Hepatitis C virus clearance after discontinuation of pegylated interferon alpha-2a monotherapy in a child.
The present patient was a 4-year-old boy. His hepatitis C virus genotype was 2a, and his viral load was high (1400,000 U/mL). The pretreatment liver biopsy revealed no fibrosis or malignancy and mild chronic hepatitis; his Knodell's histological activity (HAI) score was 4. Single nucleotide polymorphism of IL28B (rs8099917) was major type. The patient began antiviral treatment with pegylated interferon alpha 2a (90 μg/week). At week 9, serum HCV RNA became undetectable, with a sensitivity of 50 copies/mL. Antiviral treatment was discontinued at week 11 because the ALT level increased to 610 U/L. After discontinuation of therapy, the patient's serum HCV RNA status became positive again. The serum viral load increased to 100,000 U/mL. During this period, he had been observed without medication. Sixteen months after stopping treatment, serum HCV became undetectable. Over a 4-year period, HCV RNA became negative and his anti-HCV antibody titer gradually decreased. In conclusion, though antiviral therapy resulted in failure or incomplete therapy, a reduced viral load resulted in viral clearance in the present patient. Interleukin 28B genotype might have association with the clearance of hepatitis C virus after discontinuation of antiviral therapy.


Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group.
The Response Assessment in Neuro-Oncology (RANO) Working Group is an international, multidisciplinary effort to develop new standardized response criteria for clinical trials in brain tumors. The RANO group identified knowledge gaps relating to the definitions of tumor response and progression after the use of surgical or surgically based treatments. To outline a proposal for new response and progression criteria for the assessment of the effects of surgery and surgically delivered therapies for patients with gliomas. The Surgery Working Group of RANO identified surgically related end-point evaluation problems that were not addressed in the original Macdonald criteria, performed an extensive literature review, and used a consensus-building process to develop recommendations for how to address these issues in the setting of clinical trials. Recommendations were formulated for surgically related issues, including imaging changes associated with surgical resection or surgically mediated adjuvant local therapies, the determination of progression in the setting where all enhancing tumor has been removed, and how new enhancement should be interpreted in the setting where local therapies that are known to produce nonspecific enhancement have been used. Additionally, the terminology used to describe the completeness of surgical resections has been recognized to be inconsistently applied to enhancing vs nonenhancing tumors, and a new set of descriptors is proposed. The RANO process is intended to produce end-point criteria for clinical trials that take into account the effects of prior and ongoing therapies. The RANO criteria will continue to evolve as new therapies and technologies are introduced into clinical trial and/or practice.


IκB kinase activity drives fetal lung macrophage maturation along a non-M1/M2 paradigm.
In preterm infants, exposure to inflammation increases the risk of bronchopulmonary dysplasia, a chronic, developmental lung disease. Although macrophages are the key cells that initiate lung inflammation, less is known about lung macrophage phenotype and maturation. We hypothesized that fetal lung macrophages mature into distinct subpopulations during mouse development, and that activation could influence macrophage maturation. Expression of the fetal macrophage markers CD68, CD86, CD206, Ym1, fibrinogen-like protein 2, and indolamine-2, 3-dioxygenase was developmentally regulated, with each marker having different temporal patterns. Flow cytometry analysis showed macrophages within the fetal lung were less diverse than the distinctly separate subpopulations in newborn and adult lungs. Similar to adult alveolar macrophages, fetal lung macrophages responded to the TLR4 agonist LPS and the alternative activation cytokines IL-4 and IL-13. Using a macrophage-specific constitutively active IκB Kinase transgenic model (IKFM), we demonstrated that macrophage activation increased proinflammatory gene expression and reduced the response of fetal lung macrophages to IL-4 and IL-13. Activation also increased fetal lung macrophage proliferation. Fetal IKFM lungs contained increased percentages of more mature, CD11b(low)F4/80(high) cells that also expressed higher levels of the alternative activation markers CD204 and CD206. Development of fetal lung macrophages into mature alveolar macrophages may therefore include features of both proinflammatory and alternative activation paradigms.


Applying dynamic simulation modeling methods in health care delivery research-the SIMULATE checklist: report of the ISPOR simulation modeling emerging good practices task force.
Health care delivery systems are inherently complex, consisting of multiple tiers of interdependent subsystems and processes that are adaptive to changes in the environment and behave in a nonlinear fashion. Traditional health technology assessment and modeling methods often neglect the wider health system impacts that can be critical for achieving desired health system goals and are often of limited usefulness when applied to complex health systems. Researchers and health care decision makers can either underestimate or fail to consider the interactions among the people, processes, technology, and facility designs. Health care delivery system interventions need to incorporate the dynamics and complexities of the health care system context in which the intervention is delivered. This report provides an overview of common dynamic simulation modeling methods and examples of health care system interventions in which such methods could be useful. Three dynamic simulation modeling methods are presented to evaluate system interventions for health care delivery: system dynamics, discrete event simulation, and agent-based modeling. In contrast to conventional evaluations, a dynamic systems approach incorporates the complexity of the system and anticipates the upstream and downstream consequences of changes in complex health care delivery systems. This report assists researchers and decision makers in deciding whether these simulation methods are appropriate to address specific health system problems through an eight-point checklist referred to as the SIMULATE (System, Interactions, Multilevel, Understanding, Loops, Agents, Time, Emergence) tool. It is a primer for researchers and decision makers working in health care delivery and implementation sciences who face complex challenges in delivering effective and efficient care that can be addressed with system interventions. On reviewing this report, the readers should be able to identify whether these simulation modeling methods are appropriate to answer the problem they are addressing and to recognize the differences of these methods from other modeling approaches used typically in health technology assessment applications.


Simultaneous acquisition of multiple orders of intermolecular multiple-quantum coherence images in vivo.
Until recently, NMR imaging with intermolecular multiple-quantum coherences (iMQCs) has been based on the acquisition of a single echo. In vivo studies of iMQC image contrast would greatly benefit from a method that could acquire several orders of quantum coherence during the same acquisition. This would enable comparison of the image contrast for various orders and eliminate image coregistration problems between scans. It has previously been demonstrated that multiple orders of iMQC images can be simultaneously acquired of a simple phantom. Here, we examine the technique and its effect on biological tissue, both in vivo and in vitro. First, we establish the effectiveness of the iMQC sequence in vivo using earthworms as specimens. We then further show that the multi-CRAZED sequence enhances detection of next generation (nanoparticle) contrast agents on excised tumor tissue.


Facet-Independent Oxygen Evolution Activity of Pure β-NiOOH: Different Chemistries Leading to Similar Overpotentials.
β-Nickel oxyhydroxide (β-NiOOH) is a promising electrocatalyst for the oxygen evolution reaction (OER), which is the more difficult half-reaction involved in water splitting. In this study, we revisit the OER activities of the two most abundant crystallographic facets of pristine β-NiOOH, the (0001) and (1010) facets, which expose 6-fold-lattice-oxygen-coordinated and 5-fold-lattice-oxygen-coordinated Ni sites, respectively. To this end, we model various active sites on these two facets using hybrid density functional theory, which includes a fraction of the exact nonlocal Fock exchange in the electronic description of the system. By evaluating thermodynamic OER overpotentials, we show that the two active sites considered on each crystallographic facet demonstrate OER activities remarkably different from each other. However, the lowest OER overpotentials calculated for the two facets were found to be similar to each other and comparable to the overpotential for the 4-fold-lattice-oxygen-coordinated Ni site on the (1211) facet of β-NiOOH previously examined in J. Am. Chem. Soc. 2019 , 141 , 1 , 693 - 705 . This finding shows that all of the low-index facets investigated so far could be responsible for the experimentally observed OER activity of pristine β-NiOOH. However, the lowest overpotential active sites on these three crystallographic facets operate via different mechanisms, underscoring the importance of considering multiple OER pathways and intermediates on each crystallographic facet of a potential electrocatalyst. Specifically, our work demonstrates that consideration of previously overlooked active sites, transition-metal-ion oxidation states, reaction intermediates, and lattice-oxygen-stabilization are critical to reveal the lowest overpotential OER pathways on pristine β-NiOOH.


Induction of mesothelioma by a single intrascrotal administration of multi-wall carbon nanotube in intact male Fischer 344 rats.
The present study assessed a carcinogenic hazard of multi-wall carbon nanotube (MWCNT) in intact (not genetically modified) rodents. MWCNT (1 mg/kg body weight, 7 animals), crocidolite (2 mg/kg body weight, 10 animals) or vehicle (2% carboxymethyl cellulose, 5 animals) was administered to male Fischer 344 rats (12 weeks old) by a single intrascrotal injection. Rats were autopsied immediately after death, when becoming moribund or at the end of the maximal observation period scheduled to be 52 weeks. After 37-40 weeks, however, 6 MWCNT-treated animals died or became moribund due to intraperitoneally disseminated mesothelioma (6/7, 85.7%) with bloody ascites. Peritoneal mesothelium was generally hypertrophic, and numerous nodular or papillary lesions of mesothelioma and mesothelial hyperplasia were developed. While mesothelioid cells were predominant in relatively early stage tumors, advanced stage mesotheliomas were constituted by 2 portions occupied by mesothelioid cells on the surface and spindle-shaped sarcomatous cells in the depth. In the latter, the histological transition was apparently observed between these 2 portions. Mesotheliomas were invasive to adjacent organs and tissues, and frequently metastasized into the pleura. Only 1 rat survived for 52 weeks in the MWCNT-treated group, and similar findings except mesothelioma were observed. All 10 crocidolite-treated and 5 vehicle-treated rats survived for 52 weeks without any particular changes except deposition of asbestos in the former case. It is thus indicated that MWCNT possesses carcinogenicity causing mesothelioma at a high rate in intact male rats under the present experimental conditions. The present data identifies a carcinogenic hazard of MWCNT and will serve as one of the indispensable evidences to be used for the risk assessment crucial for not only protection and improvement of human health and welfare, but also safe and acceptable development and prevalence of this and similar upcoming materials.


Separation of collagen-bound and porous bone water transverse relaxation in mice: proposal of a multi-step approach.
The separation and quantification of collagen-bound water (CBW) and pore water (PW) components of the cortical bone signal are important because of their different contribution to bone mechanical properties. Ultrashort TE (UTE) imaging can be used to exploit the transverse relaxation from CBW and PW, allowing their quantification. We tested, for the first time, the feasibility of UTE measurements in mice for the separation and quantification of the transverse relaxation of CBW and PW in vivo using three different approaches for T2 * determination. UTE sequences were acquired at 4.7 T in six mice with 10 different TEs (50-5000 μs). The transverse relaxation time T2 * of CBW (T2 *cbw ) and PW (T2 *pw ) and the CBW fraction (bwf) were computed using a mono-exponential (i), a standard bi-exponential (ii) and a new multi-step bi-exponential (iii) approach. Regions of interest were drawn at multiple levels of the femur and vertebral body cortical bone for each mouse. The sum of the normalized squared residuals (Res) and the homogeneity of variance were tested to compare the different methods. In the femur, approach (i) yielded mean T2 * ± standard deviation (SD) of 657 ± 234 μs. With approach (ii), T2 *cbw , T2 *pw and bwf were 464 ± 153 μs, 15 777 ± 10 864 μs and 57.6 ± 9.9%, respectively. For approach (iii), T2 *cbw , T2 *pw and bwf were 387 ± 108 μs, 7534 ± 2765 μs and 42.5 ± 6.2%, respectively. Similar values were obtained from vertebral bodies. Res with approach (ii) was lower than with the two other approaches (p < 0.007), but T2 *pw and bwf variance was lower with approach (iii) than with approach (ii) (p < 0.048). We demonstrated that the separation and quantification of cortical bone water components with UTE sequences is feasible in vivo in mouse models. The direct bi-exponential approach exhibited the best approximation to the measured signal curve with the lowest residuals; however, the newly proposed multi-step algorithm resulted in substantially lower variability of the computed parameters. Copyright © 2016 John Wiley & Sons, Ltd.


Noninvasive ventilation initiation in clinical practice: A six-year prospective, observational study.
Despite evidence supporting the role of noninvasive ventilation (NIV) in diverse populations, few publications describe how NIV is used in clinical practice. To describe NIV initiation in a teaching hospital that has a guideline, and to characterize temporal changes in NIV initiation over time. A prospective, observational study of continuous positive airway pressure ventilation (CPAP) or bilevel NIV initiation from January 2000 to December 2005 was conducted. Registered respiratory therapists completed a one-page data collection form at NIV initiation. Over a six-year period, NIV was initiated in 623 unique patients (531 bilevel NIV, 92 CPAP). Compared with bilevel NIV, CPAP was initiated more often using a nasal interface, with a machine owned by the patient, and for chronic conditions, especially obstructive sleep apnea. Whereas CPAP was frequently initiated and continued on the wards, bilevel NIV was most frequently initiated and continued in the emergency department, intensive care unit and the coronary care unit. Patients initiated on bilevel NIV were more likely to be female (OR 1.8, 95% CI 1.08 to 2.85; P=0.02) and to have an acute indication compared with CPAP initiations (OR 7.5, 95% CI 1.61 to 34.41; P=0.01). Bilevel NIV was initiated more often in the emergency department than in the intensive care unit (OR 5.8, 95% CI 0.89 to 38.17; P=0.07). Bilevel NIV initiation increased from 2000 to 2005. The present study illustrates how NIV is used in clinical practice and confirms that NIV initiation has increased over time.


Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors.
Polycythemia Vera (PV) is a myeloproliferative disorder (MPD) that is commonly characterized by mutant JAK2 (JAK2V617F) signaling, erythrocyte overproduction, and a propensity for thrombosis, progression to myelofibrosis, or acute leukemia. In this study, JAK2V617F expression by human hematopoietic progenitors promoted erythroid colony formation and erythroid engraftment in a bioluminescent xenogeneic immunocompromised mouse transplantation model. A selective JAK2 inhibitor, TG101348 (300 nM), significantly inhibited JAK2V617F+ progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG101348 treatment decreased GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibited STAT5 as well as GATA S310 phosphorylation. Thus, TG101348 may be an effective inhibitor of JAK2V617F+ MPDs in clinical trials.


Collaborative Processes in Science and Literature: an In-Depth Look at the Cases of CERN and SIC.
In this paper we examine how the process of collaboration works in science and literature. In the first part, we discuss the features of scientific collaboration and literary collaboration and the differences between them. In the second part, we analyze two processes of collaboration, each from a different field: the case of CERN and high-energy physics and the case of Scrittura Industriale Collettiva and its Great Open Novel. Lastly, we try to compare those two processes and deduce the common traits of a successful collaboration.


Transcriptional up-regulation of the human androgen receptor by androgen in bone cells.
Androgen regulation of androgen receptor (AR) expression has been observed in a variety of tissues, generally as inhibition, and is thought to attenuate cellular responses to androgen. AR is expressed in osteoblasts, the bone-forming cell, suggesting direct actions of androgens on bone. Here we characterized the effect of androgen exposure on AR gene expression in human osteoblastic SaOS-2 and U-2 OS cells. Treatment of osteoblastic cells with the nonaromatizable androgen 5alpha-dihydrotestosterone increased AR steady state messenger RNA levels in a time- and dose-dependent fashion. Reporter assays with 2.3 kilobases of the proximal 5'-flanking region of the human AR promoter linked to the chloramphenicol acetyltransferase gene in transfected cultures showed that up-regulation of AR promoter activity by androgen was time and dose dependent. Treatment with other steroid hormones, including progesterone, 17beta-estradiol, and dexamethasone, was without effect. The antiandrogen hydroxyflutamide completely antagonized androgen up-regulation. Thus, in contrast to many other androgen target tissues, androgen exposure increases steady state AR messenger RNA levels in osteoblasts. This regulation occurs at least partially at the level of transcription, is mediated by the 5'-promoter region of the AR gene, and is dependent on functional AR. These results suggest that physiological concentrations of androgens have significant effects on AR expression in skeletal tissue.


Comparative genomics study reveals Red Sea Bacillus with characteristics associated with potential microbial cell factories (MCFs).
Recent advancements in the use of microbial cells for scalable production of industrial enzymes encourage exploring new environments for efficient microbial cell factories (MCFs). Here, through a comparison study, ten newly sequenced Bacillus species, isolated from the Rabigh Harbor Lagoon on the Red Sea shoreline, were evaluated for their potential use as MCFs. Phylogenetic analysis of 40 representative genomes with phylogenetic relevance, including the ten Red Sea species, showed that the Red Sea species come from several colonization events and are not the result of a single colonization followed by speciation. Moreover, clustering reactions in reconstruct metabolic networks of these Bacillus species revealed that three metabolic clades do not fit the phylogenetic tree, a sign of convergent evolution of the metabolism of these species in response to special environmental adaptation. We further showed Red Sea strains Bacillus paralicheniformis (Bac48) and B. halosaccharovorans (Bac94) had twice as much secreted proteins than the model strain B. subtilis 168. Also, Bac94 was enriched with genes associated with the Tat and Sec protein secretion system and Bac48 has a hybrid PKS/NRPS cluster that is part of a horizontally transferred genomic region. These properties collectively hint towards the potential use of Red Sea Bacillus as efficient protein secreting microbial hosts, and that this characteristic of these strains may be a consequence of the unique ecological features of the isolation environment.


[Angiomyofibroblastoma-like tumors].
Angiomyofibroblastomas are rare, benign, slow-growing tumors, that occurring predominantly in vulvar lesions of premenopausal women. In male patients only few cases are reported (angiomyofibroblastoma-like tumors). They occur mostly in scrotal and inguinal regions. We report a case of left scrotal angiomyofibroblastoma-like tumor in a 52-years old man. After a biopsy for histological examination, a complete surgical excision was performed. At 12 months' follow-up the patient is asymptomatic, and no tumor signs were was found on by abdominal computed tomography.


Results of the self-expandable BA9 stent for treatment of large angle coronary bifurcation.
Since the advent of coronary angioplasty the treatment of bifurcation lesions has always proved a complex issue resulting in lower angiographic success rates, increased risk of restenosis, higher rates of dissection, myocardial infarction, and acute vessel closure. The advent of coronary stenting reduced the risks, but in-stent restenosis was noted to be frequent at the ostium of the side branch; for this reasons two-stent techniques were developed to try to combat this phenomenon. Novel dedicated stents have recently been developed to provide easier access to the SB and to scaffold more effectively its ostium, matching the stent configuration more closely to the anatomy of the bifurcation. Most of bifurcation lesions that require treatment and which have a wide angle involving the left main coronary artery (LMCA). The impact of the angle and the asymmetry of bifurcation on flow dynamic are very important and may influence clinical outcome. More recently, percutaneous coronary intervention (PCI) to treat wide angle disease has increased in frequency, and is associated with improvements in interventional techniques and adjunctive drug therapy. Several studies have shown that stenting in LMCA, especially using drug-eluting stents (DES), is a safe and effective treatment strategy both at mid- and long-term follow-up. The AXXESS System is a self-expanding, conically-shaped stent from nitinol (nickel-titanium alloy) with strut thickness, specifically designed to conform to the anatomy at the level of the bifurcation carina. A special version of the AXXESS System has been designed for left main bifurcation lesions, allowing for larger diameters (up to 4.75 mm) and distinct bifurcation angles (flare-end diameters of 8, 10 and 12 mm). The AXXENT trial is the first study to evaluate the vascular response of the self-expanding biolimus-eluting AXXESS stent for the treatment of LMCA bifurcation lesions. It was designed to evaluate the safety and efficacy of the AXXESS biolimus-eluting stent for the treatment of LMCA bifurcation lesions, that showed good results in terms of stent thrombosis and TLR at 6 months follow-up. Technical modifications and stent innovations may further improve both the angiographic and clinical outcomes for patients with wide angle bifurcation disease treated by PCI. Moreover a long term follow-up is needful to demonstrate better safety and efficacy of these new dedicated bifurcation devices.


Prospective evaluation of intravascular volume status in critically ill patients: does inferior vena cava collapsibility correlate with central venous pressure?
In search of a standardized noninvasive assessment of intravascular volume status, we prospectively compared the sonographic inferior vena cava collapsibility index (IVC-CI) and central venous pressures (CVPs). Our goals included the determination of CVP behavior across clinically relevant IVC-CI ranges, examination of unitary behavior of IVC-CI with changes in CVP, and estimation of the effect of positive end-expiratory pressure (PEEP) on the IVC-CI/CVP relationship. Prospective, observational study was performed in surgical/medical intensive care unit patients between October 2009 and July 2013. Patients underwent repeated sonographic evaluations of IVC-CI. Demographics, illness severity, ventilatory support, CVP, and patient positioning were recorded. Correlations were made between CVP groupings (<7, 7-12, 12-18, 19+) and IVC-CI ranges (<25, 25-49, 50-74, 75+). Comparison of CVP (2-unit quanta) and IVC-CI (5-unit quanta) was performed, followed by assessment of per-unit ΔIVC-CI/ΔCVP behavior as well as examination of the effect of PEEP on the IVC-CI/CVP relationship. We analyzed 320 IVC-CI/CVP measurement pairs from 79 patients (mean [SD] age, 55.8 [16.8] years; 64.6% male; mean [SD] Acute Physiology and Chronic Health Evaluation II, 11.7 [6.21]). Continuous data for IVC-CI/CVP correlated poorly (R = 0.177, p < 0.01) and were inversely proportional, with CVP less than 7 noted in approximately 10% of the patients for IVC-CIs less than 25% and CVP less than 7 observed in approximately 85% of patients for IVC-CIs greater than or equal to 75%. Median ΔIVC-CI per unit CVP was 3.25%. Most measurements (361 of 320) were collected in mechanically ventilated patients (mean [SD] PEEP, 7.76 [4.11] cm H2O). PEEP-related CVP increase was approximately 2 mm Hg to 2.5 mm Hg for IVC-CIs greater than 60% and approximately 3 mm Hg to 3.5 mm Hg for IVC-CIs less than 30%. PEEP also resulted in lower IVC-CIs at low CVPs, which reversed with increasing CVPs. When IVC-CI was examined across increasing PEEP ranges, we noted an inverse relationship between the two variables, but this failed to reach statistical significance. IVC-CI and CVP correlate inversely, with each 1 mm Hg of CVP corresponding to 3.3% median ΔIVC-CI. Low IVC-CI (<25%) is consistent with euvolemia/hypervolemia, while IVC-CI greater than 75% suggests intravascular volume depletion. The presence of PEEP results in 2 mm Hg to 3.5 mm Hg of CVP increase across the IVC-CI spectrum and lower collapsibility at low CVPs. Although IVC-CI decreased with increasing degrees of PEEP, this failed to reach statistical significance. While this study represents a step forward in the area of intravascular volume estimation using IVC-CI, our findings must be applied with caution owing to some methodologic limitations. Diagnostic study, level III. Prognostic study, level III.


Variant Creutzfeldt-jakob disease: between lymphoid organs and brain.
Prion diseases are often caused by peripheral uptake of the infectious agent. To reach their ultimate target, the central nervous system (CNS), prions enter their host, replicate in lymphoid organs and spread via peripheral nerves. Once the agent has reached the CNS disease progression is rapid, resulting in neurodegeneration and death. many of these mechanisms have been uncovered using genetically modified mice. A recently published study demonstrated the presence of pathological prion protein in sympathetic ganglia of patients suffering from variant Creutzfeldt-Jakob disease, suggesting that these mechanisms might apply to humans.


Species distribution modeling reveals strongholds and potential reintroduction areas for the world's largest eagle.
The highly interactive nature of predator-prey relationship is essential for ecosystem conservation; predators have been extirpated, however, from entire ecosystems all over the Earth. Reintroductions comprise a management technique to reverse this trend. Species Distribution Models (SDM) are preemptive tools for release-site selection, and can define levels of habitat quality over the species distribution. The Atlantic Forest of South America has lost most of its apex predators, and Harpy Eagles Harpia harpyja-Earth's largest eagle-are now limited to few forest pockets in this domain. Harpy Eagles are supposedly widespread in the Amazon Forest, however, where habitat loss and degradation is advancing at a rapid pace. We aim to describe the suitability of threatened Amazonian landscapes for this eagle. We also aim to assess the suitability of remaining Atlantic Forest sites for Harpy Eagle reintroductions. Here we show that that considerable eagle habitat has already been lost in Amazonia due to the expansion of the "Arc of Deforestation", and that Amazonian forests currently represent 93% of the current distribution of the species. We also show that the Serra do Mar protected areas in southeastern Brazil is the most promising region for Harpy Eagle reintroductions in the Atlantic Forest. Reintroduction and captive breeding programs have been undertaken for Harpy Eagles, building the technical and biological basis for a successful restoration framework. Our distribution range for this species represents a 41% reduction of what is currently proposed by IUCN. Furthermore, habitat loss in Amazonia, combined with industrial logging and hunting suggest that the conservation status of this species should be reassessed. We suggest researchers and conservation practitioners can use this work to help expand efforts to conserve Harpy Eagles and their natural habitats.


Early lesions following aerosol infection of rhesus macaques (Macaca mulatta) with Mycobacterium tuberculosis strain H37RV.
As part of a study to investigate early changes following exposure to aerosols of Mycobacterium tuberculosis (Mtb), 10 rhesus macaques (Macaca mulatta) were infected with high (731 colony forming units [cfu]), medium (70 cfu) or low (7 cfu) doses of Mtb, and tissues were examined at 2 and 3 weeks post infection (wpi). Clinical disease was not observed. Results of advanced imaging and pathological findings were compared with respect to the delivered dose and time post infection. Magnetic resonance imaging revealed lesions in the lungs at these early time points ex vivo immediately prior to detailed post-mortem examination in the absence of clinical disease. In animals exposed to high and medium doses of Mtb that were studied at 2 and 3 wpi, a range of lesions including small foci of mainly mononuclear cells, primarily macrophages (granulomatous lesions), as well as obvious granulomas, were observed microscopically in the lungs, including lymphatics and hilar lymph nodes. In the low-dose group at 3 weeks, small lesions were identified in the lung and hilar lymph nodes of one animal, and the remaining two animals in this group had lesions in either lung or hilar lymph node. Acid fast bacilli were demonstrated in the lung and lymph nodes in all animals that received high and medium doses, and the lymph nodes of two animals at the low dose. A dose-dependent effect was observed with increasing dose and time post infection. Furthermore, early dissemination of bacilli to the draining, hilar lymph nodes with concomitant granulomatous lesion formation was observed. By contributing to the recognition of early lesion development due to aerosol challenge of Mtb in the rhesus macaque, this study forms a basis for further investigation of early lesions and may inform the design of future vaccine and therapeutic studies involving early time points in this species.


Transcriptional regulation of a pair-rule stripe in Drosophila.
The periodic, seven-stripe pattern of the primary pair-rule gene even-skipped (eve) is initiated by crude, overlapping gradients of maternal and gap gene proteins in the early Drosophila embryo. Previous genetic studies suggest that one of the stripes, stripe 2, is initiated by the maternal morphogen bicoid (bcd) and the gap protein hunchback (hb), while the borders of the stripe are formed by selective repression, involving the gap protein giant (gt) in anterior regions and the Krüppel (Kr) protein in posterior regions. Here, we present several lines of evidence that are consistent with this model for stripe 2 expression, including in vitro DNA-binding experiments and transient cotransfection assays in cultured cells. These experiments suggest that repression involves a competition or short-range quenching mechanism, whereby the binding of gt and Kr interferes with the binding or activity of bcd and hb activators at overlapping or neighboring sites within the eve stripe 2 promoter element. Such short-range repression could reflect a general property of promoters composed of multiple, but autonomous regulatory elements.


Abnormal placental development and early embryonic lethality in EpCAM-null mice.
EpCAM (CD326) is encoded by the tacstd1 gene and expressed by a variety of normal and malignant epithelial cells and some leukocytes. Results of previous in vitro experiments suggested that EpCAM is an intercellular adhesion molecule. EpCAM has been extensively studied as a potential tumor marker and immunotherapy target, and more recent studies suggest that EpCAM expression may be characteristic of cancer stem cells. To gain insights into EpCAM function in vivo, we generated EpCAM -/- mice utilizing an embryonic stem cell line with a tacstd1 allele that had been disrupted. Gene trapping resulted in a protein comprised of the N-terminus of EpCAM encoded by 2 exons of the tacstd1 gene fused in frame to betageo. EpCAM +/- mice were viable and fertile and exhibited no obvious abnormalities. Examination of EpCAM +/- embryos revealed that betageo was expressed in several epithelial structures including developing ears (otocysts), eyes, branchial arches, gut, apical ectodermal ridges, lungs, pancreas, hair follicles and others. All EpCAM -/- mice died in utero by E12.5, and were small, developmentally delayed, and displayed prominent placental abnormalities. In developing placentas, EpCAM was expressed throughout the labyrinthine layer and by spongiotrophoblasts as well. Placentas of EpCAM -/- embryos were compact, with thin labyrinthine layers lacking prominent vascularity. Parietal trophoblast giant cells were also dramatically reduced in EpCAM -/- placentas. EpCAM was required for differentiation or survival of parietal trophoblast giant cells, normal development of the placental labyrinth and establishment of a competent maternal-fetal circulation. The findings in EpCAM-reporter mice suggest involvement of this molecule in development of vital organs including the gut, kidneys, pancreas, lungs, eyes, and limbs.


Comparison between self-administered depression questionnaires and patients' own views of changes in their mood: a prospective cohort study in primary care.
Self-administered questionnaires are widely used in primary care and other clinical settings to assess the severity of depressive symptoms and monitor treatment outcomes. Qualitative studies have found that changes in questionnaire scores might not fully capture patients' experience of changes in their mood but there are no quantitative studies of this issue. We examined the extent to which changes in scores from depression questionnaires disagreed with primary care patients' perceptions of changes in their mood and investigated factors influencing this relationship. Prospective cohort study assessing patients on four occasions, 2 weeks apart. Patients (N = 554) were recruited from primary care surgeries in three UK sites (Bristol, Liverpool and York) and had reported depressive symptoms or low mood in the past year [68% female, mean age 48.3 (s.d. 12.6)]. Main outcome measures were changes in scores on patient health questionnaire (PHQ-9) and beck depression inventory (BDI-II) and the patients' own ratings of change. There was marked disagreement between clinically important changes in questionnaire scores and patient-rated change, with disagreement of 51% (95% CI 46-55%) on PHQ-9 and 55% (95% CI 51-60%) on BDI-II. Patients with more severe anxiety were less likely, and those with better mental and physical health-related quality of life were more likely, to report feeling better, having controlled for depression scores. Our results illustrate the limitations of self-reported depression scales to assess clinical change. Clinicians should be cautious in interpreting changes in questionnaire scores without further clinical assessment.


Neurodegenerative Disease Mortality among Former Professional Soccer Players.
Neurodegenerative disorders have been reported in elite athletes who participated in contact sports. The incidence of neurodegenerative disease among former professional soccer players has not been well characterized. We conducted a retrospective cohort study to compare mortality from neurodegenerative disease among 7676 former professional soccer players (identified from databases of Scottish players) with that among 23,028 controls from the general population who were matched to the players on the basis of sex, age, and degree of social deprivation. Causes of death were determined from death certificates. Data on medications dispensed for the treatment of dementia in the two cohorts were also compared. Prescription information was obtained from the national Prescribing Information System. Over a median of 18 years, 1180 former soccer players (15.4%) and 3807 controls (16.5%) died. All-cause mortality was lower among former players than among controls up to the age of 70 years and was higher thereafter. Mortality from ischemic heart disease was lower among former players than among controls (hazard ratio, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P = 0.02), as was mortality from lung cancer (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.001). Mortality with neurodegenerative disease listed as the primary cause was 1.7% among former soccer players and 0.5% among controls (subhazard ratio [the hazard ratio adjusted for competing risks of death from ischemic heart disease and death from any cancer], 3.45; 95% CI, 2.11 to 5.62; P<0.001). Among former players, mortality with neurodegenerative disease listed as the primary or a contributory cause on the death certificate varied according to disease subtype and was highest among those with Alzheimer's disease (hazard ratio [former players vs. controls], 5.07; 95% CI, 2.92 to 8.82; P<0.001) and lowest among those with Parkinson's disease (hazard ratio, 2.15; 95% CI, 1.17 to 3.96; P = 0.01). Dementia-related medications were prescribed more frequently to former players than to controls (odds ratio, 4.90; 95% CI, 3.81 to 6.31; P<0.001). Mortality with neurodegenerative disease listed as the primary or a contributory cause did not differ significantly between goalkeepers and outfield players (hazard ratio, 0.73; 95% CI, 0.43 to 1.24; P = 0.24), but dementia-related medications were prescribed less frequently to goalkeepers (odds ratio, 0.41; 95% CI, 0.19 to 0.89; P = 0.02). In this retrospective epidemiologic analysis, mortality from neurodegenerative disease was higher and mortality from other common diseases lower among former Scottish professional soccer players than among matched controls. Dementia-related medications were prescribed more frequently to former players than to controls. These observations need to be confirmed in prospective matched-cohort studies. (Funded by the Football Association and Professional Footballers' Association.).


Characteristics and prediction of RNA structure.
RNA secondary structures with pseudoknots are often predicted by minimizing free energy, which is NP-hard. Most RNAs fold during transcription from DNA into RNA through a hierarchical pathway wherein secondary structures form prior to tertiary structures. Real RNA secondary structures often have local instead of global optimization because of kinetic reasons. The performance of RNA structure prediction may be improved by considering dynamic and hierarchical folding mechanisms. This study is a novel report on RNA folding that accords with the golden mean characteristic based on the statistical analysis of the real RNA secondary structures of all 480 sequences from RNA STRAND, which are validated by NMR or X-ray. The length ratios of domains in these sequences are approximately 0.382L, 0.5L, 0.618L, and L, where L is the sequence length. These points are just the important golden sections of sequence. With this characteristic, an algorithm is designed to predict RNA hierarchical structures and simulate RNA folding by dynamically folding RNA structures according to the above golden section points. The sensitivity and number of predicted pseudoknots of our algorithm are better than those of the Mfold, HotKnots, McQfold, ProbKnot, and Lhw-Zhu algorithms. Experimental results reflect the folding rules of RNA from a new angle that is close to natural folding.


Rainfall and river flows are predictors for beta-glucuronidase positive Escherichia coil accumulation in mussels and Pacific oysters from the Dart Estuary (England).
Rainfall and river flows are environmental variables influencing the microbial status of bivalve mollusc harvesting areas. This study investigated spatial and temporal relationships between rainfall, river flows and concentrations of Escherichia coli in mussels (Mytilus spp.) and Pacific oysters (C. gigas) from three harvesting areas in the Dart Estuary over the period 1996-2009. Mussels growing on the riverbed were found to be more contaminated than oysters growing in the water column. A step change in the levels of the microbial indicator was identified in both species from all harvesting areas. The highest levels of E. coli were detected when total rainfall exceeded 2 mm and water levels in the main tributaries exceeded the mean flow. The magnitude of response in levels of E. coli to these hydrological events varied between species and monitoring points, but was consistently higher between the 3rd and 4th days after the rainfall event. This lag time is assumed to result from catchment topography and geology determining peak levels of runoff at the headwaters 12-24 h after rainfall events. It is considered that future risk management measures may include sampling targeting hydrograph events.


Revision of the genus Erythromelana Townsend (Diptera: Tachinidae) and analysis of its phylogeny and diversification.
The Neotropics harbor an enormous diversity of tachinid flies (Diptera: Tachinidae), yet the fauna remains poorly understood. This is especially true of the tribe Blondeliini, which is particularly diverse in this region and in great need of taxonomic attention. Here, the Neotropical blondeliine genus Erythromelana Townsend is revised. This genus is widely distributed from southern Mexico to northern Argentina, with the Andes being a hotspot of diversity. Known hosts belong to the genus Eois Hübner (Lepidoptera: Geometridae). This revision includes the redescription of three previously described species and the description of 11 new species based on characteristics of adults and immatures. The new species are E. arciforceps sp. nov., E. catarina sp. nov., E. convexiforceps sp. nov., E. cryptica sp. nov., E. curvifrons sp. nov., E. distincta sp. nov., E. ecuadoriana sp. nov., E. eois sp. nov., E. leptoforceps sp. nov., E. napensis sp. nov., and E. woodi sp. nov. A morphological database of 62 characters was constructed to assess morphological variation within and among species and species groups using Principal Components Analysis. Means and medians for these morphological traits were calculated to infer phylogenetic relationships using parsimony. Additionally, a maximum likelihood phylogenetic analysis was performed using COI mtDNA sequences for a subset of eight species. Nominal species E. obscurifrons (Wulp) is treated as a nomen dubium within Erythromelana. Two species previously assigned to Erythromelana appear to represent distinct genera with unclear relationships to this genus and are reinstated as monotypic genera: Myiodoriops marginalis Townsend and Euptilodegeeria obumbrata (Wulp), revived status. Biological and phylogenetic data are used to infer modes of diversification within Erythromelana.


Perforin proteostasis is regulated through its C2 domain: supra-physiological cell death mediated by T431D-perforin.
The pore forming, Ca2+-dependent protein, perforin, is essential for the function of cytotoxic lymphocytes, which are at the frontline of immune defence against pathogens and cancer. Perforin is a glycoprotein stored in the secretory granules prior to release into the immune synapse. Congenital perforin deficiency causes fatal immune dysregulation, and is associated with various haematological malignancies. At least 50% of pathological missense mutations in perforin result in protein misfolding and retention in the endoplasmic reticulum. However, the regulation of perforin proteostasis remains unexplored. Using a variety of biochemical assays that assess protein stability and acquisition of complex glycosylation, we demonstrated that the binding of Ca2+ to the C2 domain stabilises perforin and regulates its export from the endoplasmic reticulum to the secretory granules. As perforin is a thermo-labile protein, we hypothesised that by altering its C2 domain it may be possible to improve protein stability. On the basis of the X-ray crystal structure of the perforin C2 domain, we designed a mutation (T431D) in the Ca2+ binding loop. Mutant perforin displayed markedly enhanced thermal stability and lytic function, despite its trafficking from the endoplasmic reticulum remaining unchanged. Furthermore, by introducing the T431D mutation into A90V perforin, a pathogenic mutation, which results in protein misfolding, we corrected the A90V folding defect and completely restored perforin's cytotoxic function. These results revealed an unexpected role for the Ca2+-dependent C2 domain in maintaining perforin proteostasis and demonstrated the possibility of designing perforin with supra-physiological cytotoxic function through stabilisation of the C2 domain.


Sound disrupts sleep-associated brain oscillations in rodents in a meaning-dependent manner.
Sleep is essential but places animals at risk. Filtering acoustic information according to its relevance, a process generally known as sensory gating, is crucial during sleep to ensure a balance between rest and danger detection. The mechanisms of this sensory gating and its specificity are not understood. Here, we tested the effect that sounds of different meaning have on sleep-associated ongoing oscillations. We recorded EEG and EMG from mice during REM and NREM sleep while presenting sounds with or without behavioural relevance. We found that sound presentation per se, in the form of a neutral sound, elicited a weak or no change in the power of sleep-state-dependent EEG during REM and NREM sleep. In contrast, the presentation of a sound previously conditioned in an aversive task, elicited a clear and fast decrease in the EEG power during both sleep phases, suggesting a transition to lighter sleep without awakening. The observed changes generally weakened over training days and were not present in animals that failed to learn. Interestingly, the effect could be generalized to unfamiliar neutral sounds if presented following conditioned training, an effect that depended on sleep phase and sound type. The data demonstrate that sounds are differentially gated during sleep depending on their meaning and that this process is reflected in disruption of sleep-associated brain oscillations without behavioural arousal.


The cost of assisted outpatient treatment: can it save states money?
The authors assessed a state's net costs for assisted outpatient treatment, a controversial court-ordered program of community-based mental health services designed to improve outcomes for persons with serious mental illness and a history of repeated hospitalizations attributable to nonadherence with outpatient treatment. A comprehensive cost analysis was conducted using 36 months of observational data for 634 assisted outpatient treatment participants and 255 voluntary recipients of intensive community-based treatment in New York City and in five counties elsewhere in New York State. Administrative, budgetary, and service claims data were used to calculate and summarize costs for program administration, legal and court services, mental health and other medical treatment, and criminal justice involvement. Adjusted effects of assisted outpatient treatment and voluntary intensive services on total service costs were examined using multivariate time-series regression analysis. In the New York City sample, net costs declined 43% in the first year after assisted outpatient treatment began and an additional 13% in the second year. In the five-county sample, costs declined 49% in the first year and an additional 27% in the second year. Psychotropic drug costs increased during the first year after initiation of assisted outpatient treatment, by 40% and 44% in the city and five-county samples, respectively. Regression analyses revealed significant declines in costs associated with both assisted outpatient treatment and voluntary participation in intensive services, although the cost declines associated with assisted outpatient treatment were about twice as large as those seen for voluntary services. Assisted outpatient treatment requires a substantial investment of state resources but can reduce overall service costs for persons with serious mental illness. For those who do not qualify for assisted outpatient treatment, voluntary participation in intensive community-based services may also reduce overall service costs over time, depending on characteristics of the target population and local service system.


Robust color texture features under varying illumination conditions.
Under varying illumination, both the statistical and structural contents of color texture are modified, leading to changes in the observed texture surface. We model the effect of illumination as a perturbation on an ideal color texture and show that the spectra of the ambient light have a significant impact on the observed texture patterns in the individual color channels. Motivated by studies in human color constancy, we propose a correlation-based transformation that minimizes the effect of illumination variation in color texture analysis. Experimental results are included, which validate the performance of the proposed minvariance model in the analysis of color texture.


Acceptability of locally produced ready-to-use therapeutic foods in Ethiopia, Ghana, Pakistan and India.
Successful treatment of severe acute malnutrition has been achieved with ready-to-use therapeutic food (RUTF), but only 15% of children with severe acute malnutrition receive RUTF. The objective of this study was to determine whether new formulations of RUTF produced using locally available ingredients were acceptable to young children in Ethiopia, Ghana, Pakistan and India. The local RUTFs were formulated using a linear programming tool that allows for inclusion of only local ingredients and minimizes cost. The study consisted of 4 two-arm, crossover, site-randomized food acceptability trials to test the acceptability of an alternative RUTF formula compared with the standard peanut-based RUTF containing powdered milk. Fifty children with moderate wasting in each country were enrolled in the 2-week study. Acceptability was measured by overall consumption, likeability and adverse effects reported by caregivers. Two of the four RUTFs did not include peanut, and all four used alternative dairy proteins rather than milk. The ingredient cost of all of the RUTFs was about 60% of standard RUTF. In Ethiopia, Ghana and India, the local RUTF was tolerated well without increased reports of rash, diarrhoea or vomiting. Children consumed similar amounts of local RUTF and standard RUTF and preferred them similarly as well. In Pakistan, local RUTF was consumed in similar quantities, but mothers perceived that children did not enjoy it as much as standard RUTF. Our results support the further investigation of these local RUTFs in Ethiopia, Ghana and India in equivalency trials and suggest that local RUTFs may be of lower cost.


Attitudes towards pressure ulcer prevention: a psychometric evaluation of the Swedish version of the APuP instrument.
The primary aim was to conduct a psychometric evaluation of the Attitude towards Pressure ulcer Prevention (APuP) instrument in a Swedish context. A further aim was to describe and compare attitudes towards pressure ulcer prevention between registered nurses (RNs), assistant nurses (ANs) and student nurses (SNs). In total, 415 RNs, ANs and SNs responded to the questionnaire. In addition to descriptive and comparative statistics, confirmatory factor analyses were performed. Because of a lack of support for the instrument structure, further explorative and consecutive confirmatory tests were conducted. Overall, positive attitudes towards pressure ulcer prevention were identified for all three groups, but SNs reported lower attitude scores on three items and a higher score on one item compared to RNs and ANs. The findings indicated no support in this Swedish sample for the previously reported five-factor model of APuP. Further explorative and confirmative factor analyses indicated that a four-factor model was most interpretable: (i) Priority (five items), (ii) Competence (three items), (iii) Importance (three items) and (iv) Responsibility (two items). The five-factor solution could not be confirmed. Further research is recommended to develop a valid and reliable tool to assess nurses' attitudes towards pressure ulcer prevention working across different settings on an international level.


How does the age gap between partners affect their survival?
I use hazard regression methods to examine how the age difference between spouses affects their survival. In many countries, the age difference between spouses at marriage has remained relatively stable for several decades. In Denmark, men are, on average, about three years older than the women they marry. Previous studies of the age gap between spouses with respect to mortality found that having a younger spouse is beneficial, while having an older spouse is detrimental for one's own survival. Most of the observed effects could not be explained satisfactorily until now, mainly because of methodological drawbacks and insufficiency of the data. The most common explanations refer to selection effects, caregiving in later life, and some positive psychological and sociological effects of having a younger spouse. The present study extends earlier work by using longitudinal Danish register data that include the entire history of key demographic events of the whole population from 1990 onward. Controlling for confounding factors such as education and wealth, results suggest that having a younger spouse is beneficial for men but detrimental for women, while having an older spouse is detrimental for both sexes.


Biochemical characterization and DNA repair pathway interactions of Mag1-mediated base excision repair in Schizosaccharomyces pombe.
The Schizosaccharomyces pombe mag1 gene encodes a DNA repair enzyme with sequence similarity to the AlkA family of DNA glycosylases, which are essential for the removal of cytotoxic alkylation products, the premutagenic deamination product hypoxanthine and certain cyclic ethenoadducts such as ethenoadenine. In this paper, we have purified the Mag1 protein and characterized its substrate specificity. It appears that the substrate range of Mag1 is limited to the major alkylation products, such as 3-mA, 3-mG and 7-mG, whereas no significant activity was found towards deamination products, ethenoadducts or oxidation products. The efficiency of 3-mA and 3-mG removal was 5-10 times slower for Mag1 than for Escherichia coli AlkA whereas the rate of 7-mG removal was similar to the two enzymes. The relatively low efficiency for the removal of cytotoxic 3-methylpurines is consistent with the moderate sensitivity of the mag1 mutant to methylating agents. Furthermore, we studied the initial steps of Mag1-dependent base excision repair (BER) and genetic interactions with other repair pathways by mutant analysis. The double mutants mag1 nth1, mag1 apn2 and mag1 rad2 displayed increased resistance to methyl methanesulfonate (MMS) compared with the single mutants nth1, apn2 and rad2, respectively, indicating that Mag1 initiates both short-patch (Nth1-dependent) and long-patch (Rad2-dependent) BER of MMS-induced damage. Spontaneous intrachromosomal recombination frequencies increased 3-fold in the mag1 mutant suggesting that Mag1 and recombinational repair (RR) are both involved in repair of alkylated bases. Finally, we show that the deletion of mag1 in the background of rad16, nth1 and rad2 single mutants reduced the total recombination frequencies of all three double mutants, indicating that abasic sites formed as a result of Mag1 removal of spontaneous base lesions are substrates for nucleotide excision repair, long- and short-patch BER and RR.


Youth gambling: not a safe bet.
To increase awareness and knowledge of the growing problem of adolescent gambling. Some risk factors have been established for adolescent gambling. Many of the risk factors for gambling behavior can be addressed in effective prevention of problem gambling. There is an association between some psychiatric comorbid conditions and problem gambling (i.e. depression). Current treatment modalities are based on adult experiences and need further investigation for adolescents. Prevention strategies and education of youth, parents, teachers, educators, and professionals are essential in targeting this serious problem. Given the increasing overall prevalence of adolescent gambling, it is imperative that pediatricians appreciate that gambling problems can also afflict adolescents. There is a clear link between problem gambling in adolescence and pathologic gambling in adulthood. Thus, like other addictive behaviors (cigarette smoking, alcohol and drug use), youth and parents should be screened and counseled about the risks associated with excessive gambling.


An evidence-based group coping intervention for women living with HIV and history of childhood sexual abuse.
Women living with HIV/AIDS and a history of childhood sexual abuse often exhibit sexual trauma symptoms and elevated rates of HIV-risk behaviors. In this paper, we describe a coping skills group intervention that reduced traumatic stress and sexual-risk behavior in a recent randomized clinical trial. We focused on clinical issues that emerged among female participants receiving the intervention. Clinical observations showed that recognizing connections between trauma, psychological distress, and high risk behaviors was a new and powerful experience for many participants. Participants successfully applied psychoeducational material, expressing an increased sense of power and control over their relationships and behaviors as they developed more adaptive cognitive and behavioral skills. Women expressed high levels of satisfaction with the intervention. Recommendations for clinical practice are provided.


Regeneration of skeletal muscle in streptozotocin-induced diabetic rats.
The present study analyzes the regeneration of skeletal muscle in diabetic rats. Intravenous injection of streptozotocin (STZ) was used to induce diabetes. Six weeks later the extensor digitorum longus (EDL) muscles from diabetic rats were either transplanted into diabetic or normal hosts to initiate regeneration. Normal EDL muscle transplants in normal and diabetic hosts were also performed for comparison. One, 2, 4, and 12 weeks after transplantation, the EDL regenerates were morphologically analyzed. Regeneration and formation of neuromuscular junctions were observed in all transplants, including diabetic regenerates in diabetic hosts. The overall mass and myofiber size of the diabetic EDL regenerate in the diabetic host was significantly reduced in spite of complete regeneration. Recovery of the diabetic muscle mass and the myofiber size was observed after transplantation into normal hosts. A reduction in mass and myofiber size was observed in normal EDL muscles transplanted into diabetic hosts. It is concluded that poor recovery of diabetic muscle is related to metabolic and structural alterations in the diabetic host, rather than to innate capacity of the muscle to per se undergo regeneration and reinnervation. The observed enhancement in recovery of diabetic muscle after transplantation in a normal host and deterioration of normal muscle after transplantation in a diabetic host shows that the host environment determines the success of muscle regeneration.


Mixed affective states and the natural history of manic-depressive psychosis.
Since neither the unipolar nor the bipolar theories of manic-depressive psychosis explain all its features, an alternative model was tested. The hypotheses are that mixed affective psychoses represent a superimposition on hypomania of a second type of depression which can sometimes develop from the depressive phase of manic-depressive psychosis, and that schizophrenia occurring in the course of a manic-depressive illness is an alternative to mixed affective psychosis. From an examination of the clinical histories of a random sample of people with bipolar manic-depressive psychosis, evidence was found to support both ideas.


Microtubule Cytoskeleton and Spermatogenesis-Lesson From Studies of Toxicant Models.
Studies have shown that mammalian testes, in particular the Sertoli cells, are highly susceptible to exposure of environmental toxicants, such as cadmium, perfluorooctanesulfonate, phthalates, 2,5-hexanedione and bisphenol A. However, important studies conducted by reproductive toxicologists and/or biologists in the past have been treated as toxicology reports per se. Yet, many of these studies provided important mechanistic insights on the toxicant-induced testis injury and reproductive dysfunction, relevant to the biology of the testis and spermatogenesis. Furthermore, recent studies have shown that findings obtained from toxicant models are exceedingly helpful tools to unravel the biology of testis function in particular spermatogenesis, including specific cellular events associated with spermatid transport to support spermiogenesis and spermiation. In this review, we critically evaluate some recent data, focusing primarily on the molecular structure and role of microtubules in cellular function, illustrating the importance of toxicant models to unravel the biology of microtubule cytoskeleton in supporting spermatogenesis, well beyond information on toxicology. These findings have opened up some potential areas of research which should be carefully evaluated in the years to come.


Do the changes in the behaviours of cattle during parasitism with Ostertagia ostertagi have a potential diagnostic value?
We investigated the magnitude of temporal changes in activity, posture and feeding behaviour of cattle infected with Ostertagia ostertagi, and their reversal after treatment with an anthelmintic. Twenty-six, 3-month-old, Holstein-Friesian bulls were allocated to one of three treatment groups. Bulls in two of those (groups P and PA) received 100,000 larvae on three occasions (Days 0, 7 and 14) and the remaining animals served as controls (C). The PA group also received an anthelmintic on Day 31. Parasite eggs appeared in the faeces of P and PA bulls from Day 17; from approximately the same time blood pepsinogen levels increased and body weight (BW) gain decreased (P<0.001). The reduction in BW gain persisted until Day 45 for P animals only. There was a decrease in the number of steps taken for P and PA animals, as well as lying and standing episode frequency, by 41 and 44% respectively (P<0.001) from Day 21 onwards. The average lying and standing episode duration increased by 52 and 55% respectively (P<0.001) from the same time in P and PA compared to C bulls. In addition, meal frequency showed a tendency to decrease for P animals only (P=0.039) from Day 39, and this was the only aspect of feeding behaviour affected by parasitism. All behaviours, returned to control levels within a week of anthelmintic drenching of PA bulls, apart from the number of steps taken. Although BW gain and pepsinogen also started to recover after drenching, these had not returned to control levels by Day 45. The magnitude of the changes in activity, and standing and lying episode frequency and duration suggest that these might have a diagnostic value, especially as all can now be monitored by automated means. However, these behaviours did not show the rapid changes we expected before parasitism manifested clinically and following recovery.


New agents for treating dry eye syndrome.
Dry eye syndrome (DES) is characterized by an inadequate volume and/or quality of tears resulting in chronic ocular surface irritation and inflammation. Affecting up to 30 % of adults, DES has a considerable impact on visual function and quality of life. DES may complicate allergic ocular disease and allergy medication may exacerbate DES. The pathophysiology of DES involves osmotic, mechanical and inflammatory insults to the tear film, epithelium and subepithelial nerve plexus. Various immune-related molecular targets have been the focus of research aimed at developing new therapeutic agents for treating DES. This article provides an overview of established, new and future agents for treating DES.


Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis.
Hepatic steatosis is often associated with insulin resistance and obesity and can lead to steatohepatitis and cirrhosis. In this study, we have demonstrated that hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), two enzymes critical for lipolysis in adipose tissues, also contribute to lipolysis in the liver and can mobilize hepatic triglycerides in vivo and in vitro. Adenoviral overexpression of HSL and/or ATGL reduced liver triglycerides by 40-60% in both ob/ob mice and mice with high fat diet-induced obesity. However, these enzymes did not affect fasting plasma triglyceride and free fatty acid levels or triglyceride and apolipoprotein B secretion rates. Plasma 3-beta-hydroxybutyrate levels were increased 3-5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in beta-oxidation. Expression of genes involved in fatty acid transport and synthesis, lipid storage, and mitochondrial bioenergetics was unchanged. Mechanistic studies in oleate-supplemented McA-RH7777 cells with adenoviral overexpression of HSL or ATGL showed that reduced cellular triglycerides could be attributed to increases in beta-oxidation as well as direct release of free fatty acids into the medium. In summary, hepatic overexpression of HSL or ATGL can promote fatty acid oxidation, stimulate direct release of free fatty acid, and ameliorate hepatic steatosis. This study suggests a direct functional role for both HSL and ATGL in hepatic lipid homeostasis and identifies these enzymes as potential therapeutic targets for ameliorating hepatic steatosis associated with insulin resistance and obesity.


Understanding Angiography-Based Aneurysm Flow Fields through Comparison with Computational Fluid Dynamics.
Hemodynamics is thought to be an important factor for aneurysm progression and rupture. Our aim was to evaluate whether flow fields reconstructed from dynamic angiography data can be used to realistically represent the main flow structures in intracranial aneurysms. DSA-based flow reconstructions, obtained during interventional treatment, were compared qualitatively with flow fields obtained from patient-specific computational fluid dynamics models and quantitatively with projections of the computational fluid dynamics fields (by computing a directional similarity of the vector fields) in 15 cerebral aneurysms. The average similarity between the DSA and the projected computational fluid dynamics flow fields was 78% in the parent artery, while it was only 30% in the aneurysm region. Qualitatively, both the DSA and projected computational fluid dynamics flow fields captured the location of the inflow jet, the main vortex structure, the intrasaccular flow split, and the main rotation direction in approximately 60% of the cases. Several factors affect the reconstruction of 2D flow fields from dynamic angiography sequences. The most important factors are the 3-dimensionality of the intrasaccular flow patterns and inflow jets, the alignment of the main vortex structure with the line of sight, the overlapping of surrounding vessels, and possibly frame rate undersampling. Flow visualization with DSA from >1 projection is required for understanding of the 3D intrasaccular flow patterns. Although these DSA-based flow quantification techniques do not capture swirling or secondary flows in the parent artery, they still provide a good representation of the mean axial flow and the corresponding flow rate.


One-step fabrication of robust fabrics with both-faced superhydrophobicity for the separation and capture of oil from water.
In this work, a facile and inexpensive one-step sonochemistry irradiation method was developed for the fabrication of SiO2 nanoparticles functionalized with octadecyltrimethoxysilane and their in situ incorporation into cotton fabrics. The double sides of as-prepared fabrics show both superhydrophobic and superoleophilic properties simultaneously with a high water contact angle of 159 ± 1° and an oil contact angle of 0°. Thus, it can be used to separate and capture a series of oils from water, like kerosene, toluene and chloroform, etc. In addition, the as-prepared fabrics still have superhydrophobicity with a water contact angle of above 150° after 40 separation cycles with the separation efficiency for the kerosene-water mixture always above 94.6%. More importantly, the as-prepared fabrics showed robust and stable superhydrophobic properties towards hot water, many corrosive solutions (acidic, basic, salt liquids) and mechanical abrasion. Therefore, this reported fabric has the advantages of scalable fabrication, high separation efficiency, stable recyclability, and excellent durability, exhibiting the strong potential for industrial production.


A double-blind placebo-controlled randomized trial of adalimumab in the treatment of hidradenitis suppurativa.
Hidradenitis suppurativa (HS) has an impact on patients' quality of life. Treatment of HS is generally unsatisfactory, thus new treatments are needed. To test the efficacy of adalimumab in HS. This was a prospective, randomized, double-blinded, placebo-controlled, two-centre clinical trial conducted in Denmark. Inclusion criteria were age above 18 years and a clinical diagnosis of moderate to severe HS defined as Hurley stage II or III for at least 6 months. The patients were randomized 1:2 (placebo/active). Actively treated patients received adalimumab 80 mg subcutaneously (s.c.) at baseline followed by 40 mg s.c. every other week for 12 weeks. Placebo-treated patients received identical-looking injections with no active ingredient. The medicine was dispensed in sequentially numbered computer-randomized containers. Participants, care givers and those assessing the outcomes were blinded to group assignment. The primary efficacy endpoints were changes in the HS scores (Sartorius and Hurley scoring systems). Secondary efficacy endpoints included changes in pain (visual analogue scale), days with lesions and Dermatology Life Quality Index, and evaluation of scarring. Recruitment was terminated early due to expiry date of trial medication. Twenty-one patients were included, of whom 15 received adalimumab and six received placebo. All participants were analysed according to the intention to treat principle. A significant reduction was seen in Sartorius score after 6 weeks and an almost significant reduction was seen after 12 weeks of active treatment (-10·7 vs. 7·5, P = 0·024 and -11·3 vs. 5·8, P = 0·07) when compared with the placebo group. A significant reduction in HS severity was gained after 6 weeks. No long-term curative effect was uniformly seen.


Effect of coping thickness and background type on the masking ability of a zirconia ceramic.
The masking ability of zirconia ceramics as copings is unclear. The purpose of this in vitro study was to evaluate the effect of coping thickness and background type on the masking ability of a zirconia ceramic and to determine zirconia coping thickness cut offs for masking the backgrounds investigated. Thirty zirconia disks in 3 thickness groups of 0.4, 0.6, and 0.8 mm were placed on 9 backgrounds to measure CIELab color attributes using a spectrophotometer. The backgrounds included A1, A2, and A3.5 shade composite resin, A3 shade zirconia, nickel-chromium alloy, nonprecious gold-colored alloy, amalgam, black, and white. ΔE values were measured to determine color differences between the specimens on the A2 shade composite resin background and the same specimens on the other backgrounds. The color change (ΔE) values were compared with threshold values for acceptability (ΔE=5.5) and perceptibility (ΔE=2.6). Repeated measures ANOVA, the Bonferroni test, and 1-sample t tests were used to analyze data (α=.05). Mean ΔE values ranged between 1.44 and 7.88. The zirconia coping thickness, the background type, and their interaction affected the CIELab and ΔE values (P<.001). To achieve ideal masking, the minimum thickness of a zirconia coping should be 0.4 mm for A1 and A3.5 shade composite resin, A3 shade zirconia, and nonprecious gold-colored alloy, 0.6 mm for amalgam, and 0.8 mm for nickel-chromium alloy.


Silencing of thrombospondin-1 is critical for myc-induced metastatic phenotypes in medulloblastoma.
Mechanisms by which c-Myc (Myc) amplification confers aggressive medulloblastoma phenotypes are poorly defined. Here, we show using orthotopic models that high Myc expression promotes cell migration/invasion and induces metastatic tumors, which recapitulate aggressive histologic features of Myc-amplified primary human medulloblastoma. Using ChIP-chip analysis, we identified cell migration and adhesion genes, including Tsp-1/THBS1, ING4, PVRL3, and PPAP2B, as Myc-bound loci in medulloblastoma cells. Expression of Tsp-1 was most consistently and robustly diminished in medulloblastoma cell lines and primary human tumors with high Myc expression (n = 101, P = 0.032). Strikingly, stable Tsp-1 expression significantly attenuated in vitro transformation and invasive/migratory properties of high Myc-expressing medulloblastoma cells without altering cell proliferation, whereas RNA interference-mediated Myc knockdown was consistently accompanied by increased Tsp-1 levels and reduced cell migration and invasion in medulloblastoma cells. Chromatin immunoprecipitation (ChIP) assays revealed colocalization of Myc and obligate partner Max and correlated diminished RNA polymerase II occupancy (∼3-fold decrease, P < 0.01) with increased Myc binding at a core Tsp-1 promoter. Reporter gene and/or gel shift assays confirmed direct repression of Tsp-1 transcription by Myc and also identified JPO2, a Myc interactor associated with metastatic medulloblastoma, as a cofactor in Myc-mediated Tsp-1 repression. These findings indicate the Myc-regulatory network targets Tsp-1 via multiple mechanisms in medulloblastoma transformation, and highlight a novel critical role for Tsp-1 in Myc-mediated aggressive medulloblastoma phenotypes.


COPI-coated ER-to-Golgi transport complexes segregate from COPII in close proximity to ER exit sites.
Transport of proteins between the endoplasmic reticulum and Golgi apparatus is mediated by two distinct membrane coat complexes, COPI and COPII. Genetic, biochemical and morphological data have accumulated into a model which suggests a sequential mode of action with COPII mediating the selection of cargo and formation of transport vesicles at the ER membrane for ER-to-Golgi transport and COPI mediating recycling of the transport machinery from post-ER membranes. To test this transport model directly in vivo, and to study the precise temporal sequence of COPI and COPII action in ER-to-Golgi transport, we have used time lapse microscopy of living cells to visualise simultaneously the dynamics of COPII and COPI, as well as COPII and GFP tagged secretory markers in living cells. The majority of COPII labelling appears tightly associated with ER membranes that move only within a limited area (less than 2 microm). Secretory cargo segregates from these sites and is then transported to the Golgi apparatus without any apparent association with COPII. COPI-coated transport complexes are seen to form adjacent to the COPII sites on the ER before segregating and moving directionally towards the Golgi apparatus. COPII is not present on these transport complexes and remains associated with the ER. These data demonstrate for the first time directly in vivo that ER-to-Golgi transport is organised in two steps characterised by a sequential mode of action of COPII and COPI.


PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling.
G-protein-coupled receptors (GPCRs) are involved in many physiological processes and are therefore key drug targets1. Although detailed structural information is available for GPCRs, the effects of lipids on the receptors, and on downstream coupling of GPCRs to G proteins are largely unknown. Here we use native mass spectrometry to identify endogenous lipids bound to three class A GPCRs. We observed preferential binding of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) over related lipids and confirm that the intracellular surface of the receptors contain hotspots for PtdIns(4,5)P2 binding. Endogenous lipids were also observed bound directly to the trimeric Gαsβγ protein complex of the adenosine A2A receptor (A2AR) in the gas phase. Using engineered Gα subunits (mini-Gαs, mini-Gαi and mini-Gα12)2, we demonstrate that the complex of mini-Gαs with the β1 adrenergic receptor (β1AR) is stabilized by the binding of two PtdIns(4,5)P2 molecules. By contrast, PtdIns(4,5)P2 does not stabilize coupling between β1AR and other Gα subunits (mini-Gαi or mini-Gα12) or a high-affinity nanobody. Other endogenous lipids that bind to these receptors have no effect on coupling, highlighting the specificity of PtdIns(4,5)P2. Calculations of potential of mean force and increased GTP turnover by the activated neurotensin receptor when coupled to trimeric Gαiβγ complex in the presence of PtdIns(4,5)P2 provide further evidence for a specific effect of PtdIns(4,5)P2 on coupling. We identify key residues on cognate Gα subunits through which PtdIns(4,5)P2 forms bridging interactions with basic residues on class A GPCRs. These modulating effects of lipids on receptors suggest consequences for understanding function, G-protein selectivity and drug targeting of class A GPCRs.


The role of human innate immune factors in nasal colonization by Staphylococcus aureus.
Staphylococcus aureus colonization of the human nares predisposes to sometimes severe auto-infection. To investigate whether genetic polymorphism affects the S. aureus carriage status, sequence variation in alpha-defensin and beta-defensin, and mannose-binding lectin (MBL) genes were determined for a group of volunteers (n=109) with known S. aureus nasal carriage status. DEFA1/3 expression was measured in a subset of the volunteers (n=32). None of the single nucleotide polymorphisms studied could clearly distinguish the (non) carriage groups. S. aureus carriers differed from non-carriers in baseline level of HNP1-3 peptide production (median: 218 versus 89mug/ml, P=0.016). No association between HNP1-3 levels and the individual sequence polymorphisms was documented. The combined copy numbers of DEFA1/A3 genes ranged from 5 to 23 per diploid genome. A linear correlation between combined copy numbers and HNP1-3 peptide concentrations in nasal secretions of non-carriers was noted (r(2)=0.8991). DEFA3 gene was absent in 25% of the individuals. MBL haplotype A was overrepresented in persistent S. aureus carriers (87% vs. 67%; P=0.038). In conclusion, defensin gene polymorphism, both in sequence and in gene copy numbers, does not seem to be involved in S. aureus carriage predisposition. However, MBL haplotypes do so significantly. Baseline HNP1-3 production is more the consequence of S. aureus colonization than a reason for the (non) carrier status.


Occipitoaxial spinal interarticular stabilization with vertebral artery preservation for atlantal lateral mass failure.
The treatment of craniocervical instability caused by diverse conditions remains challenging. Different techniques have been described to stabilize the craniocervical junction. The authors present 2 cases in which tumoral destruction of the C-1 lateral mass caused craniocervical instability. A one-stage occipitoaxial spinal interarticular stabilization (OASIS) technique with titanium cages and posterior occipitocervical instrumentation was used to reconstruct the C-1 lateral mass and stabilize the craniocervical junction. The ipsilateral vertebral artery was preserved. The OASIS technique offers single-stage tumor resection, C-1 lateral mass reconstruction, and stabilization with a loadsharing construct. It could be an option in the treatment of select cases of C-1 lateral mass failure.


Response suppression produces a switch-cost for spatially compatible saccades.
Executive function supports the rapid alternation between tasks for online reconfiguration of attentional and motor goals. The oculomotor literature has found that a prosaccade (i.e., saccade to veridical target location) preceded by an antisaccade (i.e., saccade mirror symmetrical to a target) elicits an increase in reaction time (RT), whereas the converse switch does not. This switch-cost has been attributed to the antisaccade task's requirement of inhibiting a prosaccade (i.e., response suppression) and transforming a target's coordinate (i.e., vector inversion)-executive processes thought to contribute to a task-set inertia that proactively interferes with the planning of a subsequent prosaccade. It is, however, unclear whether response suppression and vector inversion contribute to a task-set inertia or whether the phenomenon relates to a unitary component (e.g., response suppression). Here, the same stimulus-driven (SD) prosaccades (i.e., respond at target onset) as used in previous work were used with minimally delayed (MD) prosaccades (i.e., respond at target offset) and arranged in an AABB paradigm (i.e., A = SD prosaccade, B = MD prosaccade). MD prosaccades provide the same response suppression as antisaccades without the need for vector inversion. RTs for SD task-switch trials were longer and more variable than their task-repeat counterparts, whereas values for MD task-switch and task-repeat trials did not reliably differ. Moreover, SD task-repeat and task-switch movement times and amplitudes did not vary and thus demonstrate that a switch-cost is unrelated to a speed accuracy trade-off. Accordingly, results suggest the executive demands of response suppression is sufficient to engender the persistent activation of a non-standard task-set that selectively delays the planning of a subsequent SD prosaccade.


Evaluation of clinical usefulness of a medical monitor equipped with an organic electroluminescence panel in comparison with liquid crystal display monitors.
The medical liquid crystal display (LCD) monitor is a conventionally used imaging device for diagnosis and during endoscopic surgery. Recently, a medical organic electroluminescence panel, the organic light-emitting diode (OLED) monitor, was made available commercially. The advantages of the OLED monitor include good color reproducibility, high contrast, and high video responsiveness. In this nonclinical study, we compared the clinical usefulness and image quality of the OLED monitor and those of the LCD monitor using videos of gynecologic endoscopic surgeries. Monitors were set for blind evaluation. Five evaluators with varying experience in endoscopic surgery evaluated 21 surgery videos played simultaneously on an OLED monitor and two LCD monitors for 2 to 3 minutes twice. Evaluators judged 13 clinical usefulness indices and 11 image quality indices using a 5-point scale (1, very good; 5, very poor) for each video. The mean scores of clinical usefulness indices of the OLED monitor and the LCD monitors 1 and 2 were 2.2 to 2.7, 2.1 to 3.3, and 3.0 to 3.2, respectively. Of seven indices measured, five including motion response, the ability to differentiate organs, recognize lesions, and reproduce actual images, and the general impression of picture quality were statistically superior with use of the OLED monitor compared with the LCD monitor 1, and two including ability to distinguish blood vessels and the ureters were statistically superior with use of the LCD monitor 1 compared with the OLED monitor. The mean scores of image quality indices of the OLED monitor and the LCD monitors 1 and 2 were 1.8 to 3.2, 2.6 to 3.6, and 2.8 to 4.0, respectively. Each index of the OLED monitor was superior to or comparable with those of the LCD monitors. We conclude that the OLED monitor is superior to the LCD monitors insofar as several video presentation characteristics required in gynecologic endoscopic surgery. These findings suggest that the OLED monitor is expected to contribute detailed assessment of organs and the operative field.


Bacillus Calmette-Guérin in the management of superficial bladder cancer.
Intravesical Bacillus Calmette-Guérin (BCG) is the mainstay of superficial bladder cancer treatment. We performed a literature search through Medline/Pubmed using key words 'Bacillus Calmette-Guérin', 'intravesical', 'bladder neoplasm' and 'immunotherapy' for published data in the English language from 1970 to 2007 to review the current status of intravesical therapy and practice recommendations. The exact mechanism of action of intravesical BCG is yet to be elucidated. However, it appears that it is mediated by the local immune response, mainly through T-helper cell response. It reduces the recurrence rate by an average of 40% and progression by more than 20% in papillary tumors over the patients without BCG therapy. However, progression prevention is seen only in series which have used maintenance therapy at least for one year. It is effective in CIS of bladder with a response rate of more than 40% and prevention of progression in one-fourth patients. Most acceptable dose, induction treatment and maintenance therapy protocols are discussed. However, these are yet to be confirmed in large randomized trials. Intravesical BCG is well tolerated in most of the patients with mild to moderate side-effects in induction therapy; however, most patients do not complete maintenance therapy due to side-effects which is the most common concern at the present time.


Laser acupuncture effect on fetal well-being during induction of labor.
Labor induction with traditional drugs is sometimes associated with fetal complications as fetal distress or death. The aim of this study was to evaluate the effect of labor induction by laser acupuncture on fetal well-being in post-term pregnancy. Nulliparous women at 40 weeks or greater were randomized to sham laser group versus laser acupuncture group. Each session consisted of laser application on bilateral points LI 4, SP 6, BL 31, and BL 32. The study was conducted in Cairo University, National Institute of Laser Enhanced Sciences. Sixty nulliparous women were randomized into laser acupuncture group n = 30 and control group n = 30. Women were treated in both groups in three consecutive days in post-date pregnancy. Results (66.6%) showed a significant difference in rate of normal vaginal delivery (NVD) between acupuncture group (50%) and control group (50%) (p = 0.002). There was no significant difference of enrollment delivery time between laser acupuncture and sham groups (p > 0.05). There were six cases of cesarean section (CS) due to no fetal movement with normal cardiotocography (CTG). Laser acupuncture has no effect on fetus, and its effect on fetal movement needs more investigations. Laser can induce labor if the cervical length is less than 1 cm and dilation (0).


Predictors of mortality in 2,249 nonagenarians--the Danish 1905-Cohort Survey.
: To elucidate whether well-known predictions of mortality are reduced or even reversed, or whether mortality is a stochastic process in the oldest old. : A multidimensional survey of the Danish 1905 cohort conducted in 1998 with follow-up of vital status after 15 months. : Denmark. : All Danes born in 1905, irrespective of physical and mental status were approached. Two thousand two hundred sixty-two persons of 3,600 participated in this survey. : Professional interviewers collected data concerning sociodemographic factors, smoking, alcohol consumption, body mass index, physical and cognitive performance, and health during a visit at the participant's residency. Cox regression models were used to evaluate predictors of mortality. : Five hundred seventy-nine (25.7%) of the 2,249 participants eligible for the analysis died during the 15 months follow-up. Multivariate analyses showed that marital status, education, smoking, obesity, consumption of alcohol, and number of self-reported diseases were not associated with mortality. Disability and cognitive impairment were significant risk factors in men and women. In addition poor self-rated health was associated with an increase in mortality in women. : In the oldest old, several known predictors of mortality, such as sociodemographic factors, smoking, and obesity, have lost their importance, but a high disability level, poor physical and cognitive performance, and self-rated health (women only), predict mortality, which shows that mortality in the oldest old is not a stochastic process.


Progesterone receptor signaling in the initiation of pregnancy and preservation of a healthy uterus.
Infertility and reproductive-associated disease are global problems in the world today affecting millions of women. A successful pregnancy requires a healthy uterus ready to receive and support an implanting embryo. As an endocrine organ, the uterus is dependent on the secretions of the ovarian hormones estrogen and progesterone which signal via their cognate receptors, the estrogen and progesterone receptors. The progesterone receptor not only functions using classical nuclear receptor signaling, but also participates in non-genomic signaling at the cellular membrane. The complexity of progesterone signaling is further enhanced by the existence of multiple isoforms and post-translational regulation via kinases and transcription coregulators. This dynamic means of regulation of the progesterone receptor is evidenced in its necessary role in a successful pregnancy. Within early pregnancy, the progesterone receptor elicits activation of its target genes in a spatiotemporal manner in order to allow for successful embryo attachment and uterine decidualization. Additionally, appropriate progesterone signaling is important for the prevention of uterine disease such as endometrial cancer, endometriosis, and leiomyoma. The utilization of progesterone receptor modulators in the treatment of these devastating uterine diseases is promising. This review presents a general overview of progesterone receptor structure, function, and regulation and highlights its important role in the establishment of pregnancy and as a therapeutic target in uterine disease.


GTP Cyclohydrolase Drives Breast Cancer Development and Promotes EMT in an Enzyme-Independent Manner.
GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. The catalysis of BH4 biosynthesis is tightly regulated for physiological neurotransmission, inflammation, and vascular tone. Paradoxically, BH4 has emerged as an oncometabolite regulating tumor growth, but the effects on tumor development remain controversial. Here, we found that GCH1 potentiated the growth of triple-negative breast cancer (TNBC) and HER2+ breast cancer and transformed nontumor breast epithelial cells. Independent of BH4 production, GCH1 protein induced epithelial-to-mesenchymal transition by binding to vimentin (Vim), which was mediated by HSP90. Conversely, GCH1 ablation impaired tumor growth, suppressed Vim in TNBC, and inhibited EGFR/ERK signaling while activating the p53 pathway in estrogen receptor-positive tumor cells. GCH1 deficiency increases tumor cell sensitivity to HSP90 inhibition and endocrine treatments. In addition, high GCH1 correlated with poor breast cancer survival. Together, this study reveals an enzyme-independent oncogenic role of GCH1, presenting it as a potential target for therapeutic development. GTP cyclohydrolase functions as an oncogene in breast cancer and binds vimentin to induce epithelial-to-mesenchymal transition independently of its enzyme activity, which confers targetable vulnerabilities for developing breast cancer treatment strategies.


Hemoglobin concentration, total hemoglobin mass and plasma volume in patients: implications for anemia.
In practice, clinicians generally consider anemia (circulating hemoglobin concentration < 120 g.l-1 in non-pregnant females and < 130 g.l-1 in males) as due to impaired hemoglobin synthesis or increased erythrocyte loss or destruction. Rarely is a rise in plasma volume relative to circulating total hemoglobin mass considered as a cause. But does this matter? We explored this issue in patients, measuring hemoglobin concentration, total hemoglobin mass (optimized carbon monoxide rebreathing method) and thereby calculating plasma volume in healthy volunteers, surgical patients, and those with inflammatory bowel disease, chronic liver disease or heart failure. We studied 109 participants. Hemoglobin mass correlated well with its concentration in the healthy, surgical and inflammatory bowel disease groups (r=0.687-0.871, P<0.001). However, they were poorly related in liver disease (r=0.410, P=0.11) and heart failure patients (r=0.312, P=0.16). Here, hemoglobin mass explained little of the variance in its concentration (adjusted R2=0.109 and 0.052; P=0.11 and 0.16), whilst plasma volume did (R2 change 0.724 and 0.805 in heart and liver disease respectively, P<0.0001). Exemplar patients with identical (normal or raised) total hemoglobin masses were diagnosed as profoundly anemic (or not) depending on differences in plasma volume that had not been measured or even considered as a cause. The traditional inference that anemia generally reflects hemoglobin deficiency may be misleading, potentially resulting in inappropriate tests and therapeutic interventions to address 'hemoglobin deficiency' not 'plasma volume excess'. Measurement of total hemoglobin mass and plasma volume is now simple, cheap and safe, and its more routine use is advocated.


Phenomenology and neural correlates of implicit and emergent motor awareness in patients with anosognosia for hemiplegia.
Anosognosia for hemiplegia (AH) is characterized by a lack of awareness of motor disorders and appears associated with fronto-temporal-parietal damage. Neuropsychological evidence indicates that behavioral indices of residual forms of motor awareness may co-exist with explicit denial of impairment. Here we explore whether the attempt by AH patients to perform an action may disclose residual forms of motor awareness and whether such forms are underpinned by different neural structures. Twelve hemiplegic patients affected by AH were tested in tasks assessing: (i) implicit awareness (IA), indexed by discrepancies between verbal reports and actual motor behavior; (ii) emergent awareness (EA), indexed by increased verbal awareness induced by the attempt to perform actions. IA and EA were found in five and three patients, respectively. Lesion analysis indicates that while the lack of IA is associated with damage to subcortical white matter anterior to the basal ganglia, lack of EA is linked to damage to cortical regions including insulo-frontal, temporal and parietal structures. Our results indicate that deficits in explicit and implicit awareness are associated with lesions involving different cortico-subcortical structures. Moreover, the results show that the attempt to perform an action may ameliorate body awareness deficits and have implications for rehabilitation.


p38 MAPK regulation of transcription factor targets in muscle and heart of the hibernating bat, Myotis lucifugus.
Mammalian hibernation combines a profound net metabolic rate suppression with the selective up-regulation of key genes whose protein products address specific metabolic needs of the hibernator. The signal transduction pathways and transcription factors involved in regulating hibernation-responsive gene expression are of great interest. The present study suggests an important role for the p38 mitogen-activated protein kinase (p38 MAPK) and selected downstream transcription factors under its control (CREB, ATF-2, Elk-1) in the metabolic response by skeletal muscle during hibernation of little brown bats, Myotis lucifugus. Western blotting was used to quantify both total protein and levels of the phosphorylated, active forms of p38 MAPK, CREB, ATF-2 and Elk-1 in both skeletal muscle and heart of euthermic and hibernating bats. The p38 MAPK pathway was not apparently activated in heart during torpor but skeletal muscle showed strong increases (2.2-11-fold) in the amounts of phosphorylated p38 T180/Y182, CREB S133, ATF-2T69/71 and Elk-1(S383) in the torpid versus aroused state. By contrast both total and phosphorylated levels of Elk-1 in heart were reduced during hibernation to just 30% of the euthermic values. These data implicate p38 MAPK and its transcription factor targets, CREB, ATF-2 and Elk-1 in skeletal muscle maintenance during hibernation.