Rotational-vibrational resonance states.
Resonance states are characterized by an energy that is above the lowest dissociation threshold of the potential energy hypersurface of the system and thus resonances have finite lifetimes. All molecules possess a large number of long- and short-lived resonance (quasibound) states. A considerable number of rotational-vibrational resonance states are accessible not only via quantum-chemical computations but also by spectroscopic and scattering experiments. In a number of chemical applications, most prominently in spectroscopy and reaction dynamics, consideration of rotational-vibrational resonance states is becoming more and more common. There are different first-principles techniques to compute and rationalize rotational-vibrational resonance states: one can perform scattering calculations or one can arrive at rovibrational resonances using variational or variational-like techniques based on methods developed for determining bound eigenstates. The latter approaches can be based either on the Hermitian (L2, square integrable) or non-Hermitian (non-L2) formalisms of quantum mechanics. This Perspective reviews the basic concepts related to and the relevance of shape and Feshbach-type rotational-vibrational resonance states, discusses theoretical methods and computational tools allowing their efficient determination, and shows numerical examples from the authors' previous studies on the identification and characterization of rotational-vibrational resonances of polyatomic molecular systems.


First Report of Spruce Needle Drop Associated with Setomelanomma holmii on Spruce in Illinois.
Spruce needle drop (also known as sudden needle drop of spruce, both referred to as SNEED) is a condition consistently associated with the fungus Setomelanomma holmii. While the pathogenicity of this fungus is still under investigation, it has been reported to cause the discoloration and needle drop of older needles on white spruce (Picea glauca) and Colorado blue spruce (P. pungens) (1). In the spring and summer of 2011, the University of Illinois Plant Clinic received several samples of Norway spruce (P. abies) and Colorado blue spruce branches that all exhibited the same symptoms: browning of older needles followed by needle drop. Solitary, black, globose, 105 to 230 μm diameter pseudothecia were observed on the upper surface of the branches and bud scales with a dissecting microscope. Many of the fruiting structures contained setae. When examined under a compound microscope, asci were bitunicate, 60 to 100 × 10.5 to 15 μm (mean 71.9 × 12.7 μm), and contained eight pale brown, three-septate, 15.5 to 22.5 × 5.5 to 9 μm (mean 19.4 × 5 μm) ascospores. On the basis of the asci and ascospores, the fungus was tentatively identified as S. holmii. To confirm the identification, single-ascospore colonies were cultured on acid potato dextrose agar. DNA was extracted from the mycelia of a single colony and amplified with PCR using universal fungal primers (2). The amplified DNA was sequenced and assembled using the primers NS1, NS3, NS5, and NS7 in the forward direction and NS2, NS4, NS6, and NS8 in the reverse direction (2). When the consensus sequence was compared with all accessions in the National Center for Biotechnology Information GenBank nucleotide collection, it had 100% homology to the S. holmii 18S ribosomal gene (Accession No. AY161121, isolated from a sample of P. pungens collected in France). S. holmii was first observed in the United States in 1998 (1). Although it has been tentatively identified on the basis of morphological characteristics in many states in the Midwest, this is the first time it has been conclusively identified in Illinois to our knowledge. Additionally, this is the first time Norway spruce has been confirmed as a host of S. holmii based on genetic sequencing in Illinois. Sporulation has been observed from mid-May through early August. Currently, the presence of S. holmii has been confirmed in 14 counties in central and northern Illinois. References: (1) A. Rossman et al. Can. J. Bot. 80:1209, 2002. (2) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al. eds. Academic Press, San Diego, CA, 1990.


The emergence of porcine circovirus 2b genotype (PCV-2b) in swine in Canada.
Since late 2004, the swine industry in the province of Quebec has experienced a significant increase in death rate related to postweaning multisystemic wasting syndrome (PMWS). To explain this phenomenon, 2 hypotheses were formulated: 1) the presence of a 2nd pathogen could be exacerbating the porcine circovirus 2 (PCV-2) infection, or 2) a new and more virulent PCV-2 strain could be infecting swine. In 2005, 13 PMWS cases were submitted to the Quebec provincial diagnostic laboratory and PCV-2 was the only virus that could be found consistently by PCR in all 13 samples. The PCR detection results obtained for other viruses revealed the following: 61.5% were positive for porcine reproductive and respiratory syndrome virus, 30.8% for swine influenza virus, 15.4% for porcine parvovirus, 69.2% for swine torque teno virus (swTTV), 38.5% for swine hepatitis E virus (swHEV) and 84.6% for Mycoplasma hyorhinis; transmissible gastroenteritis virus and porcine respiratory coronavirus (TGEV/PRCV) was not detected. Sequences of the entire genome revealed that these PCV-2 strains belonged to a genotype (named PCV-2b) that has never been reported in Canada. Further sequence analyses on 83 other Canadian PCV-2 positive cases submitted to the provincial diagnostic laboratory during years 2005 and 2006 showed that 79.5% of the viral sequences obtained clustered in the PCV-2b genotype. The appearance of the PCV-2b genotype in Canada may explain the death rate increase related to PMWS, but this relationship has to be confirmed.


Ventral striatal dopamine reflects behavioral and neural signatures of model-based control during sequential decision making.
Dual system theories suggest that behavioral control is parsed between a deliberative "model-based" and a more reflexive "model-free" system. A balance of control exerted by these systems is thought to be related to dopamine neurotransmission. However, in the absence of direct measures of human dopamine, it remains unknown whether this reflects a quantitative relation with dopamine either in the striatum or other brain areas. Using a sequential decision task performed during functional magnetic resonance imaging, combined with striatal measures of dopamine using [(18)F]DOPA positron emission tomography, we show that higher presynaptic ventral striatal dopamine levels were associated with a behavioral bias toward more model-based control. Higher presynaptic dopamine in ventral striatum was associated with greater coding of model-based signatures in lateral prefrontal cortex and diminished coding of model-free prediction errors in ventral striatum. Thus, interindividual variability in ventral striatal presynaptic dopamine reflects a balance in the behavioral expression and the neural signatures of model-free and model-based control. Our data provide a novel perspective on how alterations in presynaptic dopamine levels might be accompanied by a disruption of behavioral control as observed in aging or neuropsychiatric diseases such as schizophrenia and addiction.


Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study.
To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome. Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles. General medicine community clinics. 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days. Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles. Main efficacy variable: change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms). Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment. Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.


A longitudinal study of students' depression at one medical school.
Using a standardized measure of depression at three assessment points, to examine depression in medical students during their training. Students entering the University of Massachusetts Medical School in the fall in 1987, 1988, and 1989 were mailed a recruitment letter and baseline questionnaire four weeks prior to the start of classes. Subsequent assessments took place in the middles of year 2 and year 4 and included only the students who had participated in the baseline assessment. The baseline assessment included the Center for Epidemiological Studies Depression (CES-D) scale, the Bortner Type A Behavior scale, the Spielberger Trait Anger scale, and the Spielberger Anger Expression scale. In addition, the baseline package included a rating of perceived stress, a demographics questionnaire, and a social-life survey. The follow-up assessments included the CES-D scale, the rating of perceived stress level, and the social-life survey. Analytic methods used were univariate descriptive statistics, correlation, and multiple-linear-regression analyses, two-sample t-tests, analysis of variance, and chi-square tests. Of the initial pool of 300 students, 264 responded at the baseline assessment (88% response rate; 53% men); 171 of these participated in the year-2 assessment (65% response rate; 51% men), and 126 participated in the year-4 assessment (48% response rate; 48% men); a total of 99 students participated in all three assessments. CES-D scores > or =80th percentile were obtained for 18% of the entering students. This rose to 39% at year 2 and 31% at year 4 (p = .0001). No gender difference was found at baseline; however, the women experienced higher depression levels than did the men at year 2 (p = .004) and at year 4 (p = .04). Overall, gender and increases in perceived stress (from baseline to year 2) were significant predictors of increased CES-D scores (from baseline to year 2; p = .01 and p = .0001, respectively). For the women, increased perceived stress, angerin, and frequency of social contacts outside work/school were significant predictors of the magnitude of increases in CES-D scores (baseline to year 2; p = .0001, p = .02, and p = .03, respectively). These preliminary data support the view that, upon entering medical school, students' emotional status resembles that of the general population. However, the rise in depression scores and their persistence over time suggest that emotional distress during medical school is chronic and persistent rather than episodic. Also, the women had more significant increases in depression scores than did the men.


A comparison between six- and four-week intervals in surveillance of oral anticoagulant treatment.
We determined whether international normalized ratio (INR) monitoring at 6 weeks rather than 4 weeks would benefit patients and reduce costs. Patients receiving stable oral anticoagulation treatment (target INR, 3.0) with a prosthetic mechanical heart valve for more than 6 months were randomized for a maximum interval between INR determinations of 6 weeks (group 1, n = 59) or 4 weeks (group 2 [control], n = 65). Patients were followed up for 2 years. The primary end point of the study was the biologic risk of overanticoagulation or underanticoagulation, estimated as the rate of values at risk (INR, < 1.5 and > 5). The rates of INR values at risk for hemorrhagic (INR, > 5) or thromboembolic (INR, < 1.5) complications were 3.27% in group 1 and 3.09% in group 2 (P = .81). The INRs of patients in group 1 trended toward higher values, but no difference between groups was observed in time spent at various INR ranges by using the method of linear change. The mean time between INR determinations was 24.9 +/- 18.1 days (1.20 per month) in group 1 and 22.5 +/- 9.5 days (1.33 per month) in group 2 (P < .0003). For patients in stable condition with a prosthetic heart valve who are monitored at an anticoagulation clinic, a 6-week interval between INR determinations does not increase the biologic risk of thromboembolic or hemorrhagic events.


Influence of interfacial rheology on drainage from curved surfaces.
Thin lubrication flows accompanying drainage from curved surfaces surround us (e.g., the drainage of the tear film on our eyes). These draining aqueous layers are normally covered with surface-active molecules that render the free surface viscoelastic. The non-Newtonian character of these surfaces fundamentally alters the dynamics of drainage. We show that increased film stability during drainage can occur as a consequence of enhanced surface rheology. Increasing the surfactant layer viscosity decreases the rate of drainage; however, this retarding influence is most pronounced when the insoluble surfactant layer has significant elasticity. We also present a simple theoretical model that offers qualitative support to our experimental findings.


Targeting NF-κB/AP-2β signaling to enhance antitumor activity of cisplatin by melatonin in hepatocellular carcinoma cells.
Cisplatin is a common chemotherapeutic drug for cancer treatment, but its effect is limited because of its cytotoxicity and chemoresistance. The combinational use of cisplatin with some natural compounds has provided a potential option to improve its effect and lower its side effects in cancer treatment. Here, we investigated the role of melatonin in the regulation of cisplatin-mediated antitumor activity in hepatocellular carcinoma cells. The combined treatment of cisplatin with melatonin significantly inhibited cell proliferation and resulted in a corresponding decrease of the IC50 values of cisplatin in four hepatocellular carcinoma cell lines. Cotreatment with melatonin also increased the cisplatin-induced apoptosis in hepatocellular carcinoma cells compared with cisplatin treatment alone. Further mechanism studies showed that the combined treatment of melatonin and cisplatin enhanced the cleavage of caspase-3, caspase-9 and poly-(ADP-ribose) polymerase (PARP), decreased the expression of Bcl-2 and p-IKKα/β, suppressed the nuclear translocation of NF-κB p50/p65 proteins, and abrogated the binding of p65 to COX-2 promoter, thereby inhibiting COX-2 expression. Furthermore, melatonin was found to synergistically enhance cisplatin-mediated inhibition of AP-2β and hTERT expression. Overexpression of AP-2β reversely rescued this inhibition mediated by the combined treatment of these two drugs. Collectively, our results demonstrated that melatonin sensitizes the cisplatin-mediated growth suppression of cells via the inactivation of NF-κB/COX-2 and AP-2β/hTERT signaling in hepatocellular carcinoma cells.


Cost-effectiveness Analysis of Denosumab in the Prevention of Skeletal-related Events in Patients with Prostate Cancer in Kazakhstan.
Bone mass loss (BML) is one of the adverse effects of oncological chemotherapy, especially in cases of hormonal types of cancer, such as a prostate cancer (PC). BML is strongly associated with skeletal-related events (SREs), therefore decreasing the quality of patient's life. Denosumab shows an advantage over zoledronic acid (ZA) in delaying the first onset of SREs and subsequent SREs in adults with PC in several phase III clinical trials. Since generic ZA recently became available, the purpose of the present study was to assess the cost-effectiveness of denosumab vs. brand or generic ZA in the prevention of SREs in Kazakhstani patients with PC. A Markov model was constructed in Tree-Age Pro 2013 software program with 4-week model cycles to analyze the cost-effectiveness of the treatments from the perspective of Ministry of Health (MoH) over a 10-year PC cohort. Direct costs (in Kazakhstani monetary units "tenge" in 2014) included costs of drug, SRE (pathologic fracture, surgery to bone, radiation to bone, spinal cord compression), and adverse events treatment. All costs were discounted for 3% per year. Effectiveness was appraised based on the number of SREs. Health states were defined according to SRE occurrence, SRE history, and death. The model assumed that a maximum of 1 SRE could occur in each cycle. Transition probabilities were derived from the relevant phase III trials. Results were present in the incremental total cost per SRE avoided. One-way sensitivity analyses were performed to examine the robustness of the model. Over the 10-year period, denosumab incurred 103,091 tenge higher costs than brand ZA, 677,133 tenge higher costs than generic ZA, and 0.58 fewer SREs per patient with PC. The estimated incremental total direct costs per SRE avoided with the use of denosumab were 177,743 tenge (instead of brand ZA) and 1,167,470 tenge (instead of generic ZA). Results were robust to one-way sensitivity analyses. With the assumption that brand and generic ZAs are equally effective in the prevention of SREs in PC patients, denosumab seems to be a cost-effective alternative for brand ZA (insignificant difference in costs - less than 5%) and a costly alternative for generic ZA from the perspective of MoH of Kazakhstan.


Energetics of nestling growth and parental effort in Antarctic fulmarine petrels.
Antarctic fulmarine petrels breed in some of the coldest conditions encountered by any bird and their young grow twice as fast as predicted allometrically. To examine the energetic consequences of fast growth in a cold environment, we used the doubly labeled water technique to measure field metabolic rates of adults (three species) and different-aged nestlings (four species) of Antarctic fulmarine petrels in the Rauer Islands, East Antarctica: Antarctic fulmar Fulmarus glacialoides, Antarctic petrel Thalassoica antarctica, Cape petrel Daption capense and snow petrel Pagodroma nivea. We used our data to assess parental effort and, together with literature values on nestling growth and resting metabolic rate, to construct and partition nestling energy budgets. Nestling total energy expenditure and peak daily metabolic rate were significantly higher than predicted allometrically (33-73% and 17-66% higher, respectively), and the relative cost of growth in nestling petrels was among the highest reported for birds (54-72 kJ g(-1)). Parental effort during the nestling-feeding period was identical in adult Cape and Antarctic petrels (3.5 times basal metabolic rate, BMR), and was somewhat (but not significantly) higher in snow petrels (4.6 times BMR). These values are comparable to those of other high-latitude procellariiform birds. Thus, despite the constraints of a compressed breeding season, cold temperatures and fast-growing nestlings, adult Antarctic fulmarine petrels do not work harder than procellariid adults whose chicks grow much more slowly. Our findings suggest that obtaining sufficient food is generally not a constraint for adult fulmarine petrels and that factors operating at the tissue level limit nestling growth rate.


Kinesin and dynein superfamily proteins and the mechanism of organelle transport.
Cells transport and sort proteins and lipids, after their synthesis, to various destinations at appropriate velocities in membranous organelles and protein complexes. Intracellular transport is thus fundamental to cellular morphogenesis and functioning. Microtubules serve as a rail on which motor proteins, such as kinesin and dynein superfamily proteins, convey their cargoes. This review focuses on the molecular mechanism of organelle transport in cells and describes kinesin and dynein superfamily proteins.


Estimating prevalence, incidence, and disease-related mortality for patients with epilepsy in managed care organizations.
The purpose of the present study was to apply computer algorithms to an administrative data set to identify the prevalence of epilepsy, incidence of epilepsy, and epilepsy-related mortality of patients in a managed care organization (MCO). The study population consisted of members enrolled in Lovelace Health Plan, a component of Lovelace Health Systems, a statewide MCO headquartered in Albuquerque, New Mexico. Patient records were obtained from July 1996 to June 2001. Four logistic regression models with high sensitivity and specificity were applied to 1-, 3-, and 5-year time frames in which members were continuously enrolled in the MCO. Incidence was defined for patients who did not have an epilepsy-associated code in the 18 months before the first diagnosis entry. Mortality estimates in the population also were assessed by using a matched control group and linkage to a statewide death registry. The data yielded estimated prevalence rates of 7-10 per 1,000, depending on age, sex, ethnicity, and time interval. Annualized incidence was 47 per 100,000 for members continuously enrolled for 3 years and 71 per 100,000 for members continuously enrolled for 5 years. Crude mortality rates were 2-2.5 times higher for epilepsy patients identified with the algorithms than for the matched controls. Conditional logistic regression indicated that the odds of death for epilepsy patients as compared with controls ranged from 1.24 to 2.06. Accurate estimation of prevalence, incidence, and mortality rates for epilepsy is an essential component of disease management in MCOs. The algorithms in this project can be used to monitor trends in prevalence, incidence, and mortality to inform decisions critical to improving the health care needs and quality of life for patients with epilepsy.


The impact of polyphenols on chondrocyte growth and survival: a preliminary report.
Imbalances in the functional binding of fibroblast growth factors (FGFs) to their receptors (FGFRs) have consequences for cell proliferation and differentiation that in chondrocytes may lead to degraded cartilage. The toxic, proinflammatory, and oxidative response of cytokines and FGFs can be mitigated by dietary polyphenols. We explored the possible effects of polyphenols in the management of osteoarticular diseases using a model based on the transduction of a mutated human FGFR3 (G380R) in murine chondrocytes. This mutation is present in most cases of skeletal dysplasia and is responsible for the overexpression of FGFR3 that, in the presence of its ligand, FGF9, results in toxic effects leading to altered cellular growth. Different combinations of dietary polyphenols derived from plant extracts were assayed in FGFR3 (G380R) mutated murine chondrocytes, exploring cell survival, chloride efflux, extracellular matrix (ECM) generation, and grade of activation of mitogen-activated protein kinases. Bioactive compounds from Hibiscus sabdariffa reversed the toxic effects of FGF9 and restored normal growth, suggesting a probable translation to clinical requests in humans. Indeed, these compounds activated the intracellular chloride efflux, increased ECM generation, and stimulated cell proliferation. The inhibition of mitogen-activated protein kinase phosphorylation was interpreted as the main mechanism governing these beneficial effects. These findings support the rationale behind the encouragement of the development of drugs that repress the overexpression of FGFRs and suggest the dietary incorporation of supplementary nutrients in the management of degraded cartilage.


A brief report: the use of high-frequency oscillatory ventilation for severe pulmonary contusion.
Severe pulmonary contusions are a common cause of acute respiratory distress syndrome (ARDS) and are associated with significant morbidity. High frequency oscillatory ventilation (HFOV) is a ventilatory mode that employs a lung protective strategy consistent with the ARDSNet low tidal volume ventilation strategy and may result in reduced morbidity. The objective of this report is to examine the impact of HFOV on blunt trauma patients with severe pulmonary contusions who failed or were at a high risk of failing conventional mechanical ventilation. We undertook a retrospective chart review of all patients at our institution who received HFOV for severe pulmonary contusions. Patients were placed on HFOV when their mean airway pressure (mP(aw)) surpassed 30 cm H2O and their FIO2 was greater than 0.6. Baseline demographic data including injury severity score (ISS), length of time requiring HFOV, total ventilator days, and inhospital mortality were collected. Serial determinations of oxygenation index (OI) and the PaO2/FIO2 ratio (P/F) were made up to 72 hours after initiation of HFOV. A linear mixed model was used to analyze the slope (beta) of the regression line of P/F versus time and that of OI versus time. Seventeen patients were identified who underwent HFOV for ARDS due primarily to pulmonary contusions. Mean ISS was 36.6, mean APACHE II score was 21.7, and the mean time before initiation of HFOV was 2.0 days. P/F increased significantly after HFOV was initiated (beta = 12.1; 95% confidence interval 7.9 to 16.4, p < 0.001). OI significantly decreased after HFOV implementation (beta = -1.8; 95% confidence interval -2.3 to -1.3, p < 0.001). Mortality rate was 17.6%. The early use of HFOV appears to be safe and efficacious in blunt trauma patients sustaining pulmonary contusions, and results in a rapid improvement in OI and the P/F ratio.


Variability of Myocardial Strain During Isometric Exercise in Subjects With and Without Heart Failure.
Background: Fast strain-encoded cardiac magnetic resonance imaging (cMRI, fast-SENC) is a novel technology potentially improving characterization of heart failure (HF) patients by quantifying cardiac strain. We sought to describe the impact of isometric handgrip exercise (HG) on cardiac strain assessed by fast-SENC in HF patients and controls. Methods: Patients with stable HF and controls were examined using cMRI at rest and during HG. Left ventricular (LV) global longitudinal strain (GLS) and global circumferential (GCS) were derived from image analysis software using fast-SENC. Strain change < -0.5 and > +0.5 was classified as increase and decrease, respectively. Results: The study population comprised 72 subjects, including HF with reduced, mid-range and preserved ejection fraction and controls (HFrEF n = 18 HFmrEF n = 18, HFpEF n = 17, controls: n = 19). In controls, LV GLS remained stable in 36.8%, increased in 36.8% and decreased in 26.3% of subjects during HG. In HF subgroups, similar patterns of LV GLS response were observed (HFpEF: stable 41.2%, increase 35.3%, decrease: 23.5%; HFmrEF: stable 50.0%, increase 16.7%, decrease: 33.3%; HFrEF: stable 33.3%, increase 22.2%, decrease: 44.4%, p = 0.668). Mean change between LV GLS at rest and during HG ranged close to zero with broad standard deviation in all subgroups and was not significantly different between subgroups (+1.2 ± 5.4%, -0.6 ± 8.3%, -1.7 ± 10.7%, and -3.1 ± 19.4%, p = 0.746 in controls, HFpEF, HFmrEF and HFrEF, respectively). However, the absolute value of LV GLS change-irrespective of increase or decrease-was significantly different between subgroups with 4.4 ± 3.2% in controls, 5.9 ± 5.7% in HFpEF, 6.8 ± 8.3% in HFmrEF and 14.1 ± 13.3% in HFrEF (p = 0.005). The absolute value of LV GLS change significantly correlated with resting LVEF, NTproBNP and Minnesota Living with Heart Failure questionnaire scores. Conclusion: The response to isometric exercise in LV GLS is heterogeneous in all HF subgroups and in controls. The absolute value of LV GLS change during HG exercise is elevated in HF patients and associated with measures of HF severity. The diagnostic utility of fast-SENC strain assessment in conjunction with HG appears to be limited. Trial Registration: URL: https://www.drks.de; Unique Identifier: DRKS00015615.


Clinically applicable deep learning for diagnosis and referral in retinal disease.
The volume and complexity of diagnostic imaging is increasing at a pace faster than the availability of human expertise to interpret it. Artificial intelligence has shown great promise in classifying two-dimensional photographs of some common diseases and typically relies on databases of millions of annotated images. Until now, the challenge of reaching the performance of expert clinicians in a real-world clinical pathway with three-dimensional diagnostic scans has remained unsolved. Here, we apply a novel deep learning architecture to a clinically heterogeneous set of three-dimensional optical coherence tomography scans from patients referred to a major eye hospital. We demonstrate performance in making a referral recommendation that reaches or exceeds that of experts on a range of sight-threatening retinal diseases after training on only 14,884 scans. Moreover, we demonstrate that the tissue segmentations produced by our architecture act as a device-independent representation; referral accuracy is maintained when using tissue segmentations from a different type of device. Our work removes previous barriers to wider clinical use without prohibitive training data requirements across multiple pathologies in a real-world setting.


Effects of Temperature on Development of Lymantria dispar asiatica and Lymantria dispar japonica (Lepidoptera: Erebidae).
Periodic introductions of the Asian subspecies of gypsy moth, Lymantria dispar asiatica Vnukovskij and Lymantria dispar japonica Motschulsky, in North America are threatening forests and interrupting foreign trade. Although Asian gypsy moth has similar morphology to that of European and North American gypsy moth, it has several traits that make it a greater threat, the most important being the flight capability of females. Asian gypsy moth is not yet established in North America; however, infestations have been detected multiple times in Canada and the United States. To facilitate detection and eradication efforts, we evaluated the effect of a range of temperatures on development time, survivorship, and fertility of eight populations of Asian gypsy moth. There were significant impacts of temperature and population on these life history characteristics. The larval developmental rate increased with temperature until it reached an optimum at 29 °C. Larvae experienced significant molting problems at the highest and lowest temperatures tested (10 °C and 30 °C). At 30 °C, female fitness was markedly compromised, as evidenced by reduced fecundity and fertility. This suggests that development and survival of Asian gypsy moth may be limited by summer temperature extremes in the Southern United States. We also determined the degree-day requirements for two critical life stages and two populations of Asian gypsy moth, which represent the extremes in latitude, to predict the timing for biopesticide application and adult trap deployment. Our data will benefit pest managers in developing management strategies, pest risk assessments, and timing for implementation of management tactics.


Identification of a novel lytic peptide for the treatment of solid tumours.
Originally known as host defence peptides for their substantial bacteriotoxic effects, many cationic antimicrobial peptides also exhibit a potent cytotoxic activity against cancer cells. Their mode of action is characterized mostly by electrostatic interactions with the plasma membrane, leading to membrane disruption and rapid necrotic cell death. In this work, we have designed a novel cationic peptide of 27 amino acids (Cypep-1), which shows efficacy against a number of cancer cell types, both in vitro and in vivo, while normal human fibroblasts were significantly less affected. Surface plasmon resonance experiments as well as liposome leakage assays monitored by fluorescence spectroscopy revealed a substantial binding affinity of Cypep-1 to negatively charged liposomes and induced significant leakage of liposome content after exposure to the peptide. The observed membranolytic effect of Cypep-1 was confirmed by scanning electron microscopy (SEM) as well as by time-lapse confocal microscopy. Pharmacokinetic profiling of Cypep-1 in rats showed a short plasma half-life after i.v. injection, followed mainly by retention in the liver, spleen and kidneys. Extremely low concentrations within the organs of the central nervous system indicated that Cypep-1 did not pass the blood-brain-barrier. Local treatment of 4T1 murine mammary carcinoma allografts by means of a single local bolus injection of Cypep-1 led to a significant reduction of tumour growth in the following weeks and prolonged survival. Detailed histological analysis of the treated tumours revealed large areas of necrosis. In sum, our findings show that the novel cationic peptide Cypep-1 displays a strong cytolytic activity against cancer cells both in vitro and in vivo and thus holds a substantial therapeutic potential.


RRAS: A key regulator and an important prognostic biomarker in biliary atresia.
To characterize the differentially expressed gene profiles in livers from biliary atresia (BA) patients including, ascertain genes, functional categories and pathways that play a central role in the pathogenesis of BA, and identify the novel prognostic markers for BA. Liver tissue samples from control patients, neonatal cholestasis patients, and BA patients at the age of < 60 d, 60-90 d, and > 90 d were pooled for DNA microarray analysis. Bioinformatics analysis was performed using, series test cluster of gene ontology, and Pathway-Finder software. Reverse-transcription polymerase chain reaction was performed to confirm changes in selected genes. Relation between RRAS gene expression and prognosis of 40 BA patients was analyzed in a 2-year follow-up study. The 4 identified significant gene expression profiles could confidently separate BA liver tissue from normal and other diseased liver tissues. The included genes were mainly involved in inflammation response and reconstruction of cellular matrix. The significant pathways associated with BA were primarily involved in autoimmune response, activation of T lymphocytes and its related cytokines. The RRAS, POMC, SLC26A6 and STX3 genes were important regulatory modules in pathogenesis of BA. The expression of RRAS was negatively correlated with the elimination rate of jaundice and positively correlated with the occurrence rate of cholangitis. Autoimmune response mediated by T lymphocytes may play a vital role in the pathogenesis of BA. The RRAS gene is an important regulatory module in the pathogenesis of BA, which may serve as a novel prognostic marker for BA.


Chemical coupling of a monoclonal antisurfactant protein-B antibody to human urokinase for targeting surfactant-incorporating alveolar fibrin.
Intraalveolar fibrin formation is a common histopathological finding in acute inflammatory and chronic interstitial lung diseases. Incorporation of hydrophobic surfactant components into polymerizing fibrin results in a severe loss of surface activity, altered mechanical and structural clot properties, and a reduced susceptibility toward fibrinolytic degradation. Such events have been implicated in atelectasis formation, impairment of gas exchange, and provocation of fibroproliferative changes. In an effort to address the unique features of alveolar fibrin, we designed a hybrid molecule consisting of a monoclonal antibody against surfactant protein SP-B (8B5E) and the catalytic domain of urokinase (B-chain), which was termed MABUC. The urokinase B-chain was prepared by limited reduction of human two-chain-urokinase and subsequent affinity purification and coupled to the antibody using a heterobifunctional cross-linker. Purification of the chimeric protein included gel filtration chromatography and affinity chromatography. An ELISA-like microtiter plate assay, based on the immunological detection of the SP-B moiety and the fibrinolytic activity of the u-PA domain, was developed for the detection of the hybrid molecule. Chromogenic substrate assays, (125)I-based fibrin plate assays, and active site titration were performed to analyze the specific fibrinolytic activity of the conjugate. MABUC was found to fully retain the ability of SP-B binding and the fibrinolytic activity of u-PA. In addition, MABUC was noted to be 1.5-2-fold more effective in the dissolution of surfactant embedding clots and to be approximately 3-fold more resistant against PAI-1, the predominant fibrinolysis inhibitor in the alveolar compartment, as compared to the native u-PA. The superiority of MABUC was particularly prominent (>5-fold efficacy) when investigating clot material incorporating both PAI-1 and surfactant, as a mimicry of alveolar fibrin. We conclude that urokinase and 8B5E can be cross-linked chemically, thus yielding a fibrinolytic enzyme with enhanced substrate specifity for surfactant-containing clots and higher PAI-1 resistance as compared to native u-PA.


Effectiveness of strengthened stimulation during acupuncture for the treatment of allergic rhinitis: study protocol for a randomized controlled trial.
The traditional Chinese theory of acupuncture emphasizes that the intensity of acupuncture must reach a threshold to generate de qi (a specific and compound sensation during the acupuncture), which is necessary to achieve the best therapeutic effect. However, the notion that de qi must be achieved for maximum benefit has not been confirmed by modern scientific evidence. This study aims to compare the efficacy of acupuncture with either strong (intended to elicit de qi) or weak stimulation among patients with allergic rhinitis. This study compares real versus sham acupuncture in 140 patients with a history of persistent allergic rhinitis (PER) or intermittent allergic rhinitis (IAR) and with a positive skin prick test (SPT). The trial will be conducted in the Teaching Hospital of Chengdu University of Traditional Chinese Medicine (China). In the study, patients will be randomly assigned into two groups by computer-generated randomization and assessed prior to treatment. They will then receive 12 sessions of treatments for 4 consecutive weeks and have a follow-up phase lasting 12 weeks. The main outcome measures include the primary and secondary indicators. Primary indicators are subjective symptoms scores as evaluated by visual analogue scales (VAS), rhinoconjunctivitis quality of life questionnaires (RQLQ), and the Modified Massachusetts General Hospital acupuncture sensation scale, Chinese version (C-MMASS). The secondary indicators are the results of laboratory examinations, such as serum allergen-specific immunoglobulin E (sIgE) nasal inflammatory cells counts (mast cells, eosinophils, and T cells), and nitric oxide concentration in nasal excretion. The use of anti-allergic medication will also be recorded as one of the secondary indicators. Furthermore, adverse events will be recorded and analyzed. Intention-to-treat analysis (ITT) and per-protocol (PP) analysis will be performed to test and verify the results in this trial. The results of this trial will demonstrate the efficacy of using acupuncture to treat allergic rhinitis and verify whether the effectiveness of acupuncture is related to the needle sensation de qi. Chinese Clinical Trial Registry: ChiCTR-TRC-13003594 (registered on 16 August 2013, and the first patient was randomized on 27 September 2013).


Proximal femoral allografting in revision total hip arthroplasty: stabilization of the host-graft junction with tension band fixation.
Large deficiencies of the metaphysis and proximal diaphysis present a significant challenge to the orthopaedic surgeon undertaking revision of failed total hip arthroplasty. Proximal femoral allograft-prosthetic reconstruction may enable revision in such situations. Secure fixation is essential to successful integration and function of these allograft-prosthetic constructs. We report our experience in 7 revision total hip arthroplasties in 5 patients. Proximal femoral allograft-prosthetic reconstruction was undertaken on all 7 hips using a technique of tension band fixation for securely fixing allograft to host bone at their interface to further minimize motion at the junction site and maximize union. Radiographic evidence of union at the interface was noted in 6 of 7 hips. Mean Harris hip score increased from 18 preoperatively to 83 postoperatively, with a mean follow-up of 78 months (range, 56-116 months).


Growth and lipid class composition of the Arctic pelagic amphipod Themisto libellula.
Carnivorous zooplankton is a key element to the energy transfer through the arctic food web, linking lipid rich herbivores to the top predators. We investigated the growth and lipid dynamic of the Arctic pelagic amphipod Themisto libellula in Kongsfjorden (Svalbard, 79°N) from May to October 2007. Additional samplings were performed in spring and summer 2006 and further north in Rijpfjorden (80°N), in September 2006 and 2007. In Kongsfjorden, the first free-swimming stages (3 mm) appeared early May and reached their adult length (25 mm), in October. During their first year, they grew according to a Von Bertalanffy model and most probably constituted a single cohort. Juveniles had the highest growth rate (0.19 mm day-1) and revealed relatively low total lipid (TL) content (about 2.5% wet weight (WW)) with phospholipids as the major lipid class. Sub-adults showed a distinct decrease of growth rates which coincided with the increase of neutral lipid storage, reflecting a switch in energy allocation, from somatic growth to lipid storage. Indeed wax esters (WE) increased up to 48.5% TL on average in adults in 2006 while triacylglycerols (TAG) remained almost constant below 25.2% TL. The absence of lipid accumulation (in disproportion of the weight) in 2007 could be explained by a higher metabolism of T. libellula or preys of lower quality. In Rijpfjorden, adults in their second year continued accumulating lipid (up to 10% WW) with high and similar proportions of both lipid classes, WE and TAG. We highlighted that T. libellula exhibited a variable lipid metabolism along its life cycle depending on its physiological needs and environmental conditions.


Optogenetics in the teaching laboratory: using channelrhodopsin-2 to study the neural basis of behavior and synaptic physiology in Drosophila.
Here we incorporate recent advances in Drosophila neurogenetics and "optogenetics" into neuroscience laboratory exercises. We used the light-activated ion channel channelrhodopsin-2 (ChR2) and tissue-specific genetic expression techniques to study the neural basis of behavior in Drosophila larvae. We designed and implemented exercises using inexpensive, easy-to-use systems for delivering blue light pulses with fine temporal control. Students first examined the behavioral effects of activating glutamatergic neurons in Drosophila larvae and then recorded excitatory junctional potentials (EJPs) mediated by ChR2 activation at the larval neuromuscular junction (NMJ). Comparison of electrically and light-evoked EJPs demonstrates that the amplitudes and time courses of light-evoked EJPs are not significantly different from those generated by electrical nerve stimulation. These exercises introduce students to new genetic technology for remotely manipulating neural activity, and they simplify the process of recording EJPs at the Drosophila larval NMJ. Relatively little research work has been done using ChR2 in Drosophila, so students have opportunities to test novel hypotheses and make tangible contributions to the scientific record. Qualitative and quantitative assessment of student experiences suggest that these exercises help convey principles of synaptic transmission while also promoting integrative and inquiry-based studies of genetics, cellular physiology, and animal behavior.


ACE gene insertion/deletion polymorphism in childhood idiopathic nephrotic syndrome.
The aim of this study was to determine the distribution of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, and its effects on clinical, laboratory, histological findings, treatment responses and progression to end-stage renal disease in childhood idiopathic nephrotic syndrome (NS). 227 children diagnosed with idiopathic NS were included in the study. Eighty-three of patients were steroid resistant and 77 of patients were focal segmental glomerulosclerosis. The control group was consisted of 287 unrelated healthy adult volunteers. ACE gene I/D polymorphism were analyzed by using PCR based method. In the entire group of children with NS, the frequencies of the II, ID, and DD genotypes of ACE gene were 13.7%, 38.3% and 48%, respectively. D allele frequency was higher in NS group than control group (0.67 vs. 0.56, p=0.001). Percentage of frequent relapser patients was found more frequently in ID or DD genotype (38.7%) than II genotype (15%) when only steroid sensitive patients were evaluated (p=0.045). The D-allele frequency was 0.65, 0.69 and 0.68 respectively in focal segmental glomerulosclerosis, biopsy proven minimal change and entire minimal change group (p>0.05) and 0.69 and 0.64 respectively in steroid sensitive and resistant groups (p>0.05). D allele frequency was not significantly different in patients with or without end-stage renal disease (0.64 vs. 0.67 respectively, p>0.005) when 115 patients who were at least five year follow-up were evaluated. The D allele frequency was higher in NS patients than healthy controls and DD or ID genotype was related with frequent relapses. ACE gene I/D polymorphism was not important in laboratory and histological findings and progression of the disease in children with NS.


Modeling of the near to far acoustic fields of an echolocating bottlenose dolphin and harbor porpoise.
Echolocation signals emitted by odontocetes can be roughly classified into three broad categories: broadband echolocation signals, narrowband high-frequency echolocation signals, and frequency modulated clicks. Previous measurements of broadband echolocation signal propagation in the bottlenose dolphin (Tursiops truncatus) did not find any evidence of focusing as the signals travel from the near-field to far-field. Finite element analysis (FEA) of high-resolution computed tomography scan data was used to examine signal propagation of broadband echolocation signals of dolphins and narrowband echolocation signals of porpoises. The FEA results were used to simulate the propagation of clicks from phonic lips, traveling through the forehead, and finally transmission into the water. Biosonar beam formation in the near-field and far-field, including the amplitude contours for the two species, was determined. The finite element model result for the simulated amplitude contour in the horizontal plane was consistent with prior direct measurement results for Tursiops, validating the model. Furthermore, the simulated far-field transmission beam patterns in both the vertical and horizontal planes were also qualitatively consistent with results measured from live animals. This study indicates that there is no evidence of convergence for either Tursiops or Phocoena as the sound propagates from the near-field to the far-field.


Evidence for the role of endogenous carbon monoxide in memory processing.
For a decade and a half, nitric oxide (NO) has been implicated in memory processing across a wide variety of tasks and species. Comparatively, endogenously produced carbon monoxide (CO) has lagged behind as a target for research into the pharmacological processes underlying memory formation. This is surprising given that CO is formed in memory-associated brain regions, is structurally similar to NO, and along with NO can activate guanylate cyclase, which is an enzyme well characterized in memory processing. Nevertheless, a limited number of electrophysiological investigations have concluded that endogenous CO is involved in long-term potentiation. Although not evidence for a role in memory per se, these studies did point to the possible importance of CO in memory processing. In addition, there is now evidence to suggest that endogenous CO is important in avoidance learning and possible for other tasks. This review therefore seeks to promote endogenous CO as a potentially important target for memory research.


Antithetical actions of mitoxantrone and doxorubicin on ryanodine-sensitive Ca++ release channels of rat cardiac sarcoplasmic reticulum: evidence for a competitive mechanism.
The anthracenedione mitoxantrone (MTX) is examined for activity toward ryanodine-sensitive Ca++ release channels (i.e., ryanodine receptors; RyR) from rat cardiac SR singly or in combination with doxorubicin (DXR). MTX and DXR exhibit antithetical activities toward RyR. Under conditions promoting channel closure, DXR enhances the binding of [3H]ryanodine (EC50 = 44 microM), whereas MTX has higher affinity (EC50 = 25 microM) but > 10-fold lower activity towards activating RyR. Unlike DXR, MTX assayed under conditions promoting channel activation inhibits the binding of [3H]ryanodine (IC50 = 3.3 microM) and does not alter the potency with which Ca++ activates RyR in the presence or absence of Mg++. In the presence of Mg++, MTX does not alter kobs and slows k-1 for [3H]ryanodine binding, whereas DXR accelerates kobs with little change in k-1. The antithetical behavior of MTX and DXR at the RyR raises the possibility that MTX antagonizes the ability of DXR to activate the RyR when the drugs are present in combination. In consonance with this hypothesis, MTX inhibits DXR (60 microM)-sensitized [3H]ryanodine-binding sites in a dose-dependent manner (IC50 = 8.4 microM) and shifts the EC50 for DXR-activated [3H]ryanodine-binding without reducing the maximum occupancy attained at high DXR concentration, revealing the competitive nature of the interaction of DXR and MTX. MTX singly does not alter active Ca++ accumulation by SR but is shown to fully inhibit DXR-induced Ca++ release. The results suggest that MTX antagonizes DXR-activated RyR by binding to mutually exclusive sites and may provide a rational basis for combination therapy aimed at extending the current dose limits of DXR.


AlloRep: A Repository of Sequence, Structural and Mutagenesis Data for the LacI/GalR Transcription Regulators.
Protein families evolve functional variation by accumulating point mutations at functionally important amino acid positions. Homologs in the LacI/GalR family of transcription regulators have evolved to bind diverse DNA sequences and allosteric regulatory molecules. In addition to playing key roles in bacterial metabolism, these proteins have been widely used as a model family for benchmarking structural and functional prediction algorithms. We have collected manually curated sequence alignments for >3000 sequences, in vivo phenotypic and biochemical data for >5750 LacI/GalR mutational variants, and noncovalent residue contact networks for 65 LacI/GalR homolog structures. Using this rich data resource, we compared the noncovalent residue contact networks of the LacI/GalR subfamilies to design and experimentally validate an allosteric mutant of a synthetic LacI/GalR repressor for use in biotechnology. The AlloRep database (freely available at www.AlloRep.org) is a key resource for future evolutionary studies of LacI/GalR homologs and for benchmarking computational predictions of functional change.


Eight problems with literature reviews and how to fix them.
Traditional approaches to reviewing literature may be susceptible to bias and result in incorrect decisions. This is of particular concern when reviews address policy- and practice-relevant questions. Systematic reviews have been introduced as a more rigorous approach to synthesizing evidence across studies; they rely on a suite of evidence-based methods aimed at maximizing rigour and minimizing susceptibility to bias. Despite the increasing popularity of systematic reviews in the environmental field, evidence synthesis methods continue to be poorly applied in practice, resulting in the publication of syntheses that are highly susceptible to bias. Recognizing the constraints that researchers can sometimes feel when attempting to plan, conduct and publish rigorous and comprehensive evidence syntheses, we aim here to identify major pitfalls in the conduct and reporting of systematic reviews, making use of recent examples from across the field. Adopting a 'critical friend' role in supporting would-be systematic reviews and avoiding individual responses to police use of the 'systematic review' label, we go on to identify methodological solutions to mitigate these pitfalls. We then highlight existing support available to avoid these issues and call on the entire community, including systematic review specialists, to work towards better evidence syntheses for better evidence and better decisions.


[Forensic psychiatric systems in the world].
The study aims to approach forensic psychiatry within different contexts. It endeavors to show how this specific psychiatry science area is influenced by legal and cultural aspects. The bibliography reviewed had in view understanding the different ways of how to deal with law within the psychiatric sphere, from a cultural point of view. there is a great heterogeneity, of different nature (legal, political, cultural, and religious) that enrich, but at the same time makes difficult, a debate about this issue. there are two great obstacles to achieve a good knowledge about the practice of forensic psychiatry all over the world. The first one is represented by a heterogeneity that makes difficult its description in a comprehensible way. The second is the lack of knowledge of the cultural diverse realities. These difficulties should be a stimulus for newer studies of this characteristic. Only in this way it becomes possible to gradually increase the comprehension of this issue.


Outcomes of neurogenic bowel management in individuals living with a spinal cord injury for at least 10 years.
To describe bowel management and its outcomes in individuals living with a spinal cord injury (SCI) for at least 10 years. Cross-sectional multicenter study. Dutch community. Individuals (N=258; age range, 28-65y) who acquired their SCI between 18 and 35 years of age, who were at least 10 years post-SCI, and who used a wheelchair for their daily mobility. Not applicable. The International SCI Bowel Function Basic Data Set, the neurogenic bowel dysfunction (NBD) score, and a single item on satisfaction with bowel management. Mean time since injury (TSI) was 24±9 years. Seventy-four percent used ≥1 conservative bowel management method, specifically digital evacuation (35%) and mini enemas (31%). Transanal irrigation (TAI) and surgical interventions were used by 11% and 8%, respectively. Perianal problems were reported by 45% of the participants. Severe NBD was present in 36% of all participants and in 40% of those using a conservative method. However, only 14% were (very) dissatisfied with their current bowel management. Dissatisfaction with bowel management was significantly associated with constipation and severe NBD. With increasing TSI, there was a nonsignificant trend observed toward a decline in dissatisfaction with bowel management and a significant decline in severe NBD. Although satisfaction rates were high, more than a third of the participants reported severe NBD and perianal problems. Apart from severe NBD, there were no significant associations between bowel problems and TSI. Conservative methods were most often used, but some of these methods were also significantly associated with the presence of severe NBD. Longitudinal research is necessary to provide more knowledge concerning the course of NBD with increasing TSI.


Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model.
Combination therapies for melanoma that target immune-regulatory networks are entering clinical practice, and more are under investigation in preclinical or clinical studies. Adenosine plays a key role in regulating melanoma progression. We investigated the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody (mAb) in combination with either modulators of adenosine receptors (AR) activation or an inhibitor of adenosine production in a murine model of melanoma. We found that treatment with APCP, selective inhibitor of the adenosine-generating nucleotidase CD73, enhanced the activity of anti-CTLA4 mAb, by improving tumor immune response. Blockade of the adenosine A2a receptor (A2aR), which plays a critical role in the regulation of T-cell functions, significantly reduced melanoma growth. Most importantly, combination therapy including an A2aR antagonist with anti-CTLA4 mAb markedly inhibited tumor growth and enhanced anti-tumor immune responses. Targeting A3R and CTLA4 was not as effective in limiting melanoma growth as targeting A2aR. These data suggest that the efficacy of anti-CTLA4 melanoma therapy may be improved by targeting multiple mechanisms of immune suppression within tumor tissue, including CD73 or A2a receptor.


Cutaneous manifestations of deep mycosis: an experience in a tropical pathology laboratory.
Cutaneous manifestations of deep mycotic infection are fraught with delayed or misdiagnosis from mainly cutaneous neoplastic lesions. This study is designed to present our experience of these mycoses in a pathology laboratory in the tropics. A clinicopathologic analysis of deep mycotic infections was conducted over a 15 years period Formalin fixed and paraffin wax processed biopsies were stained with hematoxylin and eosin, periodic acid Schiff (PAS), and Grocott's methenamine silver (GMS) for the identification of fungus specie. Patients' bio-data and clinical information were obtained from records. Twenty males and seven females presented with 6 months to 6 years histories of varying symptoms of slow growing facial swellings, nodules, subcutaneous frontal skull swelling, proptosis, nasal blockage, epistaxis, discharging leg sinuses, flank mass, convulsion and pain. Of the 27 patients, four gave antecedent history of trauma, two had recurrent lesions which necessitated maxilectomy, two presented with convulsion without motor dysfunction while one had associated erosion of the small bones of the foot. None of the patients had debilitating illnesses such as diabetes mellitus, tuberculosis, and HIV infection. Tissue histology revealed histoplasmosis (10), mycetoma (9), subcutaneous phycomycosis (6), and phaeohyphomycosis (2). Deep mycoses may present primarily as cutaneous lesions in immunocompetent persons and often elicit distinct histologic inflammatory response characterized by granuloma formation. Diagnosis in resource constraint setting can be achieved with tissue stained with PAS and GMS which identifies implicated fungus. Clinical recognition and adequate knowledge of the pathology of these mycoses may reduce attendant patient morbidity.


Drug designs fulfilling the requirements of clinical trials aiming at personalizing medicine.
In the current era of stratified medicine and biomarker-driven therapies, the focus has shifted from predictions based on the traditional anatomic staging systems to guide the choice of treatment for an individual patient to an integrated approach using the genetic makeup of the tumor and the genotype of the patient. The clinical trial designs utilized in the developmental pathway for biomarkers and biomarker-directed therapies from discovery to clinical practice are rapidly evolving. While several issues need careful consideration, two critical issues that surround the validation of biomarkers are the choice of the clinical trial design (which is based on the strength of the preliminary evidence and marker prevalence), and biomarker assay related issues surrounding the marker assessment methods such as the reliability and reproducibility of the assay. In this review, we focus on trial designs aiming at personalized medicine in the context of early phase trials for initial marker validation, as well as in the context of larger definitive trials. Designs for biomarker validation are broadly classified as retrospective (i.e., using data from previously well-conducted randomized controlled trials (RCTs) versus prospective (enrichment, all-comers, hybrid or adaptive). We believe that the systematic evaluation and implementation of these design strategies are essential to accelerate the clinical validation of biomarker guided therapy.


Improving Quality in the Care of Patients with Inflammatory Bowel Diseases.
Efforts to improve healthcare quality were firmly established before the Institute of Medicine (IOM) historic 2000 and 2001 reports, To Err is Human Building a Safer Health System and Crossing the Quality Chasm: A New Health System for the 21st Century Despite the long-standing healthcare quality improvement (QI) efforts that date back to the turn of the 20th century, the IOM reports significantly advanced the awareness of healthcare quality deficits and the resulting risk to patients from those gaps in care. Studies immediately following the IOM reports emphasized and verified the presence of detrimental care gaps and highlighted a myriad of contributing factors. Studies focused specifically on the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis , demonstrated suboptimal patient outcomes stemming from, in part, system and provider variation. In the years that have followed, research studies have shown the persistence of suboptimal outcomes in IBD despite an awareness of key drivers for poor care quality and concerted efforts in advancing QI initiatives. In 2017, IBD advocacy groups and provider networks have demonstrated progress in furthering both pediatric and adult IBD outcomes through the use of QI methods and tools including collaborative learning networks. A significant amount of work lies ahead, however, to build upon these advances and improve IBD outcomes further. This article reviews the history of quality initiatives in healthcare, identifies ongoing gaps in IBD care with a review of current IBD improvement efforts taking place, and identifies several targets for improving IBD care quality moving forward into the 21st century.


Bio-ontologies: current trends and future directions.
In recent years, as a knowledge-based discipline, bioinformatics has been made more computationally amenable. After its beginnings as a technology advocated by computer scientists to overcome problems of heterogeneity, ontology has been taken up by biologists themselves as a means to consistently annotate features from genotype to phenotype. In medical informatics, artifacts called ontologies have been used for a longer period of time to produce controlled lexicons for coding schemes. In this article, we review the current position in ontologies and how they have become institutionalized within biomedicine. As the field has matured, the much older philosophical aspects of ontology have come into play. With this and the institutionalization of ontology has come greater formality. We review this trend and what benefits it might bring to ontologies and their use within biomedicine.


Influence of feeding raw or extruded feline diets on nutrient digestibility and nitrogen metabolism of African wildcats (Felis lybica).
The African wildcat is one of the closest ancestors to the domestic cat and is believed to have similar nutrient requirements, but research is lacking. The objective of this study was to determine the effects of feeding a high-protein extruded kibble diet vs. a raw meat diet on nutrient digestibility, nitrogen metabolism, and blood metabolite concentrations in African wildcats. Five wildcats were randomized onto either a high-protein (>50% crude protein) extruded kibble diet or a raw meat diet. The study was executed as a crossover design, with 21-d periods, consisting of a 16-d adaptation phase followed by a 4-d total fecal and urine collection phase. Cats were housed individually in metabolism cages and fed to maintain body weight (BW). A fresh fecal sample was collected for short-chain fatty acid (SCFA) and branched-chain fatty acid (BCFA) analyses. Blood was analyzed for serum chemistry and leptin concentration. Food intake (as is) did not differ (P>0.05) between diets. Food intake and fecal output (g/d DMB) were greater (P<0.05) when cats consumed the kibble diet. Protein digestibility was higher (P<0.05) when cats were fed the raw meat diet vs. the kibble diet. Nitrogen intake was greater (P<0.05) when cats consumed the kibble diet, and more (P<0.05) nitrogen was present in the feces; however, the percentage of nitrogen retained and nitrogen balance did not differ (P>0.05). Fecal scores, ammonia, SCFA, and BCFA concentrations did not differ (P>0.05) between diets. Fecal butyrate molar ratio was higher (P<0.01) when cats consumed the kibble diet. Blood analyses demonstrated few differences between diets, but alanine aminotransferase activity and bicarbonate were higher (P<0.05) when cats consumed the commercial raw meat diet. Owing to lack of differences, these data indicate that African wildcats can readily utilize a high protein extruded kibble diet, and may be able to replace a commercial raw meat diet.


Clinical impact and 'natural' course of uncorrected tricuspid regurgitation after implantation of a left ventricular assist device: an analysis of the European Registry for Patients with Mechanical Circulatory Support (EUROMACS).
Data on the impact and course of uncorrected tricuspid regurgitation (TR) during left ventricular assist device (LVAD) implantation are scarce and inconsistent. This study explores the clinical impact and natural course of uncorrected TR in patients after LVAD implantation. The European Registry for Patients with Mechanical Circulatory Support was used to identify adult patients with LVAD implants without concomitant tricuspid valve surgery. A mediation model was developed to assess the association of TR with 30-day mortality via other risk factors. Generalized mixed models were used to model the course of post-LVAD TR. Joint models were used to perform sensitivity analyses. A total of 2496 procedures were included (median age: 56 years; men: 83%). TR was not directly associated with higher 30-day mortality, but mediation analyses suggested an indirect association via preoperative elevated right atrial pressure and creatinine (P = 0.035) and bilirubin (P = 0.027) levels. Post-LVAD TR was also associated with increased late mortality [hazard ratio 1.16 (1.06-1.3); P = 0.001]. On average, uncorrected TR diminished after LVAD implantation. The probability of having moderate-to-severe TR immediately after an implant in patients with none-to-mild TR pre-LVAD was 10%; in patients with moderate-to-severe TR pre-LVAD, it was 35% and continued to decrease in patients with moderate-to-severe TR pre-LVAD, regardless of pre-LVAD right ventricular failure or pulmonary hypertension. Uncorrected TR pre-LVAD and post-LVAD is associated with increased early and late mortality. Nevertheless, on average, TR diminishes progressively without intervention after an LVAD implant. Therefore, these data suggest that patient selection for concomitant tricuspid valve surgery should not be based solely on TR grade.


The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis.
We sought to relate left ventricular ejection fraction (EF), end-systolic volume index (ESVI) and infarct size (IS), as measured in a single randomized trial, to six-month mortality after myocardial infarction (MI) treated with thrombolysis. These three prognostic indicators have never been compared in the same study group. Radionuclide angiographic and single-photon emission computed tomographic sestamibi measurements of IS were performed in 1,194 and 1,181 patients, respectively, of the 2,948 patients enrolled in the Collaborative Organization for RheothRx Evaluation (CORE) trial. Ejection fraction, ESVI and IS, as measured by central laboratories in these radionuclide substudies, were tested for their association with six-month mortality. Ejection fraction (n = 1,137; p < 0.0001), ESVI (n = 945; p = 0.055) and IS (n = 1,164; p = 0.03) were all associated with six-month mortality. Each of these measurements was significantly correlated with the other two, regardless of MI location. In an "overlap" group of 753 patients (25.5% of the population; 13 deaths) in whom all three measurements were available, EF (p = 0.001) was a stronger predictor than ESVI (p = 0.005) or IS (p = 0.01). Neither of the other two measurements added independent prognostic information. The highest risk subgroup (EF < 30%) had an 11% six-month mortality, but comprised only 95 patients (8.3%). Ejection fraction, ESVI and IS measurements performed one to two weeks after MI can each predict six-month mortality. Ejection fraction was superior to the other two measurements. However, this study had limited power to detect independent significance of ESVI or IS.


Mixed infections of trypanosomes in tsetse and pigs and their epidemiological significance in a sleeping sickness focus of Côte d'Ivoire.
In a sleeping sickness focus of Côte d'Ivoire, trypanosomes were characterized in humans, pigs and tsetse using various techniques. Out of 74 patients, all the 43 stocks isolated by KIVI (Kit for In Vitro Isolation) appeared to belong to only one zymodeme of Trypanosoma brucei gambiense group 1 (the major zymodeme Z3). The only stock isolated on rodents belonged to a different, new, zymodeme (Z50), of T. b. gambiense group 1. From 18 pigs sampled in the same locations as the patients, PCR showed a high proportion of mixed infections of T. brucei s. l. and T. congolense riverine-forest. Zymodemes of T. brucei s. l. from these pigs were different from those found in humans. From a total of 16 260 captured tsetse (Glossina palpalis palpalis), 1701 were dissected and 28% were found to be infected by trypanosomes. The most prevalent trypanosome was T. congolense riverine-forest type, followed by T. vivax, T. bruceis. l. and T. congolense savannah type, this latter being associated to the forest type of T. congolense in most cases. Mixed infections by 2 or 3 of these trypanosomes were also found. Use of a microsatellite marker allowed us to distinguish T. b. gambiense group 1 in some of the mature infections in tsetse. Differences in infection rates and in trypanosome genotypes according to the host might indicate that the pig may not be an active animal reservoir for humans in this focus.


Dietary Protein Sources and All-Cause and Cause-Specific Mortality: The Golestan Cohort Study in Iran.
Dietary protein comes from foods with greatly different compositions that may not relate equally with mortality risk. Few cohort studies from non-Western countries have examined the association between various dietary protein sources and cause-specific mortality. Therefore, the associations between dietary protein sources and all-cause, cardiovascular disease, and cancer mortality were evaluated in the Golestan Cohort Study in Iran. Among 42,403 men and women who completed a dietary questionnaire at baseline, 3,291 deaths were documented during 11 years of follow up (2004-2015). Cox proportional hazards models estimated age-adjusted and multivariate-adjusted hazard ratios (HRs) and 95% CIs for all-cause and disease-specific mortality in relation to dietary protein sources. Data were analyzed from 2015 to 2016. Comparing the highest versus the lowest quartile, egg consumption was associated with lower all-cause mortality risk (HR=0.88, 95% CI=0.79, 0.97, ptrend=0.03). In multivariate analysis, the highest versus the lowest quartile of fish consumption was associated with reduced risk of total cancer (HR=0.79, 95% CI=0.64, 0.98, ptrend=0.03) and gastrointestinal cancer (HR=0.75, 95% CI=0.56, 1.00, ptrend=0.02) mortality. The highest versus the lowest quintile of legume consumption was associated with reduced total cancer (HR=0.72, 95% CI=0.58, 0.89, ptrend=0.004), gastrointestinal cancer (HR=0.76, 95% CI=0.58, 1.01, ptrend=0.05), and other cancer (HR=0.66, 95% CI=0.47, 0.93, ptrend=0.04) mortality. Significant associations between total red meat and poultry intake and all-cause, cardiovascular disease, or cancer mortality rate were not observed among all participants. These findings support an association of higher fish and legume consumption with lower cancer mortality, and higher egg consumption with lower all-cause mortality.


[IgA nephropathy and granulomatosis with polyangiitis-overlap: a rare coexistence of two glomerular nephropathies with remission after steroids and rituximab].
Granulomatosis with polyangiitis (GPA) is an ANCA-positive systemic vasculitis that mainly involves lungs and kidneys. This condition rarely overlaps with other glomerulonephritides. A 42-year-old man with constitutional symptoms and haemophtoe was admitted to the Infectious Diseases department, where he was subjected to fibrobronchoscopy with BAL (broncho-alveolar lavage) and lung transbronchial biopsy that showed histological signs of vasculitis. The association with severe acute kidney injury with urine sediment alterations (microscopic haematuria and proteinuria) led the consultant nephrologist to a diagnosis of GPA. Thus the patient was transferred to the Nephrology department. During the hospitalization, the worsening of the clinical course and the development of alveolitis, respiratory failure, purpura, and rapidly progressive kidney failure (nephritic syndrome - serum creatinine 3 mg/dl) required the start of steroid therapy, according to EUVAS. The presence of florid crescents in 3 out of 6 glomeruli in the renal biopsy and the IgA positive immunofluorescence allowed to make a diagnosis of overlap of GPA and IgA nephropathy. Rituximab (RTX 375 mg/m² per week for 4 weeks) and plasma exchange (7 sessions) were added to steroid therapy. During follow-up, partial functional recovery was achieved after 4 months, whereas total regression, i.e. the absence of protein and red blood cells in urine sediment, was reached during the 4-years follow-up. The main therapy during the first 2 years of follow-up was RTX, followed by mycophenolate mofetil for the remaining 2 years.


Recruitment of Donor T Cells to the Eyes During Ocular GVHD in Recipients of MHC-Matched Allogeneic Hematopoietic Stem Cell Transplants.
The primary objective of the present study was to identify the kinetics and origin of ocular infiltrating T cells in a preclinical model of graft-versus-host disease (GVHD) that induces eye tissue damage. Graft-versus-host disease was induced using an major histocompatibility complex (MHC)-matched, minor histocompatibility-mismatched hematopoietic stem cell transplant (HSCT) model. This approach, which utilized congenic and EGFP-labeled donor populations, mimics a matched, clinically unrelated donor (MUD) cell transplant. Systemic and ocular GVHD were assessed at varying time points using clinical examination, intravital microscopy, immune phenotype via flow cytometric analyses, and immunohistochemical staining. Following transplant, we observed characteristic changes in GVHD-associated immune phenotype as well as clinical signs present in recipients post transplant. Notably, the kinetics of the systemic changes and the ocular damage paralleled what is observed clinically, including damage to the cornea as well as the conjunctiva and lacrimal gland. Importantly, the infiltrate contained predominantly donor CD4 as well as CD8 T cells with an activated phenotype and macrophages together with effector cytokines consistent with the presence of a TH1 alloreactive population. Overall, the findings here unequivocally demonstrated that donor T cells compose part of the corneal and ocular adnexa infiltrate in animals undergoing ocular GVHD. In total, the results describe a novel and promising preclinical model characterized by both systemic and ocular changes as detected in significant numbers of patients undergoing GVHD following allo-HSCT, which can help facilitate dissecting the underlying immune mechanisms leading to damage associated with ocular GVHD.


Assessment of Family Planning Service Availability and Readiness in 10 African Countries.
Access to family planning services and appropriate contraceptive methods is crucial for ensuring good health outcomes for women and adolescent girls. The World Health Organization worked with the U.S. Agency for International Development to develop the Service Availability and Readiness Assessment (SARA) survey to measure health facility capacity to provide end users with appropriate, high-quality health care. In this study, we looked at the service availability and readiness of health facilities to provide contraception in 10 African countries: Benin, Burkina Faso, the Democratic Republic of the Congo, Djibouti, Mauritania, Niger, Sierra Leone, Tanzania, Togo, and Uganda. This study compared SARA survey data on family planning services from each of the 10 countries. We conducted a descriptive analysis of variations in facility readiness and the availability of services, contraceptive methods, trained staff, family planning guidelines, and basic health care equipment. Overall, many of the countries surveyed had a relatively high availability of at least 1 contraceptive method. Rural facilities tended to have more availability of contraception than urban facilities, and government facilities tended to have higher availability of family planning than other providers. The countries differed in their particular dominant contraceptive method, and stock-outs of contraceptive methods were observed. Countries had overall low levels of all 6 tracer items (availability of family planning guidelines, staff trained in family planning, blood pressure apparatuses, combined oral contraceptive, injectable contraceptives, and male condoms on the day of the assessment), indicating low health system readiness. There were discrepancies between reported and observed availability of blood pressure apparatuses and family planning guides and having at least 1 staff member trained to use these tools. In all countries, unmarried adolescents appeared to have less access to family planning than the general population. Stock-outs and logistics management problems were common among the countries surveyed. Critical gaps between reported and actual availability of products and services often makes it difficult for end users to access appropriate family planning methods. To address many of the issues, additional health worker training is needed and more effort to target and support adolescents should be undertaken. To achieve universal health coverage targets for family planning, gaps in the availability and readiness of health systems to provide contraceptive products and services must be reduced.


Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice.
Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the μ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.


Positive TgAbs in patients with Graves' orbitopathy are associated with lower risk of its active form - preliminary study.
In this retrospective, single-centre cohort study, we report our 10-year experience concerning clinical manifestation, diagnosis and treatment of Graves' orbitopathy (GO), with particular regard to antithyroid antibodies in iodine sufficient Polish population. Data on thyrometabolic and immunological status of 71 patients diagnosed with GO, were collected. Also, we gathered information on the selection of the applied treatment in these cases of Graves' disease (GD): pharmacological, radioiodine or surgery. The chi-square test, correlation coefficient and univariate logistic regression analysis were used to determine the influence of clinical parameters on activity of GO. Significantly lower frequency of active GO in positive anti-thyroglobulin antibodies (TgAbs) patients was documented (p<0.05, chi-square analysis). Expectedly, concentration of antibodies against thyrotropin receptor (TRAbs) did constitute linear factor positively associated with clinical activity score (CAS) (p<0.05). Moreover, the pretreatment with radioiodine and smoking were significantly associated with the increased GO activity (p<0.05 and p<0.05, respectively). Our data suggest some kind of "protective" effect of TgAbs presence against the active form of GO.


Adenovirus-mediated sensitization to the cytotoxic drugs docetaxel and mitoxantrone is dependent on regulatory domains in the E1ACR1 gene-region.
Oncolytic adenoviruses have shown promising efficacy in clinical trials targeting prostate cancers that frequently develop resistance to all current therapies. The replication-selective mutants AdΔΔ and dl922-947, defective in pRb-binding, have been demonstrated to synergise with the current standard of care, mitoxantrone and docetaxel, in prostate cancer models. While expression of the early viral E1A gene is essential for the enhanced cell killing, the specific E1A-regions required for the effects are unknown. Here, we demonstrate that replicating mutants deleted in small E1A-domains, binding pRb (dl1108), p300/CBP (dl1104) and p400/TRRAP or p21 (dl1102) sensitize human prostate cancer cells (PC-3, DU145, 22Rv1) to mitoxantrone and docetaxel. Through generation of non-replicating mutants, we demonstrate that the small E1A12S protein is sufficient to potently sensitize all prostate cancer cells to the drugs even in the absence of viral replication and the E1A transactivating domain, conserved region (CR) 3. Furthermore, the p300/CBP-binding domain in E1ACR1 is essential for drug-sensitisation in the absence (AdE1A1104) but not in the presence of the E1ACR3 (dl1104) domain. AdE1A1104 also failed to increase apoptosis and accumulation of cells in G2/M. All E1AΔCR2 mutants (AdE1A1108, dl922-947) and AdE1A1102 or dl1102 enhance cell killing to the same degree as wild type virus. In PC-3 xenografts in vivo the dl1102 mutant significantly prolongs time to tumor progression that is further enhanced in combination with docetaxel. Neither dl1102 nor dl1104 replicates in normal human epithelial cells (NHBE). These findings suggest that additional E1A-deletions might be included when developing more potent replication-selective oncolytic viruses, such as the AdΔCR2-mutants, to further enhance potency through synergistic cell killing in combination with current chemotherapeutics.


Crown tissue proportions and enamel thickness distribution in the Middle Pleistocene hominin molars from Sima de los Huesos (SH) population (Atapuerca, Spain).
Dental enamel thickness, topography, growth and development vary among hominins. In Homo, the thickness of dental enamel in most Pleistocene hominins display variations from thick to hyper-thick, while Neanderthals exhibit proportionally thinner enamel. The origin of the thin trait remains unclear. In this context, the Middle Pleistocene human dental assemblage from Atapuerca-Sima de los Huesos (SH) provides a unique opportunity to trace the evolution of enamel thickness in European hominins. In this study, we aim to test the hypothesis if the SH molar sample approximates the Neanderthal condition for enamel thickness and/or distribution. This study includes 626 molars, both original and comparative data. We analysed the molar inner structural organization of the original collections (n = 124), belonging to SH(n = 72) and modern humans from Spanish origin (n = 52). We compared the SH estimates to those of extinct and extant populations of the genus Homo from African, Asian and European origin (estimates extracted from literature n = 502). The comparative sample included maxillary and mandibular molars belonging to H. erectus, East and North African Homo, European Middle Pleistocene Homo, Neanderthals, and fossil and extant H. sapiens. We used high-resolution images to investigate the endostructural configuration of SH molars (tissue proportions, enamel thickness and distribution). The SH molars exhibit on average thick absolute and relative enamel in 2D and 3D estimates, both in the complete crown and the lateral enamel. This primitive condition is shared with the majority of extinct and extant hominin sample, except for Neanderthals and some isolated specimens. On the contrary, the SH molar enamel distribution maps reveal a distribution pattern similar to the Neanderthal signal (with thicker enamel on the lingual cusps and more peripherally distributed), compared to H. antecessor and modern humans. Due to the phylogenetic position of the SH population, the thick condition in molars could represent the persistence of the plesiomorphic condition in this group. Still, more data is needed on other Early and Middle Pleistocene populations to fully understand the evolutionary meaning of this trait.


Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men.
Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM. We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma. T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure- and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist. OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities. Current Controlled Trials ISRCTN53177482.


Glucose, lipid, and lipoprotein levels in sheep naturally infected with Fasciola hepatica.
This study was designed to investigate serum glucose, lipid, and lipoprotein in sheep naturally infected with Fasciola hepatica. Ten healthy sheep and 15 infected with F. hepatica were used in study. Serum concentrations of total protein (TP), albumin, glucose, cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoproteins (VLDL), and serum activities of AST, ALT, GGT, and LDH were measured using a Roche-Cobas Integra 800 auto-analyzer. At day 0 (prior to treatment) and on the 28th day (after treatment) the serum concentrations of TP, albumin, glucose, cholesterol, triglyceride, HDL, LDL, and VLDL values in sheep with F. hepatica were significantly lower than those of the control group, while serum activities of AST, ALT, GGT, and LDH of lambs with F. hepatica were significantly higher than those of the control group. At day 56 (after treatment), none of the variables was significantly different between control sheep and those that received treatment for fascioliasis (P > 0.05). Nutritional management may be used to reduce the impact of fascioliasis.


Sporofaciens musculi gen. nov., sp. nov., a novel bacterium isolated from the caecum of an obese mouse.
A bacterial strain, designated WCA-9-b2T, was isolated from the caecal content of an 18-week-old obese C57BL/6NTac male mouse. According to phenotypic analyses, the isolate was rod-shaped, strictly anaerobic, spore-forming, non-motile and Gram-stain-positive, under the conditions tested. Colonies were irregular and non-pigmented. Analysis of the 16S rRNA gene sequence indicated that the isolate belonged to the order Clostridiales with Dorea longicatena ATCC 27755T (94.9 % sequence identity), Ruminococcus gnavus ATCC 29149T (94.8%) and Clostridium scindens ATCC 35704T (94.3%) being the closest relatives. Whole genome sequencing showed an average nucleotide identity <74.23 %, average amino acid identity <64.52-74.67 % and percentage of conserved proteins values <50 % against the nine closest relatives (D. longicatena, Ruminococcus gnavus, C. scindens, Dorea formicigenerans, Ruminococcus lactaris, Clostridium hylemonae, Merdimonas faecis, Faecalicatena contorta and Faecalicatena fissicatena). The genome-based G+C content of genomic DNA was 44.4 mol%. The major cellular fatty acids were C16 : 0 (24.5%), C18 : 1 cis9 (19.8 %), C16 : 0 DMA (11.7%), C18 : 0 (8.4%) and C14 : 0 (6.6%). Respiratory quinones were not detected. The predominant metabolic end products of glucose fermentation were acetate and succinate. Production of CO2 and H2 were detected. Based on these data, we propose that strain WCA-9-b2T represents a novel species within a novel genus, for which the name Sporofaciens musculi gen. nov., sp. nov. is proposed. The type strain is WCA-9-b2T (=DSM 106039T=CECT 30156T).


Isoquercitrin inhibits bladder cancer progression in vivo and in vitro by regulating the PI3K/Akt and PKC signaling pathways.
Bladder cancer is the most common malignancy of the urinary system and is also one of the 10 most common cancers of the human body. Currently, clinical treatment of bladder cancer mainly utilizes partial or total cystectomy, supplemented by conventional chemotherapy. However, such treatment has not fully improved the prognosis of patients and is associated with various side effects. Studies have found that flavonoids extracted from plants can be used in radiotherapy and chemotherapy for the prevention of postoperative recurrence and metastasis but also alone for the treatment of advanced tumors. Both applications can ameliorate clinical symptoms, improve the quality of life, and prolong the survival of patients. Based on the above information, the present study investigated the effect of isoquercitrin, a type of flavonoid found in Bidens pilosa L. extracts, on bladder cancer progression, with the goal of understanding the biological characteristics of isoquercitrin by which it participates in bladder cancer progression. Using in vitro experiments, we found that therapeutic doses of isoquercitrin significantly inhibited cell proliferation and induced apoptosis in human bladder cancer cells and that the cell cycle was arrested in the G1 phase. Isoquercitrin inhibited phosphatidylinositol 3-kinase (PI3K) and Akt phosphorylation expression levels, thus inhibiting proliferation and inducing apoptosis in the cancer cells. In addition, we found that isoquercitrin reduced protein kinase C (PKC) protein expression levels in the human bladder cancer cell lines. We also showed via in vivo experiments that isoquercitrin inhibited xenograft tumor growth in nude mice. In conclusion, our study confirmed that isoquercitrin inhibits bladder cancer progression in vivo and demonstrated that the molecular mechanism of this inhibition may be closely associated with the PI3K/Akt and PKC signaling pathways.


Evaluation of methods for improved detection of Cryptosporidium spp. in mussels (Mytilus californianus).
Bivalve molluscs concentrate Cryptosporidium oocysts from fecal-contaminated aquatic environments and are therefore useful in monitoring water quality. A real-time TaqMan polymerase chain reaction (PCR) system was developed to allow for large scale quantitative detection of Cryptosporidium spp. in mussels (Mytilus californianus). The TaqMan sensitivity and specificity were compared to conventional PCR and direct immunofluorescent antibody (DFA) assays, with and without immunomagnetic separation (IMS), to identify the best method for parasite detection in mussel hemolymph, gill washings and digestive glands. TaqMan PCR and two conventional PCR systems all detected 1 or more oocysts spiked into 1 ml hemolymph samples. The minimum oocyst detection limit in spiked 5 ml gill wash and 1 g digestive gland samples tested by TaqMan PCR and DFA was 100 oocysts, with a 1 log(10) improvement when samples were first processed by IMS. For tank exposed mussels, TaqMan and conventional PCR methods detected C. parvum in <5% of hemolymph samples. No gill washings from these same mussels tested positive by TaqMan PCR or DFA analysis even with IMS concentration. All methods detected the highest prevalence of C. parvum-positive samples in digestive gland tissues of exposed mussels. In conclusion, the most sensitive method for the detection of C. parvum in oocyst-exposed mussels was IMS concentration with DFA detection: 80% of individual and 100% of pooled digestive gland samples tested positive. TaqMan PCR was comparable to conventional PCR for detection of C. parvum oocysts in mussels and additionally allowed for automated testing, high throughput, and semi-quantitative results.


T cell-expressed CD40L potentiates the bone anabolic activity of intermittent PTH treatment.
T cells are known to potentiate the bone anabolic activity of intermittent parathyroid hormone (iPTH) treatment. One of the involved mechanisms is increased T cell secretion of Wnt10b, a potent osteogenic Wnt ligand that activates Wnt signaling in stromal cells (SCs). However, additional mechanisms might play a role, including direct interactions between surface receptors expressed by T cells and SCs. Here we show that iPTH failed to promote SC proliferation and differentiation into osteoblasts (OBs) and activate Wnt signaling in SCs of mice with a global or T cell-specific deletion of the T cell costimulatory molecule CD40 ligand (CD40L). Attesting to the relevance of T cell-expressed CD40L, iPTH induced a blunted increase in bone formation and failed to increase trabecular bone volume in CD40L(-/-) mice and mice with a T cell-specific deletion of CD40L. CD40L null mice exhibited a blunted increase in T cell production of Wnt10b and abrogated CD40 signaling in SCs in response to iPTH treatment. Therefore, expression of the T cell surface receptor CD40L enables iPTH to exert its bone anabolic activity by activating CD40 signaling in SCs and maximally stimulating T cell production of Wnt10b.