An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity.
Macrophage migration inhibitory factor (MIF) is a major proinflammatory cytokine that has been increasingly implicated in the pathogenesis of several inflammatory, autoimmune, infectious and oncogenic diseases. Accumulating evidence suggests that the tautomerase activity of MIF plays a role in modulating some of its intra- and extra-cellular activities. Therefore, the identification and development of small-molecule inhibitors targeting the catalytic activity of MIF has emerged as an attractive and viable therapeutic strategy to attenuate its function in health and disease. Herein we report a novel virtual screening protocol for the discovery of new inhibitors of MIF's tautomerase activity. Our protocol takes into account the flexibility and dynamics of the catalytic site by coupling molecular dynamics (MD) simulations aimed at modeling the protein's flexibility in solution to (i) docking with FlexX, or (ii) docking with FlexX and pharmacophoric filtering with Unity. In addition, we applied in parallel a standalone docking using the new version of Surflex software. The three approaches were used to screen the ChemBridge chemical library and the inhibitory activity of the top-ranked 333 compound obtained from each approach (1000 compound in total) was assessed in vitro using the tautomerase assay. This biochemical validation process resulted in the identification of 12 novel MIF inhibitors corresponding to a 1.2% hit rate. Six of these hits came from Surflex docking; two from FlexX docking with MD simulations and four hits were identified with MDS and pharmacophore filtering with minimal overlap between the hits from each approach. Six hits were identified with IC50 values lower than 10 microM (three hits with IC50 lower than 1 microM); four were shown to be suicide inhibitors and act via covalent modification of the N-terminal catalytic residues Pro1. One additional inhibitor, N-phenyl-N-1,3,4-thiadiazol-2-yl-thiourea, (IC50=300 nM) was obtained from FlexX docking combined to pharmacophoric filtering on one of the eight MD structures. These results demonstrate the power of integrative in silico approaches in the discovery of new modulator of MIF's tautomerase activity. The chemical diversity and mode of action of these compounds suggest that they could be used as molecular probes to elucidate the functions and biology of MIF and as lead candidates in drug developments of anti-MIF drugs.


SARS-CoV-2 Infections Among Patients With Liver Disease and Liver Transplantation Who Received COVID-19 Vaccination.
Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID-19) complications and deaths. We aimed to describe cases of SARS-CoV-2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID-19 vaccine dose. The SECURE-Liver and COVID-Hep international reporting registries were used to identify laboratory-confirmed COVID-19 in CLD and LT patients who received a COVID-19 vaccination. Of the 342 cases of lab-confirmed SARS-CoV-2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID-19 vaccination, including 12 who were fully vaccinated (≥2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID-19 occurred in patients who had a single vaccine dose within the last 1-2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID-19 infections among patients with CLD and LT recipients who had received the COVID-19 vaccination. Vaccination against SARS-CoV-2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients.


Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia.
Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10-5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10-4), rs6118 in SERPINA5 (P-value = 5.83 × 10-4), and rs5877 in SERPINC1 (P-value = 1.07 × 10-3), and the genes CAPZA2 (P-value = 4.03 × 10-4) and SERPINC1 (P-value = 1.55 × 10-3). The SNVs in the top-scoring pathway "Factors involved in megakaryocyte development and platelet production" (P-value = 3.34 × 10-4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10-8), and decrease (OR = 66.82, P-value = 5.92 × 10-9). The logistic regression models predict CTCAE grades 3-4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.


Transcriptomic atlas of mushroom development reveals conserved genes behind complex multicellularity in fungi.
The evolution of complex multicellularity has been one of the major transitions in the history of life. In contrast to simple multicellular aggregates of cells, it has evolved only in a handful of lineages, including animals, embryophytes, red and brown algae, and fungi. Despite being a key step toward the evolution of complex organisms, the evolutionary origins and the genetic underpinnings of complex multicellularity are incompletely known. The development of fungal fruiting bodies from a hyphal thallus represents a transition from simple to complex multicellularity that is inducible under laboratory conditions. We constructed a reference atlas of mushroom formation based on developmental transcriptome data of six species and comparisons of >200 whole genomes, to elucidate the core genetic program of complex multicellularity and fruiting body development in mushroom-forming fungi (Agaricomycetes). Nearly 300 conserved gene families and >70 functional groups contained developmentally regulated genes from five to six species, covering functions related to fungal cell wall remodeling, targeted protein degradation, signal transduction, adhesion, and small secreted proteins (including effector-like orphan genes). Several of these families, including F-box proteins, expansin-like proteins, protein kinases, and transcription factors, showed expansions in Agaricomycetes, many of which convergently expanded in multicellular plants and/or animals too, reflecting convergent solutions to genetic hurdles imposed by complex multicellularity among independently evolved lineages. This study provides an entry point to studying mushroom development and complex multicellularity in one of the largest clades of complex eukaryotic organisms.


Angiogenic signaling in the lungs of a metabolically suppressed hibernating mammal (Ictidomys tridecemlineatus).
To conserve energy in times of limited resource availability, particularly during cold winters, hibernators suppress even the most basic of physiologic processes. Breathing rates decrease from 40 breaths/minute to less than 1 breath/min as they decrease body temperature from 37 °C to ambient. Nevertheless, after months of hibernation, these incredible mammals emerge from torpor unscathed. This study was conducted to better understand the protective and possibly anti-inflammatory adaptations that hibernator lungs may use to prevent damage associated with entering and emerging from natural torpor. We postulated that the differential protein expression of soluble protein receptors (decoy receptors that sequester soluble ligands to inhibit signal transduction) would help identify inhibited inflammatory signaling pathways in metabolically suppressed lungs. Instead, the only two soluble receptors that responded to torpor were sVEGFR1 and sVEGFR2, two receptors whose full-length forms are bound by VEGF-A to regulate endothelial cell function and angiogenesis. Decreased sVEGFR1/2 correlated with increased total VEGFR2 protein levels. Maintained or increased levels of key γ-secretase subunits suggested that decreased sVEGFR1/2 protein levels were not due to decreased levels of intramembrane cleavage complex subunits. VEGF-A protein levels did not change, suggesting that hibernators may regulate VEGFR1/2 signaling at the level of the receptor instead of increasing relative ligand abundance. A panel of angiogenic factors used to identify biomarkers of angiogenesis showed a decrease in FGF-1 and an increase in BMP-9. Torpid lungs may use VEGF and BMP-9 signaling to balance angiogenesis and vascular stability, possibly through the activation of SMAD signaling for adaptive tissue remodeling.


The Role of Stage at Diagnosis in Colorectal Cancer Black-White Survival Disparities: A Counterfactual Causal Inference Approach.
To date, a counterfactual framework has not been used to study determinants of social inequalities in cancer. Considering the case of colorectal cancer, for which racial/ethnic differences in stage at diagnosis and survival are well documented, we quantify the extent to which black versus white survival disparities would be reduced had disparities in stage at diagnosis been eliminated in a large patient population. We obtained data on colorectal cancer patients (diagnosed between 1992 and 2005 and followed until 2010) from US-SEER (Surveillance, Epidemiology, and End Results) cancer registries. We employed a counterfactual approach to estimate the mean survival time up to the 60th month since diagnosis for black colorectal cancer patients had black-white disparities in stage at diagnosis been eliminated. Black patients survive approximately 4.0 [confidence interval (CI), 4.6-3.2] months less than white patients within five years since diagnosis. Had disparities in stage at diagnosis been eliminated, survival disparities decrease to 2.6 (CI, 3.4-1.7) months, an approximately 35% reduction. For patients diagnosed after the age of 65 years, disparities would be halved, while reduction of approximately 30% is estimated for younger patients. Survival disparities would be reduced by approximately 44% for women and approximately 26% for men. Employing a counterfactual approach and allowing for heterogeneities in black-white disparities across patients' characteristics, we give robust evidence that elimination of disparities in stage at diagnosis contributes to a substantial reduction in survival disparities in colorectal cancer. We provide the first evidence in the SEER population that elimination of inequities in stage at diagnosis might lead to larger reductions in survival disparities among elderly and women.


Optic nerve head topographic measurements and retinal nerve fiber layer thickness in physiologic large cups.
To evaluate the parameters of optic nerve head (ONH) and retinal nerve fiber layer (RNFL) in patients with large cup/disc ratio (CDR) and normal neuroretinal rim configuration who have normal perimetry (physiologic large cups, LC) and to compare these parameters with those of the normal and early glaucoma patients. Using Heidelberg retinal tomography (HRT) and optical coherence tomography (OCT), 30 patients with LC, 29 normal subjects, and 31 early glaucoma patients were examined. One eye from each subject was randomly selected. Significant differences between LC and glaucomatous eyes (GE) were found in parameters indicating loss of nerve fibers, such as rim area, rim volume, and mean RNFL thickness. However, there was no difference between LC and normal eyes (NE) in RNFL thickness, rim area, and rim volume. LC was able to be defined as a normal central excavation with a large disc and large CDR with a normal rim area. HRT ONH parameters and RNFL thickness obtained with OCT may be useful for differentiating between glaucoma and LC eyes.


Is ryanodine receptor phosphorylation key to the fight or flight response and heart failure?
In situations of stress the heart beats faster and stronger. According to Marks and colleagues, this response is, to a large extent, the consequence of facilitated Ca²+ release from intracellular Ca²+ stores via ryanodine receptor 2 (RyR2), thought to be due to catecholamine-induced increases in RyR2 phosphorylation at serine 2808 (S2808). If catecholamine stimulation is sustained (for example, as occurs in heart failure), RyR2 becomes hyperphosphorylated and "leaky," leading to arrhythmias and other pathology. This "leaky RyR2 hypothesis" is highly controversial. In this issue of the JCI, Marks and colleagues report on two new mouse lines with mutations in S2808 that provide strong evidence supporting their theory. Moreover, the experiments revealed an influence of redox modifications of RyR2 that may account for some discrepancies in the field.


Positron emission tomographic analysis of central 5-hydroxytryptamine2 receptor occupancy in healthy volunteers treated with the novel antipsychotic agent, ziprasidone.
Ziprasidone is a novel antipsychotic agent, with high affinity for dopamine D2 and serotonin (5-HT2) receptors in vitro and in animal models. The goal of this study was to determine the time course of 5-HT2 receptor occupancy (%RO) in healthy humans after a single p.o. dose. Positron emission tomography with the 5-HT2 ligand, [18F]setoperone, was performed in eight male volunteers, in the drug-naive, base-line (BL) state and 4 to 18 hr after ziprasidone (40 mg). Cerebral cortical binding potential [BP, maximum number of available receptors/KD or association rate for specific binding (k3)/dissociation rate for specific binding (k4)] was estimated using the cerebellum as reference. Transport rate from plasma to brain (K1), transport rate from brain to plasma (k2), association rate of nonspecific binding (k5) and dissociation rate of nonspecific binding (k6) were derived by fitting cerebellar time-activity curves to a three-compartment model. Fitting of cortical data to a 4-compartment model with K1/k2, k5 and k6, fixed at cerebellar values, was used to determine k3 and k4. %RO was calculated using the relation: %RO = [(BPBL-BPDRUG)/BPBL] x 100%. At BL, cortical parameter (mean +/- S.E.M) were: K1 = 0.121 +/- 0.0072 ml.min-1.g-1; k2 = 0.0581 +/- 0.004 min-1; k3 = 0.321 +/- 0.0026 min-1; k4 = 0.0957 +/- 0.0059 min-1; k5 = 0.0147 +/- 0.00066 min-1; and k6 = 0.0059 +/- 0.00042 min-1. Ziprasidone did not effect K1, k2, k5 or k6; however, k3 was reduced and k4 was elevated (P < .01). RO was nearly complete at 4 hr after dosing (98%) and remained elevated at 18 hr (46%). Plasma concentrations were well described by a biexponential function and decreased much more rapidly than RO. These results establish that ziprasidone has high potency for blocking 5-HT2 receptors in healthy humans; a potentially important characteristic of atypical antipsychotic agents.


Characterization of a plastic dosimeter based on organic semiconductor photodiodes and scintillator.
Measurement of dose delivery is essential to guarantee the safety of patients undergoing medical radiation imaging or treatment procedures. This study aimed to evaluate the ability of organic semiconductors, coupled with a plastic scintillator, to measure photon dose in clinically relevant conditions, and establish its radiation hardness. Thereby, proving organic devices are capable of being a water-equivalent, mechanically flexible, real-time dosimeter. The shelf-life of an organic photodiode was analyzed to 40 kGy by comparison of the charge-collection-efficiency of a 520 nm light emitting diode. A non-irradiated and pre-irradiated photodiode was coupled to a plastic scintillator and their response to 6 MV photons was investigated. The dose linearity, dose-per-pulse dependence and energy dependence was characterized. Finally, the percentage depth dose (PDD) between 0.5 and 20 cm was compared with ionization chamber measurements. Sensitivity to 6 MV photons was (190 ± 0.28) pC/cGy and (170 ± 0.11) pC/cGy for the non-irradiated and pre-irradiated photodiode biased at -2 V. The response was independent of the dose-per-pulse between 0.031 and 0.34 mGy/pulse. An energy dependence was found for low keV energies, explained by the energy dependence of the scintillator which plateaued between 70 keV and 1.2 MeV. The PDD was within ±3% of the ionization chamber. Coupling an organic photodiode with a plastic scintillator provided reliable measurement of a range of photon energies. Dose-per-pulse and energy independence advocate their use as a dosimeter, specifically image-guided treatment without beam-quality correction factors. Degradation effects of organic semiconducting materials deteriorate sensor response but can be stabilized.


Wafer fault measurement by coherent optical processor.
A microscope coherent optical processor based on the VanderLugt optical correlator is applied to the measurement of registration error in multilayer integrated-circuit wafers. A treatment of the effects of wafer faults on the correlation signal is given. Threshold criteria and fault-induced peak splitting of the correlation signal from reject production samples are exploited to demonstrate the easy and rapid detection of faults in partially processed integrated-circuit wafers.


Sulfation of resveratrol in human liver: evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1.
Sulfation of resveratrol, a polyphenolic compound present in grapes and wine with anticancer and cardioprotective activities, was studied in human liver cytosol. In the presence of 3'-phosphoadenosine-5'-phosphosulfate, three metabolites (M1-3) whose structures were identified by mass spectrometry and NMR as trans-resveratrol-3-O-sulfate, trans-resveratrol-4'-O-sulfate, and trans-resveratrol-3-O-4'-O-disulfate, respectively. The kinetics of M1 formation in human liver cytosol exhibited an pattern of substrate inhibition with a K(i) of 21.3 +/- 8.73 microM and a V(max)/K(m) of 1.63 +/- 0.41 microLmin(-1)mg(-1) protein. Formation of M2 and M3 showed sigmoidal kinetics with about 56-fold higher V(max)/K(m) values for M3 than for M2 (2.23 +/- 0.14 and 0.04 +/- 0.01 microLmin(-1)mg(-1)). Incubation in the presence of human recombinant sulfotransferases (SULTs) demonstrated that M1 is almost exclusively catalysed by SULT1A1 and only to a minor extent by SULT 1A2, 1A3 and 1E1, whereas M2 is selectively formed by SULT1A2. M3 is mainly catalysed by SULT1A2 and 1A3. In conclusion, the results elucidate the enzymatic pathways of resveratrol in human liver, which must be considered in humans following oral uptake of dietary resveratrol.


Endocyclophotodestruction in glaucoma patients undergoing combined surgery of pars plana vitrectomy and phacoemulsification.
The purpose of this trail was to assess the effect of a novel intraoperative endocyclophotodestruction method on intraocular pressure in patients undergoing combined procedure of phacovitrectomy to determine the efficacy of this combined surgical approach. The study sample included 87 subjects divided into 2 groups: Group I consisted of 52 patients who underwent intraoperative endocyclophotodestruction performed during phacovitrectomy. Group II consisted of 35 controls. The follow-up duration was 12 months. The preoperative (baseline) intraocular pressure (IOP) was determined and later assessed postoperatively at the following time points: on 1 day and at 1, 2, 3, 6, and 12 months. Other evaluated parameters were the number of topical antiglaucoma medications, and the cyclophotodestruction circumference-to-outflow resistance ratio (R). The mean postoperative reduction of intraocular pressure was by 4.26 mmHg at 6 months and by 4.91 mmHg at 12 months. The number of topical antiglaucoma medications was reduced postoperatively from the mean preoperative value of 1.66 to 0.69 at 6 months and 1.04 at 12 months. The results show a significant reduction of intraocular pressure in patients undergoing the combined triple-procedure surgery and postoperative decrease in the number of topical medications. The best outcomes in terms of IOP decrease and reduced number of medications were achieved in patients with low outflow coefficient. Endocyclophotodestruction is an alternative IOP-reducing technique to be used in patients with glaucoma who require phacovitrectomy. It is recommended for patients with low outflow coefficient in whom posterior pole abnormalities constitute the main indications for surgery.


Australian Twin Registry: 30 years of progress.
The Australian Twin Registry (ATR) is a national volunteer resource of twin pairs and higher-order multiples willing to consider participating in health, medical, and scientific research. The vision of the ATR is 'to realize the full potential of research involving twins to improve the health and well-being of all Australians'. The ATR has been funded continuously by the National Health and Medical Council for more than 30 years. Its core functions entail the recruitment and retention of twin members, the maintenance of an up-to-date database containing members' contact details and baseline information, and the promotion and provision of open access to researchers from all institutes in Australia, and their collaborators, in a fair and equitable manner. The ATR is administered by The University of Melbourne, which acts as custodian. Since the late 1970s the ATR has enrolled more than 40,000 twin pairs of all zygosities and facilitated more than 500 studies that have produced at least 700 peer-reviewed publications from classical twin studies, co-twin control studies, within-pair comparisons, twin family studies, longitudinal twin studies, randomized controlled trials, and epigenetics studies, as well as studies of issues specific to twins. New initiatives include: a Health and Life Style Questionnaire; data collection, management, and archiving using a secure online software program (The Ark); and the International Network of Twin Registries. The ATR's expertise and 30 years of experience in providing services to national and international twin studies has made it an important resource for research across a broad range of disciplines.


Engineered quasi-phase matching for multiple parametric generation.
We develop a rapid and efficient numeric technique for the design of arbitrary quasi-phase matched lattices for parametric generation of single and multiple pulses with any prescribed amplitude and phase profiles from fundamental frequency excitation in the regime of pump depletion. We examine the case of simultaneous of 2nd and 3rd harmonic generation in arbitrary quasi-phase matched gratings taking into account the group velocity mismatch and dispersion.


Development of a Patient Decision Aid for Syncope in the Emergency Department: the SynDA Tool.
The objective was to develop a patient decision aid (DA) to promote shared decision making (SDM) for stable, alert patients who present to the emergency department (ED) with syncope. Using input from patients, clinicians, and experts in the field of syncope, health care design, and SDM, we created a prototype of a paper-based DA to engage patients in the disposition decision (admission vs. discharge) after an unremarkable ED evaluation for syncope. In phase 1, we conducted one-on-one semistructured exploratory interviews with 10 emergency physicians and 10 ED syncope patients. In phase 2, we conducted one-on-one directed interviews with 15 emergency care clinicians, five cardiologists, and 12 ED syncope patients to get detailed feedback on DA content and design. We iteratively modified the aid using feedback from each interviewee until clarity and usability had been optimized. The 11 × 17-inch, paper-based DA, titled SynDA, includes four sections: 1) explanation of syncope, 2) explanation of future risks, 3) personalized 30-day risk estimate, and 4) disposition options. The personalized risk estimate is calculated using a recently published syncope risk-stratification tool. This risk estimate is stated in natural frequency and graphically displayed using a 100-person color-coded pictogram. Patient-oriented questions are included to stimulate dialogue between patient and clinician. At the end of the development process, patient and physician participants expressed satisfaction with the clarity and usability of the DA. We iteratively developed an evidence-based DA to facilitate SDM for alert syncope patients after an unremarkable ED evaluation. Further testing is required to determine its effects on patient care. This DA has the potential to improve care for syncope patients and promote patient-centered care in emergency medicine.


Cellular and molecular actions of dinitroaniline and phosphorothioamidate herbicides on Plasmodium falciparum: tubulin as a specific antimalarial target.
Microtubules play important roles in cell division, motility and structural integrity of malarial parasites. Some microtubule inhibitors disrupt parasite development at very low concentrations, but most of them also kill mammalian cells. However, the dinitroaniline family of herbicides, which bind specifically to plant tubulin, have inhibitory activity on plant cells but are relatively non-toxic to human cells. Certain dinitroanilines are also inhibitory to various protozoal parasites including Plasmodium. Here we demonstrate that the dinitroanilines trifluralin and oryzalin inhibited progression of erythrocytic Plasmodium falciparum through schizogony, blocked mitotic division, and caused accumulation of abnormal microtubular structures. Moreover, radiolabelled trifluralin interacted with purified, recombinant parasite tubulins but to a much lesser extent with bovine tubulins. The phosphorothioamidate herbicide amiprophos-methyl, which has the same herbicidal mechanism as dinitroanilines, also had antimalarial activity and a similar action on schizogony. These data suggest that P. falciparum tubulin contains a dinitroaniline/phosphorothioamidate-binding site that is not conserved in humans and might be a target for new antimalarial drugs.


Creating a nationally representative sample of patients from trauma centers.
The National Trauma Data Bank (NTDB) was developed as a convenience sample of registry data from contributing trauma centers (TCs), thus, inferences about trauma patients may not be valid at the national level. The NTDB National Sample was created to obtain nationally representative estimates of trauma patients treated in the US level I and II TCs. Level I and II TCs in the Trauma Information Exchange Program were identified and a random stratified sample of 100 TCs was selected. The probability-proportional-to-size method was used to select TCs and sample weights were calculated. National Sample Program estimates from 2003 to 2006 were compared with raw NTDB data, and to a subset of TCs in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample, a population-based dataset drawn from community hospitals. Weighted estimates from the NTDB National Sample range from 484,000 (2004) to 608,000 (2006) trauma incidents. Crude NTDB data over-represented the proportion of younger patients (0 years-14 years) compared with the NTDB National Sample, which does not include children's hospitals. Few TCs in Trauma Information Exchange Program are included in Healthcare Cost and Utilization Project Nationwide Inpatient Sample, but estimates based on this subset indicate a higher percentage of older patients (age 65 year or older, 23.98% versus 17.85%), lower percentage male patients, and a lower percentage of motor vehicle accidents compared with NTDB National Sample. Although nationally representative data regarding trauma patients are available in other population-based samples, they do not represent TCs patients and lack the specificity of National Sample Program data, which contains detailed information on injury mechanisms, diagnoses, and hospital treatment.


Distinct multivariate brain morphological patterns and their added predictive value with cognitive and polygenic risk scores in mental disorders.
The brain underpinnings of schizophrenia and bipolar disorders are multidimensional, reflecting complex pathological processes and causal pathways, requiring multivariate techniques to disentangle. Furthermore, little is known about the complementary clinical value of brain structural phenotypes when combined with data on cognitive performance and genetic risk. Using data-driven fusion of cortical thickness, surface area, and gray matter density maps (GMD), we found six biologically meaningful patterns showing strong group effects, including four statistically independent multimodal patterns reflecting co-occurring alterations in thickness and GMD in patients, over and above two other independent patterns of widespread thickness and area reduction. Case-control classification using cognitive scores alone revealed high accuracy, and adding imaging features or polygenic risk scores increased performance, suggesting their complementary predictive value with cognitive scores being the most sensitive features. Multivariate pattern analyses reveal distinct patterns of brain morphology in mental disorders, provide insights on the relative importance between brain structure, cognitive and polygenetic risk score in classification of patients, and demonstrate the importance of multivariate approaches in studying the pathophysiological substrate of these complex disorders.


The need for structural allograft biomechanical guidelines.
Because of their osteoconductive properties, structural bone allografts retain a theoretic advantage in biologic performance compared with artificial interbody fusion devices and endoprostheses. Present regulations have addressed the risks of disease transmission and tissue contamination, but comparatively few guidelines exist regarding donor eligibility and bone processing issues with a potential effect on the mechanical integrity of structural allograft bone. The lack of guidelines appears to have led to variation among allograft providers in terms of processing and donor screening regarding issues with recognized mechanical effects. Given the relative lack of data on which to base reasonable screening standards, we undertook basic biomechanical evaluation of one source of structural bone allograft, the femoral ring. Of our tested parameters, the minimum and maximum cortical wall thicknesses of femoral ring allograft were most strongly correlated with the axial compressive load to failure of the graft, suggesting that cortical wall thickness may be a useful screening tool for compressive resistance expected from fresh cortical bone allograft. Development of further biomechanical and clinical data to direct standard development appears warranted.


The spread of influenza A(H1N1)pdm09 in Victorian school children in 2009: implications for revised pandemic planning.
Victoria was the first state in Australia to experience community transmission of influenza A(H1N1)pdm09. We undertook a descriptive epidemiological analysis of the first 1,000 notified cases to describe the epidemic associated with school children and explore implications for school closure and antiviral distribution policy in revised pandemic plans. Records of the first 1,000 laboratory-confirmed cases of influenza A(H1N1)pdm09 notified to the Victorian Government Department of Health between 20 May and 5 June 2009 were extracted from the state's notifiable infectious diseases database. Descriptive analyses were conducted on case demographics, symptoms, case treatment, prophylaxis of contacts and distribution of cases in schools. Two-thirds of the first 1,000 cases were school-aged (5-17 years) with cases in 203 schools, particularly along the north and western peripheries of the metropolitan area. Cases in one school accounted for nearly 8% of all cases but the school was not closed until nine days after symptom onset of the first identified case. Amongst all cases, cough (85%) was the most commonly reported symptom followed by fever (68%) although this was significantly higher in primary school children (76%). The risk of hospitalisation was 2%. The median time between illness onset and notification of laboratory confirmation was four days, with only 10% of cases notified within two days of onset and thus eligible for oseltamivir treatment. Nearly 6,000 contacts were followed up for prophylaxis. With a generally mild clinical course and widespread transmission before its detection, limited and short-term school closures appeared to have minimal impact on influenza A(H1N1)pdm09 transmission. Antiviral treatment could rarely be delivered to cases within 48 hours of symptom onset. These scenarios and lessons learned from them need to be incorporated into revisions of pandemic plans.


Temperature monitoring with line scan echo planar spectroscopic imaging.
A new magnetic resonance imaging method, line scan echo planar spectroscopic imaging (LSEPSI), is shown capable of providing rapid, internally referenced temperature monitoring from water and fat chemical shifts. Orthogonal 90 degrees and 180 degrees slice selective RF pulses inclined by 45 degrees from the image plane solicit a spin echo from a tissue column. The echo is read by asymmetric sampling of 32 gradient echoes spaced 1.4-1.8 ms apart. Sixty-four adjacent columns are sequentially sampled in 4.2-6.4 s with 4,096 voxels sampled with voxel volumes of 0.08-0.13 cm3. Mixed mayonnaise/water phantoms were used to correlate LSEPSI-derived chemical shifts and thermocouple-based temperature measurements from 23 to 60 degrees C with a 1.5 T scanner. Measurement artifacts unrelated to temperature were investigated with the phantom, as was the feasibility of applying the sequence in human breast in vivo. The correlation between LSEPSI and thermocouple-based temperature measurements in the phantom was excellent (r2>0.99). Field drifts affecting the temperature measurements using the water peak alone were corrected by using the water/lipid peak difference. The sequence had an average temperature resolution of 1.4 degrees C in the phantom. The frequency difference measurement reduced the sensitivity to artifacts related to temperature. Both water and lipid peaks were detectable throughout many locations in the breast, suggesting the applicability of LSEPSI in this organ. T1-saturation losses occur in conventional and echo-planar based 2D CSI sequences using phase encoding methods with short TR periods. These losses are eliminated when individual columns are sampled in snapshot fashion with LSEPSI since the effective TR becomes the time between scans rather than excitations. T1 saturation can make small spectral peaks difficult to detect at high temperatures and generally lowers the signal-to-noise ratio of the spectra. The rapid acquisition and insensitivity to T1 saturation effects make LSEPSI an attractive technique for monitoring thermal therapies in breast using the internally referenced fat/water frequency separation.


Dynamic aspects of DGT as demonstrated by experiments with lanthanide complexes of a multidentate ligand.
Sampling of metals with the technique of diffusive gradients in thin-films (DGT) depends on the rates of diffusion and on the kinetics of interconversion of the species present. In this study the discrimination between metal complexes with different dissociation kinetics is investigated. Samplers with differentthicknesses of diffusive and resin gels were deployed in solutions containing 10 microg/L of each metal in the lanthanide (Ln) series (except Pm) and 2.0 x 10(-6) M of the ligand quin2 at an ionic strength of 0.1 M (KNO3) and pH 7.0. Diffusion coefficients of Ln3+ ions and Ln-quin2 complexes were determined in a diffusion cell experiment. The equilibrium speciation of the metals was calculated from available stability constants. The sampling rate (mass/time) was highly dependent on the dissociation-rate constant of the complexes. For complexes with dissociation kinetics that appreciably limited the uptake, the sampling rate decreased significantly with increasing deployment times (12, 24, and 76 h) and was virtually independent of the thickness of the diffusive gel. Placing a layer of diffusive gel behind the resin did not influence the accumulation of Lns in the resin gel, but doubling the thickness of the layer containing resin increased the uptake, and more so for the Lns forming less labile complexes. The Lns forming more labile complexes were enriched in the outer layer of the resin, and there was a trend toward even distribution between the outer and deeper parts of the resin layer for the Lns forming less labile complexes. The measured DGT sampling rates (mass/ time) were reasonably well predicted by a dynamic model that used independently determined kinetic constants. This new knowledge of how metal complexes behave in the sampling process paves the way for using DGT to obtain in situ kinetic information in natural waters.


Health problems during childhood and school achievement: Exploring associations between hospitalization exposures, gender, timing, and compulsory school grades.
To investigate while accounting for health at birth 1) associations between health problems during childhood, measured as hospitalizations, and school achievement in the final year of compulsory school, measured as overall grade points and eligibility for upper secondary education, 2) if and how gender moderates the association between health problems and school achievement, 3) if and how the timing of a health problem during childhood is associated with later school achievement. Analyzes were performed on a population-based cohort (n = 115 196) born in 1990 in Sweden (51.3% boys, 48.7% girls) using data from several national registries. Multiple linear regression and logistic regression were used to analyze associations between study variables. Overall grade points and eligibility for continuation to upper secondary school were lower for individuals exposed to hospitalizations. Only the association between hospitalizations and overall grade points was moderated by gender and only for ages 13-16 years. Exposure close to actual grading had worst outcomes. Health problems, measured through hospitalizations, was significantly associated with lower school achievements among Swedish children. Girls exposed to health problems requiring hospitalizations had relatively poorer school achievements as compared to boys. Health problems requiring hospitalization during junior high school had the greatest negative association with final achievement at compulsory school.


Effects of Isosorbide Mononitrate and/or Cilostazol on Hematological Markers, Platelet Function, and Hemodynamics in Patients With Lacunar Ischaemic Stroke: Safety Data From the Lacunar Intervention-1 (LACI-1) Trial.
Background: Cilostazol and isosorbide mononitrate (ISMN) are candidate treatments for cerebral small vessel disease and lacunar ischaemic stroke. As both drugs may influence hemoglobin and platelet count, and hemodynamics, we sought to assess their effects in the lacunar intervention-1 (LACI-1) trial. Methods: Fifty-seven lacunar ischaemic stroke patients were randomized to immediate ISMN, cilostazol, or their combination for 9 weeks in addition to guideline stroke prevention. A fourth group received both drugs with a delayed start. Full blood count, platelet function, peripheral blood pressure (BP), heart rate and central hemodynamics (Augmentation index, Buckberg index) were measured at baseline, and weeks 3 and 8. Differences were assessed by multiple linear regression adjusted for baseline and key prognostic variables. Registration ISRCTN 12580546. Results: At week 8, platelet count was higher with cilostazol vs. no cilostazol (mean difference, MD 35.73, 95% confidence intervals, 95% CI 2.81-68.66, p = 0.033), but no significant differences were noted for hemoglobin levels or platelet function. At week 8, BP did not differ between the treatment groups, whilst heart rate was higher in those taking cilostazol vs. no cilostazol (MD 6.42, 95% CI 1.17-11.68, p = 0.017). Buckberg index (subendocardial perfusion) was lower in those randomized to cilostazol vs. no cilostazol and in those randomized to both drugs vs. either drug. Whilst ISMN significantly increased unadjusted augmentation index (arterial stiffness, MD 21.19, 95% CI 9.08-33.31, p = 0.001), in isolation both drugs non-significantly reduced augmentation index adjusted for heart rate. Conclusions: Cilostazol increased heart rate and platelet count, and reduced Buckberg index, whilst both drugs may individually reduce arterial stiffness adjusted for heart rate. Neither drug had clinically significant effects on hemoglobin or platelet function over 8 weeks. Further assessment of the safety and efficacy of these medications following lacunar ischaemic stroke is warranted.


Bibliometric assessment of cancer research in Puerto Rico, 1903-2005.
The analysis of scientific production in Puerto Rico is largely unexplored. The main aim of this study is to present the characteristics and trends of cancer publications in Puerto Rico's biomedical journals and their relationship with the island's cancer mortality. A PubMed and a hard-copy search were performed to retrieve cancer-related articles published in the Puerto Rico Health Sciences Journal and the Boletín de la Asociación Médica de Puerto Rico from 1903 to 2005. Bibliometric indicators studied included the number of authors and references by article, first author's institutional affiliation and country, document type, and language. The study type and tumor classification were also recorded. Cancer proportional mortality (M%) in Puerto Rico and the proportion of cancer-related articles (P%) published were also evaluated. The annual percent change (APC) was estimated to assess trends. A total of 369 articles were retrieved. The institutions with the majority of publications were universities (39.6%), English was the predominant publication language (72.1%), and the principal document type was original papers (69.6%). Epidemiologic studies were the dominant study type (62.1%), and the most studied cancers were digestive (15.4%) and gynecologic (9.6%). Although the P% has increased since 1913 (APC = 1.2%), the M% increased at a faster pace (APC = 2.7%). Although a growth in the number of cancer publications is observed in these journals, it does not parallel the increase in proportional mortality. A better understanding of the cancer publications in Puerto Rico is essential to establish priorities, define future areas of research, and develop cancer control strategies.


A voltage-gated calcium-selective channel encoded by a sodium channel-like gene.
BSC1, which was originally identified by its sequence similarity to voltage-gated Na(+) channels, encodes a functional voltage-gated cation channel whose properties differ significantly from Na(+) channels. BSC1 has slower kinetics of activation and inactivation than Na(+) channels, it is more selective for Ba(2+) than for Na(+), it is blocked by Cd(2+), and Na(+) currents through BSC1 are blocked by low concentrations of Ca(2+). All of these properties are more similar to voltage-gated Ca(2+) channels than to voltage-gated Na(+) channels. The selectivity for Ba(2+) is partially due to the presence of a glutamate in the pore-forming region of domain III, since replacing that residue with lysine (normally present in voltage-gated Na(+) channels) makes the channel more selective for Na(+). BSC1 appears to be the prototype of a novel family of invertebrate voltage-dependent cation channels with a close structural and evolutionary relationship to voltage-gated Na(+) and Ca(2+) channels.


Epidural stimulation induced modulation of spinal locomotor networks in adult spinal rats.
The importance of the in vivo dynamic nature of the circuitries within the spinal cord that generate locomotion is becoming increasingly evident. We examined the characteristics of hindlimb EMG activity evoked in response to epidural stimulation at the S1 spinal cord segment in complete midthoracic spinal cord-transected rats at different stages of postlesion recovery. A progressive and phase-dependent modulation of monosynaptic (middle) and long-latency (late) stimulation-evoked EMG responses was observed throughout the step cycle. During the first 3 weeks after injury, the amplitude of the middle response was potentiated during the EMG bursts, whereas after 4 weeks, both the middle and late responses were phase-dependently modulated. The middle- and late-response magnitudes were closely linked to the amplitude and duration of the EMG bursts during locomotion facilitated by epidural stimulation. The optimum stimulation frequency that maintained consistent activity of the long-latency responses ranged from 40 to 60 Hz, whereas the short-latency responses were consistent from 5 to 130 Hz. These data demonstrate that both middle and late evoked potentials within a motor pool are strictly gated during in vivo bipedal stepping as a function of the general excitability of the motor pool and, thus, as a function of the phase of the step cycle. These data demonstrate that spinal cord epidural stimulation can facilitate locomotion in a time-dependent manner after lesion. The long-latency responses to epidural stimulation are correlated with the recovery of weight-bearing bipedal locomotion and may reflect activation of interneuronal central pattern-generating circuits.


Genome-Guided Analysis and Whole Transcriptome Profiling of the Mesophilic Syntrophic Acetate Oxidising Bacterium Syntrophaceticus schinkii.
Syntrophaceticus schinkii is a mesophilic, anaerobic bacterium capable of oxidising acetate to CO2 and H2 in intimate association with a methanogenic partner, a syntrophic relationship which operates close to the energetic limits of microbial life. Syntrophaceticus schinkii has been identified as a key organism in engineered methane-producing processes relying on syntrophic acetate oxidation as the main methane-producing pathway. However, due to strict cultivation requirements and difficulties in reconstituting the thermodynamically unfavourable acetate oxidation, the physiology of this functional group is poorly understood. Genome-guided and whole transcriptome analyses performed in the present study provide new insights into habitat adaptation, syntrophic acetate oxidation and energy conservation. The working draft genome of Syntrophaceticus schinkii indicates limited metabolic capacities, with lack of organic nutrient uptake systems, chemotactic machineries, carbon catabolite repression and incomplete biosynthesis pathways. Ech hydrogenase, [FeFe] hydrogenases, [NiFe] hydrogenases, F1F0-ATP synthase and membrane-bound and cytoplasmic formate dehydrogenases were found clearly expressed, whereas Rnf and a predicted oxidoreductase/heterodisulphide reductase complex, both found encoded in the genome, were not expressed under syntrophic growth condition. A transporter sharing similarities to the high-affinity acetate transporters of aceticlastic methanogens was also found expressed, suggesting that Syntrophaceticus schinkii can potentially compete with methanogens for acetate. Acetate oxidation seems to proceed via the Wood-Ljungdahl pathway as all genes involved in this pathway were highly expressed. This study shows that Syntrophaceticus schinkii is a highly specialised, habitat-adapted organism relying on syntrophic acetate oxidation rather than metabolic versatility. By expanding its complement of respiratory complexes, it might overcome limiting bioenergetic barriers, and drive efficient energy conservation from reactions operating close to the thermodynamic equilibrium, which might enable S. schinkii to occupy the same niche as the aceticlastic methanogens. The knowledge gained here will help specify process conditions supporting efficient and robust biogas production and will help identify mechanisms important for the syntrophic lifestyle.


Fatal jellyfish envenoming-Pediatric and geographic vulnerabilities.
Lethal jellyfish envenoming is a very rare event. Two illustrative cases of fatalities following envenomation from the multi-tentacled box jellyfish, Chironex fleckeri, are reported that involved a six-year-old boy and a three-year-old girl, both of whom had been playing in shallow beach waters in remote Northern Territory communities (Australia). A recommended approach to autopsy in suspected cases is described, which should include examination of the clothing and skin surfaces for the fine tentacles of Chironex fleckeri. In addition, the combined length and maximum width of tentacle marks should be measured/calculated and collection of unfixed tentacles with adhesive tape onto a glass slide should be undertaken to check for nematocysts. Such rare cases show that children are at higher risk of a lethal outcome, particularly if they are resident in remote coastal tropical communities.


AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis.
Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases.


Plausible self-reported dietary intakes in a residential facility are not necessarily reliable.
Comparing reported energy intakes with estimated energy requirements as multiples of basal metabolic rate (Ein:BMR) is an established method of identifying implausible food intake records. The present study aimed to examine the validity of self-reported food intakes believed to be plausible. One hundred and eighty men and women were provided with all food and beverages for two consecutive days in a residential laboratory setting. Subjects self-reported their food and beverage intakes using the weighed food diary method (WDR). Investigators covertly measured subjects' actual consumption over the same period. Subjects also reported intakes over four consecutive days at home. BMR was measured by indirect calorimetry. Average reported energy intakes were significantly lower than actual intakes (11.2 and 11.8 MJ/d, respectively, P<0.001). Two-thirds (121) of the WDR were under-reported to varying degrees. Only five of these were considered as implausible using an Ein:BMR cut-off value of 1.03*BMR. Under-reporting of food and beverage intakes, as measured by the difference between reported and actual intake, was evident at all levels of Ein;BMR. Reported energy intakes were lower still (10.2 MJ/d) while subjects were at home. Under-recording of self-reported food intake records was extensive but very few under-reported food intake records were identified as implausible using energy intake to BMR ratios. Under-recording was evident at all levels of energy intake.


Technoeconomic analysis for biofuels and bioproducts.
Technoeconomic analysis (TEA) is an approach for conducting process design and simulation, informed by empirical data, to estimate capital costs, operating costs, mass balances, and energy balances for a commercial scale biorefinery. TEA serves as a useful method to screen potential research priorities, identify cost bottlenecks at the earliest stages of research, and provide the mass and energy data needed to conduct life-cycle environmental assessments. Recent studies have produced new tools and methods to enable faster iteration on potential designs, more robust uncertainty analysis, and greater accessibility through the use of open-source platforms. There is also a trend toward more expansive system boundaries to incorporate the impact of policy incentives, use-phase performance differences, and potential impacts on global market supply.


Neonatal hippocampal volume moderates the effects of early postnatal enrichment on cognitive development.
Environmental enrichment, particularly during the early life phases of enhanced neuroplasticity, can stimulate cognitive development. However, individuals exhibit considerable variation in their response to environmental enrichment. Recent evidence suggests that certain neurophenotypes such as hippocampal size may index inter-individual differences in sensitivity to environmental conditions. We conducted a prospective, longitudinal investigation in a cohort of 75 mother-child dyads to investigate whether neonatal hippocampal volume moderates the effects of the postnatal environment on cognitive development. Newborn hippocampal volume was quantified shortly after birth (26.2 ± 12.5 days) by structural MRI. Measures of infant environmental enrichment (assessed by the IT-HOME) and cognitive state (assessed by the Bayley-III) were obtained at 6 months of age (6.09 ± 1.43 months). The interaction between neonatal hippocampal volume and enrichment predicted infant cognitive development (b = 0.01, 95 % CI [0.00, 0.02], t = 2.08, p = .04), suggesting that exposure to a stimulating environment had a larger beneficial effect on cognitive outcomes among infants with a larger hippocampus as neonates. Our findings suggest that the effects of the postnatal environment on infant cognitive development are conditioned, in part, upon characteristics of the newborn brain, and that newborn hippocampal volume is a candidate neurophenotype in this context.


Cannabinoids control spasticity and tremor in a multiple sclerosis model.
Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, delta9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis, and provides a means of evaluating more selective cannabinoids in the future.


Defining child noncompliance: an examination of temporal parameters.
This study examined compliance parameters for 53 clinic-referred and nonreferred children, ages 2 to 10 years. Although there were significant differences between the referred and nonreferred samples for percentage compliance, there were no significant differences between the referred and nonreferred samples in terms of initiation or completion latencies. The average initiation latency was 5.92 s, whereas 98% of the sample initiated compliance within 14 s. Younger children did take longer to complete tasks. Results suggest that the use of short latencies in defining noncompliance may represent overly conservative criteria.


Mood and Stress Evaluation of Adult Patients With Moyamoya Disease in Korea: Ecological Momentary Assessment Method Using a Mobile Phone App.
Moyamoya disease (MMD) is a known progressive obstructive cerebrovascular disorder. Monitoring and managing mood and stress are critical for patients with MMD, as they affect clinical outcomes. The ecological momentary assessment (EMA) method is a longitudinal study design by which multiple variable assessments can be performed over time to detect momentary fluctuations and changes in psychological dimensions such as mood and stress over time. This study aimed to identify predicting factors associated with momentary mood and stress at both the within-person and between-person levels and to examine individual fluctuation of mood over time in the short term using an EMA method combined with a mobile phone app. Participants aged older than 18 years were recruited from a tertiary hospital in Seoul, Korea, between July 2018 and January 2019. The PsyMate scale for negative affect (NA) and positive affect (PA) and the Trier Inventory for Chronic Stress Scale were uploaded on patient mobile phones. Using a mobile app, data were collected four times a day for 7 days. Pearson correlations and mixed modeling were used to predict relationships between repeatedly measured variables at both the between-person and within-person levels. The mean age of the 93 participants was 40.59 (SD 10.06) years, 66 (71%) were female, and 71 (76%) were married. Participants provided 1929 responses out of a possible 2604 responses (1929/2604, 74.08%). The mean momentary NA and PA values were 2.15 (SD 1.12) and 4.70 (SD 1.31) out of 7, respectively. The momentary stress value was 2.03 (SD 0.98) out of 5. Momentary NA, PA, and stress were correlated (P<.001) and varied over time in relation to momentary variables. Common momentary variables associated with momentary mood and stress at both the within-person (level 1) and between-person (level 2) levels were identified. Momentary NA increased when being alone and being at the hospital at both levels, whereas momentary PA increased when eating or drinking, resting, being at a café, restaurant or a public place but decreased when being alone at both levels. Momentary stress increased when being at the office, at a public place, or as the time of the day went by but decreased when resting or during the weekend. Different factors affecting mood and stress at different levels were identified. Fluctuations in individual momentary mood over time at the within-person level were captured. The EMA method using a mobile phone app demonstrated its ability to capture changes in mood and stress in various environmental contexts in patients with MMD. The results could provide baseline information for developing interventions to manage negative mood and stress of patients with MMD based on the identified predictors affecting mood and stress at two different levels.


Ultrasensitive estrogen levels at 7 years of age predict earlier thelarche: evidence from girls of the growth and obesity Chilean cohort.
Prepubertal estradiol equivalents have been inconsistently linked to age at thelarche; elucidating this relationship becomes relevant given the worldwide decline in the age of puberty onset. Thus, our aim is to assess whether prepubertal girls with higher serum levels of estradiol equivalents at age 7 have a greater risk of presenting early thelarche (ET). Nested case-control study within the Growth and Obesity Cohort Study of 1196 low-middle income children (∼50% girls) from Santiago, Chile. Girls were defined as cases (ET; n=61) if breast bud appeared prior to 8 years of age; controls (n=91) had thelarche >8 years. At 6.7 years, weight, height and waist circumference were measured and a fasting blood sample was obtained for measuring estrogen equivalent (ultrasensitive recombinant cell bioassay), DHEAS, leptin, insulin and IGF1. Beginning at 7 years old, Tanner staging was assessed prospectively twice a year and the appearance of breast bud was assessed by palpation. Mean serum estradiol-equivalent at 6.7 years was 3.9±3.6 pg/ml for cases and 3.6±2.3 pg/ml for controls. Girls with ET had a higher risk of presenting elevated estradiol-equivalent (≥5 pg/ml) at 7 years (OR=2.05, 95% CI: 0.96-4.36) than controls that was borderline significant. However, after adjusting by BMI, insulin and IGF1 at age 7, the association between estradiol-equivalent and ET was significant (OR=2.29 (95% CI: 1.05-5.01)). Chilean girls from low to middle socioeconomic status with ET exhibited double the risk of having high levels of estradiol-equivalent at 7 years than girls with a later age of thelarche. Whole-body adiposity and increased adrenal activity did not explain the observed prepubertal estrogen increase.


Biofidelity Assessment of the WIAMan Thorax by a Comparative Study With Hybrid III, THOR, and PMHS in Frontal Sled Testing.
The Warrior Injury Assessment Manikin (WIAMan) anthropomorphic test device (ATD) has been originally developed to predict and prevent injuries for occupants in military vehicles, in an underbody blast environment. However, its crash performance and biofidelity of the thoracic region have not been explored. The aim of this study was to determine and evaluate the WIAMan thoracic responses in a typical frontal sled test. The 40 kph frontal sled tests were conducted to quantify the WIAMan thoracic kinematics, chest deflection, and belt loads. Comparative biofidelities of the WIAMan thorax and other surrogates, including postmortem human surrogates (PMHSs), Hybrid III, and test device for human occupant restraint (THOR) ATDs, were assessed under comparable testing conditions. The similarities and differences between WIAMan and the other surrogates were compared and analyzed, including the motion of bilateral shoulders and T1, time histories of chest deflections, and belt loads. The CORrelation and Analysis (CORA) ratings were used to evaluate the correlations of thoracic responses between the ATDs and PMHS. Compared to the PMHS and THOR, the WIAMan experienced a similar level of left shoulder forward excursions. Larger chest deflection was exhibited in WIAMan throughout the whole duration of belt compression. Differences were found in belt loads between subject types. Overall, WIAMan had slightly lower CORA scores but showed comparable overall performance. The overall thoracic responses of WIAMan under the frontal sled test were more compliant than HIII, but still reasonable compared with PMHS and THOR. Comprehensive systematic studies on comparative biofidelity of WIAMan and other surrogates under different impact conditions are expected in future research.


Numerical Simulations of Exhaled Particles from Wearers of Powered Air Purifying Respirators.
In surgical settings, infectious particulate wound contamination is a recognized cause of post-operative infections. Powered air purifying respirators (PAPRs) are worn by healthcare workers for personal protection against contaminated aerosols. Healthcare infection preventionists have expressed concern about the possibility that infectious particles expelled from PAPR exhalation channels could lead to healthcare-associated disease, especially in operative settings where sterile procedural technique is essential. This study used computational fluid dynamics (CFD) modeling to simulate and visualize the distribution of particles exhaled by PAPR wearers. Using CFD simulations, the PAPR inside to outside ratio of particle concentrations was estimated. Also, the effects of particle sizes, supplied-air flow rates, and breathing work rates on outward leakage were evaluated. This simulation study reconstructed a geometrical model of a static median headform wearing a loose-fitting PAPR by capturing a 3D image. We defined a mathematical model for the headform and PAPR system and ran simulations with four particle sizes, three breathing workloads and two supplied-air flow rates (a total 24 configurations; 4×3×2=24) applied on the digital model of the headform and PAPR system. This model accounts for exhaled particles, but not ambient particles. Computed distributions of particles inside and outside the PAPR are displayed. The outward concentration leakage was low at surgical setting, e.g., it was about 9% for a particle size of 0.1 and 1 μm at light breathing and a 205 L/min supplied-air flow rate. The supplied-air flow rates, particle sizes, and breathing workloads had effects on the outward concentration leakage, as the outward concentration leakage increased as particle size decreased, breathing workload increased, and the supplied-air flow rate decreased. The CFD simulations can help to optimize the supplied-air flow rates. When the loose-fitting PAPR is used, exhaled particles with small size (below 1μm), or heavy breathing workloads, may generate a great risk to the sterile field and should be avoided.


The presumed atypical chemokine receptor CXCR7 signals through G(i/o) proteins in primary rodent astrocytes and human glioma cells.
SDF-1/CXCL12 binds to the chemokine receptors, CXCR4 and CXCR7, and controls cell proliferation and migration during development, tumorigenesis, and inflammatory processes. It is currently assumed that CXCR7 would represent an atypical or scavenger chemokine receptor which modulates the function of CXCR4. Contrasting this view, we demonstrated recently that CXCR7 actively mediates SDF-1 signaling in primary astrocytes. Here, we provide evidence that CXCR7 affects astrocytic cell signaling and function through pertussis toxin-sensitive G(i/o) proteins. SDF-1-dependent activation of G(i/o) proteins and subsequent increases in intracellular Ca(2+) concentration persisted in primary rodent astrocytes with depleted expression of CXCR4, but were abolished in astrocytes with depleted expression of CXCR7. Moreover, CXCR7-mediated effects of SDF-1 on Erk and Akt signaling as well as on astrocytic proliferation and migration were all sensitive to pertussis toxin. Likewise, pertussis toxin abolished SDF-1-induced activation of Erk and Akt in CXCR7-only expressing human glioma cell lines. Finally, consistent with a ligand-biased function of CXCR7 in astrocytes, the alternate CXCR7 ligand, I-TAC/CXCL11, activated Erk and Akt through β-arrestin. The demonstration that SDF-1-bound CXCR7 activates G(i/o) proteins in astrocytes could help to explain some discrepancies previously observed for the function of CXCR4 and CXCR7 in other cell types.


Body Awareness as an Important Target in Multidisciplinary Chronic Pain Treatment: Mediation and Subgroup Analyses.
The results of a recently performed randomized clinical trial showed that the effect of a multidisciplinary treatment of chronic pain patients on body awareness (BA), catastrophizing, and depression was improved by adding psychomotor therapy (PMT), an intervention targeting BA. No significant effects were found on quality of life and disability. The present follow-up study aimed to explore the relationship between improvements in BA and multidisciplinary chronic pain rehabilitation treatment outcome across treatment conditions and the possible mediating effect of BA between treatment conditions. Furthermore, the hypothesis that patients with low BA benefit more from PMT was investigated. In total, 94 patients with chronic pain participated in a randomized clinical trial comparing multidisciplinary treatment as usual (TAU) with TAU plus PMT. Outcome variables were health-related quality of life, disability, and depression. Self-efficacy and catastrophizing were the process variables of treatment and the potential mediating factors in the relationship between BA and the outcome variables. The data were analyzed by linear mixed-model analysis. Improvements in BA were related to improvements in all outcome variables across treatment conditions. The relationships were partly mediated by self-efficacy, catastrophizing, or both. In the regression model with depression as the outcome variable, the regression coefficient of treatment (ie, PMT vs. TAU) decreased by 34% and became nonsignificant when BA was added as a potential mediator. Patients with low BA seemed to benefit more from PMT than patients with high BA, especially on depression, BA, and catastrophizing. BA might be an important target of treatment to improve the multidisciplinary treatment outcome in chronic pain patients. Furthermore, PMT is an intervention that seems to provide its benefits through improving BA and may be especially beneficial for patients with low BA.


Rapid Screening of Carboxylic Acids from Waste and Surface Waters by ESI-MS/MS Using Barium Ion Chemistry and On-Line Membrane Sampling.
Negative ion tandem mass spectrometric analysis of aliphatic carboxylic acids often yields only non-diagnostic ([M - H](-)) ions with limited selective fragmentation. However, carboxylates cationized with Ba(2+) have demonstrated efficient dissociation in positive ion mode, providing structurally diagnostic product ions. We report the application of barium adducts followed by collision induced dissociation (CID), to improve selectivity for rapid screening of carboxylic acids in complex aqueous samples. The quantitative MS/MS method presented utilizes common product ions of [M - H + Ba](+) precursor ions. The mechanism of product ion formation is investigated using isotopically labeled standards and a series of structurally related carboxylic acids. The results suggest that hydrogen atoms in the β and γ positions yield common product ions ([BaH](+) and [BaOH](+)). Furthermore, the diagnostic product ion at m/z 196 serves as a qualifying ion for carboxylate species. This methodology has been successfully used in conjunction with condensed phase membrane introduction mass spectrometry (CP-MIMS), with barium acetate added directly to the methanol acceptor phase. The combination enables rapid screening of carboxylic acids directly from acidified water samples (wastewater effluent, spiked natural waters) using a capillary hollow fiber PDMS membrane immersion probe. We have applied this technique for the direct analysis of complex naphthenic acid mixtures spiked into natural surface waters using CP-MIMS. Selectivity at the ionization and tandem mass spectrometry level eliminate isobaric interferences from hydroxylated species present within the samples, which have been observed in negative electrospray ionization.


Controlling for time-since-hire in occupational studies using internal comparisons and cumulative exposure.
Employees within an occupational cohort may demonstrate a more favorable mortality experience while maintaining employment than those who leave employment. At the same time, they may experience an apparent decline in health with time-since-hire. The time-since-hire effect may occur independently of exposure but may nevertheless result in groups categorized by cumulative exposure that are not comparable. Controlling for time-since-hire appears to solve this problem. To quantify the empirical bias in estimates of exposure effect due to confounding from time-since-hire, we analyzed two occupational cohorts using Poisson regression with and without adjustment for time-since-hire or time-since-start-of-follow-up. In a cohort exposed to airborne arsenic, a strong dose-response relation with respiratory cancer mortality had been established. In a cohort exposed to external, penetrating ionizing radiation, a weak and controversial dose-response relation had been reported. The parameter estimates relating exposure to disease from the models that explicitly adjusted for time-since-hire or time-since-start-of-follow-up are within 10% of the estimates from models that did not. It appears, from this empirical analysis of two datasets, that occupational studies may not need to adjust explicitly for such time-related factors as time-since-hire or time-since-start-of-follow-up if these are implicitly controlled through other variables in the model.


The application of subjective job task analysis techniques in physically demanding occupations: evidence for the presence of self-serving bias.
The aim of this study was to determine if perceptions of physically demanding job tasks are biased by employee demographics and employment profile characteristics including: age, sex, experience, length of tenure, rank and if they completed or supervised a task. Surveys were administered to 427 Royal Australian Navy personnel who characterised 33 tasks in terms of physical effort, importance, frequency, duration and vertical/horizontal distance travelled. Results showed no evidence of bias resulting from participant characteristics, however participants who were actively involved in both task participation and supervision rated these tasks as more important than those involved only in the supervision of that task. This may indicate self-serving bias in which participants that are more actively involved in a task had an inflated perception of that task's importance. These results have important implications for the conduct of job task analyses, especially the use of subjective methodologies in the development of scientifically defensible physical employment standards. Practitioner Summary: To examine the presence of systematic bias in subjective job task analysis methodologies, a survey was conducted on a sample of Royal Australian Navy personnel. The relationship between job task descriptions and participant's demographic and job profile characteristics revealed the presence of self-serving bias affecting perceptions of task importance.


Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology.
Although most mesotheliomas present with pleural effusions, it is controversial whether mesothelioma can be diagnosed with confidence in effusion cytology. Therefore, an ancillary marker of malignant mesothelial cells applicable in effusions would be clinically valuable. BRCA-1-associated protein (BAP1) is a tumor suppressor gene, which shows biallelic inactivation in approximately half of all mesotheliomas. We investigated whether loss of BAP1 expression by immunohistochemistry can be used to support a diagnosis of mesothelioma in effusion cytology. Immunohistochemistry for BAP1 was performed on cell blocks and interpreted blinded. 43 of 75 (57%) effusions associated with confirmed mesothelioma showed negative staining with positive internal controls. Of 57 effusions considered to have atypical mesothelial cells in the absence of a definitive diagnosis of mesothelioma, 8 cases demonstrated negative staining for BAP1. On follow-up six of these patients received a definitive diagnosis of mesothelioma in the subsequent 14 months (two were lost to follow-up immediately, and mesothelioma could not be excluded). Only 5 of 100 consecutive benign effusions were interpreted as BAP1 negative. One of these patients died soon after and mesothelioma could not be excluded. On unblinded review the four other patients with apparently negative BAP1 staining but no malignancy lacked convincing positive staining in non-neoplastic cells suggesting that BAP1 immunohistochemistry may have initially been misinterpreted. 47 effusions with adenocarcinoma were BAP1 positive. We conclude that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology. We caution that interpretation of BAP1 immunohistochemistry on cell block may be difficult and that convincing positive staining in non-neoplastic cells is required before atypical cells are considered negative. We also note that BAP1 loss is not a sensitive test as it occurs in only half of all mesotheliomas and cannot be used to exclude the diagnosis.


Overcoming phase 1 delays: the critical component of obstetric fistula prevention programs in resource-poor countries.
An obstetric fistula is a traumatic childbirth injury that occurs when labor is obstructed and delivery is delayed. Prolonged obstructed labor leads to the destruction of the tissues that normally separate the bladder from the vagina and creates a passageway (fistula) through which urine leaks continuously. Women with a fistula become social outcasts. Universal high-quality maternity care has eliminated the obstetric fistula in wealthy countries, but millions of women in resource-poor nations still experience prolonged labor and tens of thousands of new fistula sufferers are added to the millions of pre-existing cases each year. This article discusses fistula prevention in developing countries, focusing on the factors which delay treatment of prolonged labor. Obstetric fistulas can be prevented through contraception, avoiding obstructed labor, or improving outcomes for women who develop obstructed labor. Contraception is of little use to women who are already pregnant and there is no reliable screening test to predict obstruction in advance of labor. Improving the outcome of obstructed labor depends on prompt diagnosis and timely intervention (usually by cesarean section). Because obstetric fistulas are caused by tissue compression, the time interval from obstruction to delivery is critical. This time interval is often extended by delays in deciding to seek care, delays in arriving at a hospital, and delays in accessing treatment after arrival. Communities can reasonably demand that governments and healthcare institutions improve the second (transportation) and third (treatment) phases of delay. Initial delays in seeking hospital care are caused by failure to recognize that labor is prolonged, confusion concerning what should be done (often the result of competing therapeutic pathways), lack of women's agency, unfamiliarity with and fear of hospitals and the treatments they offer (especially surgery), and economic constraints on access to care. Women in resource-poor countries will use institutional obstetric care when the services provided are valued more than the competing choices offered by a pluralistic medical system. The key to obstetric fistula prevention is competent obstetrical care delivered respectfully, promptly, and at affordable cost. The utilization of these services is driven largely by trust.


The covariation of multiple risk factors in primary care: a latent class analysis.
There is a need to advance the quality of healthcare by increasing knowledge about multiple risk factors and how to intervene to improve health outcomes. In an effort to better describe the presentation of multiple risks, this study involved a database review to describe the prevalence and covariation of multiple risk factors in individuals presenting to primary care. Patients with a primary care encounter from January 1, 2005 to June 30, 2005 (N = 10,043) were identified from the Department of Veteran's Affair's medical database and information about the following risk factors was extracted: alcohol use, psychiatric distress, body mass, smoking status, blood pressure, and posttraumatic stress. Exploratory and confirmatory latent class analyses identified three classes of individuals. Class 1 consisted of individuals with an overall lower level of risk for health problems, but a moderately high likelihood of elevated blood pressure. Individuals in Class 2 appeared to have the greatest need for intervention because they had a moderate to high likelihood of reporting at risk alcohol use, smoking, depression, and posttraumatic stress. Class 3 consisted of individuals reporting the co-occurrence of at risk alcohol use, smoking, and elevated blood pressure. Similar to past research, the findings highlight the need for addressing multiple risk factors in primary care. In addition, this study expands on the literature by identifying specific patterns of covariation among different risk factors that suggest avenues for research and program development.


The Mediterranean Lifestyle as a Non-Pharmacological and Natural Antioxidant for Healthy Aging.
Oxidative stress has been suggested to affect age-associated physiological dysfunction. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing age-related diseases and death. Among different dietary habits, the highly antioxidant Mediterranean dietary pattern, which includes high vegetable and fruit intake, consumption of legumes, cereals, and fish, low intake of meat and dairy derivatives, moderate red wine consumption, and use of extra-virgin olive oil, is characterized by other aspects than food, such as conviviality, sensory stimulation, socialization, biodiversity, and seasonality that can reinforce the Mediterranean diet's (MeD) beneficial effects on wellbeing, quality of life, and healthy aging. The present review aims to discuss available data on the relationship between oxidative stress and aging, biomarkers of oxidative stress status, protective effects of the MeD, and the adoption of the Mediterranean lifestyle as a non-pharmacological and natural tool to cope with oxidative stress damage for a longer life span, and-even more important-healthy aging beyond the biological, psychological, and social challenges that old age entails.


[Quantification of myocardial tomography with thallium in coronary disease. Evaluation of the Cedars-Sinai technique].
The aim of this study is to evaluate the contribution of the Cedars-Sinai quantification tomographic method (CS) in the diagnosis and localization of ischemic areas in coronary artery disease (CAD) and to optimize the threshold values proposed by CS. Fifty patients with clinical suspicion of CAD performed a maximal stress test by cycloergometer; thallium myocardial tomographic images were obtained; applying the CS program afterwards. The sensitivity and specificity variations obtained by changing the criteria for extent of myocardial hypoperfusion (range 1% to 100%) were used to calculate the new thresholds (CS-I), using the results of coronariographic studies as a reference. The data determined by qualitative analysis were compared with that obtained by quantitative analysis by means of CS and CS-I using coronary angiography as the standard of reference. The coronary angiography showed coronary disease in 37 patients. The sensitivity for the diagnosis of CAD was superior using CS (97%) at the expense of low specificity (15%) which nevertheless improved with CS-I (54%). For the location of CAD, the visual analysis was statistically significant (p < 0.05) in the left anterior descending and right coronary arteries, CS being superior in the diagnosis of 3 vessel disease. The quantification of tomographic studies with thallium by means of CS needs a readjustment of the thresholds. The tested values (CS-I) improved the CS results, although they require prospective validation. Quantitative study permits the confirmation of visual findings, being a complementary method that can be rapidly and easily interpreted, although it is not recommended as a single technique for the diagnosis of coronary disease.


4,5-bis(4-fluoroanilino)phthalimide: A selective inhibitor of the epidermal growth factor receptor signal transduction pathway with potent in vivo antitumor activity.
Deregulated signal transduction via the epidermal growth factor (EGF) receptor family of tyrosine protein kinase growth factor receptors is associated with proliferative diseases such as cancer and psoriasis. In an attempt to selectively block signal transduction from the EGF receptor, we have synthesized a new class of dianilino-phthalimide tyrosine protein kinase inhibitors with selectivity for the EGF receptor tyrosine protein kinase. 4, 5-Dianilino-phthalimide (DAPH 1) was metabolized in vitro by mouse liver fractions and in vivo. The major metabolite has been identified as 4-(4-hydroxyanilino)-5-anilino-phthalimide. To specifically block this biotransformation (hydroxylation), we have synthesized 4,5-bis(4-fluoroanilino)phthalimide (DAPH 2), a potent and selective EGF receptor tyrosine protein kinase inhibitor. DAPH 2 inhibits the EGF receptor and protein kinase C beta2 enzymes with equal potency. In cells, DAPH 2 inhibits signal output from the EGF receptor, but not from other classes of receptor protein tyrosine kinases, such as the platelet-derived growth factor receptor, fibroblast growth factor receptor, insulin-like growth factor I receptor, and insulin receptor. Selective antitumor activity was demonstrated in vivo at well-tolerated doses in mice. This publication describes the biological profile of DAPH 2 and investigates its cellular and in vivo mechanism of action.


Retrieved implants from irradiated sites in humans: a histologic/histomorphometric investigation of oral and craniofacial implants.
The aim of this report was to quantitatively and qualitatively evaluate the tissue response to bone-anchored implants retrieved from irradiated sites in patients. The material consists of 23 consecutively received Brånemark implants (Nobel Biocare AB, Göteborg, Sweden) placed in pre- or postoperatively irradiated sites. Twenty-two of the 23 implants were suitable for histologic evaluation of undecalcified sections in the light microscope. The oral implants with shorter time in situ demonstrated sparse bone to implant contact with mainly dense connective tissue in the interface. However, for implants with longer time in situ, high amounts of bone-implant contact and bone fill of threads were noted. The mean values of bone-implant contact and bone area within the thread were calculated to 40% (16-94) and 70% (13-96), respectively. The craniofacial implants, with the exception of two implants lined with a capsular formation, demonstrated mature and newly formed bone at the bone-implant interface. The mean value for bone-metal contact was calculated to 45 and 53% for two specimens. The mean value for bone area within the thread ranged from 65 to 88% for three specimens. CONCLUSION; The possibility to achieve bone anchorage of implants in irradiated tissue was supported by the findings in this study. However, due to limited material, conclusions with regard to radiation dose and bone tissue response to implants cannot be stated.


Benzoquinone from Fusarium pigment inhibits the proliferation of estrogen receptor-positive MCF-7 cells through the NF-κB pathway via estrogen receptor signaling.
Natural pigments are known for possessing a wide range of pharmacological and health-promoting properties. The pigments, produced by a new strain Fusarium (Fusarium sp. JN158) previously identified in our laboratory, were found to have 6 peaks (representing 6 compounds) by high-performance liquid chromatography with a diode-array detector (HPLC-DAD) separation. The 6th peak compound (compound VI) is a benzoquinone compound. In this study, we examined the effects of compound VI on the proliferation of breast cancer cells and aimed to elucidate the underlying mechamisms. Compound VI exerted anti-proliferative effects on MCF‑7 estrogen receptor (ER)+ cells in a dose-dependent manner (IC25, 7 µM; IC50, 11 µM), whereas it had no effect on MDA‑MB‑231 ER- cells and normal cells. The cell index (CI) began to decrease at 24 h following treatment with benzoquinone. Mechanistically, the results from molecular analysis revealed that compound VI inhibited the expression of ERα, progesterone receptor (PR), vascular endothelial growth factor (VEGF), Bcl-2, cyclin D1 and nuclear factor-κB (NF-κB) p65, while it increased the expression of cleaved caspase-3 and Bax in the MCF‑7 cells. Taken together, our findings indicate that compound VI exerts anti-proliferative effects on MCF‑7 cells through the NF-κB pathway via the regulation of ER signaling. Our data may indicate that benzoquinone from Fusarium pigment may have potential for use as an anti-proliferative agent in the treatment of breast cancer.


Smooth muscle myosin expression, isoform composition, and functional activities in rat corpus cavernosum altered by the streptozotocin-induced type 1 diabetes.
Diabetes mellitus (DM) is a quite common chronic disease, and the prevalence of erectile dysfunction (ED) is three times higher in this large population. Although diabetes-related ED has been studied extensively, the actin-myosin contractile apparatus was not examined. The mRNAs encoding smooth muscle myosin (SMM) heavy chains (MHC) and essential light chains (LC(17)) exist as several different alternatively spliced isoforms with distinct contractile properties. Recently, we provided novel data that blebbistatin (BLEB), a specific myosin II inhibitor, potently relaxed corpus cavernosum smooth muscle (CCSM). In this study, we examine whether diabetes alters SMM expression, alternative splicing, and/or functional activities, including sensitivity to BLEB. By using streptozotocin (STZ)-induced 2-mo diabetic rats, functional activities were tested in vivo by intracavernous pressure (ICP) recording during cavernous nerve stimulation and in vitro via organ bath contractility studies. SMM isoform composition was analyzed by competitive RT-PCR and total SMM, myocardin, and embryonic SMM (SMemb) expression by real-time RT-PCR. Results revealed that the blood glucose level of STZ rats was 407.0 vs. 129.5 mg/dl (control). STZ rats exhibited ED confirmed by significantly increased CCSM contractile response to phenylephrine and decreased ICP response. For STZ rats, SM-B, LC(17a) and SM2 isoforms, total SMM, and myocardin expression increased, whereas SM-A, LC(17b), and SM1 isoforms were decreased, with SMemb unchanged. BLEB was significantly more effective in relaxing STZ CCSM both in vitro and in vivo. Thus we demonstrated a novel diabetes-specific effect on alternative splicing of the SMM heavy chain and essential light chain genes to a SMM isoform composition favoring a heightened contractility and ED. A switch to a more contractile phenotype was supported further by total SMM expression increase. Moreover, the change in CCSM phenotype was associated with an increased sensitivity to BLEB, which may serve as a novel pharmacotherapy for ED.


NADPH oxidase AtrbohD and AtrbohF genes function in ROS-dependent ABA signaling in Arabidopsis.
Reactive oxygen species (ROS) have been proposed to function as second messengers in abscisic acid (ABA) signaling in guard cells. However, the question whether ROS production is indeed required for ABA signal transduction in vivo has not yet been addressed, and the molecular mechanisms mediating ROS production during ABA signaling remain unknown. Here, we report identification of two partially redundant Arabidopsis guard cell-expressed NADPH oxidase catalytic subunit genes, AtrbohD and AtrbohF, in which gene disruption impairs ABA signaling. atrbohD/F double mutations impair ABA-induced stomatal closing, ABA promotion of ROS production, ABA-induced cytosolic Ca(2+) increases and ABA- activation of plasma membrane Ca(2+)-permeable channels in guard cells. Exogenous H(2)O(2) rescues both Ca(2+) channel activation and stomatal closing in atrbohD/F. ABA inhibition of seed germination and root elongation are impaired in atrbohD/F, suggesting more general roles for ROS and NADPH oxidases in ABA signaling. These data provide direct molecular genetic and cell biological evidence that ROS are rate-limiting second messengers in ABA signaling, and that the AtrbohD and AtrbohF NADPH oxidases function in guard cell ABA signal transduction.


Accuracy of single-pass whole-body computed tomography for detection of injuries in patients with major blunt trauma.
Contrast-enhanced whole-body computed tomography (also called "pan-scanning") is considered to be a conclusive diagnostic tool for major trauma. We sought to determine the accuracy of this method, focusing on the reliability of negative results. Between July 2006 and December 2008, a total of 982 patients with suspected severe injuries underwent single-pass pan-scanning at a metropolitan trauma centre. The findings of the scan were independently evaluated by two reviewers who analyzed the injuries to five body regions and compared the results to a synopsis of hospital charts, subsequent imaging and interventional procedures. We calculated the sensitivity and specificity of the pan-scan for each body region, and we assessed the residual risk of missed injuries that required surgery or critical care. A total of 1756 injuries were detected in the 982 patients scanned. Of these, 360 patients had an Injury Severity Score greater than 15. The median length of follow-up was 39 (interquartile range 7-490) days, and 474 patients underwent a definitive reference test. The sensitivity of the initial pan-scan was 84.6% for head and neck injuries, 79.6% for facial injuries, 86.7% for thoracic injuries, 85.7% for abdominal injuries and 86.2% for pelvic injuries. Specificity was 98.9% for head and neck injuries, 99.1% for facial injuries, 98.9% for thoracic injuries, 97.5% for abdominal injuries and 99.8% for pelvic injuries. In total, 62 patients had 70 missed injuries, indicating a residual risk of 6.3% (95% confidence interval 4.9%-8.0%). We found that the positive results of trauma pan-scans are conclusive but negative results require subsequent confirmation. The pan-scan algorithms reduce, but do not eliminate, the risk of missed injuries, and they should not replace close monitoring and clinical follow-up of patients with major trauma.


Kainate receptor-mediated modulation of hippocampal fast spiking interneurons in a rat model of schizophrenia.
Kainate receptor (KAR) subunits are believed to be involved in abnormal GABAergic neurotransmission in the hippocampus (HIPP) in schizophrenia (SZ) and bipolar disorder. Postmortem studies have shown changes in the expression of the GluR5/6 subunits of KARs in the stratum oriens (SO) of sectors CA2/3, where the basolateral amygdala (BLA) sends a robust projection. Previous work using a rat model of SZ demonstrated that BLA activation leads to electrophysiological changes in fast-spiking interneurons in SO of CA2/3. The present study explores KAR modulation of interneurons in CA2/3 in response to BLA activation. Intrinsic firing properties of these interneurons through KAR-mediated activity were measured with patch-clamp recordings from rats that received 15 days of picrotoxin infusion into the BLA. Chronic BLA activation induced changes in the firing properties of CA2/3 interneurons associated with modifications in the function of KARs. Specifically, the responsiveness of these interneurons to activation of KARs was diminished in picrotoxin-treated rats, while the after-hyperpolarization (AHP) amplitude was increased. In addition, we tested blockers of KAR subunits which have been shown to have altered gene expression in SO sector CA2/3 of SZ subjects. The GluR5 antagonist UBP296 further decreased AP frequency and increased AHP amplitude in picrotoxin-treated rats. Application of the GluR6/7 antagonist NS102 suggested that activation of GluR6/7 KARs may be required to maintain the high firing rates in SO interneurons in the presence of KA. Moreover, the GluR6/7 KAR-mediated signaling may be suppressed in PICRO-treated rats. Our findings indicate that glutamatergic activity from the BLA may modulate the firing properties of CA2/3 interneurons through GluR5 and GluR6/7 KARs. These receptors are expressed in GABAergic interneurons and play a key role in the synchronization of gamma oscillations. Modulation of interneuronal activity through KARs in response to amygdala activation may lead to abnormal oscillatory rhythms reported in SZ subjects.