Is there a relationship between spondyloarthritis and periodontitis? A case-control study.
To compare the frequency and severity of periodontitis in patients with spondyloarthritis (SpA) with healthy control individuals, through the evaluation of clinical, serological and microbiological periodontal condition. Patients with a diagnosis of SpA (n=78) and biological disease-modifying antirheumatic drug (bDMARD) naive fulfilling the Assessment of SpondyloArthritis international Society (ASAS) classification criteria as well as 156 healthy controls matched for age/gender were included. Two trained and calibrated periodontologists performed the periodontal clinical assessment. The presence of periodontitis and its severity were determined according to the criteria established by the Centers for Disease Control and Prevention-American Academy of Periodontology. The clinical periodontal variables, IgG1/IgG2 antibodies against Porphyromonas gingivalis andperiodontopathic bacterial identification, were also established. Comparisons of periodontal characteristics between the patients with SpA and the control group were performed using univariable analyses. A logistic regression analyses was performed to calculate the OR (95% CI) for diagnosis of periodontitis in patients with SpA and matched controls. A diagnosis of periodontitis was established in 56% in patients with SpA versus 69% of healthy controls (P≤ 0.01). Severe periodontitis was found in 3% versus 12% in SpA versus healthy controls, respectively (P≤ 0.01). There was no significant increase of frequency of any periodontal variable, IgG1/IgG2 antibodies against P. gingivalis or the presence of periodontopathic bacteria between patients with SpA and control group. Periodontitis was not positively associated with a diagnosis of SpA (OR: 0.57, 95% CI 0.32 to 1.00, P=0.05) in the logistic regression analyses. We found a lower rather than a higher frequency and severity of periodontitis in patients with SpA in comparison with healthy control individuals. Our findings suggest that there is no positive association between SpA and periodontitis in Colombian patients.


Ketamine for Migraine in the Emergency Department.
Ketamine is utilized often in the emergency department (ED) for rapid sequence intubation, procedural sedation, and acute pain management. The treatment of migraine headache in the ED varies widely and is dependent on several factors including migraine cause, previous successful abortive methods, and provider preference. Several medications are currently employed to treat acute migraine including nonsteroidal anti-inflammatory drugs, triptans, antihistamines, prochlorperazine, and corticosteroids, among others. Interest in ketamine as an abortive agent to treat migraine has increased as evidenced by recent studies evaluating its use in the ED. This review examines the data regarding the use of ketamine to treat migraine headache. The concept of treating migraine headache with ketamine has been studied for more than 20 years. Early studies conducted primarily in the outpatient setting evaluated ketamine through multiple routes of administration and differing migraine causes with varying results. These early data seem to suggest that ketamine provides relief from headache severity but provides little information regarding the optimal dose and route of administration. Recent active comparator and placebo-controlled trials in the ED utilizing subdissociative doses of ketamine (0.2-0.3 mg/kg intravenously) show conflicting results. To confound the decision regarding its use further, ED providers encounter differing recommendations regarding its place in therapy. Current data suggest that ketamine may provide pain relief to patients with migraine headache. Although there may be a role for ketamine in certain cases after more robust evidence becomes available, currently it is premature to incorporate ketamine into routine use. Several questions remain to be answered including its overall efficacy, place in therapy, dosage, and risk of undesirable side effects.


Shapes matter: examining the optical response evolution in stretched aluminium nanoparticles via time-dependent density functional theory.
Using first-principles time-dependent density functional theory calculations, we investigate the shape-anisotropy effects on the optical response of a spherical aluminium nanoparticle subjected to a stretching process in different directions. Progressively increased stretching in one direction resulted in prolate spheroid (nanorice) geometries and produced a couple of well-distinguishable dominant peaks together with some satellite peaks in the UV-visible region of the electromagnetic spectrum. On the other hand, progressively increased stretching in two directions caused multiple peaks to appear in the UV-visible region of the electromagnetic spectrum. We believe that our findings can be beneficial for the emerging and potentially far-reaching field of aluminum plasmonics.


Gastrointestinal transit measurements in mice with 99mTc-DTPA-labeled activated charcoal using NanoSPECT-CT.
Gastrointestinal (GI) disorders are commonly associated with chronic conditions such as diabetes, obesity, and hypertension. Direct consequences are obstipation or diarrhea as opposite aspects of the irritable bowel syndrome, and more indirectly, alteration of appetite, feeling of fullness, flatulence, bloatedness, and eventually leading to altered absorption of nutrients. Moreover, GI retention and passage times have been recognized as important factors in determining the release site and hence the bioavailability of orally administered drugs. To facilitate the understanding of physiological and pathological processes involved, it is necessary to monitor the gut motility in animal models. Here, we describe a method for studying the GI transit time using technetium-labeled activated charcoal diethylenetriaminepentaacetic acid (99mTc-Ch-DTPA) detected by single-photon emission computed tomography (SPECT). Tc-DTPA was adsorbed onto activated charcoal and administered orally to trypan blue-tainted (n = 4) 129SvEv mice (50 to 80 MBq/animal, n = 11). The exact distribution and movement of radioactivity in the gastrointestinal tract was measured at intervals of 1, 3, 6, 12, and 22 h by SPECT-CT. In addition, in order to validate the imaging of GI transient time, loperamide (0.25 mg/animal, n = 3) was used to delay the GI transit. The transit time measured as the peak radioactivity occurring in the rectum was 6 to 7 h after gavaging of 99mTc-Ch-DTPA. After 1 h, the bolus had passed into the small intestine and entered the cecum and the colon. At 6 and 8 h, the cecum, the ascending, transverse, and descending colon, and the rectum showed significant labeling. Several pellets were stored in the rectum for defecation. After 22 h, little activity remained in the stomach and none was detected in the transverse colon or other GI locations. In contrast, 6 h after administration of loperamide, only the cecum and part of the transverse colon were labeled. After 22 h, both structures retained significant amount of label. This delay has been verified by non-radiolabeled dye trypan blue GI measurements (n = 4). Here, we present the first non-invasive study of mouse GI transit time, allowing clear differentiation between vehicle- and loperamide-treated animals. This technique is useful for the investigation of GI motility in mice.


Crystal structures of Toxoplasma gondii pterin-4a-carbinolamine dehydratase and comparisons with mammalian and parasite orthologues.
The enzyme pterin-4a-carbinolamine dehydratase (PCD) is important for the recycling of pterins within eukaryotic cells. A recombinant expression system for PCD from the apicomplexan parasite Toxoplasma gondii has been prepared, the protein purified and crystallised. Single crystal X-ray diffraction methods have produced a high-resolution structure (1.6A) of the apo-enzyme and a low-resolution structure (3.1A) of a complex with a substrate-like ligand dihydrobiopterin (BH(2)). Analysis of the hydrogen bonding interactions that contribute to binding BH(2) suggest that the ligand is present in an enol tautomeric state, which makes it more similar to the physiological substrate. The enzyme can process (R)- and (S)-forms of pterin-4a-carbinolamine and the ligand complex suggests that His61 and His79 are placed to act independently as general bases for catalysis of the individual enantiomers. Comparisons with orthologues from other protozoan parasites (Plasmodium falciparum and Leishmania major) and with rat PCD, for which the structure is known, indicate a high degree of sequence and structure conservation of this enzyme. The molecular determinants of ligand recognition and PCD reactivity are therefore highly conserved across species.


Educational needs in adults with congenitally malformed hearts.
The number of adults with congenitally malformed hearts is growing, and there is an increasing demand for their continuous follow-up. At present, different programmes have been established for adults with congenital cardiac disease, but there is a lack of knowledge regarding how education and psychosocial support should be given to achieve effects. Before developing educational programmes, it is necessary to be aware of the perspective of the patients. The aim of our study, therefore, was to describe how adults with congenitally malformed hearts experience their educational needs. The study had a qualitative design. We interviewed 16 adults, aged from 19 to 55 years, with congenitally malformed hearts. Two-way communication emerged as crucial to individualising education. Without good communication, those with congenitally malformed hearts, receiving information from providers of healthcare, are unable to transfer the information received. Thus, individualised education gives access to knowledge and the tools required to manage important areas in life, such as the congenital cardiac malformation, physical activity, the situation of life, treatment, and resources available for healthcare. The information given should provide easy access to knowledge through proper educational materials and methods, and be given with respect for the individual. This is facilitated if the education is tailored to the requirements of the individual in a holistic approach, and is provided through good communication. Our investigation shows that a structured educational programme needs to start from the perspective of the individual patient, and that two-way communication needs to be taken into consideration to enhance knowledge.


Assessment of early occlusal caries pre- and post-sealant application--an imaging approach.
Clinicians have difficulty assessing and monitoring early occlusal caries. Traditional clinical exam and radiographs are unable to detect the subtle alterations in enamel indicative of de- or re-mineralization, particularly under dental sealants. Although clinicians have used laser fluorescence (LF) to address this gap, this modality has demonstrated weak correlation with histology. The International Caries Detection and Assessment System (ICDAS-II) has demonstrated high sensitivity and specificity for caries detection, but since it is based on visual assessment, it is of no use in areas beneath the most commonly used dental sealants which are opaque. Optical coherence tomography (OCT) is an emergent assessment tool which has demonstrated great promise in detecting and quantifying caries, including areas beneath commonly used dental sealants and composites. However, OCT has not yet been widely integrated into clinical dental practice, perhaps because OCT imaging does not provide an easily accessible diagnostic outcome for clinicians. The objective of this ex vivo study was to use OCT-images of sound and carious occlusal surfaces in combination with a simple algorithm to compare the caries detection ability of OCT with tools clinicians may be more familiar with (LF and radiography), and with an established valid and reliable clinical assessment tool (ICDAS-II). One hundred twenty extracted teeth with sound or naturally carious occlusal surfaces were imaged with OCT, LF, radiography, and examined clinically with the ICDAS-II. Teeth were randomized to one of two dental sealants recommended for use with LF. A novel simple algorithm was used to interpret OCT-based images. The accuracy of caries severity assessments of the OCT-based diagnosis, LF, ICDAS-II, and digital radiography were compared to the 4-point histological analysis gold standard. OCT and ICDAS-II caries severity assessments demonstrated high sensitivity (94.0%; 92.3%) and specificity (85.0%; 83.3%), LF demonstrated low sensitivity (65.2%) but high specificity (97.6%), and digital radiography demonstrated low sensitivity (67.1%) with moderate specificity (79.5%) on unsealed occlusal surfaces. OCT-based caries severity assessments of sealed teeth demonstrated high specificity (97.6%), sensitivity (89.9%), excellent positive predictive value (98.6%), and negative predictive value (83.3%). Despite our use of LF recommended dental sealants, in the presence of sealants, LF assessment of caries severity demonstrated high sensitivity (95.1%), but extremely low specificity (10.3%), positive predictive value (68.8%), and negative predictive value (50.0%). This study found that OCT-based imaging combined with a simple diagnostic algorithm accurately assessed the severity of natural early caries on occlusal surfaces in extracted teeth both in the absence and presence of dental sealant. The findings of this study support the clinical use of OCT imaging for assessment and monitoring progression of early non-cavitated caries lesions on occlusal surfaces including areas under dental sealants.


Biochemical analysis of hepatic lipid in alcoholic and diabetic and control subjects.
Percutaneous needle biopsy specimens of liver were obtained from alcoholic, diabetic and control patients. Micro-methods of lipid separation and quantification were employed to determine the detailed nature of hepatic lipid. Triglyceride is the major accumulating liver lipid in both alcoholic and diabetic patients. Cholesteryl ester levels were raised in both alcoholic and diabetic patients but only diabetic patients had significantly increased free cholesterol and phospholipid levels. Determination of phospholipid/free cholesterol ratios revealed a significant decrease in alcoholic cirrhosis compared with controls. Fatty acid ester analysis of hepatic phospholipid and triglyceride revealed significant differences between alcoholic patients and controls but not between diabetic patients and controls. An increased ratio of non-essential/essential fatty acids was found in the patients with alcoholic liver disease whereas those of diabetic patients were similar to the controls.


Structure and calcium-binding properties of Frq1, a novel calcium sensor in the yeast Saccharomyces cerevisiae.
The FRQ1 gene is essential for growth of budding yeast and encodes a 190-residue, N-myristoylated (myr) calcium-binding protein. Frq1 belongs to the recoverin/frequenin branch of the EF-hand superfamily and regulates a yeast phosphatidylinositol 4-kinase isoform. Conformational changes in Frq1 due to N-myristoylation and Ca(2+) binding were assessed by nuclear magnetic resonance (NMR), fluorescence, and equilibrium Ca(2+)-binding measurements. For this purpose, Frq1 and myr-Frq1 were expressed in and purified from Escherichia coli. At saturation, Frq1 bound three Ca(2+) ions at independent sites, which correspond to the second, third, and fourth EF-hand motifs in the protein. Affinity of the second site (K(d) = 10 microM) was much weaker than that of the third and fourth sites (K(d) = 0.4 microM). Myr-Frq1 bound Ca(2+) with a K(d)app of 3 microM and a positive Hill coefficient (n = 1.25), suggesting that the N-myristoyl group confers some degree of cooperativity in Ca(2+) binding, as seen previously in recoverin. Both the NMR and fluorescence spectra of Frq1 exhibited very large Ca(2+)-dependent differences, indicating major conformational changes induced upon Ca(2+) binding. Nearly complete sequence-specific NMR assignments were obtained for the entire carboxy-terminal domain (residues K100-I190). Assignments were made for 20% of the residues in the amino-terminal domain; unassigned residues exhibited very broad NMR signals, most likely due to Frq1 dimerization. NMR chemical shifts and nuclear Overhauser effect (NOE) patterns of Ca(2+)-bound Frq1 were very similar to those of Ca(2+)-bound recoverin, suggesting that the overall structure of Frq1 resembles that of recoverin. A model of the three-dimensional structure of Ca(2+)-bound Frq1 is presented based on the NMR data and homology to recoverin. N-myristoylation of Frq1 had little or no effect on its NMR and fluorescence spectra, suggesting that the myristoyl moiety does not significantly alter Frq1 structure. Correspondingly, the NMR chemical shifts for the myristoyl group in both Ca(2+)-free and Ca(2+)-bound myr-Frq1 were nearly identical to those of free myristate in solution, indicating that the fatty acyl chain is solvent-exposed and not sequestered within the hydrophobic core of the protein, unlike the myristoyl group in Ca(2+)-free recoverin. Subcellular fractionation experiments showed that both the N-myristoyl group and Ca(2+)-binding contribute to the ability of Frq1 to associate with membranes.


The T cell STAT signaling network is reprogrammed within hours of bacteremia via secondary signals.
The delicate balance between protective immunity and inflammatory disease is challenged during sepsis, a pathologic state characterized by aspects of both a hyperactive immune response and immunosuppression. The events driven by systemic infection by bacterial pathogens on the T cell signaling network that likely control these responses have not been illustrated in great detail. We characterized how intracellular signaling within the immune compartment is reprogrammed at the single cell level when the host is challenged with a high level of pathogen. To accomplish this, we applied flow cytometry to measure the phosphorylation potential of key signal transduction proteins during acute bacterial challenge. We modeled the onset of sepsis by i.v. administration of avirulent strains of Listeria monocytogenes and Escherichia coli to mice. Within 6 h of bacterial challenge, T cells were globally restricted in their ability to respond to specific cytokine stimulations as determined by assessing the extent of STAT protein phosphorylation. Mechanisms by which this negative feedback response occurred included SOCS1 and SOCS3 gene up-regulation and IL-6-induced endocystosis of the IL-6 receptor. Additionally, macrophages were partially tolerized in their ability to respond to TLR agonists. Thus, in contrast to the view that there is a wholesale immune activation during sepsis, one immediate host response to blood-borne bacteria was induction of a refractory period during which leukocyte activation by specific stimulations was attenuated.


Pol31 and Pol32 subunits of yeast DNA polymerase δ are also essential subunits of DNA polymerase ζ.
Replication through a diverse array of DNA lesions occurs by the sequential action of two translesion synthesis (TLS) DNA polymerases (Pols), in which one inserts the nucleotide opposite the lesion and the other carries out the subsequent extension. By extending from the nucleotide inserted by another Pol, Polζ plays an indispensable role in mediating lesion bypass. Polζ comprises the Rev3 catalytic and Rev7 accessory subunits. Pol32, a subunit of the replicative polymerase Polδ, is also required for Polζ-dependent TLS, but how this Polδ subunit contributes to Polζ function in TLS has remained unknown. Here we show that yeast Polζ is a four-subunit enzyme containing Rev3, Rev7, Pol31, and Pol32; in this complex, association with Pol31/Pol32 is mediated via binding of the Rev3 C terminus to Pol31. The functional requirement of this complex is supported by evidence that mutational inactivation of Rev3's ability to bind Pol31 abrogates Polζ's role in TLS in yeast cells. These findings identify an unexpected role of Pol31 and Pol32 as two essential subunits of Polζ, and clarify why these proteins are required for Polζ-dependent TLS, but not for TLS mediated by Polη in yeast cells. To distinguish the four-subunit complex from the two-subunit Polζ, we designate the four-subunit enzyme "Polζ-d," where "-d" denotes the Pol31/Pol32 subunits of Polδ.


Premium subsidy programs: who enrolls, and how do they fare?
Little is known about who enrolls in state premium subsidy programs or enrollees' experiences. This study surveyed parents of children enrolled in two programs with identical income eligibility requirements: Oregon's State Children's Health Insurance Program (SCHIP) and its premium subsidy program (FHIAP). Parents choosing FHIAP were more likely to be employed, to speak English, to have prior experience with premiums and private health insurance, and to perceive insurance as protection against future health care needs. Despite copayment requirements and more restricted benefits in FHIAP, there were few differences in access to care between children enrolled in the two programs.


Caffeine exposure during pregnancy: Is it safe?
Numerous studies have examined the association between maternal caffeine consumption and infant and childhood health outcomes and the results have been inconsistent. The study of maternal caffeine intake and infant and childhood health outcomes is prone to methodologic challenges. In this review, we examine the existing evidence juxtaposed with the epidemiologic design challenges that color the interpretation of the study results presented. In light of methodologic/interpretation challenges, it seems reasonable to infer that exposure to low levels of caffeine is probably not associated with substantial infant and childhood adversities. However, more research is needed using well designed studies that address methodologic challenges.


Informal caregivers in Chile: the equity dimension of an invisible burden.
Population aging is driving a process of increase in long-term care needs in Chile and many countries around the world. In this context, this article asks about the consequences of this increase in informal caregivers, emphasizing the inequity issues arising from these changes. Using the CASEN 2017 survey, caregivers are identified and matched to people with long-term care needs. Results show that most caregivers are women, and a large fraction of them are also elderly; this is similar to what has been found previously in developed countries. Caregivers have fewer opportunities than non-caregivers, which translates into lower income-generating ability and higher poverty. The nature of these tasks creates a vicious cycle in which people get trapped with increasing needs and fewer resources to meet them. Important differences arise between caregivers and the rest of the population. Even more concerning is that these disparities are avoidable to some extent, adding an equity dimension to the problem. This emphasizes the need for the generation of policies that will support caregivers and meet their needs.


[Gender differences among persons with HIV admitted to a university reference center in São Paulo, Brazil].
The number of women living with HIV has increased in Brazil, demanding special attention to women's needs. To evaluate gender differences at an HIV reference center in São Paulo, 1,072 patient medical records from 1998 and 2002 were reviewed. As compared to male counterparts, women tended to be younger and have less schooling, and higher proportions of women were married and heterosexual. Thirty-six percent of women had undergone HIV testing because of an HIV+ partner. In contrast, 43% of men had undergone testing because of AIDS symptoms. At admission, 55% of men and 38% of women had an AIDS diagnosis. Women presented higher CD4+ cell counts and a higher proportion of undetectable HIV viral loads. No difference in access to antiretroviral therapy was seen after stratification for clinical status. Although the observed gender differences in socio-demographic characteristics emphasize women's social vulnerability to HIV, as compared to men, women in this cohort sought specialized care at earlier stages of infection. Knowledge about particular gender characteristics at admission to a reference center may contribute to organizing services delivery, improving care, and maximizing benefits.


Foldable water-activated reserve battery with diverse voltages.
A reserve battery is a device which is inert until its activation and generates electricity by injecting an electrolyte for the purpose of immediate use. Due to a relatively short history and the use in restricted fields, reserve batteries have not attracted attention without any technical advance such as be being flexible and foldable. In this study, we demonstrate a way of fabricating a flexible and even foldable reserve battery which is activated by various solutions. A paper electrode composed of cellulose and carbon nanotube, which is working as a cathode, was assembled with a sheet of an aluminum anode. The injection of a NaCl solution resulted in approximately 0.7 V while a KOH solution led to a much higher voltage of 1.3 V than the NaCl electrolyte. Impedance analysis unveiled that the best discharge performance was found in the reserve battery showing the smallest semicircle in impedance spectra, irrespective of electrolytes. And, folding the battery did not degrade the discharge performance, compared with an unfolded battery. Furthermore, the battery cell was even activated by seawater, resulting in about 0.7 V and a nice discharge performance. We think that our battery system can be extended to other reserve batteries requiring flexibility and foldability.


Retirement Expectations of Older Workers with Arthritis and Diabetes Compared with Those of Workers with No Chronic Diseases.
ABSTRACTWe know little about the retirement plans of adults with chronic diseases. This research recruited Canadian workers 50-67 years of age from a national panel of 80,000 individuals (arthritis, n = 631; diabetes, n = 286; both arthritis and diabetes, n = 111; no chronic disabling conditions, n = 538). A cross-sectional survey asked participants about their expected age of retirement, future work plans, whether they were retiring sooner than planned, and bridged retirement. Chi-square analyses, analyses of variance, and regression analyses examined expectations and factors associated with them. Despite health difficulties, workers with arthritis and diabetes had retirement plans similar to those of healthy controls and consistent with normative expectations of working to a traditional retirement age. However, more respondents with arthritis or diabetes reported bridged retirement than healthy controls. Contrary to predictions, health factors accounted for less of the variance in retirement expectations than other factors. These findings point to the complexity surrounding retirement expectations and highlight person-job fit rather than disease factors alone.


Cold controlled chemistry.
Collisions of molecules in a thermal gas are difficult to control. Thermal motion randomizes molecular encounters and diminishes the effects of external radiation or static electromagnetic fields on intermolecular interactions. The effects of the thermal motion can be reduced by cooling molecular gases to low temperatures. At temperatures near or below 1 K, the collision energy of molecules becomes less significant than perturbations due to external fields. At the same time, inelastic scattering and chemical reactions may be very efficient in low-temperature molecular gases. The purpose of this article is to demonstrate that collisions of molecules at temperatures below 1 K can be manipulated by external electromagnetic fields and to discuss possible applications of cold controlled chemistry. The discussion focuses on molecular interactions at cold (0.001-2 K) and ultracold (<0.001 K) temperatures and is based on both recent theoretical and experimental work. The article concludes with a summary of current challenges for theory and experiment in the research of cold molecules and cold chemistry.


Comparative study between polarimetric and intensity-based surface plasmon resonance sensors in the spectral mode.
There is a debate on whether phase measurement in surface plasmon resonance (SPR) sensors give better resolution than intensity measurement. In this work, we show that each one of the modes can give better resolution depending on the metal layer thickness chosen, as well as the available noise levels in the system. We propose a three point polarimetric approach to extract the ellipsometric parameters and phase information in the spectral mode. It is shown that the polarimetric measurement at its optimal thickness range gives up to seven-fold higher resolution than the intensity, especially at noise levels of off the shelf spectrometers. When noise levels are very low, the resolution in the two modes becomes nearly equal. The same is true when considering the whole SPR curve rather than single point detection. However, it is clearly shown both experimentally and theoretically that the polarimetric measurements at their optimal range give much better resolution than the intensity.


Reasons for working and their relationship to retirement attitudes, job satisfaction and occupational self-efficacy of bridge employees.
Although the Baby Boomers are the fastest growing segment of the U.S. population and they are quickly approaching retirement age, research has widely neglected to look at the reasons as to why many of them intend on opting for bridge employment as opposed to completely retiring. This study examined the relationships among four reasons for working (social, personal, financial, and generative) and three attitudinal responses to bridge employment (job satisfaction, retirement attitudes, and occupational self-efficacy). In a sample of 108 recent retirees holding bridge employment positions, it was found that generativity served as a reliable predictor of job satisfaction and attitudes toward retirement, whereas the social reason for work was only a reliable predictor of attitudes toward retirement.


Principle-based concept analysis: recognition in the context of nurse-patient interactions.
This paper is a report of a principle-based concept analysis of recognition in the context of nurse-patient interactions. Recognition is a concept employed in practice and research. Since nursing is patient-centred and care is problem-driven, the specificity and accuracy of recognition may have an impact on how nurses label patient phenomena, interventions initiated and patient outcomes. The data set included 98 English language articles published from 1997 to 2008 and retrieved through Medline and CINAHL searches. Principle-based concept analysis was used to examine the state of the science according to major perspectives of the philosophy of science. Conceptual components were integrated into a theoretical definition and the process of recognition was conceptually modelled. The scientific literature dealing with recognition in the context of nurse-patient interactions relies on implied meaning. Recognition is a process marked by an awareness of evidence coupled with the formulation of a conceptual label summarizing the identified pattern of patient phenomena. Contextual features of the nurse, patient and organization are relevant during nurse-patient interactions, resulting in pivotal points in nursing care. These pivotal points are the moments of recognition when the nurse consciously applies a summary label to interpreted evidence. Outcomes of recognition include a choice to act or not to act, each option carrying significant outcomes for nurses, patients, and at times, organizations. A working definition was produced that will serve as a foundation for future concept-driven research to advance the concept toward greater precision and usefulness in nursing science.


Comparative analysis of the effects of ghrelin and unacylated ghrelin on luteinizing hormone secretion in male rats.
Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of diverse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.


New methods for computational decomposition of whole-mount in situ images enable effective curation of a large, highly redundant collection of Xenopus images.
The precise anatomical location of gene expression is an essential component of the study of gene function. For most model organisms this task is usually undertaken via visual inspection of gene expression images by interested researchers. Computational analysis of gene expression has been developed in several model organisms, notably in Drosophila which exhibits a uniform shape and outline in the early stages of development. Here we address the challenge of computational analysis of gene expression in Xenopus, where the range of developmental stages of interest encompasses a wide range of embryo size and shape. Embryos may have different orientation across images, and, in addition, embryos have a pigmented epidermis that can mask or confuse underlying gene expression. Here we report the development of a set of computational tools capable of processing large image sets with variable characteristics. These tools efficiently separate the Xenopus embryo from the background, separately identify both histochemically stained and naturally pigmented regions within the embryo, and can sort images from the same gene and developmental stage according to similarity of gene expression patterns without information about relative orientation. We tested these methods on a large, but highly redundant, collection of 33,289 in situ hybridization images, allowing us to select representative images of expression patterns at different embryo orientations. This has allowed us to put a much smaller subset of these images into the public domain in an effective manner. The 'isimage' module and the scripts developed are implemented in Python and freely available on https://pypi.python.org/pypi/isimage/.


Two methods of calculating thorax kinematics in children with myelomeningocele.
The purpose of this study was to determine the importance of model and cardan angle sequence for calculating thorax kinematics. Patients with myelomeningocele often show a significant lateral bending and large trunk rotation over the gait cycle. The temporal pattern and magnitudes of these rotations are important for clinical decision-making. Two common thorax models and two orders of rotation in calculating the thoracic kinematics are compared. Thoracic kinematics in eight myelomeningocele patients were studied retrospectively. Four markers were placed on the trunk in addition to the lower limb markers. Each child walked at a self-selected speed over the walkway in bare feet. The spatial position and orientation of each segment were computed from the marker position at 2% of the gait cycle. Cardan angles for two thorax models were calculated using two different orders of rotation with respect to both the laboratory and the pelvic reference systems. The results showed that differences between models in the coronal and transverse planes were greater than in the sagittal plane. The changes in the modelling technique yielded the greatest differences when comparing between models. Clinical significant differences were found between changes in different thorax models and between the sequences of rotation for subjects with pathological thoracic motion. This clearly indicates that existing thorax models based on indirect marker placement may give misleading kinematic measurements. Different rotation sequences also lead to different results and an analysis of these suggests that the conventional sequence (flexion, lateral bending, axial rotation), is preferable for the thorax. Accurate measurement of thoracic motion will enhance our understanding of both the pathological and compensatory mechanism in the gait pattern of children with myelomeningocele. Furthermore, the current investigation on thorax kinematics will lead to calculation of the motion of the center of mass and future methodology to calculate thoracic kinetics.


A centimeter-scale sub-10 nm gap plasmonic nanorod array film as a versatile platform for enhancing light-matter interactions.
Strongly coupled plasmonic nanostructures with sub-10 nm gaps can enable intense electric field enhancements which greatly benefit the various light-matter interactions. From the point view of practical applications, such nanostructures should be of low-cost, facile fabrication and processing, large-scale with high-yield of the ultrasmall gaps, and easy for integration with other functional components. However, nowadays techniques for reliable fabrication of these nanostructures usually involve complex, time-consuming, and expensive lithography procedures, which are limited either by their low-throughput or the small areas obtained. On the other hand, so far most of the studies on the sub-10 nm gap nanostructures mainly focused on the surface-enhanced Raman scattering and high-harmonic generations, while leaving other nonlinear optical properties unexplored. In this work, using a scalable process without any lithography procedures, we demonstrated a centimeter-scale ordered plasmonic nanorod array film (PNRAF) with well-defined sub-10 nm interparticle gaps as a versatile platform for strongly enhanced light-matter interactions. Specifically, we showed that due to its plasmon-induced localized electromagnetic field enhancements, the Au PNRAF could exhibit extraordinary intrinsic multi-photon avalanche luminescence (MAPL) and nonlinear saturable absorption (SA). Furthermore, the PNRAF can be easily integrated with semiconductor quantum dots (SQDs) as well as wide bandgap semiconductors to strongly enhance their fluorescence and photocurrent response, respectively. Our method can be easily generalized to nanorod array films consisting of other plasmonic metals and even semiconductor materials, which can have multiple functionalities derived from different materials. Overall, the findings in our study have offered a potential strategy for design and fabrication of nanostructures with ultrasmall gaps for future photonic and optoelectronic applications.


Age-related macular degeneration and risk for stroke.
Age-related macular degeneration (AMD) affects 7 million persons 40 years of age and older in the United States. Risk factors for the disease are similar to those for stroke. To determine what relationship, if any, exists between AMD and incident clinical stroke. Prospective cohort study. The population-based Atherosclerosis Risk in Communities Study, which was conducted in Minnesota, Maryland, Mississippi, and North Carolina. 10 405 persons between 49 and 73 years of age who had no history of stroke or coronary heart disease. Participants had retinal photographs taken between 1993 and 1995. A standardized protocol was used to evaluate the photographs for the presence of drusen and other signs of AMD. Incident stroke events were identified and validated by reviewing case records. There were 498 early-stage and 10 late-stage cases of AMD in the cohort (n = 508). Over a 10-year period, 241 persons had an incident stroke event. After adjusting for age, sex, ethnicity, and site, the authors found that persons with early-stage AMD had a higher cumulative incidence of stroke than those without the disease (4.08% vs. 2.14%). The presence of early-stage AMD was associated with a higher adjusted risk for stroke (hazard ratio, 1.87 [95% CI, 1.21 to 2.88]). Further adjustment for systolic blood pressure, diabetes, cigarette smoking, and use of antihypertensive medications did not substantially alter this association (hazard ratio, 1.85 [CI, 1.19 to 2.87]). The authors found that the association between early-stage AMD and stroke varied by study site and patient ethnicity. Multivariable-adjusted hazard ratios were 3.15 and 1.07 in samples of white patients in Minnesota and Maryland, respectively; 3.77 in a sample of African-American patients in Mississippi; and 0.33 in a sample of mostly white patients (91%) in North Carolina. No site included sufficient numbers of both African-American and white patients to determine whether ethnicity contributed to the observed differences by study site. There were few cases of late-stage AMD, and the cohort assembly method prohibited full understanding of variation by ethnicity and site. Middle-aged persons with signs of early-stage AMD have a higher risk for stroke independent of traditional stroke risk factors.


Identification of Blood-Brain Barrier-Associated Proteins in the Human Brain.
The blood-brain barrier (BBB) is essential for cerebral homeostasis and controls the selective passage of molecules traveling in and out of the brain. Despite the crucial role of the BBB in a variety of brain diseases and its relevance for the development of drugs, there is little known about its molecular architecture. In particular, the composition of the basal lamina between the astrocytic end-feet and the endothelial cells is only partly known. Here, we present a proteomic analysis of the basal lamina of the human BBB. We combined laser capture microdissection with shotgun proteomics for selective enrichment and identification of specific proteins present in the cerebral microvasculature and arachnoidal vessels collected from normal human brain tissue specimens. Proteins found to be associated with the blood-brain barrier were validated by immunohistochemistry. Expression of membrane protein MLC1 was found in all brain barriers. Phosphoglucomutase-like protein 5 appeared to be variably present along the outer part of intracerebral vessels, and multidrug resistance protein 1 was identified in both intracerebral, as well as arachnoidal blood vessels. The results demonstrate the presence of so far unidentified proteins in the human BBB and illustrate topic differences in their expression. In conclusion, we showed that sample purification by microdissection followed by shotgun proteomics provides a list of proteins identified in the BBB. Subsequent immunohistochemistry detailed the respective expression sites of membrane protein MLC1 and phosphoglucomutase-related protein 5. The role of the identified proteins in the functioning of the BBB needs further investigations.


Speech- and sound-segmentation in dyslexia: evidence for a multiple-level cortical impairment.
Developmental dyslexia involves deficits in the visual and auditory domains, but is primarily characterized by an inability to translate the written linguistic code to the sound structure. Recent research has shown that auditory dysfunctions in dyslexia might originate from impairments in early pre-attentive processes, which affect behavioral discrimination. Previous studies have shown that whereas dyslexic individuals are deficient in discriminating sound distinctions involving consonants or simple pitch changes, discrimination of other sound aspects, such as tone duration, is intact. We hypothesized that such contrasts that can be discriminated by dyslexic individuals when heard in isolation are difficult to identify when occurring within words or structurally similar complex sound patterns. In the current study, we addressed how segments of pseudo-words and their non-speech counterparts are processed in dyslexia. We assessed the detection of long-duration differences in segments of these stimuli and identified the brain processes that could be associated with the behavioral results. Consistent with previous studies, we found no early cortical sound-duration discrimination deficit in dyslexia. However, differences between impaired and non-impaired readers were found in the brain processes associated with sound-change recognition as well as in the behavioral performance. This suggests that even when the early, automatic, sound discrimination processes are intact in dyslexic individuals, deficits in the later, attention-dependent processes may lead to impaired perception of speech and other complex sounds.


Harbour seals (Phoca vitulina) can steer by the stars.
Offshore orientation in marine mammals is still a mystery. For visual orientation during night-time foraging and travelling in the open seas, seals cannot rely on distant terrestrial landmarks, and thus might use celestial cues as repeatedly shown for nocturnally migrating birds. Although seals detect enough stars to probably allow for astronavigation, it was unclear whether they can orient by the night sky. The widely accepted cognitive mechanism for bird night-time orientation by celestial cues is a time-independent star compass with learned geometrical star configurations used to pinpoint north as the rotational centre of the starry sky while there is no conclusive evidence for a time-compensated star compass or true star navigation. Here, we present results for two harbour seals orienting in a custom made swimming planetarium. Both seals learned to highly accurately identify a lodestar out of a pseudo-randomly oriented, realistic projection of the northern hemisphere night sky. Providing the first evidence for star orientation capability in a marine mammal, our seals' outstanding directional precision would allow them to steer by following lodestars of learned star courses, a celestial orientation mechanism that has been known to be used by Polynesian navigators but has not been considered for animals yet.


Thermal transport properties of MoS2 and MoSe2 monolayers.
The isolation of single- to few-layer transition metal dichalcogenides opens new directions in the application of two-dimensional materials to nanoelectronics. The characterization of thermal transport in these new low-dimensional materials is needed for their efficient implementation, either for general overheating issues or specific applications in thermoelectric devices. In this study, the lattice thermal conductivities of single-layer MoS2 and MoSe2 are evaluated using classical molecular dynamics methods. The interactions between atoms are defined by Stillinger-Weber-type empirical potentials that are developed to represent the structural, mechanical, and vibrational properties of the given materials. In the parameterization of the potentials, a stochastic optimization algorithm, namely particle swarm optimization, is utilized. The final parameter sets produce quite consistent results with density functional theory in terms of lattice parameters, bond distances, elastic constants, and vibrational properties of both single-layer MoS2 and MoSe2. The predicted thermal properties of both materials are in very good agreement with earlier first-principles calculations. The discrepancies between the calculations and experimental measurements are most probably caused by the pristine nature of the structures in our simulations.


Clinical presentation and prognostic factors of spinal dural arteriovenous fistulas: an overview.
Spinal dural arteriovenous fistulas (AVFs), the most common type of spinal cord vascular malformation, can be a challenge to diagnose and treat promptly. The disorder is rare, and the presenting clinical symptoms and signs are nonspecific and insidious at onset. Spinal dural AVFs preferentially affect middle-aged men, and patients most commonly present with gait abnormality or lower-extremity weakness and sensory disturbances. Symptoms gradually progress or decline in a stepwise manner and are commonly associated with pain and sphincter disturbances. Surgical or endovascular disconnection of the fistula has a high success rate with a low rate of morbidity. Motor symptoms are most likely to improve after treatment, followed by sensory disturbances, and lastly sphincter disturbances. Patients with severe neurological deficits at presentation tend to have worse posttreatment functional outcomes than those with mild or moderate pretreatment disability. However, improvement or stabilization of symptoms is seen in the vast majority of treated patients, and thus treatment is justified even in patients with substantial neurological deficits. The extent of intramedullary spinal cord T2 signal abnormality does not correlate with outcomes and should not be used as a prognostic factor.


High-dose of vitamin C supplementation reduces amyloid plaque burden and ameliorates pathological changes in the brain of 5XFAD mice.
Blood-brain barrier (BBB) breakdown and mitochondrial dysfunction have been implicated in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. Besides vitamin C being as one of the important antioxidants, recently, it has also been reported as a modulator of BBB integrity and mitochondria morphology. Plasma levels of vitamin C are decreased in AD patients, which can affect disease progression. However, investigation using animal models on the role of vitamin C in the AD pathogenesis has been hampered because rodents produce with no dependence on external supply. Therefore, to identify the pathogenic importance of vitamin C in an AD mouse model, we cross-bred 5 familial Alzheimer's disease mutation (5XFAD) mice (AD mouse model) with ι-gulono-γ-lactone oxidase (Gulo) knockout (KO) mice, which are unable to synthesize their own vitamin C, and produced Gulo KO mice with 5XFAD mice background (KO-Tg). These mice were maintained on either low (0.66 g/l) or high (3.3 g/l) supplementation of vitamin C. We found that the higher supplementation of vitamin C had reduced amyloid plaque burden in the cortex and hippocampus in KO-Tg mice, resulting in amelioration of BBB disruption and mitochondrial alteration. These results suggest that intake of a larger amount of vitamin C could be protective against AD-like pathologies.


Applications of TMS to therapy in psychiatry.
Transcranial magnetic stimulation (TMS) has been applied to a growing number of psychiatric disorders as a noninvasive probe to study the underlying neurobiologic processes involved in psychiatric disorders and as a putative treatment. Transcranial magnetic stimulation is unparalleled in its ability to test the hypotheses generated by functional neuroimaging studies by modulating activity in selected neural circuits. As a focal intervention that may in some cases exert lasting effects, TMS offers the hope of targeting and ameliorating the circuitry underlying psychiatric disorders. The ultimate success of such an approach depends on our knowledge of the neural circuitry underlying these disorders, of how TMS exerts its effects, and of how to control the application of TMS to exert the desired effects. Although most clinical trials have focused on the treatment of major depression, increasing attention has been paid to schizophrenia and anxiety disorders. Many of these trials have supported a significant effect of TMS, but in some studies the effect is small and short lived. Current challenges in the field include determining how to enhance the efficacy of TMS in these disorders and how to identify patients for whom TMS may be efficacious.


Honey as a natural preservative of milk.
The anti-bacterial property and preservative nature of honey has been studied by evaluating the role of hydrogen peroxide in these properties, against bacterial strains isolated and identified from pasteurized milk samples. The antibacterial property of honey examined by agar incorporation assay and turbidometry, indicated a concentration dependent inhibition of bacterial growth in all catalase negative strains in comparison with catalase positive strains, highlighting a probable role of hydrogen peroxide. Samples of commercial milk stored at 40C in presence of honey were shown to inhibit opportunistic bacterial growth better compared to samples stored without honey. Due to the bactericidal property of hydrogen peroxide and its preservative nature, honey which is chiefly a combination of various sugars and hydrogen peroxide, can be used a preservative of milk samples.


Effect of Alkali Carbonates (Single, Binary, and Ternary) on Doped Ceria: A Composite Electrolyte for Low-Temperature Solid Oxide Fuel Cells.
Samarium-doped ceria (SDC) carbonate has become an attractive electrolyte for fuel cells because of its remarkable ion conductivity and high performance. Different doped ceria-carbonate (single-carbonate SDC, binary-carbonate SDC, and ternary-carbonate SDC) electrolytes were synthesized by the coprecipitation/oxalate method, to optimize the electrochemical performance. The structure; morphology; and thermal, optical, and surface properties have been studied using a variety of techniques. The X-ray diffraction results confirmed the successful incorporation of samarium into ceria as a crystalline structure and inclusion of carbonate, which is amorphous in nature. To analyze the conduction mechanism, direct current conductivity was measured in a H2/O2 atmosphere. Doped ceria-binary carbonate ((Li/Na)CO3-SDC) showed the best conductivity of 0.31 S cm-1 and power density of 617 mW cm-2, at 600 °C. The enhancement in the ionic conductivity and performance of the composites is due to the contribution of hybrid ions (O2-, H+). The crystallite size of the composites was in the range 21-41 nm. For the calculation of band gaps, optical absorption spectra of the synthesized powders were analyzed, and they showed a red shift with the band gap energy in the range 2.6-3.01 eV, when compared to that of pure ceria (3.20 eV).


Decreased Serum Kruppel-Like Factor 7 Level is Positively Associated with Low-Density Lipoprotein Cholesterol Level in Women with Polycystic Ovary Syndrome.
Kruppel-like factor 7 (KLF7) is associated with type 2 diabetes and obesity; however, at present the KLF7 level in polycystic ovary syndrome (PCOS) remains unreported. In this study, serum KLF7, glucose, insulin, C-reactive protein (CRP), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone concentrations were measured in 65 women with PCOS and 61 healthy controls. Body mass index (BMI) in PCOS and the control group were all < 25 kg/m2. The median concentration of KLF7 was 3.630 ng/mL [interquartile range (IQR): 1.547 - 7.172] in women with PCOS, which was significantly lower than that of controls (5.282 ng/mL, IQR: 3.128 - 11.263, p = 0.003). The KLF7 level was positively correlated with low-density lipoprotein cholesterol (LDL-C) (r = 0.261, p = 0.018). No significant association was observed between KLF7 and the BMI, total testosterone, and insulin resistance (IR). The KLF7 level decreased in women with PCOS. KLF7 may represent a new therapeutic target in the treatment of PCOS.


Multifunction of Chrysin in Parkinson's Model: Anti-Neuronal Apoptosis, Neuroprotection via Activation of MEF2D, and Inhibition of Monoamine Oxidase-B.
Chrysin, a flavonoid compound existing in several plants, is applied as a dietary supplement because of its beneficial effects on general human health and alleviation of neurological disorders. However, mechanisms underlying neuroprotection of chrysin has not been fully elucidated, and the effects of chrysin on the Parkinson's disease (PD) model in vivo have not been investigated. It is here shown that chrysin protects primary granular neurons against 1-methyl-4-phenylpyridinium ion insult via antiapoptosis by reversing the dysregulated expression of Bcl-2, Bax, and caspase 3. The mechanisms also involved activating transcriptional factor myocyte enhancer factor 2D (MEF2D) via regulation of AKT-GSK3β signaling. In this in vivo model of PD, chrysin rescued the dopaminergic neurons loss and alleviated the decrease in dopamine level induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Moreover, chrysin markedly inhibited monoamine oxidase-B activity in vitro and in vivo. In conclusion, chrysin exerts beneficial effects to PD, possibly through multitarget mechanisms including antineuronal apoptosis, activation of the AKT-GSK3β/MEF2D pathway, and inhibition of the MAO-B activity.


Challenges of integrating economics into epidemiological analysis of and policy responses to emerging infectious diseases.
COVID-19 has shown that the consequences of a pandemic are wider-reaching than cases and deaths. Morbidity and mortality are important direct costs, but infectious diseases generate other direct and indirect benefits and costs as the economy responds to these shocks: some people lose, others gain and people modify their behaviours in ways that redistribute these benefits and costs. These additional effects feedback on health outcomes to create a complicated interdependent system of health and non-health outcomes. As a result, interventions primarily intended to reduce the burden of disease can have wider societal and economic effects and more complicated and unintended, but possibly not anticipable, system-level influences on the epidemiological dynamics themselves. Capturing these effects requires a systems approach that encompasses more direct health outcomes. Towards this end, in this article we discuss the importance of integrating epidemiology and economic models, setting out the key challenges which such a merging of epidemiology and economics presents. We conclude that understanding people's behaviour in the context of interventions is key to developing a more complete and integrated economic-epidemiological approach; and a wider perspective on the benefits and costs of interventions (and who these fall upon) will help society better understand how to respond to future pandemics.


The Right Organ for the Right Recipient: the Ninth Annual American Society of Transplant Surgeons' State-of-the-Art Winter Symposium.
With an increasing number of individuals with end-stage organ disease and the increasing success of organ transplantation, the demand for transplants has steadily increased. This growth has led to a greater need to utilize organs from as many donors as possible. As selection criteria have become less stringent to accommodate increasing demand, transplant outcomes are more strongly influenced by recipient and donor factors; thus, finding the right organ for the right recipient is more important than ever. The Ninth Annual American Society of Transplant Surgeons (ASTS) State-of-the-Art Winter Symposium, entitled "The Right Organ for the Right Recipient," addressed the matching of donor organs to appropriate recipients. Representative dilemmas in the matching of donor organs with recipients were discussed. These included the following: matching by donor and recipient risk characteristics; use of organs with risk for disease transmission; biologic incompatibility; use of organs from donors after cardiac death; the justification for combined organ transplants like liver-kidney and kidney-pancreas; and the role of allocation in facilitating the matching of donors and recipients. Regardless of the particular issue, decisions about donor-recipient matching should be evidence-based, practical, and made with the goal of maximizing organ utilization while still protecting individual patient interests.


Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells.
PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1alpha) is a master regulator of mitochondrial biogenesis and plays an important role in several other aspects of energy metabolism. To identify upstream regulators of PGC-1alpha gene transcription, 10,000 human full-length cDNAs were screened for induction of the PGC-1alpha promoter. A number of activators of PGC-1alpha transcription were found; the most potent activator was the transducer of regulated CREB (cAMP response element-binding protein) binding protein (TORC) 1, a coactivator of CREB. The other two members of the TORC family, TORC2 and TORC3, also strongly activated PGC-1alpha transcription. TORCs dramatically induced PGC-1alpha gene transcription through CREB. Forced expression of TORCs in primary muscle cells induced the endogenous mRNA of PGC-1alpha and its downstream target genes in the mitochondrial respiratory chain and TCA cycle. Importantly, these changes in gene expression resulted in increased mitochondrial oxidative capacity measured by cellular respiration and fatty acid oxidation. Finally, we demonstrated that the action of TORCs in promoting mitochondrial gene expression and function requires PGC-1alpha. Previous studies had indicated that TORCs function as a calcium- and cAMP-sensitive coincidence detector and mediate individual and synergistic effects of these two pathways. Our results, together with previous findings, strongly suggest that TORCs play a key role in linking these external signals to the transcriptional program of adaptive mitochondrial biogenesis by activating PGC-1alpha gene transcription.


Ephrin type-B receptor 4 is an essential mediator in drug-resistance of acute myeloid leukemia cells to Adriamycin.
Ephrin type-B receptor 4 (EphB4) plays an important role in human carcinogenesis. This study investigated the effects of EphB4 expression in drug-resistance of acute myeloid leukemia cells to Adriamycin using myeloid leukemia cell lines with different degrees of differentiation, including an Adriamycin-resistant HL60 cell line as a model. The data showed that the EphB4 protein was differentially expressed in these myeloid leukemia cell lines, which expression was associated with sensitivity of myeloid leukemia cells to Adriamycin treatment in vitro. Furthermore, EphB4 protein stimulated by EphrinB2-Fc sensitized HL60/ADM cells to Adriamycin in a dose-dependent manner. Specifically, pre-incubation of HL60/ADM with 4 µg/ml EphrinB2-Fc protein for 30 min significantly sensitized tumor cell to Adriamycin treatment by reduction of tumor cell viability and induction of apoptosis (p<0.001), while there was no significant change in other groups (p>0.05). These data provided a proof-of-principle for further development of the EphB4-based strategy for treatment of drug-resistant leukemia.


Quality of life of survivors of pediatric intensive care.
Measuring outcome in pediatric intensive care is necessary to equate the high cost of treatment with benefits to the patient. Although mortality rates and morbidity are relatively insensitive measures of the benefits of treatment, quality of life measurement gives insight into the long-term outcomes. The aim of this study was to investigate the long-term quality of life outcome of children admitted to a pediatric intensive care unit. Prospective survey. A 13-bed pediatric intensive care unit in a university-affiliated, tertiary referral children's hospital. Patients were 432 children discharged from the pediatric intensive care unit between May 1992 and April 1994. Quality of life was measured by using the Royal Alexandra Hospital for Children Measure of Function. The scale has two components, the first part completed by the clinician after parent interview and the second part completed separately by the parent. Parents of 432 children were contacted between 3 and 24 months after discharge. Twenty-seven children (6.3%) had died after discharge from the pediatric intensive care unit; 59.3% (256) had scores indicating a normal quality of life, and 32.4% (140) had a fair quality of life with ongoing health, social, or cognitive problems requiring some intervention. Two percent of survivors (nine children) had scores indicating a poor quality of life as they had continued to experience significant or disabling health problems requiring hospitalization or the equivalent. Predictors of poor quality of life included presence of comorbidities, increased length of stay, and a diagnostic category of malignancy. Diagnostic categories of respiratory, trauma, and cardiac dysfunction were associated with a better outcome. Our results indicate that the long-term outcome in terms of quality of life after admission to a pediatric intensive care unit is good or normal for the majority of surviving children. Those children with a poor outcome are likely to have significant comorbidities or a diagnosis of malignancy.


2-Deoxy-2-[F-18]fluoro-D-glucose positron emission tomography/computed tomography in the management of melanoma.
2-Deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) is widely available as a powerful imaging modality, combining the ability to detect active metabolic processes and their morphologic features in a single exam. The role of FDG-PET is proven in a variety of cancers, including melanoma, but the estimates of sensitivity and specificity are based in the majority of the published studies on dedicated PET, not PET/CT. Therefore, we were prompted to review our experience with FDG-PET/CT in the management of melanoma. This is a retrospective study on 106 patients with melanoma (20-87 years old; average: 56.8 +/- 15.9), who had whole-body FDG-PET/CT at our institution from January 2003 to June 2005. Thirty-eight patients (35.9%) were women and 68 patients (64.1%) were men. Reinterpretation of the imaging studies for accuracy and data analysis from medical records were performed. All patients had the study for disease restaging. The primary tumor depth (Breslow's thickness) at initial diagnosis was available for 76 patients (71.7%) and ranged from 0.4 to 25 mm (average: 3.56 mm). The anatomic level of invasion in the skin (Clark's level) was determined for 70 patients (66%): 3, level II; 13, level III; 43, level IV; 11, level V. The administered dose of (18)F FDG ranged from 9.8 to 21.6 mCi (average: 15.4 +/- 1.8 mCi). FDG-PET/CT had a sensitivity of 89.3% [95% confidence interval (CI): 78.5-95] and a specificity of 88% (95% CI: 76.2-94.4) for melanoma detection. This study confirms the good results of FDG-PET/CT for residual/recurrent melanoma detection, as well as for distant metastases localization. PET/CT should be an integral part in evaluation of patients with high-risk melanoma, prior to selection of the most appropriate therapy.


Vulnerability to mood degradation during sleep deprivation is influenced by white-matter compactness of the triple-network model.
Sleep deprivation (SD) is often associated with significant shifts in mood state relative to baseline functioning. Prior work suggests that there are consistent trait-like differences among individuals in the degree to which their mood and performances are affected by sleep loss. The goal of this study was to determine the extent to which trait-like individual differences in vulnerability/resistance to mood degradation during a night of SD are dependent upon region-specific white and grey matter (WM/GM) characteristics of a triple-network model, including the default-mode network (DMN), control-execution network (CEN) and salience network (SN). Diffusion-weighted and anatomical brain data were collected from 45 healthy individuals several days prior to a 28-h overnight SD protocol. During SD, a visual analog mood scale was administered every hour from 19:15 (time point1; TP1) to 11:15 (TP17) the following morning to measure two positive and six negative mood states. Four core regions within the DMN, five within the CEN, and seven within the SN were used as regions of interest (ROIs). An index of mood resistance (IMR) was defined as the averaged differences between positive and negative mood states over 12 TPs (TP5 to TP16) relative to baseline (TP1 to TP4). For each ROI, characteristics of WM - quantitative anisotropy (QA) and mean curvature index (WM-MCI), and GM - cortical volume (CV) and GM-MCI were estimated, and used to predict IMR. WM characteristics, particularly QA, of all of regions within the DMN, and most of the regions within the CEN and SN predicted IMR during SD. In contrast, most ROIs did not show significant association between IMR and any of the GM characteristics (CV and MCI) or WM MCI. Our findings suggest that greater resilience to mood degradation induced by total SD appears to be associated with more compact axonal pathways within the DMN, CEN and SN.


Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies.
To examine cancer incidence in patients with systemic sclerosis (SSc) through a meta-analysis of population-based cohort studies. Five different databases (Medline, Scopus, CINAHL [Cumulative Index to Nursing and Allied Health Literature], Web of Science, and Cochrane Collaboration) were searched for articles published between January 1966 and May 2012; review articles and the reference lists from the articles that resulted from the search were also evaluated. Population-based cohort studies with data relevant to the determination of cancer risk in patients with SSc were included. All articles that met strict inclusion criteria were analyzed for data on population size, time of followup, and observed-to-expected cancer ratios, also known as standardized incidence ratios (SIRs). Six articles met criteria and were included in the meta-analysis. The pooled SIR for the incidence of cancer overall was 1.41 (95% confidence interval [95% CI] 1.18-1.68), and significant heterogeneity was observed as a consequence of variability in the participants, outcome, study design, and risk of bias among the studies. Men had a significantly higher pooled SIR (1.85 [95% CI 1.49-2.31]) than women (SIR 1.33 [95% CI 1.18-1.49]) (P < 0.01), and stratification for sex eliminated heterogeneity, which indicates that variability among the studies greatly contributed to differences between the sexes. There were no differences between limited cutaneous SSc and diffuse cutaneous SSc (P = 0.77). Significant increases were observed in the risk of cancer of the lung, liver, hematologic system, and bladder, as well as of non-Hodgkin's lymphoma and leukemia. SSc is associated with an increased risk of cancer, particularly lung, liver, hematologic, and bladder cancers, although absolute risk is relatively low. Men with SSc have a higher risk of developing cancer than women.


Altered development and function of the placental regions in preeclampsia and its association with long-chain polyunsaturated fatty acids.
The placenta is an essential organ formed during pregnancy that mainly transfers nutrients from the mother to the fetus. Nutrients taken up by the placenta are required for its own growth and development and to optimize fetal growth. Hence, placental function is an important determinant of pregnancy outcome. Among various nutrients, fatty acids, especially long-chain polyunsaturated fatty acids (LCPUFAs), including omega 3 and omega 6 fatty acids, are essential for placental development from the time of implantation. Studies have associated these LCPUFAs with placental development through their roles in regulating oxidative stress, angiogenesis, and inflammation, which may in turn influence their transfer to the fetus. The placenta has a heterogeneous morphology with variable regional vasculature, oxidative stress, and LCPUFA levels in healthy pregnancies depending upon the location within the placenta. However, these regional structural and functional parameters are found to be disturbed in pathological conditions, such as preeclampsia (PE), thereby affecting pregnancy outcome. Hence, the alterations in LCPUFA metabolism and transport in different regions of the PE placenta as compared with normal placenta could potentially be contributing to the pathological features of PE. The regional variations in development and function of the placenta and its possible association with placental LCPUFA metabolism and transport in normal and PE pregnancies are discussed in this review. WIREs Dev Biol 2016, 5:582-597. doi: 10.1002/wdev.238 For further resources related to this article, please visit the WIREs website.


Angiokine Wisp-1 is increased in myocardial infarction and regulates cardiac endothelial signaling.
Myocardial infarctions (MIs) cause the loss of myocytes due to lack of sufficient oxygenation and latent revascularization. Although the administration of histone deacetylase (HDAC) inhibitors reduces the size of infarctions and improves cardiac physiology in small-animal models of MI injury, the cellular targets of the HDACs, which the drugs inhibit, are largely unspecified. Here, we show that WNT-inducible secreted protein-1 (Wisp-1), a matricellular protein that promotes angiogenesis in cancers as well as cell survival in isolated cardiac myocytes and neurons, is a target of HDACs. Further, Wisp-1 transcription is regulated by HDACs and can be modified by the HDAC inhibitor, suberanilohydroxamic acid (SAHA/vorinostat), after MI injury. We observe that, at 7 days after MI, Wisp-1 is elevated 3-fold greater in the border zone of infarction in mice that experience an MI injury and are injected daily with SAHA, relative to MI alone. Additionally, human coronary artery endothelial cells (HCAECs) produce WISP-1 and are responsive to autocrine WISP-1-mediated signaling, which functionally promotes their proangiogenic behavior. Altering endogenous expression of WISP-1 in HCAECs directly impacts their network density in vitro. Therapeutic interventions after a heart attack define the extent of infarct injury, cell survival, and overall prognosis. Our studies shown here identify a potentially novel cardiac angiokine, Wisp-1, that may contribute to beneficial post-MI treatment modalities.


Control of fluxes in metabolic networks.
Understanding the control of large-scale metabolic networks is central to biology and medicine. However, existing approaches either require specifying a cellular objective or can only be used for small networks. We introduce new coupling types describing the relations between reaction activities, and develop an efficient computational framework, which does not require any cellular objective for systematic studies of large-scale metabolism. We identify the driver reactions facilitating control of 23 metabolic networks from all kingdoms of life. We find that unicellular organisms require a smaller degree of control than multicellular organisms. Driver reactions are under complex cellular regulation in Escherichia coli, indicating their preeminent role in facilitating cellular control. In human cancer cells, driver reactions play pivotal roles in malignancy and represent potential therapeutic targets. The developed framework helps us gain insights into regulatory principles of diseases and facilitates design of engineering strategies at the interface of gene regulation, signaling, and metabolism.


Phosphatidylinositol-bisphosphate regulates intercellular coupling in cardiac myocytes.
Changes in the lipid composition of cardiac myocytes have been reported during cardiac hypertrophy, cardiomyopathy, and infarction. Because a recent study indicates a relation between low phosphatidylinositol-bisphosphate (PIP(2)) levels and reduced intercellular coupling, we tested the hypothesis that agonist-induced changes in PIP(2) can result in a reduction of the functional coupling of cardiomyocytes and, consequently, in changes in conduction velocity. Intercellular coupling was measured by Lucifer Yellow dye transfer in cultured neonatal rat cardiomyocytes. Conduction velocity was measured in cardiomyocytes grown on microelectrode arrays. Intercellular coupling was reduced by angiotensin II (43.7 +/- 9.3%, N = 11) and noradrenaline (58.0 +/- 10.7%, N = 11). To test if reduced intercellular coupling after agonist stimulation was caused by PIP(2)-depletion, myocytes were stimulated by angiotensin II (57.3 +/- 5.7%, N = 14) and then allowed to recover in medium with or without wortmannin (an inhibitor of PIP(2) synthesis). Intercellular coupling fully recovered in control medium (102.1 +/- 8.9%, N = 10), whereas no recovery occurred in the presence of wortmannin (69.3 +/- 7.8%, N = 12). Inhibition of PKC, calmodulin, or arachidonic acid production did not affect the response to either angiotensin II or noradrenaline. Furthermore, decreasing or increasing PIP(2) also decreased and increased intercellular coupling, respectively. This supports the role of PIP(2) in the regulation of intercellular coupling. In beating myocytes, conduction velocity was reduced by angiotensin II stimulation, and recovery after wash out was prevented by inhibition of PIP(2) production. Reductions in PIP(2) inhibit intercellular coupling in cardiomyocytes, and stimulation by physiologically relevant agonists reduces intercellular coupling by this mechanism. The reduction in intercellular coupling lowered conduction velocity.


Models of nutrition-focused continuing education programs for nurses: a systematic review of the evidence.
Nurses are well-positioned to provide basic nutrition education and reinforce nutrition messages to patients in hospital and primary care settings. Despite this, nurses may not receive adequate training to provide this service, and there is limited opportunity for nurses to engage in nutrition-focused continuing education (CE). The aim of this review was to determine whether nurse nutrition education results in improved knowledge and practices; and explore which models of CE for nutrition may be most acceptable and effective in practice. Web of Science and Scopus were searched for case-series studies published between 2000 and 2016 that investigated changes in nutrition knowledge of nurses and midwives. Only studies that could transcend to nurses providing patient nutrition education were included. Twelve articles met the eligibility criteria. Articles are explored in terms of mode of delivery, duration of intervention and educational strategies employed. Nutrition CE programs that are delivered face-to-face or by self-directed learning manuals, which utilise active learning strategies, are positively associated with improvements in nutrition knowledge. Web-based CE and self-directed learning may be favourable modes of delivery as they may assist in addressing resource and time contraints.


Purification of multiple forms of glial growth factor.
Glial growth factors (GGFs) were purified from bovine pituitaries using an in vitro rat Schwann cell mitogenesis assay. In addition to an approximately 34-kDa species termed GGF-I, similar in molecular mass to a previously identified molecule (Lemke, G. E., and Brockes, J. P. (1984) J. Neuroscience 4, 75-83), two species named GGF-II and GGF-III were characterized with apparent molecular masses of approximately 59 and approximately 45 kDa, respectively. Highly purified preparations of all species share a similar dose-dependent stimulation of Schwann cell DNA synthesis at nanomolar concentrations. Forskolin synergizes with all three GGFs, shifting their dose dependence 3-8-fold into the sub-nanomolar range. The GGFs, which contain N-linked carbohydrate groups not essential for their in vitro mitogenic effects, are three distinct members of a novel family of glial cell mitogens.


Two carbon fluxes to reserve starch in potato (Solanum tuberosum L.) tuber cells are closely interconnected but differently modulated by temperature.
Parenchyma cells from tubers of Solanum tuberosum L. convert several externally supplied sugars to starch but the rates vary largely. Conversion of glucose 1-phosphate to starch is exceptionally efficient. In this communication, tuber slices were incubated with either of four solutions containing equimolar [U-¹⁴C]glucose 1-phosphate, [U-¹⁴C]sucrose, [U-¹⁴C]glucose 1-phosphate plus unlabelled equimolar sucrose or [U-¹⁴C]sucrose plus unlabelled equimolar glucose 1-phosphate. C¹⁴-incorporation into starch was monitored. In slices from freshly harvested tubers each unlabelled compound strongly enhanced ¹⁴C incorporation into starch indicating closely interacting paths of starch biosynthesis. However, enhancement disappeared when the tubers were stored. The two paths (and, consequently, the mutual enhancement effect) differ in temperature dependence. At lower temperatures, the glucose 1-phosphate-dependent path is functional, reaching maximal activity at approximately 20 °C but the flux of the sucrose-dependent route strongly increases above 20 °C. Results are confirmed by in vitro experiments using [U-¹⁴C]glucose 1-phosphate or adenosine-[U-¹⁴C]glucose and by quantitative zymograms of starch synthase or phosphorylase activity. In mutants almost completely lacking the plastidial phosphorylase isozyme(s), the glucose 1-phosphate-dependent path is largely impeded. Irrespective of the size of the granules, glucose 1-phosphate-dependent incorporation per granule surface area is essentially equal. Furthermore, within the granules no preference of distinct glucosyl acceptor sites was detectable. Thus, the path is integrated into the entire granule biosynthesis. In vitro C¹⁴C-incorporation into starch granules mediated by the recombinant plastidial phosphorylase isozyme clearly differed from the in situ results. Taken together, the data clearly demonstrate that two closely but flexibly interacting general paths of starch biosynthesis are functional in potato tuber cells.


Identification and characterization of a selective radioligand for ELOVL6.
ELOVL6, a member of the elongation of very long-chain fatty acids (ELOVL) family, has recently been identified as the rate-limiting enzyme for the elongation of palmitoyl-CoA. ELOVL6 deficient mice are protected from high-fat diet induced insulin resistance, suggesting that ELOVL6 might be a promising target for the treatment of metabolic disorders. Despite the increasing interest in Elovl6 as a therapeutic target, the lack of chemical tools for this enzyme has limited further elucidation of the biochemical and pharmacological properties of ELOVL6. We have identified Compound-A, a potent inhibitor for ELOVL6, by screening our company library and subsequently optimizing hit compounds. Compound-A potently inhibited human and mouse ELOVL6 and displayed >100-fold greater selectivity for ELOVL6 over other ELOVL family members. Consistent with its potent and selective inhibitory activity toward ELOVL6, [(3)H]Compound-A bound to ELOVL6 with high affinity while showing no specific binding to other ELOVL enzymes. The observation that [(3)H]Compound-A bound to ELOVL6 in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH suggests that Compound-A might recognize an enzyme-substrate complex, e.g. an acyl-enzyme intermediate. Collectively, these observations demonstrate that Compound-A and its tritiated form are useful tools for biochemical and pharmacological characterization of ELOVL6.


Biliary stricture in living-related donor liver transplantation: management with balloon dilation.
Biliary stricture is a recipient graft complication, occurring late in the post-operative period, which appears to occur with increased frequency in living-related donor liver transplantation (LRD LTx). We reviewed the experience at the University of Minnesota in managing a biliary complication of LRD LTx. Since January 1997, 13 LRD transplants have been performed using the technique of transplantation of the left lateral segments with a small portion of segment IV. All patients had hepaticojejunostomies using a Roux-en-Y loop. Of the 11 surviving patients, eight had evidence of cholangitis (Gram-negative sepsis, two patients; ascending cholangitis, three patients; or unexplained fever with elevated liver enzymes, three patients) 4-8 months after otherwise successful transplantation. Six of the patients underwent percutaneous transhepatic cholangiography (PTC) with demonstration of a stenosis at the site of the biliary anastomosis. Repeated dilation of the anastomosis led to resolution of the stenoses, normalization of liver enzymes, and prevention of further episodes of infection. No patient required revision of the hepaticojejunostomy. Computed axial tomography evidence of ductal stenosis may be subtle in this group of patients, but PTC is diagnostic. We suggest a high index of suspicion of biliary stricture in the LRD LTx population. Biliary dilation reduces the risk of life-threatening sepsis.


A comparison of the effects of naloxone upon body weight loss and suppression of fixed-ratio operant behavior in morphine-dependent rats.
Rats were trained to press a lever (respond) under a fixed-ratio 20 schedule for food presentation. Administration of 10 or 25 mg of naloxone (NX) per kg i.p. to drug-naive rats supressed responding whereas 1 mg of NX per kg was without effect. However, administration of 0.25 mg of NX per kg to rats which had received 10 or 15 mg of morphine sulfate per kg 48 hours previously induced small, but statistically reliable, decrements in responding. Rats implanted with one pellet containing 75 mg of morphine base displayed tolerance to the depressant effects of the morphine pellet within 2 days after implantation. A systematic study of the effects of naloxone given to morphine tolerant-dependent rats revealed good concordance between the amount of weight lost and the severity of behavioral disruption, within the same subject, after administration of the antagonist. Although 0.03 mg of NX per kg given 3 to 6 days after pellet implantation significantly suppressed responding, 0.1 mg of NX per kg was required to produce a significant reduction in body weight. Semiweekly injections of 1 mg of NX per kg continued to suppress responding up to 4 weeks after implantation of a single morphine pellet. The body weight changes were significant only up to 3 weeks after implantation. The data suggest that disruption of fixed-ratio responding is a sensitive indicator of antagonist-precipitated morphine withdrawal.


Frontal alpha asymmetry as a pathway to behavioural withdrawal in depression: Research findings and issues.
Depression has been described as a process of behavioural withdrawal from overwhelming aversive stressors, and which manifests itself in the diagnostic symptomatology for Major Depressive Disorder (MDD). The underlying neurobiological pathways to that behavioural withdrawal are suggested to include greater activation in the right vs the left frontal lobes, described as frontal EEG asymmetry. However, despite a previous meta-analysis that provided overall support for this EEG asymmetry hypothesis, inconsistencies and several methodological confounds exist. The current review examines the literature on this issue, identifies inconsistencies in findings and discusses several key research issues that require addressing for this field to move towards a defensible theoretical model of depression and EEG asymmetry. In particular, the position of EEG asymmetry in the brain, measurement of severity and symptoms profiles of depression, and the effects of gender are considered as potential avenues to more accurately define the specific nature of the depression-EEG asymmetry association.


Percutaneous retrograde posterior column acetabular fixation: is the sciatic nerve safe? A cadaveric study.
The purpose of this cadaveric study was to determine the proximity of the neurologic structures to the path of the screw inserted percutaneously into the ischial tuberosity. Cadaver study. Ten screws were inserted in 10 limbs (5 cadavers) under fluoroscopic guidance. Dissection was then performed to expose the head of the screw and was extended laterally to expose the sciatic nerve, the posterior cutaneous nerve of the thigh, and its inferior cluneal branches. The distance from the screw head to the sciatic nerve, posterior cutaneous nerve of the thigh, and the inferior cluneal nerves. The distance from the center of the screw head to the sciatic nerve averaged 58 mm (range, 40-70 mm). The average distance between the screw head and the posterior cutaneous nerve of the thigh was 42 mm (range, 30-60 mm). The inferior cluneal branches were the closest to the path of the screw with an average distance of 3.5 mm in 6 specimens (range, 1-6 mm) and were injured by the screw in 3 and could not be located in another specimen. The sciatic nerve and the posterior cutaneous nerve of the thigh appear to be safe during retrograde percutaneous screw fixation of a posterior column acetabular fracture through a central entry point in the ischial tuberosity. However, the inferior cluneal nerves that are responsible for the cutaneous sensitivity of the lower half of the gluteal region are at risk of injury.


Leakage of beta-lactamase: a second mechanism for antibiotic potentiation by amdinocillin.
Discrepancies were observed between results of different beta-lactamase induction tests with amdinocillin, which appeared to be a strong inducer in whole-cell assays but a weak inducer in assays with cell-free sonic extracts. Results of a nitrocephin-disk test with constitutive beta-lactamase producers indicated that the positive results obtained in whole-cell assays were due to drug-produced leakage of enzyme from the cell and not to induction. Imipenem was also found to cause leakage of beta-lactamase from a similar number of constitutive enzyme producers, while cefoxitin was much less likely to cause leakage. A split-dose regimen was employed to treat mice infected with a strain of Enterobacter cloacae which appeared to leak enzyme on exposure to amdinocillin. Results indicated that prior treatment with amdinocillin significantly enhanced (P less than 0.025) the efficacy of azlocillin, an enzyme-labile drug, but did not affect the efficacy of cefotaxime, a relatively enzyme-stable drug. Conversely, prior treatment with amdinocillin did not potentiate the efficacy of either azlocillin or cefotaxime in the treatment of mice infected with an Escherichia coli strain that was highly susceptible to all three drugs. Thus, it appears that amdinocillin may potentiate the activity of other beta-lactam drugs not only by binding to a complementary penicillin-binding protein but also by causing leakage of beta-lactamase from the cell. This effect may be related to its ability to bind to penicillin-binding protein 2 and subsequently produce changes in outer membrane permeability.


Antifibrogenic Activities of CYP11A1-derived Vitamin D3-hydroxyderivatives Are Dependent on RORγ.
Previous studies showed that noncalcemic 20(OH)D3, a product of CYP11A1 action on vitamin D3, has antifibrotic activity in human dermal fibroblasts and in a bleomycin mouse model of scleroderma. In this study, we tested the role of retinoic acid-related orphan receptor γ (RORγ), which is expressed in skin, in the action of CYP11A1-derived secosteroids using murine fibroblasts isolated from the skin of wild-type (RORγ +/+), knockout (RORγ -/-), and heterozygote (RORγ +/-) mice. CYP11A1-derived 20(OH)D3, 20,23(OH)2D3, 1,20(OH)2D3, and 1,20,23(OH)3D3 inhibited proliferation of RORγ +/+ fibroblasts in a dose-dependent manner with a similar potency to 1,25(OH)2D3. Surprisingly, this effect was reversed in RORγ +/- and RORγ -/- fibroblasts, with the most pronounced stimulatory effect seen in RORγ -/- fibroblasts. All analogs tested inhibited TGF-β1-induced collagen synthesis in RORγ +/+ fibroblasts and the expression of other fibrosis-related genes. This effect was curtailed or reversed in RORγ -/- fibroblasts. These results show that the antiproliferative and antifibrotic activities of the vitamin D hydroxy derivatives are dependent on a functional RORγ. The dramatic changes in the transcriptomes of fibroblasts of RORγ -/- versus wild-type mice following treatment with 20(OH)D3 or 1,20(OH)2D3 provide a molecular basis to explain, at least in part, the observed phenotypic differences.


Dissection of the extracellular human interferon gamma receptor alpha-chain into two immunoglobulin-like domains. Production in an Escherichia coli thioredoxin gene fusion expression system and recognition by neutralizing antibodies.
The extracellular interferon gamma receptor alpha-chain (IFN gamma R) is believed to comprise two discrete approximately 110 amino acid immunoglobulin-like domains, perhaps similar to those seen in the crystal structure of the extracellular human growth hormone receptor [De Vos, A. M., Ultsch, M., & Kossiakoff, A. (1992) Science 255, 306-312], a distant relative in the cytokine receptor superfamily. In accord with this idea, we show that these IFN gamma R immunoglobulin-like domains can be produced separately in a soluble form with a native-like fold. The N-terminal domain (residues 1-108), with a Cys105 to Ser105 mutation, was produced at a high level, in a soluble form, as a thioredoxin-interferon gamma receptor fragment fusion protein in the cytoplasm of Escherichia coli. Upon extraction, the receptor Cys60-Cys68 disulfide bond formed spontaneously, to generate a native-like structure directly without the need for refolding. Cleavage of the fusion protein by enterokinase released the receptor fragment (approximately 12 kDa), which was recognized by several neutralizing antibodies with affinities, measured using surface plasmon resonance technology, that were essentially indistinguishable from those seen with the full length extracellular IFN gamma R produced in eukaryotic cells. Circular dichroism and 1D 1H nuclear magnetic resonance spectra indicated that the receptor fragment adopts a folded state, with mainly beta-sheet and reverse turn secondary structure. The second membrane-proximal Ig-like domain of the IFN gamma R (residues 90-229) was produced, albeit less efficiently, and characterized in a similar way. The production of these two independently folded proteins provides experimental support for the two domain organization of the IFN gamma R and opens new avenues for structural studies on these Ig-like molecules by NMR and crystallographic methods.


Incidental diagnosis of diseases on un-enhanced helical computed tomography performed for ureteric colic.
Patients presenting in the emergency room with flank pain suggestive of acute ureteric colic may have alternative underlying conditions mimicking ureteric stones. An early diagnosis and appropriate treatment for other causes of flank pain is important. The majority of centers around the world are increasingly using un-enhanced helical CT (UHCT) for evaluation of ureteric colic. This study was conducted to determine the incidence and spectrum of significant incidental diagnoses established or suggested on UHCT performed for suspected renal/ureteric colic. Urologist and radiologist reviewed 233 consecutive UHCT, performed for suspected renal/ureteral colic along with assessment of the medical records. Radiological diagnoses of clinical entities not suspected otherwise were analyzed. All other relevant radiological, biochemical and serological investigations and per-operative findings were also noted. Ureteral calculi were identified in 148 examinations (64%), findings of recent passage of calculi in 10 (4%) and no calculus in 75 examinations (32%). Overall the incidental findings (additional or alternative diagnosis) were found in 28 (12%) CT scans. Twenty (71%) of these diagnoses were confirmed by per-operative findings, biopsy, and other radiological and biochemical investigations or on clinical follow up. A wide spectrum of significant incidental diagnoses can be identified on UHCT performed for suspected renal/ureteral colic. In the present series of 233 consecutive CT examinations, the incidence of incidental diagnosis was 12%.