exercises with a class-based exercise programme can be recommended to patients, clinicians and service providers.


Cascade synthesis of polyoxygenated 6H,11H-[2]benzopyrano-[4,3-c][1]benzopyran-11-ones.
2-(methoxymethoxymethyl)aryllead triacetates, obtained in situ from the corresponding arylboronic acids, reacted with 4-hydroxycoumarins, leading to 3-(2-methoxymethoxymethyl)aryl-4-hydroxycoumarin derivatives in good to high yields. These compounds underwent a cascade sequence of reactions, deprotection-halogenation-annulation, to afford polyoxygenated tetracyclic 6H,11H-[2]benzopyrano-[4,3-c] [1]benzopyran-11-ones in good yields. Some compounds showed a moderate cytotoxicity against human epithelial mammary HBL100 cells.


Detecting 20 nm wide defects in large area nanopatterns using optical interferometric microscopy.
Due to the diffraction limited resolution and the presence of speckle noise, visible laser light is generally thought to be impractical for finding deep subwavelength defects in patterned semiconductor wafers. Here, we report on a nondestructive low-noise interferometric imaging method capable of detecting nanoscale defects within a wide field of view using visible light. The method uses a common-path laser interferometer and a combination of digital image processing techniques to produce 70 μm by 27 μm panoramic phase and amplitude images of the test nanopattern. Significant noise reduction and high sensitivity are achieved, which enables successful detection of several different types of sparse defects with sizes on the order of 20 nm wide by 100 nm long by 110 nm tall.


Performance of Israeli versus U.S. preschool children on the Miller Assessment for Preschoolers.
The Miller Assessment for Preschoolers (MAP) is a scale that can be used to evaluate preschool children with suspected preacademic problems. Before implementing the MAP in Israel, it was necessary to determine whether the U.S. norms were applicable to the Israeli preschool population. In a pilot study carried out in Israel, the Hebrew version of the MAP was administered to 2 age groups of 30 children each. The scores of Israeli children were compared with the U.S. norms on each of the MAP's 27 subtests, the five performance indices, and the total score. There were no significant differences between the Israeli sample and the U.S. standardization sample in either age group on the MAP total score; significant differences were found in both age groups on the Foundations Index and on some specific subtests. Israeli children performed below U.S. norms on the Foundations Index. These findings indicate that the performance of Israeli children overall in these two age groups is not significantly different from the performance of U.S. children. If future research demonstrates that these findings are stable across all age groups and for larger samples, the implication is that the MAP can be administered and scored in Israel with the scoring methodology and normative information developed in the United States. However, because of the poorer performance of Israeli children on the Foundations Index, we recommend that specific Israeli norms be developed.


Differences in gene expression between mouse and human for dynamically regulated genes in early embryo.
Infertility is a worldwide concern that can be treated with in vitro fertilization (IVF). Improvements in IVF and infertility treatment depend largely on better understanding of the molecular mechanisms for human preimplantation development. Several large-scale studies have been conducted to identify gene expression patterns for the first five days of human development, and many functional studies utilize mouse as a model system. We have identified genes of possible importance for this time period by analyzing human microarray data and available data from online databases. We selected 70 candidate genes for human preimplantation development and investigated their expression in the early mouse development from oocyte to the 8-cell stage. Maternally loaded genes expectedly decreased in expression during development both in human and mouse. We discovered that 25 significantly upregulated genes after fertilization in human included 13 genes whose orthologs in mouse behaved differently and mimicked the expression profile of maternally expressed genes. Our findings highlight many significant differences in gene expression patterns during mouse and human preimplantation development. We also describe four cancer-testis antigen families that are also highly expressed in human embryos: PRAME, SSX, GAGE and MAGEA.


Genetic architecture of plasma adiponectin overlaps with the genetics of metabolic syndrome-related traits.
Adiponectin, a hormone secreted by adipose tissue, is of particular interest in metabolic syndrome, because it is inversely correlated with obesity and insulin sensitivity. However, it is not known to what extent the genetics of plasma adiponectin and the genetics of obesity and insulin sensitivity are interrelated. We aimed to evaluate the heritability of plasma adiponectin and its genetic correlation with the metabolic syndrome and metabolic syndrome-related traits and the association between these traits and 10 ADIPOQ single nucleotide polymorphisms (SNPs). We made use of a family-based population, the Erasmus Rucphen Family study (1,258 women and 967 men). Heritability analysis was performed using a polygenic model. Genetic correlations were estimated using bivariate heritability analyses. Genetic association analysis was performed using a mixed model. Plasma adiponectin showed a heritability of 55.1%. Genetic correlations between plasma adiponectin HDL cholesterol and plasma insulin ranged from 15 to 24% but were not significant for fasting glucose, triglycerides, blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR), and C-reactive protein. A significant association with plasma adiponectin was found for ADIPOQ variants rs17300539 and rs182052. A nominally significant association was found with plasma insulin and HOMA-IR and ADIPOQ variant rs17300539 after adjustment for plasma adiponectin. The significant genetic correlation between plasma adiponectin and HDL cholesterol and plasma insulin should be taken into account in the interpretation of genome-wide association studies. Association of ADIPOQ SNPs with plasma adiponectin was replicated, and we showed association between one ADIPOQ SNP and plasma insulin and HOMA-IR.


Aqueous outflow-enhancing effect of tert-butylhydroquinone: involvement of AP-1 activation and MMP-3 expression.
To test the effect of stimulators of activator protein (AP)-1, on expression of stromelysin (MMP-3) in human TM cells and on aqueous outflow in perfused human anterior segments. Change in MMP-3 expression was determined by immunoassay of proMMP-3 levels in the media of cultured human TM cells. Anterior segments of human donor eyes with or without glaucoma were perfused with vehicle or the AP-1 stimulator tert-butylhydroquinone (tBHQ). The outflow rates or intraocular pressure (IOP), and proMMP-3 levels in the perfusate were monitored. AP-1 stimulators, such as beta-naphthoflavone, 3-methylcholanthrene, and tBHQ, significantly upregulated (2-4-fold) TM cell expression of MMP-3. The stimulatory effect of tBHQ was concentration dependent, with an EC(50) of approximately 3 micro M, and was blocked by concomitant treatment with 100 nM SR11302, which sequesters AP-1. When nonglaucomatous human eyes were perfused with tBHQ (10 micro M), both outflow rates and perfusate proMMP-3 level increased significantly within the first 24 hours. The outflow effect of tBHQ was suppressed when SR11302 (100 nM) was added in the perfusate. tBHQ also lowered the IOP by more than 40% in perfused glaucomatous eyes. An AP-1 activator, tBHQ, upregulated expression of MMP-3 in cultured human TM cells and perfused human eyes and enhanced outflow ex vivo. These effects were blocked by sequestering AP-1, suggesting that activation of AP-1 can lead to increased MMP-3 production in the TM, which in turn improves outflow facility. This unique mechanism may provide a novel therapy for glaucoma.


A unique sequence of the NZW I-E beta chain and its possible contribution to autoimmunity in the (NZB x NZW)F1 mouse.
The (NZB x NZW)F1 mouse strain develops a syndrome of accelerated autoimmunity including severe renal disease and early death. Evidence suggests that class II molecules play a central role in this process. Previous studies have suggested that the NZW strain contributes at least one gene to the development of accelerated autoimmunity that is linked to the H-2 complex, and antibodies to murine class II molecules have been used to ameliorate disease in (NZB x NZW)F1 mice. We therefore wished to sequence the class II molecules from NZW mice to identify any unique sequences that may contribute to disease development. We constructed oligonucleotide primers corresponding to the 5' and 3' regions of the second exon of class II genes from a variety of haplotypes, and used these primers in a polymerase chain reaction to sequence the second exon of the NZW I-A alpha, I-A beta, and I-E beta genes. We report that the second exons of NZW I-A alpha, I-A beta, and I-E alpha are identical to their counterparts of the previously sequenced u haplotype, and that the second exon of NZW I-E beta is identical to its counterpart from u except for a single base change that results in a substitution of arginine for threonine at amino acid 72. This base and amino acid are identical to those found at the same positions in the s haplotype.


Electro-optic single-crystalline organic waveguides and nanowires grown from the melt.
Organic nonlinear optical materials have proven to possess high and extremely fast nonlinearities compared to conventional inorganic crystals, allowing for sub-1-V driving voltages and modulation bandwidths of over 100 GHz. Compared to more widely studied poled electro-optic polymers, organic electro-optic crystals exhibit orders of magnitude better thermal and photochemical stability. The lack of available structuring techniques for organic crystals has been the major drawback for exploring their potential for photonic structures. Here we present a new approach to fabricate high-quality electro-optic single crystal waveguides and nanowires of configurationally locked polyene DAT2 (2-(3-(2-(4-dimethylaminophenyl)vinyl)-5,5-dimethylcyclohex-2-enylidene)malononitrile). The high-index-contrast waveguides (delta(n) = 0.54 +/- 0.04) are grown from the melt between two anodically bonded borosilicate glass wafers, which are structured and equipped with electrodes prior to bonding. Electro-optic phase modulation is demonstrated for the first time in the non-centrosymmetric DAT2 single crystalline channel waveguides at a wavelength of 1.55 microm. We also show that this technique in combination with DAT2 material allows for the fabrication of single-crystalline nanostructures inside large-area devices with crystal thicknesses below 30 nm and lengths of above 7 mm.


Sodium-assisted passivation of grain boundaries and defects in Cu2ZnSnSe4 thin films.
The long stagnation of the photo-conversion efficiency of kesterites below 13% is a source of frustration in the scientific community. In this study, we investigated the effects of sodium on the passivation of grain boundaries and defects in Cu2ZnSnSe4 (CZTSe) grown on a soda-lime glass (SLG) and borosilicate (BS) glass. Because BS glass does not inherently contain sodium, we placed a thin layer of NaF between CZTSe and Mo. The composition of the samples is Cu-poor and Zn-rich. The distribution of sodium and its contributions to phase formation and defects were examined by cross-sectional energy-dispersive X-ray profiling, Raman scattering spectroscopy and imaging, surface potential and photoluminescence. From the experimental results, it can be strongly claimed that sodium ions segregate predominantly near the grain boundaries and reduce CuZn-related defects. These local surface imaging analyses provided the exact locations of the secondary phases. In particular, the photo-assisted scanning probe method enabled us to observe the changes in the optoelectrical properties of the thin films and the carrier behavior within the materials. Further studies with distinct alkali ions and optimal processing conditions will pave a way to improve the performance of kesterite solar cells.


Dialectical behavior therapy for adolescents with repeated suicidal and self-harming behavior: a randomized trial.
We examined whether a shortened form of dialectical behavior therapy, dialectical behavior therapy for adolescents (DBT-A) is more effective than enhanced usual care (EUC) to reduce self-harm in adolescents. This was a randomized study of 77 adolescents with recent and repetitive self-harm treated at community child and adolescent psychiatric outpatient clinics who were randomly allocated to either DBT-A or EUC. Assessments of self-harm, suicidal ideation, depression, hopelessness, and symptoms of borderline personality disorder were made at baseline and after 9, 15, and 19 weeks (end of trial period), and frequency of hospitalizations and emergency department visits over the trial period were recorded. Treatment retention was generally good in both treatment conditions, and the use of emergency services was low. DBT-A was superior to EUC in reducing self-harm, suicidal ideation, and depressive symptoms. Effect sizes were large for treatment outcomes in patients who received DBT-A, whereas effect sizes were small for outcomes in patients receiving EUC. Total number of treatment contacts was found to be a partial mediator of the association between treatment and changes in the severity of suicidal ideation, whereas no mediation effects were found on the other outcomes or for total treatment time. DBT-A may be an effective intervention to reduce self-harm, suicidal ideation, and depression in adolescents with repetitive self-harming behavior. Clinical trial registration information-Treatment for Adolescents With Deliberate Self Harm; http://ClinicalTrials.gov/; NCT00675129.


Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29).
Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. NCT01005199.


Coverage of malaria protection in pregnant women in sub-Saharan Africa: a synthesis and analysis of national survey data.
Insecticide-treated nets and intermittent preventive treatment with sulfadoxine-pyrimethamine are recommended for the control of malaria during pregnancy in endemic areas in Africa, but there has been no analysis of coverage data at a subnational level. We aimed to synthesise data from national surveys about these interventions, accounting for disparities in malaria risk within national borders. We extracted data for specific strategies for malaria control in pregnant women from national malaria policies from endemic countries in Africa. We identified the most recent national household cluster-sample surveys recording intermittent preventive treatment with sulfadoxine-pyrimethamine and use of insecticide-treated nets. We reconciled data to subnational administrative units to construct a model to estimate the number of pregnant women covered by a recommended intervention in 2007. 45 (96%) of 47 countries surveyed had a policy for distribution of insecticide-treated nets for pregnant women; estimated coverage in 2007 was 4·7 million (17%) of 27·7 million pregnancies at risk of malaria in 32 countries with data. 39 (83%) of 47 countries surveyed had an intermittent preventive treatment policy; in 2007, an estimated 6·4 million (25%) of 25·6 million pregnant women received at least one dose of treatment and 19·8 million (77%) visited an antenatal clinic (31 countries). Estimated coverage was lowest in areas of high-intensity transmission of malaria. Despite success in a few countries, coverage of insecticide-treated nets and intermittent preventive treatment in pregnant African women is inadequate; increased efforts towards scale-up are needed. The Malaria in Pregnancy Consortium and Wellcome Trust.


Chief cells possess a receptor with high affinity for PACAP and VIP that stimulates pepsinogen release.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide of the secretin-vasoactive intestinal peptide (VIP) family. To investigate whether PACAP alters chief cell function, we prepared isolated chief cells (> 90% pure) from guinea pig stomach. PACAP-38, PACAP-27, VIP, and secretin all caused a threefold increase in pepsinogen release. The dose-response curves of PACAP-38, PACAP-27, and VIP were biphasic, whereas with secretin it was not. The first phase comprised 40% of maximal release, and each of the three peptides (PACAP-38, PACAP-27, and VIP) were equipotent (EC50 0.1-0.3 nM). For the second phase, comprising 60% of maximal release, the relative potencies were PACAP-38 > PACAP-27 = VIP. 125I-labeled secretin, 125I-VIP, and 125I-PACAP-27 all demonstrated saturable binding to chief cells. Binding of both 125I-PACAP-27 and 125I-VIP was inhibited completely and with similar potencies by PACAP-38, PACAP-27, and VIP. Secretin had a > 500-fold lower affinity than PACAP-38 for displacing both 125I-PACAP-27 and 125I-VIP. With 125I-secretin, secretin was the most potent, and was 197 times more potent than PACAP-38, which was 6-8 times more potent than both PACAP-27 and VIP. We conclude that both PACAP-38 and PACAP-27 stimulate pepsinogen secretion from dispersed chief cells. In contrast to a number of other tissues, no evidence for a high-affinity receptor that interacted only with PACAP was found. PACAP and VIP interact with equal high affinity with a common receptor and with low affinity with the secretin receptor.


Orthostatic Tremor and Orthostatic Myoclonus: Weight-bearing Hyperkinetic Disorders: A Systematic Review, New Insights, and Unresolved Questions.
Orthostatic tremor (OT) and orthostatic myoclonus (OM) are weight-bearing hyperkinetic movement disorders most commonly affecting older people that induce "shaky legs" upon standing. OT is divided into "classical" and "slow" forms based on tremor frequency. In this paper, the first joint review of OT and OM, we review the literature and compare and contrast their demographic, clinical, electrophysiological, neuroimaging, pathophysiological, and treatment characteristics. A PubMed search up to July 2016 using the phrases "orthostatic tremor," "orthostatic myoclonus," "shaky legs," and "shaky legs syndrome" was performed. OT and OM should be suspected in older patients reporting unsteadiness with prolonged standing and/or who exhibit cautious, wide-based gaits. Surface electromyography (SEMG) is necessary to verify the diagnoses. Functional neuroimaging and electrophysiology suggest the generator of classical OT lies within the cerebellothalamocortical network. For OM, and possibly slow OT, the frontal, subcortical cerebrum is the most likely origin. Clonazepam is the most useful medication for classical OT, and levetiracetam for OM, although results are often disappointing. Deep brain stimulation appears promising for classical OT. Rolling walkers reliably improve gait affected by these disorders, as both OT and OM attenuate when weight is transferred from the legs to the arms. Orthostatic hyperkinesias are likely underdiagnosed, as SEMG is often unavailable in clinical practice, and thus may be more frequent than currently recognized. The shared weight-bearing induction of OT and OM may indicate a common pathophysiology. Further research, including use of animal models, is necessary to better define the prevalence and pathophysiology of OT and OM, in order to improve their treatment, and provide additional insights into basic balance and gait mechanisms.


Issues in bioethics: ethics in health policy and guidelines in healthcare.
The development of policies in health and healthcare should incorporate ethical premises as well as thoughtful consideration of the values pertinent to the particular society and the goals to be achieved by specific policies. Social inequalities, changing values, and emergent challenges to traditional beliefs, add complexities that require a thorough analysis to compile policies that are fair and equitable. This article provides some recommendations for clinicians, health administrators, policy makers and technocrats who often grapple with complex health issues.


Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin.
Numerous studies have identified an increased risk of cancer in type 2 diabetes. We explored the association between antidiabetic therapies and cancer-related mortality in patients with type 2 diabetes, postulating that agents that increase insulin levels might promote cancer. This was a population-based cohort study using administrative databases from Saskatchewan Health. Cancer-related mortality was compared among inception cohorts of metformin users and sulfonylurea monotherapy users. Multivariate Cox regression was used to estimate the hazard ratio (HR) of cancer-related mortality, after adjusting for age, sex, insulin use, and chronic disease score. All statistical tests were two-sided. We identified 10,309 new users of metformin or sulfonylureas with an average follow-up of 5.4 +/- 1.9 years (means +/- SD). The mean age for the cohort was 63.4 +/- 13.3 years, and 55% were men. Cancer mortality over follow-up was 4.9% (162 of 3,340) for sulfonylurea monotherapy users, 3.5% (245 of 6,969) for metformin users, and 5.8% (84 of 1,443) for subjects who used insulin. After multivariate adjustment, the sulfonylurea cohort had greater cancer-related mortality compared with the metformin cohort (adjusted HR 1.3 [95% CI 1.1-1.6]; P = 0.012). Insulin use was associated with an adjusted HR of cancer-related mortality of 1.9 (95% CI 1.5-2.4; P < 0.0001). Patients with type 2 diabetes exposed to sulfonylureas and exogenous insulin had a significantly increased risk of cancer-related mortality compared with patients exposed to metformin. It is uncertain whether this increased risk is related to a deleterious effect of sulfonylurea and insulin or a protective effect of metformin or due to some unmeasured effect related to both choice of therapy and cancer risk.


Access to timely formal dementia care in Europe: protocol of the Actifcare (ACcess to Timely Formal Care) study.
Previous findings indicate that people with dementia and their informal carers experience difficulties accessing and using formal care services due to a mismatch between needs and service use. This mismatch causes overall dissatisfaction and is a waste of the scarce financial care resources. This article presents the background and methods of the Actifcare (ACcess to Timely Formal Care) project. This is a European study aiming at best-practice development in finding timely access to formal care for community-dwelling people with dementia and their informal carers. There are five main objectives: 1) Explore predisposing and enabling factors associated with the use of formal care, 2) Explore the association between the use of formal care, needs and quality of life and 3) Compare these across European countries, 4) Understand the costs and consequences of formal care services utilization in people with unmet needs, 5) Determine the major costs and quality of life drivers and their relationship with formal care services across European countries. In a longitudinal cohort study conducted in eight European countries approximately 450 people with dementia and informal carers will be assessed three times in 1 year (baseline, 6 and 12 months). In this year we will closely monitor the process of finding access to formal care. Data on service use, quality of life and needs will be collected. The results of Actifcare are expected to reveal best-practices in organizing formal care. Knowledge about enabling and predisposing factors regarding access to care services, as well as its costs and consequences, can advance the state of the art in health systems research into pathways to dementia care, in order to benefit people with dementia and their informal carers.


Quantitative imaging reveals real-time Pou5f3-Nanog complexes driving dorsoventral mesendoderm patterning in zebrafish.
Formation of the three embryonic germ layers is a fundamental developmental process that initiates differentiation. How the zebrafish pluripotency factor Pou5f3 (homologous to mammalian Oct4) drives lineage commitment is unclear. Here, we introduce fluorescence lifetime imaging microscopy and fluorescence correlation spectroscopy to assess the formation of Pou5f3 complexes with other transcription factors in real-time in gastrulating zebrafish embryos. We show, at single-cell resolution in vivo, that Pou5f3 complexes with Nanog to pattern mesendoderm differentiation at the blastula stage. Later, during gastrulation, Sox32 restricts Pou5f3-Nanog complexes to the ventrolateral mesendoderm by binding Pou5f3 or Nanog in prospective dorsal endoderm. In the ventrolateral endoderm, the Elabela / Aplnr pathway limits Sox32 levels, allowing the formation of Pou5f3-Nanog complexes and the activation of downstream BMP signaling. This quantitative model shows that a balance in the spatiotemporal distribution of Pou5f3-Nanog complexes, modulated by Sox32, regulates mesendoderm specification along the dorsoventral axis.


Metabolic effects of Crocus sativus and protective action against non-alcoholic fatty liver disease in diabetic rats.
Non-alcoholic fatty liver disease (NAFLD) is the result of the accumulation of adipose tissue deposits in the liver and it is associated with type 2 diabetes. Crocus sativus (saffron) is known for its antioxidant and its potential hypoglycemic effects. We investigated the role of saffron on NAFLD in diabetic rats. Thirty adult male rats were allocated into three groups; control (n=10), which received normal diet; streptozotocin (STZ) group (n=10), which received normal chow diet, 10% fructose in their drinking water and STZ (40 mg/kg body weight; STZ-saffron group (n=10), which followed the same dietary and pharmacological pattern as STZ group and were additionally supplemented with saffron (100 mg/kg/day). Metabolic profile was measured and histopathological examination of the liver was evaluated. STZ group exhibited the highest glucose levels at the end of the experiment (P<0.05), while there was no difference between control and STZ-saffron group (584 vs. 213 mg/dl vs. 209 mg/dl, respectively). STZ group revealed higher percentage of steatosis (5-33%) when compared to the other two groups (P<0.005). Saffron exhibits both hypoglycemic and hepatoprotective actions. Yet, further studies enlightening the exact mechanisms of saffron's mode of actions are required.


Plasma cell endometritis in women with symptomatic bacterial vaginosis.
To evaluate the endometrial microbiology and histopathology in women with symptomatic bacterial vaginosis but no signs or symptoms of upper genital tract disease or other vaginal or cervical infections. Endometrial biopsies were performed on 41 women complaining of vaginal discharge or pelvic pain at a sexually transmitted disease clinic. These women had neither culture nor serologic evidence of Neisseria gonorrhoeae or Chlamydia trachomatis infection. Twenty-two women with bacterial vaginosis diagnosed by Gram stain examination of vaginal fluid, but with neither signs nor symptoms of upper genital tract infection, were compared with 19 women who had no evidence of bacterial vaginosis on vaginal fluid Gram stain. Endometrial biopsies were evaluated for histopathologic evidence of plasma cell endometritis and were cultured for N gonorrhoeae, C trachomatis, aerobic and anaerobic bacteria, Mycoplasma species, and Ureaplasma urealyticum. Ten of 22 women with bacterial vaginosis had plasma cell endometritis, compared with one of 19 controls (odds ratio [OR] 15, 95% confidence interval [CI] 2-686; P < .01). Bacterial vaginosis-associated organisms were cultured from the endometria of nine of 11 women with and eight of 30 women without plasma cell endometritis (OR 12.4, 95% CI 2-132; P = .002). Plasma cell endometritis was frequently present in women with bacterial vaginosis and without other vaginal or cervical infections. This suggests the possibility of an association between bacterial vaginosis and nonchlamydial, nongonococcal, upper genital tract infection.


Developmental significance of D quadrant micromeres 2d and 4d in the oligochaete annelid Tubifex tubifex.
The annelidTubifex tubifex is a cosmopolitan freshwater oligochaete and a member of the Spiralia, a large group of invertebrate phyla displaying spiral development. Because its developing eggs are easily obtained in the laboratory, this animal has long been used as material for developmental studies, especially spiralian embryology. In spiralian embryos, it has long been known that one blastomere at the four-cell stage, the D cell, and its direct descendants play an important role in axial pattern formation. Various studies have suggested that the D quadrant functions as the organizer of the embryonic axes in molluscs and annelids, and it has recently been demonstrated that the D quadrant micromeres, 2d(11) and 4d, which had been transplanted to an ectopic position in an otherwise intact embryo induce a secondary embryonic axis to give rise to the formation of duplicated heads and/or tails. That 2d and 4d play a pivotal role in Tubifex embryonic development was first suggested from the classic cell-ablation experiments carried out in the early 1920s, and this has been confirmed by the recent cell-ablation/restoration experiments using cell-labeling with lineage tracers. These studies have also shown that in the operated embryos, none of the remaining cells can replace the missing 2d and 4d and that both 2d and 4d are determined as ectodermal and mesodermal precursors, respectively, at the time of their birth. The anteroposterior polarity of these micromeres is also specified at the time of their birth, suggesting that nascent 2d and 4d are specified in their axial properties as well as in cell fate decision.


A numerical study on learning curves in stochastic multilayer feedforward networks.
The universal asymptotic scaling laws proposed by Amari et al. are studied in large scale simulations using a CM5. Small stochastic multilayer feedforward networks trained with backpropagation are investigated. In the range of a large number of training patterns t, the asymptotic generalization error scales as 1/t as predicted. For a medium range t a faster 1/t2 scaling is observed. This effect is explained by using higher order corrections of the likelihood expansion. It is shown for small t that the scaling law changes drastically, when the network undergoes a transition from strong overfitting to effective learning.


Chronic allograft nephropathy score before sirolimus rescue predicts allograft function in renal transplant patients.
Chronic allograft nephropathy (CAN) is a major indication for initiation of sirolimus (SRL) in renal transplantation (TX) to prevent deterioration of renal function. We evaluated whether the CAN score at time of sirolimus rescue (SRL-R) predicts renal allograft function. CAN score is the sum of the following 4 categories: glomerulopathy (cg, 0-3), interstitial fibrosis (ci, 0-3), tubular atrophy (ct, 0-3), and vasculopathy (cv, 0-3). This is a retrospective cohort study of renal transplant recipients from July 2001 to March 2004. Immunosuppression consisted of preconditioning with rabbit anti-thymocyte globulin or alemtuzumab and maintenance with tacrolimus (TAC) monotherapy with spaced weaning, if applicable, SRL-R was achieved by conversion from TAC, or by addition to reduced doses of TAC. Ninety patients received SRL. Thirty-three of these patients met the inclusion criteria of the following: (1) receipt of SRL for >6 months, and (2) follow-up of > or =6 months. There were 16 patients in the low-CAN (0-4) group and 17 patients in the high-CAN (>4) group. Cockcroft-Gault (C-G) glomerular filtration rate (GFR) was calculated at SRL-R and at 1, 3, 6, and 12 months. The DeltaGFR was significantly better in the low-CAN group at 1, 3, and 6 months. A trend toward an improved DeltaGFR was present at 12 months in the low-CAN group (P = .16). CAN scoring at the time of SRL-R predicts recovery of renal allograft function (as measured using DeltaGFR), and should be used in preference to biochemical markers (Cr and C-G GFR), which may not be reliable predictors.


Inhibitory effects of Aristotelia chilensis water extract on 2,4-Dinitrochlorobenzene induced atopic-like dermatitis in BALB/c Mice.
Maqui berry (Aristotelia chilensis) has been reported to have anti-glycation, anti-inflammation, lipogenesis-inhibiting activities highly related to its anti-oxidation function, but practical efficacy studies on immunological mechanisms for atopic dermatitis, have not been reported yet. This study investigated the immune regulation mechanism of Aristotelia chilensis water extract (ACWE) related to atopic-like dermatitis . Antioxidant and anti-inflammatory effects of ACWE was assayed. Atopy inhibitory effect was evaluated using in vitro cell study and in vivo 2,4-dinitrochlorobenzene (DNCB)-induced mouse atopic-like dermatitis model. ACWE has good antioxidant activities, and atopic indications were improved in ACWE group in DNCB-induced atopic-like dermatitis model of BALB/c mice. In spleen cells from mice, ACWE increased interferon-gamma (IFN-γ) levels, and decreased interleukin-4 (IL-4) levels compared with the DNCB control. ACWE was efficacious for atopic dermatitis which indicates that ACWE might have potential as an agent for atopic dermatitis.


Vaccines to prevent pneumonia in children - a developing country perspective.
Pneumonia accounted for 15% of the 6.3 million deaths among children younger than five years in 2013, a total of approximately 935,000 deaths worldwide. Routine vaccination against common childhood illnesses has been identified as one of the most cost-effective strategies to prevent death from pneumonia. Vaccine-preventable or potentially preventable diseases commonly linked with respiratory tract infections include Streptococcus pneumoniae, Haemophilus influenza type-b (Hib), pertussis, influenza, measles, and tuberculosis. Although here have been great strides in the development and administration of effective vaccines, the countries that carry the largest disease burdens still struggle to vaccinate their children and newer conjugated vaccines remain out of reach for many. The Global Vaccine Action Plan (GVAP) has identified priority areas for innovation in research in all aspects of immunisation development and delivery to ensure equitable access to vaccines for all.


Envelope glycoprotein mobility on HIV-1 particles depends on the virus maturation state.
Human immunodeficiency virus type 1 (HIV-1) assembles as immature particles, which require the proteolytic cleavage of structural polyprotein Gag and the clustering of envelope glycoprotein Env for infectivity. The details of mechanisms underlying Env clustering remain unknown. Here, we determine molecular dynamics of Env on the surface of individual HIV-1 particles using scanning fluorescence correlation spectroscopy on a super-resolution STED microscope. We find that Env undergoes a maturation-induced increase in mobility, highlighting diffusion as one cause for Env clustering. This mobility increase is dependent on Gag-interacting Env tail but not on changes in viral envelope lipid order. Diffusion of Env and other envelope incorporated proteins in mature HIV-1 is two orders of magnitude slower than in the plasma membrane, indicating that HIV-1 envelope is intrinsically a low mobility environment, mainly due to its general high lipid order. Our results provide insights into dynamic properties of proteins on the surface of individual virus particles.To become infectious, HIV-1 particles undergo a maturation process involving the clustering of envelope glycoprotein Env. Here, Chojnacki et al. employ super-resolution STED-FCS microscopy to study dynamics of Env molecules on HIV-1 particles and show that Env undergoes a maturation-induced increase in mobility.


Octadecaneuropeptide, benzodiazepine ligand, -like immunoreactivity in rat central nervous system, plasma and peripheral tissues.
Using a specific radioimmunoassay we have investigated the distribution of octadecaneuropeptide (a putative endogenous ligand at the benzodiazepine receptor)-like immunoreactivity (ODN-IR) in rat brain and peripheral tissues. Highest concentrations in brain were found in the hypothalamus, cerebellum and substantia nigra. Significant concentrations of ODN-IR were found in all peripheral tissues studied and in plasma. Chromatographic analysis revealed several molecular forms; one major form, indistinguishable from the synthetic peptide, was found predominantly in peripheral tissues and in plasma, while another major form, of higher molecular weight, was found in brain, peripheral tissues and plasma. Although ODN-IR was present in the synaptosomal fraction, concentrations in the microsomal fraction were higher than for other neuropeptides studied.


Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: A report from the Marfan Treatment Trialists' Collaboration.
A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of β-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial. A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus β-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online (http://www.ctsu.ox.ac.uk/research/meta-trials).


Epidermal growth factor-like domain repeat of stabilin-2 recognizes phosphatidylserine during cell corpse clearance.
Exposure of phosphatidylserine (PS) on the cell surface occurs early during apoptosis and serves as a recognition signal for phagocytes. Clearance of apoptotic cells by a membrane PS receptor is one of the critical anti-inflammatory functions of macrophages. However, the PS binding receptors and their recognition mechanisms have not been fully investigated. Recently, we reported that stabilin-2 is a PS receptor that mediates the clearance of apoptotic cells, thus releasing the anti-inflammatory cytokine, transforming growth factor beta. In this study, we showed that epidermal growth factor (EGF)-like domain repeats (EGFrp) in stabilin-2 can directly and specifically recognize PS. The EGFrps also competitively impaired apoptotic cell uptake by macrophages in in vivo models. We also showed that calcium ions are required for stabilin-2 to mediate phagocytosis via EGFrp. Interestingly, at least four tandem repeats of EGF-like domains were required to recognize PS, and the second atypical EGF-like domain in EGFrp was critical for calcium-dependent PS recognition. Considering that PS itself is an important target molecule for both apoptotic cells and nonapoptotic cells during various cellular processes, our results should help elucidate the molecular mechanism by which apoptotic cell clearance in the human body occurs and also have implications for targeting PS externalization of nonapoptotic cells.


Aptamer-Based Proteomic Platform Identifies Novel Protein Predictors of Incident Heart Failure and Echocardiographic Traits.
We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals. We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia. Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (P<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (P<3.8×10-5; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (P<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (P=0.001). A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.


Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle.
The periodic destruction of RAG-2 at the G1-to-S transition couples V(D)J recombination to the G0 and G1 cell cycle phases and coordinates RAG-mediated DNA cleavage with DNA repair by nonhomologous end joining. To define the mechanism by which this occurs, we reproduced cell cycle-dependent regulation of the V(D)J recombinase in a cell-free system. The ubiquitin-proteasomal pathway carries out destruction of RAG-2 in lysates of S phase cells and during S phase in vivo. Remarkably, the Skp2-SCF ubiquitin ligase, which plays a central role in cell cycle regulation through the destruction of p27, mediates ubiquitylation of RAG-2 in vitro and degradation of RAG-2 in vivo. The regulation of antigen receptor gene assembly by Skp2-SCF provides an unexpected and direct mechanistic link between DNA recombination and the cell cycle.


Human papillomavirus (HPV) genotyping by HPV DNA chip in cervical cancer and precancerous lesions.
The human papillomavirus (HPV) is a well-known cause of cervical cancer. HPV tests are used as an adjunct test to decrease the false-negative rate of cytological screening. However, attempts are being made to replace the cytological screening with HPV tests. Therefore, this study was performed to examine the possibility of using HPV tests as screening test. The results of the tests that were performed at the same time including the ThinPrep cytology, the high-risk group hybrid capture II (HC-II) test, the HPV DNA chip (HD-C) test, and a punch biopsy were compared in 400 women who were referred to us due to abnormal cytology or cervicogram. The accuracy of each test was then evaluated, and the type of virus was investigated using a HD-C test. The positive predictive values detected by the high-risk group HC-II test and HD-C test according to the histological diagnosis outcomes were 56.8 and 53.8%, respectively, for cervicitis; 91.5 and 91.5%, respectively, for cervical intraepithelial neoplasia I (CIN I); 88.1% and 81.0%, respectively, for CIN II; 88.6 and 84.2%, respectively, for CIN III, and 92.5 and 88.7%, respectively, for cancer (in 53 patients). The most prevalent types of HPV according to the HPV tests were types 16, 58, 18, and 52 in which type 16 was detected in the more advanced lesions. The sensitivity was 88.4% for the ThinPrep cytology, 89.9% for the HC-II for the high-risk group, and 86.2% for the HD-C test. These results suggest the possibility of using the HC-II and HD-C tests as screening tests, which have a similar sensitivity as the ThinPrep cytology. Nonetheless, randomized controlled trials will be needed before the actual application of the HPV tests as screening tests. Despite the fact that the importance of HPV type 16 in cancer development was confirmed, the prevalence of types 58 and 52 were relatively high compared with those found in other studies, showing a need for further studies on this subject. These HPV types need to be considered in vaccine development.


Diverse sources of C. difficile infection identified on whole-genome sequencing.
It has been thought that Clostridium difficile infection is transmitted predominantly within health care settings. However, endemic spread has hampered identification of precise sources of infection and the assessment of the efficacy of interventions. From September 2007 through March 2011, we performed whole-genome sequencing on isolates obtained from all symptomatic patients with C. difficile infection identified in health care settings or in the community in Oxfordshire, United Kingdom. We compared single-nucleotide variants (SNVs) between the isolates, using C. difficile evolution rates estimated on the basis of the first and last samples obtained from each of 145 patients, with 0 to 2 SNVs expected between transmitted isolates obtained less than 124 days apart, on the basis of a 95% prediction interval. We then identified plausible epidemiologic links among genetically related cases from data on hospital admissions and community location. Of 1250 C. difficile cases that were evaluated, 1223 (98%) were successfully sequenced. In a comparison of 957 samples obtained from April 2008 through March 2011 with those obtained from September 2007 onward, a total of 333 isolates (35%) had no more than 2 SNVs from at least 1 earlier case, and 428 isolates (45%) had more than 10 SNVs from all previous cases. Reductions in incidence over time were similar in the two groups, a finding that suggests an effect of interventions targeting the transition from exposure to disease. Of the 333 patients with no more than 2 SNVs (consistent with transmission), 126 patients (38%) had close hospital contact with another patient, and 120 patients (36%) had no hospital or community contact with another patient. Distinct subtypes of infection continued to be identified throughout the study, which suggests a considerable reservoir of C. difficile. Over a 3-year period, 45% of C. difficile cases in Oxfordshire were genetically distinct from all previous cases. Genetically diverse sources, in addition to symptomatic patients, play a major part in C. difficile transmission. (Funded by the U.K. Clinical Research Collaboration Translational Infection Research Initiative and others.).


Fingerprinting rotons in a dipolar condensate: super-Poissonian peak in the atom-number fluctuations.
We demonstrate that measurements of atom-number fluctuations in a trapped dipolar condensate can reveal the presence of the elusive roton excitation. The key signature is a super-Poissonian peak in the fluctuations as the size of the measurement cell is varied, with the maximum occurring when the size is comparable to the roton wavelength. The magnitude of this roton feature is enhanced with temperature. The variation in fluctuations across the condensate demonstrates that the roton excitations are effectively confined to propagate in the densest central region, realizing a density trapped roton gas. While our main results are based on full numerical solutions of the mean-field equations, we also develop and validate a simple local density theory. Finally, we consider fluctuations measured within a washer-shaped cell which filters out the contribution of modes with nonzero angular momentum and provides a signal sensitive to individual roton modes.


Find the weakest link. A comparison between demographic, genetic and demo-genetic metapopulation extinction times.
While the ultimate causes of most species extinctions are environmental, environmental constraints have various secondary consequences on evolutionary and ecological processes. The roles of demographic, genetic mechanisms and their interactions in limiting the viabilities of species or populations have stirred much debate and remain difficult to evaluate in the absence of demography-genetics conceptual and technical framework. Here, I computed projected times to metapopulation extinction using (1) a model focusing on the effects of species properties, habitat quality, quantity and temporal variability on the time to demographic extinction; (2) a genetic model focusing on the dynamics of the drift and inbreeding loads under the same species and habitat constraints; (3) a demo-genetic model accounting for demographic-genetic processes and feedbacks. Results indicate that a given population may have a high demographic, but low genetic viability or vice versa; and whether genetic or demographic aspects will be the most limiting to overall viability depends on the constraints faced by the species (e.g., reduction of habitat quantity or quality). As a consequence, depending on metapopulation or species characteristics, incorporating genetic considerations to demographically-based viability assessments may either moderately or severely reduce the persistence time. On the other hand, purely genetically-based estimates of species viability may either underestimate (by neglecting demo-genetic interactions) or overestimate (by neglecting the demographic resilience) true viability. Unbiased assessments of the viabilities of species may only be obtained by identifying and considering the most limiting processes (i.e., demography or genetics), or, preferentially, by integrating them.


Molecular insight into Italian canine parvovirus heterogeneity and comparison with the worldwide scenario.
Canine parvovirus is one of the most frequent pathogens of young dogs, causing severe clinical manifestations. Its phenotypic variability led to an antigenic-based classification into different variants, which have been reported worldwide. To update the Italian distribution of CPV, a molecular survey was performed on 100 geographically-annotated samples collected from 2008 to 2015 by full VP2 sequencing. All three antigenic variants (CPV-2a, 2b, 2c) were detected during the studied period, being CPV-2a the most prevalent (60%). Locally, CPV appeared widely distributed, without any regional or temporal clustering, demonstrating an outstanding and uncontrolled within-country viral spreading. The Italian sequences were also contextualized in the International scenario. The analysis of CPV worldwide molecular epidemiology highlighted the remarkable genetic heterogeneity of the circulating strains and their broad distribution. In fact, a frequent viral exchange among Countries, was proven both over short and long distances, involving haplotypes persisting through time. The reported information on viral dissemination patterns appears crucial for understanding the introduction routes of new variants or strains, which could complicate the epidemiological scenario, affect the disease patterns, show possible differential virulence and clinical relevance of emerging strains especially, and impair the vaccine efficacy.