Pharmacotherapy of paraphilias with long-acting agonists of luteinizing hormone-releasing hormone: a systematic review.
In addition to psychotherapy, pharmacotherapy is an important treatment option for paraphilias, especially in sexual offenders. Cyproterone acetate (CPA) and medroxyprogesterone acetate (MPA) are commonly used but can have serious side effects. Selective serotonin reuptake inhibitors (SSRIs) may also be effective in less severe cases. Recent research shows that luteinizing hormone-releasing hormone (LHRH) agonists may offer a new treatment option for treatment of paraphilic patients. MEDLINE was searched for clinical trials, case-control studies, case reports, and other clinically and theoretically important literature published between 1980 and November 2002 on the treatment of paraphilia with LHRH agonists. Keywords included LHRH agonists, GnRH- agonists, antiandrogens, paraphilia, pedophilia, and sex offenders. We found 4 case reports, 1 case- control study, 7 open uncontrolled studies, and 1 study comparing patients receiving CPA with those receiving LHRH agonist treatment in forensic hospitals. In total, the studies reported on a sample of 118 treated patients with different forms of paraphilias (sadism, pedophilia, exhibitionism, voyeurism). Nearly all of the studies used self-reports to measure the effects of medication. Duration of follow-up was between 6 months and 7 years and revealed that there were no relapses if patients remained under treatment. Patients previously treated with other agents like CPA, MPA, or SSRIs reported better effects when taking LHRH agonists. Although there is a need for further research, LHRH agonists offer a treatment option for patients with severe paraphilia. We propose a differentiated pharmacologic treatment regarding side effects, symptomatology, and severity.


Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease.
Failure-free survival, defined as the absence of relapse, non-relapse mortality or addition of another systemic therapy, has been proposed as a potential endpoint for clinical trials, but its use has only been reported for single-center studies. We measured failure-free survival in a prospective observational cohort of patients (n=575) with both newly diagnosed and existing chronic graft-versus-host disease from nine centers. Failure was observed in 389 (68%) patients during the observation period. The median follow up of all patients was 30.9 months, and the median failure-free survival was 9.8 months (63% at 6 months, 45% at 1 year, and 29% at 2 years). Of the variables measured at enrollment, ten were associated with shorter failure-free survival: higher National Institutes of Health 0-3 skin score, higher National Institutes of Health 0-3 gastrointestinal score, worse range of motion summary score, lower forced vital capacity (%), bronchiolitis obliterans syndrome, worse quality of life, moderate to severe hepatic dysfunction, absence of treatment for gastric acid, female donor for male recipient, and prior grade II-IV acute graft-versus-host disease. Addition of a new systemic treatment, the major cause of failure, was associated with an increased risk of subsequent non-relapse mortality (hazard ratio=2.06, 95% confidence interval: 1.29-3.32; P<0.003) and decreased survival (hazard ratio=1.51, 95% confidence interval: 1.04-2.18; P<0.03). These results show that fewer than half of patients on systemic treatment will be failure-free survivors at 1 year, and fewer than a third will reach 2 years without experiencing failure. Better treatments are needed for chronic graft-versus-host disease. Clinicaltrials.gov identifier: NCT00637689.


Trimodality management of sinonasal undifferentiated carcinoma and review of the literature.
Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive malignancy with optimal management remains unclear. We performed a review of the impact of trimodality approach on SNUC outcome. This is a single-institution retrospective study of 18 patients, who were managed between 1997 and 2009. The median age at presentation was 52 years (28 to 82). Nine patients (50%) were female. Three patients had stage II disease and underwent surgery alone, 12 had stages III and IVa and underwent surgery combined with chemoradiation, and 3 had stage IVb and underwent definitive chemoradiation. Patients who underwent preoperative, postoperative, and definitive chemoradiation received 60, 66, and 70 Gy of radiation, respectively. In all patients receiving concurrent chemoradiation, cisplatin was used, at a dose of 100 mg/m every 3 weeks for 3 cycles. Neoadjuvant chemotherapy included docetaxel, cisplatin, and 5-fluorouracil (TPF) every 3 weeks for 2 to 3 cycles. After a median follow-up of 26 months (16 to 120), a total of 8 patients (44%) have experienced the following: 1 persistent disease (5.5%), 4 local failure (22%), and 3 distant metastases (DM, 16.5%). Five of the 8 patients had preexisting cranial nerve deficits or gross cranial invasion. The 2-, 3-, and 4-year local control (LC), disease-free survival (DFS), and overall survival (OS) were 78%, 72%, and 56%; 75%, 65%, and 52%; and 75%, 50%, and 48%, respectively. Trimodality approach provided 83% LC and 92% DM-free survival, whereas other modalities provided 50% LC and 33% DM-free survival. The causes of death for the entire cohort were DM and local invasion. Acute chemoradiotherapy toxicity was 100% grades 1 and 2 dermatitis, mucositis, and fatigue, 55% developed grades 1 and 2 dysphagia, and 6% had grade 3 mucositis. Long-term toxicity was 28% grade 1 xerostomia, 11% retinopathy and optic neuropathy, and 6% orbital exenteration and grade 3 peripheral neuropathy. SNUC is an aggressive neoplasm that frequently presents at an advanced stage. Our data show that trimodality approach in the form of surgery combined with chemoradiation seems to offer better LC and lower DM compared with other modalities.


Elapid venom toxins: multiple recruitments of ancient scaffolds.
Nigroxins A and B, two myotoxic phospholipases A2 (PLA2s) from the venom of the American elapid Micrurus nigrocinctus, belong to a new PLA2 subclass. Their primary structures were established and compared with those of PLA2s that have already been studied with respect to myotoxic activity. The combination of amino acid residues Arg15, Ala100, Asn108 and a hydrophobic residue at position 109 is present exclusively in class I PLA2s that display myotoxic activity. These residues cluster within a surface region rich in positive charges and are suggested to play a role in the interaction with the target membrane of the muscle fibers. It is concluded that the myotoxic PLA2s resulted from recruitment of an ancient scaffold. Dendrotoxins and alpha-neurotoxins are similarly derived from other old structures, which are, however, now also present in nontoxic proteins that are widely distributed throughout the animal kingdom. The evolutionary pathways by which elapid PLA2s acquired myotoxicity and dendrotoxins acquired K+-channel blocker activity are traced. They demonstrate how existing scaffolds were adapted stepwise to serve toxic functions by exchange of a few surface-exposed residues.


ASPP2 binds Par-3 and controls the polarity and proliferation of neural progenitors during CNS development.
Cell polarity plays a key role in the development of the central nervous system (CNS). Interestingly, disruption of cell polarity is seen in many cancers. ASPP2 is a haplo-insufficient tumor suppressor and an activator of the p53 family. In this study, we show that ASPP2 controls the polarity and proliferation of neural progenitors in vivo, leading to the formation of neuroblastic rosettes that resemble primitive neuroepithelial tumors. Consistent with its role in cell polarity, ASPP2 influences interkinetic nuclear migration and lamination during CNS development. Mechanistically, ASPP2 maintains the integrity of tight/adherens junctions. ASPP2 binds Par-3 and controls its apical/junctional localization without affecting its expression or Par-3/aPKC lambda binding. The junctional localization of ASPP2 and Par-3 is interdependent, suggesting that they are prime targets for each other. These results identify ASPP2 as a regulator of Par-3, which plays a key role in controlling cell proliferation, polarity, and tissue organization during CNS development.


Binding sites of cytoplasmic effectors TRAF1, 2, and 3 on CD30 and other members of the TNF receptor superfamily.
CD30 is present on the surfaces of malignant cells from patients with Hodgkin's lymphoma, anaplastic large cell lymphoma, and other lymphomas. The yeast two hybrid genetic screen method was used to identify molecular effectors which mediate CD30 signalling events. Clones corresponding to genes coding for TRAF1, TRAF2, and TRAF3 molecules, postulated to be involved in signalling via the TNF and CD40 receptors, were isolated. In this report, we show that the CD30 intracellular tail contains two motifs that bind TRAFs. The more amino terminal motif, 558PHYPEQET565, binds TRAF2 and 3, while the more carboxyl terminal motif, 576MLSVEEEG583, binds TRAF1 and 2. We show that these amino acid motifs are conserved in TNFRp75 and CD40 and that sequences in these receptors homologous to TRAF-binding sequences found in CD30 can selectively bind the TRAFs in a predictable manner.


Prenatal testing for Huntington's disease in the Netherlands from 1998 to 2008.
This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.


A repeated point prevalence survey of antimicrobial use in specialized cancer care hospital of Pakistan: findings and implications.
Background: The extensive use of broad-spectrum antimicrobials in immunocompromised patients is inevitable in situations where culture and sensitivity testing is challenging. However, their overuse leads to an increase in antimicrobial resistance (AMR), which is a growing concern. Method: A repeated point prevalence survey (PPS) was conducted to assess the pattern of antimicrobial prescribing in a specialized cancer care hospital in Pakistan using the methodology employed by the European Centre of Disease Prevention and Control. Results: Out of 313 hospitalized patients, 156 (49.8%) were prescribed one or more antimicrobials, 82 (50.9) in 2017 and 74 (48.7) in 2018. The average bed occupancy in the hospital was 80.3%. Fever in neutropenic patients (20.2%), lower respiratory tract infections (17.8%), and sepsis (14.9%) were the three most common clinical indications. The total number of prescribed antimicrobials was 242, of whom, 41 (16.9%) were given orally and 201 (83.1%) were given parenterally. The most commonly used antimicrobials were piperacillin plus enzyme inhibitor (31.8%), meropenem (7.9%), ceftriaxone (6.2%) and vancomycin (6.2%). Of the total prescribed antimicrobials, 42 (17.3%) antimicrobials were used in surgical departments, 89 (36.8) in adult medical departments, 73 (30.1%) in pediatric medical departments and 38 (15.7) in the intensive care unit (ICU). In addition to these antibacterials, there was relatively high use of antivirals (acyclovir; 4.1%) and antifungals (fluconazole; 3.7%, amphotericin B; 2.9%). Conclusion: The study concluded that broad-spectrum antimicrobial usage in cancer hospitals in Pakistan is high, which can be a risk factor for the emergence of AMR. Repeated PPS is a fruitful way to maintain a focus on inappropriate antimicrobial use and develop pertinent intervention programs targeteing specific issues to improve future use.


Fluid management of severe falciparum malaria in African children.
Most African children with severe malaria who die do so on the day of admission as a result of the complications of falciparum malaria. We highlight the value of a rapid structured triage assessment to look for emergency signs that will prioritize initial management and implementation of basic life support. This can be delivered with few resources and by non-specialist medical personnel. Reduction in case fatality can only come through the wider appreciation of the need for and application of supportive therapies to treat the life-threatening complications. Hypovolaemia has emerged as a common feature of children presenting with severe malaria complicated by acidosis. Early recognition and prompt treatment may lead to improvements in outcome. We discuss the new evidence supporting the role of hypovolaemia in severe malaria and potential treatment options whilst awaiting the results of clinical trials.


Analysis of repeated hemoglobin measures in full-term, normal birth weight Kenyan children between birth and four years of age. III. The Asemobo Bay Cohort Project.
Anemia is an important public health problem. During very early childhood numerous factors affect hemoglobin (Hb) concentration over time, making single cross-sectional measurements difficult to interpret when studying the natural history of anemia or evaluating anemia control strategies. We analyzed repeated Hb measures contributed by 942 Kenyan children between birth and 48 months of life using a mixed effects model, with a regression spline used to describe the population mean Hb profile, and random intercepts and slopes and first-order autoregressive correlation structure to accommodate the within-individual correlation among the repeated Hb measures. The approach facilitates the study of time-stationary and time-varying covariates that influence Hb in early life. The fitted mean Hb profile obtained from the analytic model is consistent with the observed mean Hb of the study population. Village of residence was associated with greatest difference in mean Hb at time of birth (16 versus 19 g/dL; P < 0.0001). Monthly weight-for-age was also associated with mean Hb after 3 months of age. This is the first description of an analysis strategy specifically for repeated Hb measures collected in a longitudinal field study in Africa. The strategy will facilitate improved study of time-varying covariates thought to influence pediatric anemia.


Leishmania donovani infection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanism.
The failure of Leishmania, an intracellular pathogen, to stimulate a pro-inflammatory response following entry into macrophages has been well reported. This occurs in spite of the fact that ligands for the toll-like receptors (TLR) have been recently shown on the parasite surface and their role in disease protection well documented. The outcome of infection in leishmaniasis is determined by the Th1 versus Th2 nature of the effector response and the generation of IL-12 and IL-10 by the infected macrophages is important for this decision. We evaluated the effect of L. donovani infection of monocytes (cell line THP-1, and monocytes derived from human peripheral blood) on Pam3cys (TLR2 ligand) and lipopolysaccharide (TLR4 ligand) stimulated production of IL-12p40 and IL-10. L. donovani infection caused suppression of TLR2 and TLR4-stimulated IL-12p40, with an increase in IL-10 production. Parasites also modulated the TLR2-stimulated mitogen-activated protein kinase (MAPK) pathway by suppressing MAPK P(38) phosphorylation and activating extracellular regulated kinase (ERK)1/2 phosphorylation. These effects could be reversed either by using a MAPK P(38) activator, anisomycin, or ERK1/2 inhibitor, U0126. L. donovani caused modulation of TLR2-stimulated MAPK pathways in a contact-dependent mechanism. In addition parasite structural integrity but not viability was required for suppression of TLR2-stimulated IL-12p40 and activation of IL-10. These observations suggest that L. donovani has evolved survival strategies that subvert the pro-inflammatory response generated through TLRs.


Piezoelectric inkjet printing of a cross-hatch immunoassay on a disposable nylon membrane.
The development of a cost-effective method for manufacturing immunoassays is a key step towards their commercial use. In this study, a piezoelectric inkjet printer and a nylon membrane were used to fabricate a disposable immunoassay. Using a piezoelectric inkjet printer, a cross-hatch pattern of goat anti-mouse antibody (GalphaM) and rabbit anti-horseradish peroxidase (RalphaHRP) antibody were deposited on the nylon membrane. These patterns were subsequently treated with a solution containing rabbit anti-goat antibody labeled with horseradish peroxidase (RalphaG-HRP). The effectiveness of the immobilization process was examined using tetramethylbenzidine (TMB), which oxidizes in the presence of HRP to form a visible precipitate. Optical evaluation of the TMB precipitate was used to assess the precision of the features in the inkjet-printed pattern as well as antibody functionality following inkjet printing. Uniform patterns that contained functional antibodies were fabricated using the piezoelectric inkjet printer. These results suggest that piezoelectric inkjet printing may be used to fabricate low-cost disposable immunoassays for biotechnology and healthcare applications.


Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient.
Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation (P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).


Characteristics and predictors of death among hospitalized HIV-infected patients in a low HIV prevalence country: Bangladesh.
Predictors of death in hospitalized HIV-infected patients have not been previously reported in Bangladesh. The primary aim of this study was to determine predictors of death among hospitalized HIV-infected patients at a large urban hospital in Bangladesh. A study was conducted in the HIV in-patient unit (Jagori Ward) of icddr,b's Dhaka Hospital. Characteristics of patients who died during hospitalization were compared to those of patients discharged from the ward. Bivariate analysis was performed to determine associations between potential risk factors and death. Multivariable logistic regression was used to identify factors independently associated with death. Of 293 patients admitted to the Jagori Ward, 57 died during hospitalization. Most hospitalized patients (67%) were male and the median age was 35 (interquartile range: 2-65) years. Overall, 153 (52%) patients were diagnosed with HIV within 6 months of hospitalization. The most common presumptive opportunistic infections (OIs) identified were tuberculosis (32%), oesophageal candidiasis (9%), Pneumocystis jirovecii pneumonia (PJP) (8%), and histoplasmosis (7%). On multivariable analysis, independent predictors of mortality were CD4 count ≤200 cells/mm3 (adjusted odds ratio [aOR]: 16.6, 95% confidence interval [CI]: 3.7-74.4), PJP (aOR: 18.5, 95% CI: 4.68-73.3), oesophageal candidiasis (aOR: 27.5, 95% CI: 5.5-136.9), malignancy (aOR:15.2, 95% CI: 2.3-99.4), and bacteriuria (aOR:7.9, 95% CI: 1.2-50.5). Being on antiretroviral therapy prior to hospitalization (aOR: 0.2, 95% CI: 0.06-0.5) was associated with decreased mortality. This study showed that most patients who died during hospitalization on the Jagori Ward had HIV-related illnesses which could have been averted with earlier diagnosis of HIV and proper management of OIs. It is prudent to develop a national HIV screening programme to facilitate early identification of HIV.


Direct and inverse discrete Zernike transform.
An invertible discrete Zernike transform, DZT is proposed and implemented. Three types of non-redundant samplings, random, hybrid (perturbed deterministic) and deterministic (spiral) are shown to provide completeness of the resulting sampled Zernike polynomial expansion. When completeness is guaranteed, then we can obtain an orthonormal basis, and hence the inversion only requires transposition of the matrix formed by the basis vectors (modes). The discrete Zernike modes are given for different sampling patterns and number of samples. The DZT has been implemented showing better performance, numerical stability and robustness than the standard Zernike expansion in numerical simulations. Non-redundant (critical) sampling along with an invertible transformation can be useful in a wide variety of applications.


Spring viremia of carp (SVC).
Spring viremia of carp (SVC) is an important disease affecting cyprinids, mainly common carp Cyprinus carpio. The disease is widespread in European carp culture, where it causes significant morbidity and mortality. Designated a notifiable disease by the Office International des Epizooties, SVC is caused by a rhabdovirus, spring viremia of carp virus (SVCV). Affected fish show destruction of tissues in the kidney, spleen and liver, leading to hemorrhage, loss of water-salt balance and impairment of immune response. High mortality occurs at water temperatures of 10 to 17 degrees C, typically in spring. At higher temperatures, infected carp develop humoral antibodies that can neutralize the spread of virus and such carp are protected against re-infection by solid immunity. The virus is shed mostly with the feces and urine of clinically infected fish and by carriers. Waterborne transmission is believed to be the primary route of infection, but bloodsucking parasites like leeches and the carp louse may serve as mechanical vectors of SVCV. The genome of SVCV is composed of a single molecule of linear, negative-sense, single-stranded RNA containing 5 genes in the order 3'-NPMGL-5' coding for the viral nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and polymerase, respectively. Polyacrylamide gel electrophoresis of the viral proteins, and sequence homologies between the genes and gene junctions of SVCV and vesicular stomatitis viruses, have led to the placement of the virus as a tentative member of the genus Vesiculovirus in the family Rhabdoviridae. These methods also revealed that SVCV is not related to fish rhabdoviruses of the genus Novirhabdovirus. In vitro replication of SVCV takes place in the cytoplasm of cultured cells of fish, bird and mammalian origin at temperatures of 4 to 31 degrees C, with an optimum of about 20 degrees C. Spring viremia of carp can be diagnosed by clinical signs, isolation of virus in cell culture and molecular methods. Antibodies directed against SVCV react with the homologous virus in serum neutralization, immunofluorescence, immunoperoxidase, or enzyme-linked immunosorbent assays, but they cross-react to various degrees with the pike fry rhabdovirus (PFR), suggesting the 2 viruses are closely related. However, SVCV and PFR can be distinguished by certain serological tests and molecular methods such as the ribonuclease protection assay.


Geometric mechanics and the dynamics of asteroid pairs.
The purpose of this paper is to describe the general setting for the application of techniques from geometric mechanics and dynamical systems to the problem of asteroid pairs. The paper also gives some preliminary results on transport calculations and the associated problem of calculating binary asteroid escape rates. The dynamics of an asteroid pair, consisting of two irregularly shaped asteroids interacting through their gravitational potential is an example of a full-body problem or FBP in which two or more extended bodies interact. One of the interesting features of the binary asteroid problem is that there is coupling between their translational and rotational degrees of freedom. General FBPs have a wide range of other interesting aspects as well, including the 6-DOF guidance, control, and dynamics of vehicles, the dynamics of interacting or ionizing molecules, the evolution of small body, planetary, or stellar systems, and almost any other problem in which distributed bodies interact with each other or with an external field. This paper focuses on the specific case of asteroid pairs using techniques that are generally applicable to many other FBPs. This particular full two-body problem (F2BP) concerns the dynamical evolution of two rigid bodies mutually interacting via a gravitational field. Motivation comes from planetary science, where these interactions play a key role in the evolution of asteroid rotation states and binary asteroid systems. The techniques that are applied to this problem fall into two main categories. The first is the use of geometric mechanics to obtain a description of the reduced phase space, which opens the door to a number of powerful techniques, such as the energy-momentum method for determining the stability of equilibria and the use of variational integrators for greater accuracy in simulation. Second, techniques from computational dynamic systems are used to determine phase space structures that are important for transport phenomena and dynamic evolution.


Sustained preferential processing of social threat cues: bias without competition?
Stimuli of high emotional significance such as social threat cues are preferentially processed in the human brain. However, there is an ongoing debate whether or not these stimuli capture attention automatically and weaken the processing of concurrent stimuli in the visual field. This study examined continuous fluctuations of electrocortical facilitation during competition of two spatially separated facial expressions in high and low socially anxious individuals. Two facial expressions were flickered for 3000 msec at different frequencies (14 and 17.5 Hz) to separate the electrocortical signals evoked by the competing stimuli ("frequency tagging"). Angry faces compared to happy and neutral expressions were associated with greater electrocortical facilitation over visual areas only in the high socially anxious individuals. This finding was independent of the respective competing stimulus. Heightened electrocortical engagement in socially anxious participants was present in the first second of stimulus viewing and was sustained for the entire presentation period. These results, based on a continuous measure of attentional resource allocation, support the view that stimuli of high personal significance are associated with early and sustained prioritized sensory processing. These cues, however, do not interfere with the electrocortical processing of a spatially separated concurrent face, suggesting that they are effective at capturing attention, but are weak competitors for resources.


Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth In Vivo.
Eukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another α-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K. In silico studies showed that compounds with a coumarin-chalcone core have high predicted binding affinities for eEF-2K. Using in vitro studies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells. In vivo systemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent and in vivo effective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors.


Bisubstrate inhibitor approach for targeting mitotic kinase Haspin.
During the past decade, the basophilic atypical kinase Haspin has emerged as a key player in mitosis responsible for phosphorylation of Thr3 residue of histone H3. Here, we report the construction of conjugates comprising an aromatic fragment targeted to the ATP-site of Haspin and a peptide mimicking the N-terminus of histone H3. The combination of effective solid phase synthesis procedures and a high throughput binding/displacement assay with fluorescence anisotropy readout afforded the development of inhibitors with remarkable subnanomolar affinity toward Haspin. The selectivity profiles of novel conjugates were established by affinity studies with a model basophilic kinase (catalytic subunit of cAMP-dependent protein kinase) and by a commercial 1-point inhibition assay with 43 protein kinases.


THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis.
Transthyretin (TTR) amyloidosis is a rare, life-threatening, systemic, autosomal dominant condition occurring in adults, with two main forms: hereditary (associated with TTR gene mutations) and wild-type. Studies indicate considerable heterogeneity in disease presentation, with predominantly polyneuropathic, predominantly cardiac, or mixed phenotypes. THAOS - the Transthyretin Amyloidosis Outcomes Survey - is the first global, multicenter, longitudinal, observational survey that collects data on the natural history of TTR amyloidosis (ClinicalTrials.gov: NCT00628745). This paper presents data on signs and symptoms, neurological and cardiac assessments, biomarkers and quality of life in the patients enrolled in THAOS from its inception in December 2007 to September 2011. At the time of this analysis, data were available from 611 symptomatic patients with hereditary TTR amyloidosis, 67 symptomatic patients with wild-type TTR amyloidosis, and 274 currently asymptomatic individuals with a TTR mutation. Nineteen countries were participating in the registry. The largest patient groups came from Portugal (n = 453), the USA (n = 129), Italy (n = 70), and Japan (n = 68). Predominant symptom presentation in patients with hereditary TTR amyloidosis differed according to the underlying disease-causing mutation (polyneuropathy for Val30Met, cardiomyopathy for Val122Ile and Leu111Met, and mixed for Glu89Gln). However, each mutation was associated with clear multisystem involvement. Similarly, although cardiomyopathy was predominant in patients with wild-type TTR amyloidosis, many also showed symptoms consistent with neuropathy. Quality of life in patients with hereditary TTR amyloidosis, but not asymptomatic carriers of disease-causing mutations, was severely impaired relative to that of the age-matched general US population. This preliminary analysis highlights the considerable phenotypic heterogeneity for neurological and cardiac manifestations in patients with hereditary and wild-type TTR amyloidosis and the necessity of providing multidisciplinary care. THAOS registry data will help better characterize the diverse presentation and course of TTR amyloidosis worldwide and aid in improving and standardizing diagnosis and treatment.


Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.
Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).


A Visual Task Management Application for Acute Ischemic Stroke Care.
Background: To maximize the effect of intravenous (IV) thrombolysis and/or endovascular therapy (EVT) for acute ischemic stroke (AIS), stroke centers need to establish a parallel workflow on the basis of a code stroke (CS) protocol. At Kokura Memorial Hospital (KMH), we implemented a CS system in January 2014; however, the process of information sharing within the team has occasionally been burdensome. Objective: To solve this problem using information communication technology (ICT), we developed a novel application for smart devices, named "Task Calc. Stroke" (TCS), and aimed to investigate the impact of TCS on AIS care. Methods: TCS can visualize the real-time progress of crucial tasks for AIS on a dashboard by changing color indicators. From August 2015 to March 2017, we installed TCS at KMH and recommended its use during normal business hours (NBH). We compared the door-to-computed tomography time, the door-to-complete blood count (door-to-CBC) time, the door-to-needle for IV thrombolysis time, and the door-to-puncture for EVT time among three treatment groups, one using TCS ("TCS-based CS"), one not using TCS ("phone-based CS"), and one not based on CS ("non-CS"). A questionnaire survey regarding communication problems was conducted among the CS teams at 3 months after the implementation of TCS. Results: During the study period, 74 patients with AIS were transported to KMH within 4.5 h from onset during NBH, and 53 were treated using a CS approach (phone-based CS: 26, TSC-based CS: 27). The door-to-CBC time was significantly reduced in the TCS-based CS group compared to the phone-based CS group, from 31 to 19 min (p = 0.043). Other processing times were also reduced, albeit not significantly. The rate of IV thrombosis was higher in the TCS-based CS group (78% vs. 46%, p = 0.037). The questionnaire was correctly filled in by 34/38 (89%) respondents, and 82% of the respondents felt a reduction in communication burden by using the TCS application. Conclusions: TCS is a novel approach that uses ICT to support information sharing in a parallel CS workflow in AIS care. It shortens the processing times of critical tasks and lessens the communication burden among team members.


Replication of hepatitis C virus in peripheral blood mononuclear cells. Effect of alpha-interferon therapy.
Hepatitis C virus (HCV) is a positive-stranded RNA virus which replicates through a negative-stranded RNA intermediate. Using a PCR procedure to detect positive and negative strands, we investigated the existence of HCV replication in lymphoid cells. Both positive and negative strands were found in the peripheral blood mononuclear cells (PBMC) of all patients (n = 10) with untreated chronic hepatitis C. No HCV sequences were detected in PBMC in any of the 8 healthy controls. Fifteen patients with chronic hepatitis C were studied at the end of a 12-month course of alpha-interferon therapy. The positive strand was detected in PBMC in all 9 non-responder patients, and the negative strand in 7. In contrast, in PBMC from responder patients (n = 6) the positive strand was found in 4 and the negative strand in only 2 cases. These results demonstrate that HCV can infect PBMC and replicate in these cells and that interferon seems to exert an inhibitory effect on this process. Persistence of HCV-RNA in PBMC may help explain disease relapse after successful interferon therapy.


Regional and social differences concerning overweight, participation in health check-ups and vaccination. Analysis of data from a whole birth cohort of 6-year old children in a prosperous German city.
Studies on health inequalities still focus mostly on adults. Research about social disparities and health in children is slowly increasing, also in Germany, but these studies are mostly restricted to individual social variables derived from the parents to determine social class. This paper analyses the data of the medical check-up prior to school enrolment to determine differences concerning overweight, participation in health check-ups and immunization; it includes individual social variables but also regional variables describing the social environment of the children. The dataset includes 9,353 children who started school in 2004 in Munich, Germany. Three dependent variables are included (i.e. overweight, health check-ups, vaccinations). The individual level social variables are: children's sex, mother tongue of the parents, Kindergarten visit. On the small scale school district level, two regional social variables could be included as well, i.e. percentage of single-parent households, percentage of households with low educational level. Associations are assessed by cross tables and regression analyses. The regional level variables are included by multilevel analyses. The analyses indicate that there is a large variation between the school districts concerning the three dependent variables, and that there is no district with very 'problematic values' for all three of them (i.e. high percentage of overweight, low levels of health check-ups and vaccinations). Throughout the bivariate and multivariate analyses, the mother tongue of the children's parents shows the most pronounced association with these dependent variables; i.e. children growing up in non-German-speaking families tend to be more overweight and don't visit preventive check-ups as often as children of German-speaking parents. An opposite association can be seen concerning vaccinations. Regional level influences are present as well, but they are rather small when the individual level social variables are controlled for. The dataset of the medical check-up prior to school enrolment offers a great opportunity for public health research, as it comprises a whole age cohort. The number and scope of variables is quite limited, though. On one hand, it includes only few variables on health or health related risks. On the other, it would be important to have more information from the region where the children live, e.g. the availability of community and health care services for parents and children, social networks of families with children, areas where children can play outside, traffic noise and air pollution. Despite these shortcomings, the need for specific interventions can already be derived from the data analyzed here, e.g. programs to reduce overweight in children should focus on parents with a mother tongue other than German.


Perceived breast cancer risk: heuristic reasoning and search for a dominance structure.
Studies suggest that people construct their risk perceptions by using inferential rules called heuristics. The purpose of this study was to identify heuristics that influence perceived breast cancer risk. We examined 11 interviews from women of diverse ethnic/cultural backgrounds who were recruited from community settings. Narratives in which women elaborated about their own breast cancer risk were analyzed with Argument and Heuristic Reasoning Analysis methodology, which is based on applied logic. The availability, simulation, representativeness, affect, and perceived control heuristics, and search for a dominance structure were commonly used for making risk assessments. Risk assessments were based on experiences with an abnormal breast symptom, experiences with affected family members and friends, beliefs about living a healthy lifestyle, and trust in health providers. Assessment of the potential threat of a breast symptom was facilitated by the search for a dominance structure. Experiences with family members and friends were incorporated into risk assessments through the availability, simulation, representativeness, and affect heuristics. Mistrust in health providers led to an inappropriate dependence on the perceived control heuristic. Identified heuristics appear to create predictable biases and suggest that perceived breast cancer risk is based on common cognitive patterns.


Uranium in framboidal pyrite from a naturally bioreduced alluvial sediment.
Samples of a naturally bioreduced, U-contaminated alluvial sediment were characterized with various microscopic and spectroscopic techniques and wet chemical extraction methods. The objective was to investigate U association and interaction with minerals of the sediment. Bioreduced sediment comprises approximately 10% of an alluvial aquifer adjacent to the Colorado River, in Rifle, CO, that was the site of a former U milling operation. Past and ongoing research has demonstrated that bioreduced sediment is elevated in solid-associated U, total organic carbon, and acid-volatile sulfide, and depleted in bioavailable Fe(III) confirming that sulfate and Fe(III) reduction have occurred naturally in the sediment. SEM/EDS analyses demonstrated that framboidal pyrites (FeS(2)) of different sizes ( approximately 10-20 microm in diameter), and of various microcrystal morphology, degree of surface weathering, and internal porosity were abundant in the <53 microm fraction (silt + clay) of the sediment and absent in adjacent sediments that were not bioreduced. SEM-EMPA, XRF, EXAFS, and XANES measurements showed elevated U was present in framboidal pyrite as both U(VI) and U(IV). This result indicates that U may be sequestered in situ under conditions of microbially driven sulfate reduction and pyrite formation. Conversely, such pyrites in alluvial sediments provide a long-term source of U under conditions of slow oxidation, contributing to the persistence of U of some U plumes. These results may also help in developing remedial measures for U-contaminated aquifers.


Insulin-like growth factor II receptor-α is a novel stress-inducible contributor to cardiac damage underpinning doxorubicin-induced oxidative stress and perturbed mitochondrial autophagy.
Doxorubicin (DOX) is an anthracycline antibiotic commonly employed for the treatment of various cancers. However, its therapeutic uses are hampered by side effects associated with cumulative doses during the course of treatment. Whereas deregulation of autophagy in the myocardium has been involved in a variety of cardiovascular diseases, the role of autophagy in DOX-induced cardiomyopathy remains debated. Our earlier studies have shown that DOX treatment in a rat animal model leads to increased expression of the novel stress-inducible protein insulin-like growth factor II receptor-α (IGF-IIRα) in cardiac tissues, which exacerbated the cardiac injury by enhancing oxidative stress and p53-mediated mitochondria-dependent cardiac apoptosis. Through this study, we investigated the contribution of IGF-IIRα to dysregulation of autophagy in heart using both in vitro H9c2 cells (DOX treated, 1 µM) and in vivo transgenic rat models (DOX treated, 5 mg/kg ip for 6 wk) overexpressing IGF-IIRα specifically in the heart. We found that IGF-IIRα primarily localized to mitochondria, causing increased mitochondrial oxidative stress that was severely aggravated by DOX treatment. This was accompanied by a significant perturbation in mitochondrial membrane potential and increased leakage of cytochrome c, causing increased cleaved caspase-3 activity. There were significant alterations in phosphorylated AMP-activated protein kinase (p-AMPK), phosphorylated Unc-51 like kinase-1 (p-ULK1), PARKIN, PTEN-induced kinase 1 (PINK1), microtubule-associated protein 1 light chain 3 (LC3), and p62 proteins, which were more severely disrupted under the combined effect of IGF-IIRα overexpression plus DOX. Finally, LysoTracker Red staining showed that IGF-IIRα overexpression causes lysosomal impairment, which was rescued by rapamycin treatment. Taken together, we found that IGF-IIRα leads to mitochondrial oxidative stress, decreased antioxidant levels, disrupted mitochondrial membrane potential, and perturbed mitochondrial autophagy contributing to DOX-induced cardiomyopathy.


Hypothyroidism in patients with colorectal carcinoma treated with fluoropyrimidines.
Targeted therapy with tyrosine kinase inhibitors, including vascular endothelial growth factor receptors, has been demonstrated to induce hypothyroidism and thyroid dysfunction. Cancer patients with thyroid dysfunction may be underdiagnosed and undertreated. Thyroid function in colorectal cancer patients receiving fluoropyrimidine-based chemotherapy with or without bevacizumab was evaluated at baseline and monthly. In the present study, 3 of 27 (11.1%) patients who received fluoropyrimidine-based chemotherapy developed a thyroid-stimulating hormone (TSH) level >10 µU/ml, and 13 (48.1%) developed an elevation above the upper limit of the normal range. No difference in TSH elevation was noted between the bevacizumab and chemotherapy-alone group (50 vs. 45%; P=1.00, respectively). Three (11.1%) patients developed a TSH level >10 µU/ml and 2 with hypothyroidism were treated with thyroid hormone replacement therapy. We demonstrated that bevacizumab does not affect thyroid function but fluoropyrimidines may induce thyroid dysfunction in patients with colorectal cancer. Further investigation is required to clarify the mechanism of fluoropyrimidine-induced thyroid dysfunction.


Analysis of TCR Vbeta repertoire and cytokine gene expression in patients with idiopathic dilated cardiomyopathy.
Although the etiopathogenesis of idiopathic dilated cardiomyopathy (IDC) is still unclear, it is widely accepted that a complex interplay between viral infections and immune mechanisms is the basis of disease genesis. Previously, we showed that heart-infiltrating T cells of patients suffering from acute, fulminant Coxsackie virus B3+-IDC shared a preferential usage of three variable gene segments of the T cell receptor beta chain-(TCR-Vbeta) encoding families Vbeta3, 7 and 13.1. This indicated the possible presence of a superantigen-driven immune response. Here, we further investigated the IDC immunological scenario by analysing different phenotypes of heart-infiltrating cells: TCR repertoires, cytokine expression and presence of enterovirus-specific antigens. IDC patients who underwent heart transplantation at different times after the onset of heart failure were studied. A cardiac infiltrate of CD4+ and CD8+ T cells was present together with activated macrophages. Furthermore, the same Vbeta gene families, previously found to be skewed in hearts from fulminant cases of CVB3+-IDC, together with two additional Vbeta gene families, Vbeta1 and 5B, were increased. IL-1beta, IL-2, IL-6 and IFN-gamma were expressed in the myocardium while others, like IL-4 were not. In conclusion, an orchestrated complex of immune mechanisms seems to be the basis of IDC etiopathogenesis.


Applications of short-coherence digital holography in microscopy.
We present an optical system based on short-coherence digital holography suitable for the imaging of three-dimensional microscopic objects. The short temporal coherence properties of the light source allow optical sectioning of the sample. Proper reconstruction of different layers within biological samples is possible up to a depth of a few hundred micrometers, but multiple scattering and inhomogeneities in the refractive index reduce the imaging quality for deeper layers. We have studied the possibility of numerically correcting sample-induced aberrations, and we now propose a method of improving image quality. Numerical simulations and preliminary experimental results show that compensation of these aberrations is possible to some extent.


Breeding programmes for smallholder sheep farming systems: II. Optimization of cooperative village breeding schemes.
A simulation study was conducted to optimize a cooperative village-based sheep breeding scheme for Menz sheep of Ethiopia. Genetic gains and profits were estimated under nine levels of farmers' participation and three scenarios of controlled breeding achieved in the breeding programme, as well as under three cooperative flock sizes, ewe to ram mating ratios and durations of ram use for breeding. Under fully controlled breeding, that is, when there is no gene flow between participating (P) and non-participating (NP) flocks, profits ranged from Birr 36.9 at 90% of participation to Birr 21.3 at 10% of participation. However, genetic progress was not affected adversely. When there was gene flow from the NP to P flocks, profits declined from Birr 28.6 to Birr -3.7 as participation declined from 90 to 10%. Under the two-way gene flow model (i.e. when P and NP flocks are herded mixed in communal grazing areas), NP flocks benefited from the genetic gain achieved in the P flocks, but the benefits declined sharply when participation declined beyond 60%. Our results indicate that a cooperative breeding group can be established with as low as 600 breeding ewes mated at a ratio of 45 ewes to one ram, and the rams being used for breeding for a period of two years. This study showed that farmer cooperation is crucial to effect genetic improvement under smallholder low-input sheep farming systems.


[Calmette Hospital, Phnom Penh, Cambodia. Assessment of the implementation of the Medical Information System (SIM). Global analysis of the 1998 results].
Calmette is a national university hospital with 220 adult beds. It has emergency, surgical, medical and gynecology and obstetrics departments, along with a radiology unit, a laboratory for medical analyses, a central pharmacy and an outpatient clinic. This hospital has an unusual statute, with managerial autonomy and a system of cost recovery that currently provides 64% of the hospital's income. Since 1994, it has benefited from a French cooperation program. The French NGO, Médecins du Monde, has been present at Calmette since 1990, providing support for <<Medicine B>>, the indigent sector of the medical department. The aim of the Medical Information System (SIM) is to develop a simple, reliable and reproducible system so that, for every action undertaken at the hospital (hospitalization, day hospital and outpatient clinic) the following pieces of information are recorded: 1) the disease; 2) the type of patient; 3) the type of management; 4) the means used to treat the patient; 5) the cost. Data are collected and analyzed using programs created with EPIINFO software (CDC, WHO), using the EPIGLUE module. In 1998, 10,814 admissions were recorded at Calmette Hospital, 7,811 (72.2%) of which were to the Emergency Department and 3,003 (27.2%) of which were direct admissions to other wards. We analyzed 10,603 (95%) computerized medical summaries (RMI). About 50% of beds were occupied in the maternity and gynecology ward whereas almost 90% of beds were occupied in the surgical and emergency wards. AIDS and tuberculosis were the conditions most frequently treated by the medical department, despite a marked increase in more specialized areas of medicine such as cardiology and diabetology. The surgical department reflected the concentration on emergency services of the hospital, with cranial traumatism the primary reason for admission for the hospital as a whole. The mean age of patients was 27 years for the maternity ward and 49 years for the medicine A ward. The mortality rate was about 5% for the medical wards (mainly due to AIDS) and almost 50% in the emergency department (cerebrovascular neurologic disease, cranial traumatism). The proportion of nonpaying patients was high (about 40% in terms of stays in hospital and about 50% of all days spent in hospital). The training of a Cambodian manager for the SIM is a key priority. The point of the SIM is to use the treated data it produces to improve management and decision-making. The data it produces should be used to define the profile of the patients treated, both from a medical point of view and in terms of their ability to pay. This is a fundamental step towards identifying activities that should receive priority as part of a development strategy for a structure evolving in a highly competitive environment. The SIM data are also invaluable for the short-term management of the hospital through the contribution they make to the development of effective analytical accounting, making it possible to evaluate costs and to adjust charges appropriately. Finally, the involvement of the SIM in the setting up and functioning of the Comité de Lutte Contre les Infections Nosocomiales (CLIN; the Hospital-Acquired Infections Committee) in 1999 to 2000 is not utopia, it is the logical continuation of improvements in the overall quality of care It involves, in particular, the training of nurses and head nurses, initiated by nurses acting as technical assistants in the French cooperation program. The definition of the role of the hygiene nurse and the selection of such a nurse from the trained head nurses are also part of this process.


Differences in modifiable feeding factors by overweight status in Latino infants.
Obesity prevalence remains disproportionally high for young American children from low-socioeconomic and ethnic minorities. Modifiable feeding factors may lead to infant overfeeding and an increased risk for obesity. This study explored differences in modifiable feeding factors by overweight status (>85% weight-for-length) in the first year of life of Latino infants. Data were obtained from a cross-sectional pilot study of 62 low-income immigrant Latina mothers and their infants (ages 4-12 months). Measures included maternal feeding practices, feeding pattern, infant's 24-hour dietary recall, and maternal perception of infant weight. Chi-square and t-tests were used for comparisons between healthy weight and overweight infants. Birth weight z-scores did not significantly differ by weight status. Overweight status was not associated with maternal feeding practices, feeding pattern or infant dietary intake. A trend toward significance was seen in the maternal perception of infant weight. Overweight infants were similar to healthy weight infants in their birth weight z-scores and supports the premise that modifiable feeding factors are in play and thus targeted early feeding interventions may prove effective in decreasing obesity risk in Latinos.


The discrepancy between admission and discharge diagnoses: Underlying factors and potential clinical outcomes in a low socioeconomic country.
The discrepancy between admission and discharge diagnosis can lead to possible adverse patient outcomes. There are gaps in integrated studies, and less is understood about its characteristics and effects. Therefore, this study was conducted to determine the frequency, characteristics, and outcomes of diagnostic discrepancies at admission and discharge. This retrospective study reviewed the admitting and discharge diagnoses of adult patients admitted at Aga Khan University Hospital (AKUH), Internal Medicine Department between October 2018 and February 2019. The frequency and outcomes of discrepancies in patient diagnoses were noted among Emergency Department (ED) physician versus admitting physician, admitting physician versus discharge physician, and ED physician versus discharge physician for the full match, partial match, and mismatch diagnoses. The studied outcomes included interdepartmental transfer, Intensive Care Unit (ICU) transfer, in-hospital mortality, readmission within 30 days, and the length of stay. For simplicity, we only analyzed the factors for the discrepancy among ED physicians and discharge physicians. Out of 537 admissions, there were 25.3-27.2% admissions with full match diagnoses while 18.6-19.4% and 45.3-47.9% had mismatch and partial match diagnoses respectively. The discrepancy resulted in an increased number of interdepartmental transfers (5-5.8%), ICU transfers (5.6-8.7%), in-hospital mortality (8-11%), and readmissions within 30 days in ED (14.4%-16.7%). A statistically significant difference was observed for the ward's length of stay with the most prolonged stay in partially matched diagnoses (6.3 ± 5.4 days). Among all the factors that were evaluated for the diagnostic discrepancy, older age, multi-morbidities, level of trainee clerking the patient, review by ED faculty, incomplete history, and delay in investigations at ED were associated with significant discrepant diagnoses. Diagnostic discrepancies are a relevant and significant healthcare problem. Fixed patient or physician characteristics do not readily predict diagnostic discrepancies. To reduce the diagnostic discrepancy, emphasis should be given to good history taking and thorough physical examination. Patients with older age and multi-morbidity should receive significant consideration.


Nuclear depolarization and absolute sensitivity in magic-angle spinning cross effect dynamic nuclear polarization.
Over the last two decades solid state Nuclear Magnetic Resonance has witnessed a breakthrough in increasing the nuclear polarization, and thus experimental sensitivity, with the advent of Magic Angle Spinning Dynamic Nuclear Polarization (MAS-DNP). To enhance the nuclear polarization of protons, exogenous nitroxide biradicals such as TOTAPOL or AMUPOL are routinely used. Their efficiency is usually assessed as the ratio between the NMR signal intensity in the presence and the absence of microwave irradiation εon/off. While TOTAPOL delivers an enhancement εon/off of about 60 on a model sample, the more recent AMUPOL is more efficient: >200 at 100 K. Such a comparison is valid as long as the signal measured in the absence of microwaves is merely the Boltzmann polarization and is not affected by the spinning of the sample. However, recent MAS-DNP studies at 25 K by Thurber and Tycko (2014) have demonstrated that the presence of nitroxide biradicals combined with sample spinning can lead to a depolarized nuclear state, below the Boltzmann polarization. In this work we demonstrate that TOTAPOL and AMUPOL both lead to observable depolarization at ≈110 K, and that the magnitude of this depolarization is radical dependent. Compared to the static sample, TOTAPOL and AMUPOL lead, respectively, to nuclear polarization losses of up to 20% and 60% at a 10 kHz MAS frequency, while Trityl OX63 does not depolarize at all. This experimental work is analyzed using a theoretical model that explains how the depolarization process works under MAS and gives new insights into the DNP mechanism and into the spin parameters, which are relevant for the efficiency of a biradical. In light of these results, the outstanding performance of AMUPOL must be revised and we propose a new method to assess the polarization gain for future radicals.


Post-irradiation pericardial malignant mesothelioma with deletion of p16: a case report.
Malignant mesotheliomas are rather uncommon neoplasms associated primarily with asbestos exposure; however, they may also arise as second primary malignancies after radiation therapy, with a latency period of 15-25 years. Numerous studies have reported an association between pleural malignant mesothelioma and chest radiation performed for other malignancies; on the other hand, post-irradiation mesotheliomas of the pericardium have been reported in only a few published cases to date, and no homozygous deletion of 9p21 has been described in such cases. We report the case of a 48-year-old man with a history of Hodgkin's lymphoma and no prior asbestos exposure who developed pericardial malignant epithelioid mesothelioma. We further discuss the cytologic, histologic, immunophenotypic, and fluorescence in situ hybridization findings in this case. To our knowledge, this is the first well-documented case of post-radiation pericardial malignant mesothelioma showing homozygous deletion of 9p21. Homozygous deletion of 9p21, the locus harboring the p16 gene, is present in post-irradiation pericardial malignant mesothelioma.


Intensive prolonged exposure therapy for combat-related posttraumatic stress disorder: Design and methodology of a randomized clinical trial.
Combat-related posttraumatic stress disorder (PTSD) is the most common psychological health condition in military service members and veterans who have deployed to the combat theater since September 11, 2001. One of the highest research priorities for the Department of Defense and the Department of Veterans Affairs is to develop and evaluate the most efficient and efficacious treatments possible for combat-related PTSD. However, the treatment of combat-related PTSD in military service members and veterans has been significantly more challenging than the treatment of PTSD in civilians. Randomized clinical trials have demonstrated large posttreatment effect sizes for PTSD in civilian populations. However, recent randomized clinical trials of service members and veterans have achieved lesser reductions in PTSD symptoms. These results suggest that combat-related PTSD is unique. Innovative approaches are needed to augment established evidence-based treatments with targeted interventions that address the distinctive elements of combat-related traumas. This paper describes the design, methodology, and protocol of a randomized clinical trial to compare two intensive prolonged exposure therapy treatments for combat-related PTSD in active duty military service members and veterans and that can be administered in an acceptable, efficient manner in this population. Both interventions include intensive daily treatment over a 3-week period and a number of treatment enhancements hypothesized to result in greater reductions in combat-related PTSD symptoms. The study is designed to advance the delivery of care for combat-related PTSD by developing and evaluating the most potent treatments possible to reduce PTSD symptomatology and improve psychological, social, and occupational functioning.


Prenatal bisphenol a exposure leads to reproductive hazards on male offspring via the Akt/mTOR and mitochondrial apoptosis pathways.
Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals and humans, exposure has been associated with male spermatogenesis dysfunction. However, it is largely unknown if this association has a fetal origin. The aim of this research is to explore the mechanism whereby prenatal BPA exposure exerts its reproductive toxicities on spermatogenesis in male offspring. We fed pregnant SD rats BPA at doses ranging from 1 to 100 mg/kg body weight during gestation days 14-21. The male offspring were euthanized at postnatal day 21, and the levels of sex hormones and reactive oxygen species (ROS), expressions of proteins and genes in the Akt/mTOR, and mitochondrial apoptosis pathways were detected. Several closely linked autophagy indexes were also measured incidentally. Additionally, semen quality of adult offspring was tested at the end of the study. The results revealed that prenatal BPA exposure can cause endocrine disruption and oxidative stress in male offspring, leading to inhibition of spermatogenesis by suppressing the Akt/mTOR pathway and activating the mitochondrial apoptosis pathway. These preliminary results indicate noteworthy and far-reaching effects of BPA on the reproductive system of male offspring. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1007-1023, 2017.


Trialkyltin Rexinoid-X Receptor Agonists Selectively Potentiate Thyroid Hormone Induced Programs of Xenopus laevis Metamorphosis.
The trialkyltins tributyltin (TBT) and triphenyltin (TPT) can function as rexinoid-X receptor (RXR) agonists. We recently showed that RXR agonists can alter thyroid hormone (TH) signaling in a mammalian pituitary TH-responsive reporter cell line, GH3.TRE-Luc. The prevalence of TBT and TPT in the environment prompted us to test whether they could also affect TH signaling. Both trialkyltins induced the integrated luciferase reporter alone and potentiated TH activation at low doses. Trimethyltin, which is not an RXR agonist, did not. We turned to a simple, robust, and specific in vivo model system of TH action: metamorphosis of Xenopus laevis, the African clawed frog. Using a precocious metamorphosis assay, we found that 1nM TBT and TPT, but not trimethyltin, greatly potentiated the effect of TH treatment on resorption phenotypes of the tail, which is lost at metamorphosis, and in the head, which undergoes extensive remodeling including gill loss. Consistent with these responses, TH-induced caspase-3 activation in the tail was enhanced by cotreatment with TBT. Induction of a transgenic reporter gene and endogenous collagenase 3 (mmp13) and fibroblast-activating protein-α (fap) genes were not induced by TBT alone, but TH induction was significantly potentiated by TBT. However, induction of other TH receptor target genes such as TRβ and deiodinase 3 by TH were not affected by TBT cotreatment. These data indicate that trialkyltins that can function as RXR agonists can selectively potentiate gene expression and resultant morphological programs directed by TH signaling in vivo.


Impact of e-resources on learning in biochemistry: first-year medical students' perceptions.
E-learning resources (e-resources) have been widely used to facilitate self-directed learning among medical students. The Department of Biochemistry at Christian Medical College (CMC), Vellore, India, has made available e-resources to first-year medical students to supplement conventional lecture-based teaching in the subject. This study was designed to assess students' perceptions of the impact of these e-resources on various aspects of their learning in biochemistry. Sixty first-year medical students were the subjects of this study. At the end of the one-year course in biochemistry, the students were administered a questionnaire that asked them to assess the impact of the e-resources on various aspects of their learning in biochemistry. Ninety-eight percent of students had used the e-resources provided to varying extents. Most of them found the e-resources provided useful and of a high quality. The majority of them used these resources to prepare for periodic formative and final summative assessments in the course. The use of these resources increased steadily as the academic year progressed. Students said that the extent to which they understood the subject (83%) and their ability to answer questions in assessments (86%) had improved as a result of using these resources. They also said that they found biochemistry interesting (73%) and felt motivated to study the subject (59%). We found that first-year medical students extensively used the e-resources in biochemistry that were provided. They perceived that these resources had made a positive impact on various aspects of their learning in biochemistry. We conclude that e-resources are a useful supplement to conventional lecture-based teaching in the medical curriculum.


Inhomogeneity of charge-density-wave order and quenched disorder in a high-Tc superconductor.
It has recently been established that the high-transition-temperature (high-Tc) superconducting state coexists with short-range charge-density-wave order and quenched disorder arising from dopants and strain. This complex, multiscale phase separation invites the development of theories of high-temperature superconductivity that include complexity. The nature of the spatial interplay between charge and dopant order that provides a basis for nanoscale phase separation remains a key open question, because experiments have yet to probe the unknown spatial distribution at both the nanoscale and mesoscale (between atomic and macroscopic scale). Here we report micro X-ray diffraction imaging of the spatial distribution of both short-range charge-density-wave 'puddles' (domains with only a few wavelengths) and quenched disorder in HgBa2CuO4 + y, the single-layer cuprate with the highest Tc, 95 kelvin (refs 26-28). We found that the charge-density-wave puddles, like the steam bubbles in boiling water, have a fat-tailed size distribution that is typical of self-organization near a critical point. However, the quenched disorder, which arises from oxygen interstitials, has a distribution that is contrary to the usually assumed random, uncorrelated distribution. The interstitial-oxygen-rich domains are spatially anticorrelated with the charge-density-wave domains, because higher doping does not favour the stripy charge-density-wave puddles, leading to a complex emergent geometry of the spatial landscape for superconductivity.


The identity and work of the ancient Egyptian surgeon.
That a well-developed and hierarchical medical profession existed in Pharaonic Egypt is without doubt. What is a matter of contention is the existence of a recognizable surgical profession, or even of the practice of surgery by medically qualified personnel. Palaeorchaeological specimens that demonstrate some form of surgical procedure are rare. Medical papyri and the treatises of the historians of antiquity provide a far more reliable source of information on surgical practice. They have indicated possible titles for surgeons, and the types of instruments used.


Hepatoprotective, antioxidant, and ameliorative effects of ginger (Zingiber officinale Roscoe) and vitamin E in acetaminophen treated rats.
Ginger is a remedy known to possess a number of pharmacological properties. This study investigated efficacy of ginger pretreatment in alleviating acetaminophen-induced acute hepatotoxicity in rats. Rats were divided into six groups; negative control, acetaminophen (APAP) (600 mg/kg single intraperitoneal injection); vitamin E (75 mg/kg), ginger (100 mg/kg), vitamin E + APAP, and ginger + APAP. Administration of APAP elicited significant liver injury that was manifested by remarkable increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), arginase activities, and total bilirubin concentration. Meanwhile, APAP significantly decreased plasma total proteins and albumin levels. APAP administration resulted in substantial increase in each of plasma triacylglycerols (TAGs), malondialdhyde (MDA) levels, and total antioxidant capacity (TAC). However, ginger or vitamin E treatment prior to APAP showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, ALP, and arginase) and total bilirubin in plasma. In addition, they remarkably ameliorated the APAP-induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger or vitamin E significantly restored TAGs, and total protein levels. Histopathological examination of APAP treated rats showed alterations in normal hepatic histoarchitecture, with necrosis and vacuolization of cells. These alterations were substantially decreased by ginger or vitamin E. Our results demonstrated that ginger can prevent hepatic injuries, alleviating oxidative stress in a manner comparable to that of vitamin E. Combination therapy of ginger and APAP is recommended especially in cases with hepatic disorders or when high doses of APAP are required.


Systematic Surface Phase Transition of Ag Thin Films by Iodine Functionalization at Room Temperature: Evolution of Optoelectronic and Texture Properties.
We show a simple room temperature surface functionalization approach using iodine vapour to control a surface phase transition from cubic silver (Ag) of thin films into wurtzite silver-iodid (β-AgI) films. A combination of surface characterization techniques (optical, electronical and structural characterization) reveal distinct physical properties of the new surface phase. We discuss the AgI thin film formation dynamics and related transformation of physical properties by determining the work-function, dielectric constant and pyroelectric behavior together with morphological and structural thin film properties such as layer thickness, grain structure and texture formation. Notable results are: (i) a remarkable increase of the work-function (by 0.9 eV) of the Ag thin layer after short a iodine exposure time (≤60 s), with simultaneous increase of the thin film transparency (by two orders of magnitude), (ii) pinning of the Fermi level at the valance band maximum upon iodine functionalization, (iii) 84% of all crystallites grain were aligned as a result of the evolution of an internal electric field. Realizing a nano-scale layer stack composed of a dielectric AgI layer on top of a metallic thin Ag layer with such a simple method has some technological implications e.g. to realize optical elements such as planar optical waveguides.


Historical change in the link between adolescent deviance proneness and marijuana use, 1979-2004.
We examined historical change in the association between adolescent deviance proneness and marijuana use using 26 years (from 1979 through 2004) of national 12th grade data from the Monitoring the Future (MTF) study. "Deviance proneness" was measured using a latent factor model of behavioral and personality characteristics that underlie both substance use and antisocial disorders. Marijuana use was measured both in terms of annual frequency of use and degree of involvement with marijuana. Separate within-gender structural equation models were used to determine whether links between deviance proneness and marijuana use were consistently significant and invariant in magnitude across 13 two-year historical cohorts. Overall results affirmed the established association between adolescent deviance proneness and both the frequency of marijuana use as well as regular use. Among male youth, the size of the association between deviance proneness and marijuana use was significantly smaller at the cohort of lowest population prevalence (1991/92) compared to cohorts marking peaks in marijuana use prevalence, thus suggesting a "softening" historical trend. By contrast, the prediction of female marijuana use from deviance proneness was not consistently related to historical shifts in population prevalence of marijuana use. Study findings point to the utility of risk-focused prevention programming that targets early precursors of both antisocial and substance use disorders.


Combined paediatric liver-kidney transplantation: analysis of our experience and literature review.
Renal insufficiency is increasingly common in end-stage liver disease and allocation of livers to this category of patient has escalated. The frequency of combined liver-kidney transplantation (CLKT) has consequently increased. Indications for CLKT in children differ from those for adults and typically include rare congenital conditions; subsequently limited numbers of this procedure have been performed in paediatric patients worldwide. Scant literature exists on the subject. Subsequent to institutional approval, a retrospective chart analysis of all paediatric CLKTs performed at the Transplant Unit, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa between January 2005 and July 2013 was conducted. Defining children as younger than 18 years of age, 43 patients had received a liver transplant since 2005, of whom 8 received a CLKT. Indications included autosomal recessive polycystic kidney disease (n=3), primary hyperoxaluria type 1 (n=4) and heterozygous factor H deficiency with atypical haemolytic uraemic syndrome (n=1). Graft combinations included whole liver and one kidney (n=5), whole liver and two kidneys (n=1) and left lateral liver segment and one kidney (n=2), all from deceased donors. Patient age ranged from 4 to 17 years (median 9) and included 4 females and 4 males. Weight ranged from 13 to 42 kg (median 22.5). We describe one in-hospital mortality. The remaining 7 patients were long-term survivors with a survival range from 6 to 65 months. Although rarely indicated in children, CLKT is an effective treatment option, appropriately utilising a scarce resource and significantly improving quality of life in the recipient.


Community health status indicators project: the development of a national approach to community health.
The Community Health Status Indicators Project (CHSI) 2008 provides 16-page reports for the 3141 counties in the United States, each of which includes more than 300 county-specific data items related to chronic and infectious diseases, birth characteristics or outcomes, causes of death, environmental health, availability of health services, behavioral risk factors, health-related quality of life, vulnerable populations, summary measures of health, and health disparities. The CHSI, originally initiated in 2000, provides county-level health profiles for all U.S. counties so that programs addressing community health can readily access community health indicators. Each county report also permits comparisons of a county's health status with similar "peer counties," with all counties, and with national Healthy People 2010 objectives. Under the leadership of a public-private partnership, the CHSI Steering Committee updated each county report and added new information and features to create CHSI 2008. This new CHSI version includes data for 1994 through 2006 from multiple surveillance systems. New features include an enhanced Web site, an Internet mapping application, and a downloadable database of the indicators for all counties.


Cigarette smoke inhalation patterns and bronchial reactivity.
The manner in which a cigarette is smoked varies considerably between individuals and may be an important determinant of the altered bronchial reactivity observed in cigarette smokers. Twenty smokers were examined to determine the relationship between cigarette smoke inhalation patterns and bronchial reactivity. Inhalation patterns were measured non-invasively with a respiratory inductive plethysmograph and these were related to the provocative concentration of histamine that caused a 20% fall in FEV1 (PC20) and to the cough threshold for inhaled citric acid. Histamine PC20 values were inversely correlated with depth and rate of inhalation. Cough threshold was inversely correlated with greater cigarette consumption and with depth of inhalation.


Peronosporomycetes (Oomycota) from a Middle Permian permineralised peat within the Bainmedart Coal Measures, Prince Charles Mountains, Antarctica.
The fossil record of Peronosporomycetes (water moulds) is rather sparse, though their distinctive ornamentation means they are probably better reported than some true fungal groups. Here we describe a rare Palaeozoic occurrence of this group from a Guadalupian (Middle Permian) silicified peat deposit in the Bainmedart Coal Measures, Prince Charles Mountains, Antarctica. Specimens are numerous and comprise two morphologically distinct kinds of ornamented oogonia, of which some are attached to hyphae by a septum. Combresomyces caespitosus sp. nov. consists of spherical oogonia bearing densely spaced, long, hollow, slender, conical papillae with multiple sharply pointed, strongly divergent, apical branches that commonly form a pseudoreticulate pattern under optical microscopy. The oogonia are attached to a parental hypha by a short truncated stalk with a single septum. Combresomyces rarus sp. nov. consists of spherical oogonia bearing widely spaced, hollow, broad, conical papillae that terminate in a single bifurcation producing a pair of acutely divergent sharply pointed branches. The oogonium bears a short truncate extension where it attaches to the parental hypha. We propose that similarities in oogonium shape, size, spine morphology and hyphal attachment between the Permian forms from the Prince Charles Mountains and other reported Peronosporomycetes from Devonian to Triassic strata at widely separated localities elsewhere in the world delimit an extinct but once cosmopolitan Palaeozoic to early Mesozoic branch of the peronosporomycete clade. We name this order Combresomycetales and note that it played an important role in late Palaeozoic and early Mesozoic peatland ecosystems worldwide.


MicroRNA-208a Increases Myocardial Endoglin Expression and Myocardial Fibrosis in Acute Myocardial Infarction.
MicroRNAs (miRs) play a role in cardiac remodelling, and acute myocardial infarction (AMI) can regulate miR expression. MiR-208a is essential for the expression of the genes involved in cardiac hypertrophy and fibrosis. MiR-208a activates endoglin expression and may result in cardiac fibrosis. The role of miR-208a and endoglin in AMI is not known. We sought to investigate the regulation of miR-208a and endoglin in AMI. Ligation of the proximal left anterior descending artery was performed in adult Sprague-Dawley rats to induce AMI. Echocardiography was used to measure heart size and left ventricular function. The TaqMan miR real-time quantitative assay was used to quantitate miR-208a. Myocardial fibrosis was detected by Masson trichrome staining. AMI and overexpression of miR-208a in the sham group without infarction significantly increased myocardial miR-208a, endoglin, and β-myosin heavy chain (β-MHC) expression. Overexpression of antagomir-208a significantly inhibited the increase of myocardial endoglin and β-MHC protein expression induced by infarction. Overexpression of mutant miR-208a in the sham group did not induce myocardial endoglin and β-MHC expression. Pretreatment with atorvastatin and the angiotensin-receptor antagonist valsartan significantly attenuated the increase of endoglin and β-MHC induced by infarction. AMI and overexpression of miR-208a in the sham group significantly increased the area of myocardial fibrosis compared with the sham group. Overexpression of antagomir-208a and pretreatment with atorvastatin and valsartan in the AMI group significantly decreased the area of myocardial fibrosis induced by infarction. MiR-208a increases endoglin expression to induce myocardial fibrosis in rats with AMI. Treatment with atorvastatin and valsartan can decrease myocardial fibrosis induced by AMI through attenuating miR-208a and endoglin expression.


Fine spatial pattern of an epiphytic lichen species is affected by habitat conditions in two forest types in the Iberian Mediterranean region.
Persistence and abundance of species is determined by habitat availability and the ability to disperse and colonize habitats at contrasting spatial scales. Favourable habitat fragments are also heterogeneous in quality, providing differing opportunities for establishment and affecting the population dynamics of a species. Based on these principles, we suggest that the presence and abundance of epiphytes may reflect their dispersal ability, which is primarily determined by the spatial structure of host trees, but also by host quality. To our knowledge there has been no explicit test of the importance of host tree spatial pattern for epiphytes in Mediterranean forests. We hypothesized that performance and host occupancy in a favourable habitat depend on the spatial pattern of host trees, because this pattern affects the dispersal ability of each epiphyte and it also determines the availability of suitable sites for establishment. We tested this hypothesis using new point pattern analysis tools and generalized linear mixed models to investigate the spatial distribution and performance of the epiphytic lichen Lobaria pulmonaria, which inhabits two types of host trees (beeches and Iberian oaks). We tested the effects on L. pulmonaria distribution of tree size, spatial configuration, and host tree identity. We built a model including tree size, stand structure, and several neighbourhood predictors to understand the effect of host tree on L. pulmonaria. We also investigated the relative importance of spatial patterning on the presence and abundance of the species, independently of the host tree configuration. L. pulmonaria distribution was highly dependent on habitat quality for successful establishment, i.e., tree species identity, tree diameter, and several forest stand structure surrogates. For beech trees, tree diameter was the main factor influencing presence and cover of the lichen, although larger lichen-colonized trees were located close to focal trees, i.e., young trees. However, oak diameter was not an important factor, suggesting that bark roughness at all diameters favoured lichen establishment. Our results indicate that L. pulmonaria dispersal is not spatially restricted, but it is dependent on habitat quality. Furthermore, new spatial analysis tools suggested that L. pulmonaria cover exhibits a distinct pattern, although the spatial pattern of tree position and size was random.


Effect of vitamin D supplementation on serum sclerostin levels in chronic kidney disease.
Vitamin D deficiency, cardiovascular disease and abnormal bone mineral metabolism are common in chronic kidney disease (CKD). Abnormal bone mineral metabolism has been linked to vascular calcification in CKD. Sclerostin has emerged as an important messenger in cross talk between bone-vascular axis. We analyzed sclerostin in subjects who participated in the randomized, double blind, placebo controlled trial investigating the effect of cholecalciferol supplementation on vascular function in non-diabetic CKD stage G3-4 and vitamin D ≤ 20 ng/ml [CTRI/2013/05/003648]. Patients were randomized (1:1) to receive either two directly observed oral doses of 300,000 IU of cholecalciferol or matching placebo at baseline and 8 weeks. Of the 120 subjects enrolled, 58 in the cholecalciferol group and 59 in the placebo group completed the study. At baseline, serum levels of sclerostin were similar in both groups (cholecalciferol - median;190pg/ml, IQR;140-260 pg/ml and placebo - median;180 pg/ml, IQR; 140-240 pg/ml, p = 0.67). 16 weeks after cholecalciferol supplementation, there was no change in level of sclerostin (mean change;1.10 pg/ml, 95%CI; -27.34 to 29.34 pg/ml, p = 0.25). However, a significant decrease in sclerostin level was noted in the placebo group (mean change; -31.94 pg/ml, 95%CI; -54.76 to -9.13 pg/ml, p = 0.002). Change (Δ) in sclerostin level at 16 weeks correlated negatively with Δ eGFR (r = -0.20, p = 0.03) and positively with Δuric acid (r = 0.37, p < 0.001) but not with Δ25(OH) D (r = 0.06, p = 0.54), Δ iPTH (r = - 0.03, p = 0.78) ΔFGF23 (r = - 0.08, p = 0.38) and Δ125 (OH)2 D (r = - 0.04, p = 0.65). In conclusion, high dose cholecalciferol supplementation did not change sclerostin levels in non-diabetic stage 3-4 CKD subjects.


An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis.
Non Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome; worrisome is the booming increase in pediatric age. To recreate the full spectrum of juvenile liver pathology and investigate the gender impact, male and female C57Bl/6 mice were fed with high fat diet plus fructose in the drinking water (HFHC) immediately after weaning (equal to 3-years old human), and disease progression followed for 16 weeks, until adults (equal to 30-years old human). 100% of subjects of both genders on HFHC diet developed steatosis in 4weeks, and some degree of fibrosis in 8weeks, with the 86% of males and 15% of females presenting a stage 2 fibrosis at 16weeks. Despite a similar final liver damage both groups, a sex difference in the pathology progression was observed. Alterations in glucose homeostasis, dyslipidemia, hepatomegaly and obese phenotype were evident from the very beginning in males with an increased hepatic inflammatory activity. Conversely, such alterations were present in females only at the end of the HFHC diet (with the exception of insulin resistance and the hepatic inflammatory state). Interestingly, only females showed an altered hepatic redox state. This juvenile model appears a good platform to unravel the underlying gender dependent mechanisms in the progression from NAFLD to NASH, and to characterize novel therapeutic approaches.


Declining complication rates with flow diversion of anterior circulation aneurysms after introduction of the Pipeline Flex: analysis of a single-institution series of 568 cases.
OBJECTIVEThe second-generation Pipeline embolization device (PED), Flex, has several design upgrades, including improved opening and the ability to be resheathed, in comparison with the original device (PED classic). The authors hypothesized that Flex is associated with a lower rate of major complications.METHODSA prospective, IRB-approved, single-institution database was analyzed for all patients with anterior circulation aneurysms treated by flow diversion. The PED classic was used from August 2011 to January 2015, and the Pipeline Flex has been used since February 2015.RESULTSA total of 568 PED procedures (252 classic and 316 Flex) were performed for anterior circulation aneurysms. The average aneurysm size was 6.8 mm. Patients undergoing treatment with the Flex device had smaller aneurysms (p = 0.006) and were more likely to have undergone previous treatments (p = 0.001). Most aneurysms originated along the internal carotid artery (89% classic and 75% Flex) but there were more anterior cerebral artery (18%) and middle cerebral artery (7%) deployments with Flex (p = 0.001). Procedural success was achieved in 96% of classic and 98% of Flex cases (p = 0.078). Major morbidity or death occurred in 3.5% of cases overall: 5.6% of classic cases, and 1.9% of Flex cases (p = 0.019). On multivariate logistic regression, predictors of major complications were in situ thrombosis (OR 4.3, p = 0.006), classic as opposed to Flex device (OR 3.7, p = 0.008), and device deployment in the anterior cerebral artery or middle cerebral artery as opposed to the internal carotid artery (OR 3.5, p = 0.034).CONCLUSIONSFlow diversion of anterior circulation cerebral aneurysms is associated with an overall low rate of major complications. The complication rate is significantly lower since the introduction of the second-generation PED (Flex).


Predictive diagnostics for Escherichia coli infections based on the clonal association of antimicrobial resistance and clinical outcome.
The ability to identify bacterial pathogens at the subspecies level in clinical diagnostics is currently limited. We investigated whether splitting Escherichia coli species into clonal groups (clonotypes) predicts antimicrobial susceptibility or clinical outcome. A total of 1,679 extraintestinal E. coli isolates (collected from 2010 to 2012) were collected from one German and 5 U.S. clinical microbiology laboratories. Clonotype identity was determined by fumC and fimH (CH) sequencing. The associations of clonotype with antimicrobial susceptibility and clinical variables were evaluated. CH typing divided the isolates into >200 CH clonotypes, with 93% of the isolates belonging to clonotypes with ≥ 2 isolates. Antimicrobial susceptibility varied substantially among clonotypes but was consistent across different locations. Clonotype-guided antimicrobial selection significantly reduced "drug-bug" mismatch compared to that which occurs with the use of conventional empirical therapy. With trimethoprim-sulfamethoxazole and fluoroquinolones, the drug-bug mismatch was predicted to decrease 62% and 78%, respectively. Recurrent or persistent urinary tract infection and clinical sepsis were significantly correlated with specific clonotypes, especially with CH40-30 (also known as H30), a recently described clonotype within sequence type 131 (ST131). We were able to clonotype directly from patient urine samples within 1 to 3 h of obtaining the specimen. In E. coli, subspecies-level identification by clonotyping can be used to significantly improve empirical predictions of antimicrobial susceptibility and clinical outcomes in a timely manner.


Timing of the expression of enamel gene products during mouse tooth development.
In order to understand the mechanisms involved in tooth development it is important to define the timing for tissue-specific gene expression. A consequence of ameloblast cell differentiation is the sequential expression of tissue-specific genes whose products form the enamel extracellular matrix. The ameloblast phenotype has been characterized as consisting of two major classes of proteins: amelogenins and non-amelogenin proteins such as anionic enamel proteins (enamelins, tuft proteins, tuftelin, sulfated proteins) and enamel proteases. The postulated functions for the anionic enamel proteins are as nucleators for hydroxyapatite crystal formation while amelogenins control the crystal size, growth and orientation. While the amelogenins have been well characterized, detailed knowledge for anionic enamel proteins has been sparse. In the present study, we designed experiments to characterize one of the anionic enamel proteins from mouse molars, tuftelin, and to determine the timing of expression of this protein during molar tooth development. Our results showed the initial detection of tuftelin transcripts within proliferating inner enamel epithelial cells at very early stages of tooth development (13 days of embryonic development equivalent to the bud stage of tooth development). These data provide direct evidence that invalidates previous dogmas that enamel proteins were synthesized by polarized, non-dividing, fully differentiated ameloblast cells. In addition, tuftelin was found to be synthesized also by dental papilla mesenchyme cells suggesting that this protein is not enamel-specific. These data taken together open the possibility that the tuftelin present in the dentino-enamel junction could be secreted by both, preodontoblast cells and preameloblast cells. It might also suggest a possible different role for tuftelin than nucleator of hydroxyapatite crystals.