Regulation of the dorsal morphogen by the Toll and torso signaling pathways: a receptor tyrosine kinase selectively masks transcriptional repression.
The dorsal (dl) nuclear gradient initiates the differentiation of the mesoderm, neuroectoderm, and dorsal ectoderm by activating and repressing gene expression in the early Drosophila embryo. This gradient is organized by a Toll signaling pathway that shares many common features with the mammalian IL-1 cytokine pathway. Here we present evidence that a second signaling pathway, controlled by the torso (tor) receptor tyrosine kinase, also modulates dl activity. Evidence is presented that the tor pathway selectively masks the ability of dl to repress gene expression but has only a slight effect on activation. Intracellular kinases that are thought to function downstream of tor, such as D-raf and the rolled MAP kinase, mediate this selective block in repression. Normally, the Toll and tor pathways are both active only at the embryonic poles, and consequently, target genes (zen and dpp) that are repressed in middle body regions are expressed at these sites. Constitutive activation of the tor pathway causes severe embryonic defects, including disruptions in gastrulation and mesoderm differentiation, as a result of misregulation of dl target genes. These results suggest that RTK signaling pathways can control gene expression by antirepression, and that multiple pathways can fine-tune the activities of a single transcription factor.


Seasonal variations and shared latrine cleaning practices in the slums of Kampala city, Uganda.
The effect of seasons on health outcomes is a reflection on the status of public health and the state of development in a given society. Evidence shows that in Sub-Saharan Africa, most infectious diseases flourish during the wet months of the year; while human activities in a context of constrained choices in life exacerbate the effects of seasons on human health. The paper argues that, the wet season and when human activities are at their peak, sanitation is most dire poor slum populations. A shared latrine cleaning observation was undertaken over a period of 6 months in the slums of Kampala city. Data was collected through facility observations, user group meetings, Focus group discussions and, key informant interviews. The photos of the observed sanitation facilities were taken and assessed for facility cleanliness or dirt. Shared latrine pictures, observations, Focus Group Discussion, community meetings and key informant interviews were analysed and subjected to an analysis over the wet, dry and human activity cycles before a facility was categorised as either 'dirty' or 'clean'. Human activity cycles also referred to as socio-economic seasons were, school days, holidays, weekends and market days. These have been called 'impure' seasons, while the 'pure' seasons were the wet and dry months: improved and unimproved facilities were negatively affected by the wet seasons and the peak seasons of human activity. Wet seasons were associated with, mud and stagnant water, flooding pits and a repugnant smell from the latrine cubicle which made cleaning difficult. During the dry season, latrines became relatively cleaner than during the wet season. The presence of many child(ren) users during school days as well as the influx of market goers for the roadside weekly markets compromised the cleaning outcomes for these shared sanitation facilities. Shared latrine cleaning in slums is impacted by seasonal variations related to weather conditions and human activity. The wet seasons made the already bad sanitation situation worse. The seasonal fluctuations in the state of shared slum sanitation relate to a wider malaise in the population and an implied capacity deficit among urban authorities. Poor sanitation in slums is part of a broader urban mismanagement conundrum pointing towards the urgent need for multiple interventions aimed at improving the general urban living conditions well beyond sanitation.


HTPheno: an image analysis pipeline for high-throughput plant phenotyping.
In the last few years high-throughput analysis methods have become state-of-the-art in the life sciences. One of the latest developments is automated greenhouse systems for high-throughput plant phenotyping. Such systems allow the non-destructive screening of plants over a period of time by means of image acquisition techniques. During such screening different images of each plant are recorded and must be analysed by applying sophisticated image analysis algorithms. This paper presents an image analysis pipeline (HTPheno) for high-throughput plant phenotyping. HTPheno is implemented as a plugin for ImageJ, an open source image processing software. It provides the possibility to analyse colour images of plants which are taken in two different views (top view and side view) during a screening. Within the analysis different phenotypical parameters for each plant such as height, width and projected shoot area of the plants are calculated for the duration of the screening. HTPheno is applied to analyse two barley cultivars. HTPheno, an open source image analysis pipeline, supplies a flexible and adaptable ImageJ plugin which can be used for automated image analysis in high-throughput plant phenotyping and therefore to derive new biological insights, such as determination of fitness.


An in vivo test to assess mefloquine 25 mg/kg for the treatment of uncomplicated falciparum malaria in Rondônia, Brazil.
Drug-resistant Plasmodium falciparum is undermining malaria control efforts worldwide. In Brazil, mefloquine (MQ) at a dose of 15 mg/kg body weight is used to treat P. falciparum. At this dose, MQ resistance developed rapidly in Thailand. Use of a higher MQ dose may retard the development of resistance. We treated 50 patients aged one to 67 years who had acute, uncomplicated P falciparum malaria using MQ 25 mg/kg. There were no serious adverse events. Two patients complained of dizziness and insomnia. Assessing evaluable patients, the day 42 cure rate was 40/42 [95.2% (95% confidence interval 83.8 to 99.4%)]. Mefloquine was efficacious and well tolerated in this small cohort from the state of Rôndonia.


"Running Water Won't Freeze": How people with advanced Parkinson's disease experience occupation.
Parkinson's disease (PD) is a progressive neurodegenerative condition often resulting in significant disability and impacting on one's ability to participate in an occupation. The present study aimed to explore how people with advanced Parkinson's disease experience the phenomenon of occupation in their daily lives in order to inform the practice of occupational therapy in palliative care. Using a phenomenological approach, in-depth interviews were undertaken with a purposive sample of 10 people in the advanced stages of Parkinson's disease. These interviews were audiotaped, transcribed verbatim, and subsequently analyzed using a thematic content analysis approach. The study received approval from the relevant university ethics committee, as well as the research network of Parkinson's UK. The experience of occupation emerged as being physical, psychological, social, and spiritual with related subthemes. Within each of these themes, participants described their experience of occupation that they valued and that were important to their daily lives. They also identified the strategies they employed to continue participating in certain occupations and described others they were no longer able to engage in and the impact of that loss. Participants' experiences crossed the domains of palliative care and suggest that adopting a palliative care approach would enhance an enhanced quality of life, experienced in terms of meaningful and valuable occupation. Disruption to participation in occupation caused them distress and frustration, suggesting that access to occupation-focused therapy would significantly improve quality of life for people with PD. As there is a strong link between the ethos of occupational therapy and palliative care, it is proposed that there is a valuable role for occupational therapy intervention to play within palliative care.


Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma.
Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3' untranslated region (3'UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of "TGF-beta regulation of extracellular matrix" and "cell cycle G1 to S check points." These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.


Expression of leukemia inhibitory factor in the endometrium in abnormal uterine cavities during the implantation window.
To investigate the expression of the implantation factors leukemia inhibitory factor (LIF), interleukin-11 (IL-11), and IL-6ST/gp130 in the endometrium to examine the relationship between loss of implantation and abnormal uterine cavity. Case-control study. Department of Obstetrics and Gynecology, Tokyo Medical University. Subjects comprised 41 patients in the abnormal uterine cavity group who underwent resection of a uterine submucosal myoma or an endometrial polyp by transcervical resectoscopy (TCR) and 18 patients in the control group who underwent laparoscopic surgery. In the abnormal uterine cavity group, endometrial tissue specimens were obtained before resection under hysteroscopy. In the control group, endometrial tissue specimens were obtained by curettage at the time of laparoscopic surgery. We divided the patients into four groups according to menstrual cycle and measured the endometrial expression of LIF, IL-11, and IL-6ST/gp130 with the use of quantitative real-time reverse-transcription polymerase chain reaction. Significant increases in LIF and IL-11 mRNA expression were recognized during the midsecretory phase of the menstrual cycle in the control group. However, no difference in IL-6ST/gp130 mRNA expression was observed in any phase during the menstrual cycle in either group. In terms of LIF and IL-11 mRNA expression at the midsecretory phase, the abnormal uterine cavity group showed a significantly decreased LIF mRNA expression compared with the control group. LIF mRNA expression was significantly decreased in abnormal uterine cavities during the midsecretory phase, indicating that endometrial cavity defects are a possible cause of poor reproductive outcomes.


Coupling asymmetry of heterotypic connexin 45/ connexin 43-EGFP gap junctions: properties of fast and slow gating mechanisms.
Although fast and slow gating mechanisms have been described in gap junctions (GJs), their relative contributions to dependence on transjunctional voltage, V(j), is still unclear. We used cell lines expressing wild-type connexin 45 (Cx45) and connexin 43 fused with enhanced green fluorescent protein (Cx43-EGFP) to examine mechanisms of gating in homo- and heterotypic GJs formed of these connexins. Macroscopically Cx45/Cx45 channels show high sensitivity to V(j). Cx45 channels demonstrate two types of gating: fast transitions between open and residual states and slow transitions between open and completely closed states. Single-channel conductance of the Cx45 channel is approximately 32 pS for the open state and approximately 4 pS for the residual state. Cx45/Cx43-EGFP heterotypic junctions exhibit very asymmetrical V(j) gating with the maximum junctional conductance shifted to V(j) positive on the Cx45 side. Conductance of single Cx45/Cx43-EGFP channels is approximately 55 pS for the open state and approximately 4 pS for the residual state, values consistent with the simple-series connection of Cx45 and Cx43-EGFP hemichannels. At V(j) = 0, the slow gate of many Cx45 hemichannels is closed in both homotypic Cx45/Cx45 and heterotypic Cx45/Cx43-EGFP junctions. Fast and slow V(j) gates of both Cx45 and Cx43 hemichannels close for relative negativity at their cytoplasmic end. Coupling mediated by Cx45/Cx43-EGFP junctions can exhibit asymmetry that can be strongly modulated by small changes in difference of holding potentials. Cx45/Cx43 junctions are likely to be found in brain and heart and may mediate rectifying electrical transmission or modulatable chemical communication.


Rearrangements of immunoglobulin gene and oncogenes in ocular adnexal pseudolymphoma.
The organization of immunoglobulin heavy chain (IgH), light chain (kappa and lambda) and T cell receptor (TCR) beta chain gene loci in 10 patients with ocular adnexal pseudolymphoma was investigated. Eight of them showed IgH gene rearrangement in at least one of the 3 restriction enzymes-digested DNAs extracted from ocular adnexal neoplasms. In contrast, none of them exhibited clonal TCR beta chain gene rearrangement. The configuration of bcl-1, bcl-2 and c-myc oncogenes was also studied by Southern blot technique. Two patients had a rearranged joining region, IgH-containing fragment that comigrated with the rearranged bcl-1 fragment. C-myc gene rearrangement was found in only one patient who also had bcl-1 gene rearrangement. In ocular adnexal pseudolymphoma, none demonstrated bcl-2 gene rearrangement; however, in bone marrow cells, one patient with systemic lymphadenopathy exhibited both IgH and bcl-2 gene rearrangements. Three genotypic subsets of these ocular adnexal pseudolymphoma can be identified by the configuration of IgH gene and related oncogenes: with germline configuration of IgH gene and bcl-1, bcl-2 and c-myc oncogenes; with rearrangement of IgH gene but germline configuration of these oncogenes; and with recombination between rearranged IgH and bcl-1 genes. These results suggest in ocular adnexal pseudolymphoma a spectrum of clonal change evolving from polyclonal to monoclonal B-population, and further to monoclonal B-population with rearranged bcl-1, c-myc and/or bcl-2 oncogenes.


Exercise, cognitive function, and aging.
Increasing the lifespan of a population is often a marker of a country's success. With the percentage of the population over 65 yr of age expanding, managing the health and independence of this population is an ongoing concern. Advancing age is associated with a decrease in cognitive function that ultimately affects quality of life. Understanding potential adverse effects of aging on brain blood flow and cognition may help to determine effective strategies to mitigate these effects on the population. Exercise may be one strategy to prevent or delay cognitive decline. This review describes how aging is associated with cardiovascular disease risks, vascular dysfunction, and increasing Alzheimer's disease pathology. It will also discuss the possible effects of aging on cerebral vascular physiology, cerebral perfusion, and brain atrophy rates. Clinically, these changes will present as reduced cognitive function, neurodegeneration, and the onset of dementia. Regular exercise has been shown to improve cognitive function, and we hypothesize that this occurs through beneficial adaptations in vascular physiology and improved neurovascular coupling. This review highlights the potential interactions and ideas of how the age-associated variables may affect cognition and may be moderated by regular exercise.


Hazardous Alcohol Use Associated with Increased Sexual Risk Behaviors Among People Who Inject Drugs.
Alcohol is associated with a multitude of severe health consequences. While risk behaviors related to illicit drug use are commonly studied among people who inject drugs (PWID), the role of alcohol use has received substantially less attention in this population. We explored whether drug and sexual risk behaviors as well as experiences of violence were associated with hazardous alcohol use in a cohort of PWID. Analyses were conducted using observational data from a prospective cohort of community-recruited HIV-negative PWID in Vancouver, Canada. We used the U.S. National Institute on Alcohol Abuse and Alcoholism definition of hazardous alcohol use (i.e., >14 drinks/wk or >4 drinks on 1 occasion for men, and >7 drinks/wk or >3 drinks on 1 occasion for women). We used multivariable generalized estimating equations (GEE) to identify the factors associated with hazardous alcohol use. Between 2006 and 2012, 1,114 HIV-negative individuals were recruited, and 186 (16.7%) reported hazardous alcohol use in the previous 6 months at baseline. In multivariable GEE analyses, having multiple sex partners (adjusted odds ratio [AOR] = 1.25), history of sexually transmitted infection (AOR = 1.50), experiencing violence (AOR = 1.36), and incarceration (AOR = 1.29) were each independently associated with hazardous alcohol use. Caucasian ethnicity (AOR = 0.56), ≥ daily heroin injection (AOR = 0.81), and engagement in addiction treatment (AOR = 0.84) were negatively associated with hazardous alcohol use (all p < 0.05). A considerable proportion of PWID reported hazardous alcohol use, which was independently associated with reporting sexual, but not drug-related, HIV risk behaviors and experiencing recent violence. Findings suggest a need to integrate regular screening and evidence-based alcohol interventions into treatment efforts for PWID.


Signalling among relatives. II. Beyond the tower of Babel.
Models of costly signalling are commonly employed in evolutionary biology in order to explain how honest communication between individuals with conflicting interests can be stable. These models have focused primarily on a single type of honest signalling equilibrium, the separating equilibrium in which any two different signallers send distinct signals, thereby providing signal receivers with complete information. In this paper, we demonstrate that in signalling among relatives (modelled using the Sir Philip Sidney game), there is not one but a large number of possible signalling equilibria, most of which are pooling equilibria in which different types of signallers may share a common signal. We prove that in a general Sir Philip Sidney game, any partition of signallers into equi-signalling classes can have a stable signalling equilibrium if and only if it is a contiguous partition, and provide examples of such partitions. A similar (but slightly stricter) condition is shown to hold when signals are transmitted through a medium with signalling error. These results suggest a solution to a problem faced by previous signalling theory models: when we consider the separating equilibrium, signal cost is independent of the frequency of individuals sending that signal and, consequently, even very rare signaller types can drastically affect signal cost. Here, we show that by allowing these rare signallers to pool with more common signallers, signal cost can be greatly reduced.


Utilization of Self-Diagnosis Health Chatbots in Real-World Settings: Case Study.
Artificial intelligence (AI)-driven chatbots are increasingly being used in health care, but most chatbots are designed for a specific population and evaluated in controlled settings. There is little research documenting how health consumers (eg, patients and caregivers) use chatbots for self-diagnosis purposes in real-world scenarios. The aim of this research was to understand how health chatbots are used in a real-world context, what issues and barriers exist in their usage, and how the user experience of this novel technology can be improved. We employed a data-driven approach to analyze the system log of a widely deployed self-diagnosis chatbot in China. Our data set consisted of 47,684 consultation sessions initiated by 16,519 users over 6 months. The log data included a variety of information, including users' nonidentifiable demographic information, consultation details, diagnostic reports, and user feedback. We conducted both statistical analysis and content analysis on this heterogeneous data set. The chatbot users spanned all age groups, including middle-aged and older adults. Users consulted the chatbot on a wide range of medical conditions, including those that often entail considerable privacy and social stigma issues. Furthermore, we distilled 2 prominent issues in the use of the chatbot: (1) a considerable number of users dropped out in the middle of their consultation sessions, and (2) some users pretended to have health concerns and used the chatbot for nontherapeutic purposes. Finally, we identified a set of user concerns regarding the use of the chatbot, including insufficient actionable information and perceived inaccurate diagnostic suggestions. Although health chatbots are considered to be convenient tools for enhancing patient-centered care, there are issues and barriers impeding the optimal use of this novel technology. Designers and developers should employ user-centered approaches to address the issues and user concerns to achieve the best uptake and utilization. We conclude the paper by discussing several design implications, including making the chatbots more informative, easy-to-use, and trustworthy, as well as improving the onboarding experience to enhance user engagement.


Genotype Imputation To Improve the Cost-Efficiency of Genomic Selection in Farmed Atlantic Salmon.
Genomic selection uses genome-wide marker information to predict breeding values for traits of economic interest, and is more accurate than pedigree-based methods. The development of high density SNP arrays for Atlantic salmon has enabled genomic selection in selective breeding programs, alongside high-resolution association mapping of the genetic basis of complex traits. However, in sibling testing schemes typical of salmon breeding programs, trait records are available on many thousands of fish with close relationships to the selection candidates. Therefore, routine high density SNP genotyping may be prohibitively expensive. One means to reducing genotyping cost is the use of genotype imputation, where selected key animals (e.g., breeding program parents) are genotyped at high density, and the majority of individuals (e.g., performance tested fish and selection candidates) are genotyped at much lower density, followed by imputation to high density. The main objectives of the current study were to assess the feasibility and accuracy of genotype imputation in the context of a salmon breeding program. The specific aims were: (i) to measure the accuracy of genotype imputation using medium (25 K) and high (78 K) density mapped SNP panels, by masking varying proportions of the genotypes and assessing the correlation between the imputed genotypes and the true genotypes; and (ii) to assess the efficacy of imputed genotype data in genomic prediction of key performance traits (sea lice resistance and body weight). Imputation accuracies of up to 0.90 were observed using the simple two-generation pedigree dataset, and moderately high accuracy (0.83) was possible even with very low density SNP data (∼250 SNPs). The performance of genomic prediction using imputed genotype data was comparable to using true genotype data, and both were superior to pedigree-based prediction. These results demonstrate that the genotype imputation approach used in this study can provide a cost-effective method for generating robust genome-wide SNP data for genomic prediction in Atlantic salmon. Genotype imputation approaches are likely to form a critical component of cost-efficient genomic selection programs to improve economically important traits in aquaculture.


Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4.
Homologs of Drosophila Mad function as downstream mediators of the receptors for transforming growth factor beta (TGF-beta)-related factors. Two homologs, the receptor-associated Smad3 and the tumor suppressor Smad4/DPC4, synergize to induce ligand-independent TGF-beta activities and are essential mediators of the natural TGF-beta response. We now show that Smad3 and Smad4 associate in homomeric and heteromeric interactions, as assessed by yeast two-hybrid and coimmunoprecipitation analyses. Heteromeric interactions are mediated through the conserved C-terminal domains of Smad3 and Smad4. In Smad3, the homomeric interaction is mediated by the same domain. In contrast, the homomeric association of Smad4 requires both the N-terminal domain and the C-terminal domain, which by itself does not homomerize. Mutations that have been associated with impaired Mad activity in Drosophila or decreased tumor suppressor activity of Smad4/DPC4 in pancreas cancer, including a short C-terminal truncation and two point mutations in the conserved C-terminal domains, impair the ability of Smad3 and Smad4 to undergo homo- and heteromeric associations. Analyses of the biological activity of Smad3 and Smad4 and their mutants show that full signaling activity correlates with their ability to undergo efficient homo- and heteromeric interactions. Mutations that interfere with these interactions result in decreased signaling activity. Finally, we evaluated the ability of Smad3 or Smad4 to induce transcriptional activation in yeast. These results correlate the ability of individual Smads to homomerize with transcriptional activation and additionally with their biological activity in mammalian cells.


Nanoparticle-Mediated Cell Capture Enables Rapid Endothelialization of a Novel Bare Metal Stent.
Incomplete endothelialization of intracoronary stents has been associated with stent thrombosis and recurrent symptoms, whereas prolonged use of dual antiplatelet therapy increases bleeding-related adverse events. Facilitated endothelialization has the potential to improve clinical outcomes in patients who are unable to tolerate dual antiplatelet therapy. The objective of this study was to demonstrate the feasibility of magnetic cell capture to rapidly endothelialize intracoronary stents in a large animal model. A novel stent was developed from a magnetizable duplex stainless steel (2205 SS). Polylactic-co-glycolic acid and magnetite (Fe3O4) were used to synthesize biodegradable superparamagnetic iron oxide nanoparticles, and these were used to label autologous blood outgrowth endothelial cells. Magnetic 2205 SS and nonmagnetic 316L SS control stents were implanted in the coronary arteries of pigs (n = 11), followed by intracoronary delivery of magnetically labeled cells to 2205 SS stents. In this study, we show extensive endothelialization of magnetic 2205 SS stents (median 98.4% cell coverage) within 3 days, whereas the control 316L SS stents exhibited significantly less coverage (median 48.9% cell coverage, p < 0.0001). This demonstrates the ability of intracoronary delivery of magnetic nanoparticle labeled autologous endothelial cells to improve endothelialization of magnetized coronary stents within 3 days of implantation.


Comparison of self-care behaviors of heart failure patients in 15 countries worldwide.
Clinicians worldwide seek to educate and support heart failure patients to engage in self-care. We aimed to describe self-care behaviors of patients from 15 countries across three continents. Data on self-care were pooled from 5964 heart failure patients from the United States, Europe, Australasia and South America. Data on self-care were collected with the Self-care of Heart Failure Index or the European Heart Failure Self-care Behavior Scale. In all the samples, most patients reported taking their medications as prescribed but exercise and weight monitoring were low. In 14 of the 22 samples, more than 50% of the patients reported low exercise levels. In 16 samples, less than half of the patients weighed themselves regularly, with large differences among the countries. Self-care with regard to receiving an annual flu shot and following a low sodium diet varied most across the countries. Self-care behaviors are sub-optimal in heart failure patients and need to be improved worldwide. Interventions that focus on specific self-care behaviors may be more effective than general educational programs. Changes in some health care systems and national policies are needed to support patients with heart failure to increase their self-care behavior.


Regulation of enterobacterial cephalosporinase production: the role of a membrane-bound sensory transducer.
In clinical isolates of Enterobacter cloacae, resistance to the newer beta-lactam antibiotics often results from overproduction of a cephalosporinase encoded by the beta-lactam-inducible ampC gene. Regulation of ampC is controlled by the divergently expressed activator gene, ampR, and a second unlinked locus. In this presentation we show that although Escherichia coli has lost its ampR gene it has retained the second regulatory locus and that this comprises the bicistronic ampDE operon. Genetic and biochemical studies define the ampD gene as encoding a repressor for ampC transcription whereas the ampE gene product is a cytoplasmic membrane protein. Inactivation of the AmpD protein by mutation causes massive overproduction of cephalosporinase which, in E. cloacae, can terminate in therapeutic failure. In contrast, loss of AmpE results in a total block in induction, despite the presence of the activator, AmpR.


Temporal and spatial patterns of Kv1.1 and Kv1.2 protein and gene expression in spinal cord white matter after acute and chronic spinal cord injury in rats: implications for axonal pathophysiology after neurotrauma.
After spinal cord injury (SCI), surviving white matter axons display axonal dysfunction associated with demyelination and altered K+ channel activity. To clarify the molecular basis of posttraumatic axonal pathophysiology after SCI, we investigated the changes in expression and distribution of the axonal K+ channel subunits Kv1.1 and Kv1.2 in spinal cord white matter after in vivo SCI in the rat. Using Western blot analysis, we found an increased expression of Kv1.1 and Kv1.2 at 2 and 6 weeks after SCI. By real-time PCR we observed an increase in Kv1.1 and Kv1.2 mRNA levels 1 day after SCI, which persisted until 6 weeks. Confocal immunohistochemistry showed a markedly dispersed labelling of Kv1.1 and Kv1.2 along the injured axons, in contrast to the tight localization of these channels to the juxtaparanodes of noninjured axons. This redistribution of Kv1.1 and Kv1.2 occurred as early as 1 h postinjury along some injured axons, and persisted at 6 weeks postinjury. In parallel with the redistribution of Kv1.1 and 1.2, contactin-associated protein (Caspr), which is normally confined to a paranodal location, also displayed a more diffuse distribution along the injured spinal cord axons. Our results suggest that the increased expression of Kv1.1 and Kv1.2 proteins is transcriptionally regulated. In contrast, the redistribution of the axonal K+ channel subunits occurs very early postinjury and probably reflects a disruption of the juxtaparanodal axonal region due to physical trauma, as shown by altered localization of Caspr.


Parallel synthesis of immunoglobulins and J chain in pokeweed mitogen-stimulated normal cells and in lymphoblastoid cell lines.
The synthesis of intracellular J chains was found to be closely associated with that of intracellular immunoglobulin, regardless of its class, during the process of B-cell differentiation. This parallelism between the synthesis of J chain and immunoglobulin was particularly evident in their coincident appearance in serial observations of pokeweed mitogen (PWM)-stimulated lymphocytes. The intensity of J-chain staining by fluorescent reagents in the stimulated cells synthesizing IgG was similar to that found in cells synthesizing IgA or IgM. Evidence was obtained that the presence of J chain in the IgG-producing cells did not reflect antecedent synthesis of IgA or IgM. T cells stimulated by phytohemagglutinin and PWM failed to show J-chain synthesis. Observations on lymphoid cell lines showed a similar parallelism between intracellular Ig and J-chain synthesis; no relation to surface Ig was found.


Measurement and significance of circulating natriuretic peptides in cardiovascular disease.
1. The major cardiovascular and renal actions of alpha-atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and the fact that the heart is strategically located to sense changes in intravascular volume indicate the importance of these peptides in the overall control of the extracellular fluid volume under normal and pathophysiological conditions.2. This review examines the clinical and diagnostic significance of the measurement of plasma natriuretic peptides in diseases of the cardiovascular system with particular emphasis on the assessment of patients with heart failure. 3. Raised plasma levels of ANP and BNP have repeatedly been found in patients with heart disease originating from diverse causes including tachycardias, valvular stenosis or ventricular dysfunction. The raised circulating levels of natriuretic peptide (ANP, N-terminal proANP and BNP in particular) are associated with (i) raised atrial and pulmonary wedge pressures; (ii) reduced ventricular systolic and diastolic function; (iii) presence (and possibly geometric form) of left ventricular hypertrophy; and (iv) severe myocardial infarction. Although both plasma ANP and BNP are raised in the presence of left ventricular hypertrophy, BNP appears to be a better index of left ventricular hypertrophy.4. Several situations where the measurement of natriuretic peptides may be of benefit in the overall assessment of heart disease are discussed. However, it is emphasized that the measurement of plasma natriuretic peptides alone appears to be of limited value as a specific diagnostic tool, given that raised levels are a consequence of haemodynamic and structural abnormalities arising from diverse pathological processes. Despite these limitations, the major value of plasma natriuretic peptides in the examination of patients with suspected heart disease rests on the premise that: (i) a normal value would not be consistent with cardiac disease; (ii) the presence of markedly raised levels may help to target those for subsequent detailed assessment of underlying cardiac dysfunction; and (iii) markedly raised levels of plasma natriuretic peptides after myocardial infarction can identify those at high risk of death.


Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics.
Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to variable metabolism of the drug through intestinal cytochrome P450 (CYP) 3A4, may contribute to poor virologic response in certain individuals with HIV infection. The purpose of this study was to characterize the influence of intestinal CYP3A4 modulation with grapefruit juice and Seville orange juice on indinavir pharmacokinetics. In an open-label, three-period crossover study, 13 healthy volunteers received indinavir 800 mg every 8 hours for 1 day and a single 800 mg dose the next morning. The last two indinavir doses were taken with 8 ounces of Seville orange juice, single-strength grapefruit juice, or water (control). Plasma samples were collected at time 0 (predose) and at 0.5, 1, 2, 3, 4, and 5 hours after the last indinavir dose. Concentration-time data were analyzed using noncompartmental methods. Coadministration of Seville orange juice and indinavir resulted in a statistically significant increase in indinavir t(max) (1.87 [1.65-2.22] vs. 1.25 [1.03-1.60] h; p < 0.05) without altering other pharmacokinetic parameter values. Grapefruit juice administration did not result in any changes in indinavir pharmacokinetics. Modulation of intestinal CYP3A4 by grapefruit juice and Seville orange juice did not alter the systemic availability of indinavir. The contribution of presystemic metabolism to indinavir interpatient variability appears to be small.


Is there a safer electrosurgical current for endoscopic sphincterotomy in patients with liver cirrhosis?
Endoscopic sphincterotomy has a higher risk of bleeding in patients with cirrhosis. Advanced Child stage and coagulopathy are well-known risk factors. We aimed to determine the role of electrosurgical currents in the development of endoscopic sphincterotomy bleeding in cirrhotic patients. The study was a retrospective observational study and included 19,642 patients who underwent endoscopic retrograde cholangiopancreatography between 2004 and 2013. The incidence of endoscopic sphincterotomy bleeding in cirrhotic patients who underwent sphincterotomy after 2009 with an electrosurgical generator applying alternating current in the pulse cut mode (Group 2) was compared with a historical control group who underwent endoscopic sphincterotomy between 2004 and 2009 via blended current (Group 1). Group 1 included 15 patients (six women, nine men, mean age: 62.2 ± 12.9 years). Group 2 included 14 patients (six women, eight men, mean age: 63.6 ± 16.9 years). There was no statistically significant difference between the demographic and clinical characteristics of the two groups. Endoscopic sphincterotomy bleeding was observed in three patients in Group 1 (two endoscopic bleeding and one clinically significant bleeding) and none of the patients in Group 2 (p = 0.77). There were no cases of perforation or pancreatitis in both groups. One patient in Group 2 developed cholangitis. Endoscopic sphincterotomy bleeding is less frequently observed in patients with cirrhosis who underwent sphincterotomy with alternating mixed current in the pulse cut mode compared with those with blended current.


Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial.
In ES-SCLC patients with residual intrathoracic disease after first-line chemotherapy, the addition of thoracic radiotherapy reduces the risk of intrathoracic recurrence, and improves 2-year survival. To identify patient subgroups for future trials investigating higher dose (extra)thoracic radiotherapy, we investigated the prognostic importance of number and sites of metastases in patients included in the CREST trial. Additional data on sites and numbers of metastases were collected from individual records of 260 patients from the top 9 recruiting centers in the randomized CREST trial (53% of 495 study patients), which compared thoracic radiotherapy (TRT) to no TRT in ES-SCLC patients after any response to chemotherapy. All patients received prophylactic cranial irradiation. The clinical characteristics and outcomes of the 260 patients analyzed here did not differ significantly from that of the other 235 patients included in the CREST trial, except that fewer patients had a WHO=0 performance status (24% vs 45%), and a higher proportion had WHO=2 (15% vs 5%; p<0.0001). No distant metastases were recorded in 5%, 39% had metastases confined to one organ, 34% to two, and 22% to three or more organ sites. Metastases were present in the liver (47%), bone (40%), lung (28%), extrathoracic (non-supraclavicular) lymph nodes (19%), supraclavicular nodes (18%), adrenals (17%) and other sites (12%). The OS (p=0.02) and PFS (p=0.04) were significantly better in patients with 2 or fewer metastases, with OS significantly worse if liver (p=0.03) and/or bone metastases (p=0.04) were present. This analysis of patients recruited from the top 9 accruing centers in the CREST trial suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases.


The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes.
Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis.


Avenues for genetic modification of radiation use efficiency in wheat.
Radiation use efficiency (RUE) of a crop is a function of several interacting physiological phenomena, each of which can be tackled independently from the point of view of genetic improvement. Although wheat breeding has not raised RUE substantially, theoretical calculations suggest room for improvement. Selection for higher rates of leaf photosynthesis at saturating light intensities (Amax) has not resulted in improved RUE of crops, perhaps in part because most leaves in a canopy are not light-saturated. However, higher Amax may be observed as a pleiotropic effect of other yield-enhancing genes (e.g. genes for reduced height). Genetic transformation of Rubisco to double its specificity for CO2 would theoretically increase Amax by perhaps 20%, and some evidence suggests that photosynthesis at sub-saturating light intensities would also be improved. However, photo-protection may be jeopardized if capacity for oxygenase activity is impaired. Photosynthetic rate of the whole eanopy can be enhanced by manipulation of leaf angle, which is under relatively simple genetic control, and possibly by manipulating leaf-N distribution throughout the canopy. Genetic diversity for adaptation of lower canopy leaves (e.g. changes in chlorophyll a:b ratio) to reduced light intensity observed in some crops needs to be investigated in wheat. Improved RUE may be achieved by increasing sink demand (i.e. kernel number) if excess photosynthetic capacity exists during grain filling, as suggested by a number of studies in which source-sink balance was manipulated. Some evidence suggests that improved sink strength may be achieved by lengthening the duration of the period for juvenile spike growth. Balancing source- and sink-strength is a complex genetic challenge since a crop will change between source and sink limitation as conditions vary during the day, and with phenological stage. Improved RUE will be partly a function of a genotype's ability to buffer itself against changes in its environment to match the demand imposed by its development. Analysis of the physiological basis of genotype by environment interactions may indicate avenues for genetic improvement. The genetic control of photosynthetic regulation may be elucidated in the future through the application of genomics. However, given a lack of specific knowledge on the genetic basis of RUE, empirical selection is currently the most powerful tool for detecting favourable genetic interactions resulting from crosses between lines with superior photosynthetic traits and other high yielding characteristics. Selection for superior segregants can be accelerated using rapidly measured physiological selection traits, such as stomatal conductance or canopy temperature depression.


Prediction of flare-ups of ulcerative colitis using quantitative immunochemical fecal occult blood test.
To examine the feasibility of predicting the flare-up of ulcerative colitis (UC) before symptoms emerge using the immunochemical fecal occult blood test (I-FOBT). We prospectively measured fecal hemoglobin concentrations in 78 UC patients using the I-FOBT every 1 or 2 mo. During a 20 mo-period, 823 fecal samples from 78 patients were submitted. The median concentration of fecal hemoglobin was 41 ng/mL (range: 0-392 500 ng/mL). There were three types of patients with regard to the correlation between I-FOBT and patient symptoms; the synchronous transition type with symptoms (44 patients), the unrelated type with symptoms (19 patients), and the flare-up predictive type (15 patients). In patients with the flare-up predictive type, the values of I-FOBT were generally low during the study period with stable symptoms. Two to four weeks before the flare-up of symptoms, the I-FOBT values were high. Thus, in these patients, I-FOBT could predict the flare-up before symptoms emerged. Flare-up could be predicted by I-FOBT in approximately 20% of UC patients. These results warrant periodical I-FOBT in UC patients.


Development of a virtual spectrometer for chiroptical spectroscopies: the case of nicotine.
The impressive advances of computational spectroscopy in most recent years are providing robust and user-friendly multifrequency virtual spectrometers, which can also be used by nonspecialists to complement experimental studies. At the heart of these developments there are latest-generation models based on Density Functional Theory for the proper treatment of stereo-electronic effects, coupled to the polarizable continuum model to deal with bulk solvent effects, and low-order perturbative treatments of anharmonic effects. Continuing our efforts to increase the range of application of virtual spectrometers, we report here about chiroptical spectroscopies with special reference to optical rotation and vibrational circular dichroism. The capabilities and possible limitations of our latest tool will be analyzed for the specific case of (S)-nicotine in vacuo and in different solvents.


Peak Timing for Complications After Adult Spinal Deformity Surgery.
Overall complication rates for adult spinal deformity (ASD) surgery have been reported; however, little data exist on the peak timing associated with specific complications. This study quantifies the peak timing for multiple complication types in an ASD cohort at minimum 2-year follow-up. Multicenter, prospective analysis of all complications after ASD surgery in a consecutively enrolled cohort was performed. Inclusion criteria were ASD, age ≥18 years, spinal fusion ≥4 levels, and minimum 2-year follow-up. Complications included major and minor and specific complication types. Peak timing of specific complications was identified and described. Regression analysis was performed to assess correlation between patient/surgical factors and complication timing. There were 280 patients who met the inclusion criteria. Mean follow-up time was 2.9 years (range, 2-5 years). Of the patients, 209 (74.6%) had at least 1 complication, accounting for 529 total complications (258 minor and 271 major). Both major and minor complications peaked at <3 months. Infection and neurologic complications peaked at <3 months. Proximal junctional kyphosis had bimodal peaks at <3 and >24 months. Implant failure peaked at 12-24 and >24 months. There was a significant positive correlation between preoperative sagittal vertical axis and total complications at 6-12 months, major complications at 24 months, and reoperation. Body mass index was associated with total complications and implant failure at 12-24 and >24 months. The peak timing of specific complications after ASD surgery is identifiable. Understanding when these complications are likely to occur may improve patient counseling, early diagnosis, and prophylactic interventions and may help inform future reimbursement models.


Biological properties of a novel coladerm-beta glucan membrane.In vitro assessment using human fibroblasts.
The purpose of this study was to prepare a coladerm-beta glucan membrane (CBGM) and to evaluate its biocompatibility, cytotoxicity, antimicrobial activity, genotoxicity and mutagenicity. The biocompatibility of the membrane was studied on the base of cell adhesion and colonization of human fibroblasts on the biomaterial surface by light microscopy. The MTT test and LDH level determination in the culture medium removed from the control and cells treated on the membrane, were used for viability and cytotoxic evaluations. Flow cytometry and gel electrophoresis were used for analysis of cell cycle and death. The antimicrobial activity of CBGM was tested using the qualitative dilution method. Ames bacteria gene mutation test and Comet assay were used for mutagenic and genotoxic studies. MTT and LDH tests confirmed that CBGM is a non-toxic biomaterial. Flow cytometry and gel electrophoresis demonstrated that the membrane did not affect the cell cycle and did not induce either necrotic or apoptotic cell death. CBGM exhibited antibacterial activity against G(-) bacteria E. sakazakii, S. marcescens, E. coli and agains G(+) sporogenic bacteria B. cereus. No antifungal activity was detected. The membrane did not induce mutagenicity in the bacterial reverse mutation test in Salmonella Typhimurium strains. Similarly, the comet assay showed that the tested fibroblast cells growing with/without the membrane did not show any statistically significant DNA damage. The CBGM has good biocompatibility, no cytotoxicity/genotoxicity/mutagenicity and it can be included as a potential scaffold for tissue engineering.


Chronic fluoride exposure-induced testicular toxicity is associated with inflammatory response in mice.
Previous studies have indicated that fluoride (F) can affect testicular toxicity in humans and rodents. However, the mechanism underlying F-induced testicular toxicity is not well understood. This study was conducted to evaluate the sperm quality, testicular histomorphology and inflammatory response in mice followed F exposure. Healthy male mice were randomly divided into four groups with sodium fluoride (NaF) at 0, 25, 50, 100 mg/L in the drinking water for 180 days. At the end of the exposure, significantly increased percentage of spermatozoa abnormality was found in mice exposed to 50 and 100 mg/L NaF. Disorganized spermatogenic cells, vacuoles in seminiferous tubules and loss and shedding of sperm cells were also observed in the NaF treated group. In addition, chronic F exposure increased testicular interleukin-17(IL-17), interleukin-17 receptor C (IL-17RC), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in transcriptional levels, as well as IL-17 and TNF-α levels in translational levels. Interestingly, we observed that F treated group elevated testicular inducible nitric oxide synthase (iNOS) mRNA level and nitric oxide (NO) concentration. Taken together, these results indicated that testicular inflammatory response could contribute to chronic F exposure induced testicular toxicity in mice.


Nuclear pores enable sustained perinuclear calcium oscillations.
Calcium signalling relies on the flux of calcium ions across membranes yet how signals in different compartments are related remains unclear. In particular, similar calcium signals on both sides of the nuclear envelope have been reported and attributed to passive diffusion through nuclear pores. However, observed differing cytosolic and nucleosolic calcium signatures suggest that the signalling machinery in these compartments can act independently. We adapt the fire-diffuse-fire model to investigate the generation of perinuclear calcium oscillations. We demonstrate that autonomous spatio-temporal calcium patterns are still possible in the presence of nuclear and cytosolic coupling via nuclear pores. The presence or absence of this autonomy is dependent upon the strength of the coupling and the maximum firing rate of an individual calcium channel. In all cases, coupling through the nuclear pores enables robust signalling with respect to changes in the diffusion constant. We show that contradictory interpretations of experimental data with respect to the autonomy of nuclear calcium oscillations can be reconciled within one model, with different observations being a consequence of varying nuclear pore permeabilities for calcium and refractory conditions of channels. Furthermore, our results provide an explanation for why calcium oscillations on both sides of the nuclear envelope may be beneficial for sustained perinuclear signaling.


Simple method of hepatic venous blood sampling in the rat.
An improved method of hepatic venous blood sampling by catheterization in rats is proposed and applied to the measurement of hepatic blood flow (HBF) by the continuous ICG infusion method in normal rats and in rats treated chronically with CC1(4). The value of HBF determined by the present method was 0.90 +/- 0.17 (SD) ml/min per g liver under ether anesthesia, which was consistent with the reported values determined by other more complicated methods. The applicability of the present method was also shown in CC1(4) chronic intoxicated rats, to give 0.64 +/- 0.11 ml/min per g liver of HBF.


Epstein-Barr virus EBNA-LP and transcription regulation properties of pRB, p107 and p53 in transfection assays.
The EBNA-LP protein (also known as EBNA-5) of Epstein-Barr virus (EBV) has been reported previously to colocalize in the nuclei of cells with the pRb protein and to bind in vitro to pRb and to the p53 protein, suggesting a role for EBNA-LP in modulation of the function of these proteins. Here we test in transfection assays whether EBNA-LP expression has any functional consequence for repression of E2F-1 activity by pRb or p107 or for activation of transcription by the p53 protein. No significant effect could be found, although the assay systems were sensitive to the established effects of simian virus 40 large T antigen and human papillo-mavirus type 16 E6 protein. There was very effective repression of GAL4/E2F-1 transactivation by p107, consistent with earlier reports and indicating that p107 can interact with the E2F-1 transactivation domain, even though p107 has been reported to bind specifically to E2F complexes containing E2F-4. The results indicate that, if the associations of EBNA-LP with pRB and p53 are physiologically relevant, they most likely affect other functions of these proteins or modulate their gene regulatory functions in ways that cannot be detected by transfection into cycling transformed cells.


Curcumin attenuates diet-induced hepatic steatosis by activating AMP-activated protein kinase.
Curcumin is a well-known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes. However, the effect of curcumin on hepatic lipid metabolism remains unclear. The aim of this study was to examine the effects of curcumin on hepatic steatosis in high-fat/cholesterol diet (HFD)-induced obese mice. Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 0.15% curcumin (HFD+C) for 11 weeks. We found that curcumin significantly lowered the body-weight and adipose tissue weight of mice in the HFD+C group compared with the findings for the HFD group (p < 0.05). The levels of total cholesterol, fasting glucose and insulin in serum were decreased, and HFD-induced impairment of insulin sensitivity was improved by curcumin supplementation (p < 0.05). Curcumin protected against the development of hepatic steatosis by reducing hepatic fat accumulation. Moreover, curcumin activated AMP-activated protein kinase (AMPK) and elevated the gene expression of peroxisome proliferator-activated receptor alpha. By contrast, curcumin suppressed the HFD-mediated increases in sterol regulatory element-binding protein-1, acetyl-CoA carboxylase 1, fatty acid synthase and cluster of differentiation 36 expression. Taken together, these findings indicate that curcumin attenuates HFD-induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic steatosis.


The use of estrogen, DHEA, and diosgenin in a sustained delivery setting as a novel treatment approach for osteoporosis in the ovariectomized adult rat model.
It is well established that the pattern of bone loss from the cortex in osteoporotic bone begins from the endosteal surface of the cortex, where there is enlargement of the medullary canal at the expense of the inner cortex. Bone loss does not occur at the periosteal surface. The objective of the following study was to induce osteoporosis in female rats by ovariectomy, followed by treatment with sustained delivery of Diosgenin (DG), dehydroepiandrosterone (DHEA), or estrogen (E) after clinical signs of osteoporosis. Female Sprague Dawley rats were divided randomly into five groups containing four rats/group. Rats comprising group 1 were left intact and served as a control group. Animals in groups 2-5 were ovariectomized (OVX) and, after a 14 day delay to allow for induction of osteoporosis, were implanted with TCPL capsules containing DG, DHEA, and E, respectively. The experiment was ceased after 33 days of treatment, at which time the vital and reproductive organs for each group were collected, weighed, and analyzed histomorphometrically for differences. Further analysis of the progression of osteoporosis in the experimental animals was obtained by performing x-ray analysis of each group on a semi-weekly basis. By collecting and analyzing the femurs from each animal, we were also able to obtain important information about the histologic changes associated with osteoporosis (left femur), as well as data regarding the effects of osteoporosis on the mechanical strength of bone via three point bending analysis (right femur). The data generated by this study revealed important information as to the efficacy and safety of the alternative treatments DHEA, E, and DG for osteoporosis. First, histomorphometric analysis revealed that treatment with DHEA, E, and DG reduced the endosteal perimeter and cortical area to values very similar to controls (intact). Second, results of the bending stress and modulus in OVX and treated animals were not statistically different from the intact control animals, which suggests that the material properties of the bone were unaltered. Third, there is an increase in total body weight associated with OVX that is reduced to control levels after replacement therapy. Finally, OVX also resulted in reproductive tissue atrophy, which was reversed by all three of the treatment regimens in this study. These data suggest that bone loss after OVX can be significantly reduced by supplementation with sustained levels of DHEA, E, and DG without jeopardizing other body organs.


External guide sequence technology: a path to development of novel antimicrobial therapeutics.
RNase P is a ribozyme originally identified for its role in maturation of tRNAs by cleavage of precursor tRNAs (pre-tRNAs) at the 5'-end termini. RNase P is a ribonucleoprotein consisting of a catalytic RNA molecule and, depending on the organism, one or more cofactor proteins. The site of cleavage of a pre-tRNA is identified by its tertiary structure; and any RNA molecule can be cleaved by RNase P as long as the RNA forms a duplex that resembles the regional structure in the pre-tRNA. When the antisense sequence that forms the duplex with the strand that is subsequently cleaved by RNase P is in a separate molecule, it is called an external guide sequence (EGS). These fundamental observations are the basis for EGS technology, which consists of inhibiting gene expression by utilizing an EGS that elicits RNase P-mediated cleavage of a target mRNA molecule. EGS technology has been used to inhibit expression of a wide variety of genes, and may help development of novel treatments of diseases, including multidrug-resistant bacterial and viral infections.


Alpha thalassaemia and the macular vasculature in homozygous sickle cell disease.
The interaction of homozygous alpha thalassaemia 2 with homozygous sickle cell (SS) disease results in a generally milder haematological picture with less intravascular sickling, less haemolysis, and higher haemoglobin levels. Clinically, patients are generally more mildly affected, though not all vaso-occlusive complications are reduced. Thus there is a possibility that the advantages gained by inhibition of sickling have been offset by the rheological disadvantages of the higher haemoglobin level. The capillary bed in the perimacular region of the posterior pole has been used to examine the degree of vaso-occlusion in age and sex matched controls with SS disease with and without homozygous alpha thalassaemia 2. The results demonstrated significantly less capillary abnormalities in the perimacular region of patients with alpha thalassaemia, though the size of the foveal avascular zone and the grading of perimacular capillary drop-out did not differ between the 2 genotypes. These results are compatible with a mild inhibitory effect of alpha thalassaemia on vaso-occlusion of the macular vasculature in SS disease.


Differential effect of lactate on synovial fibroblast and macrophage effector functions.
The synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters. Synovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using trans-well inserts. Metabolic pathways were analysed by Seahorse analyser. IL-6 secretion was determined by ELISA. Bioinformatic analysis was performed on publicly available single cell and bulk RNA sequencing datasets. We show that: i) SLC16A1 and SLC16A3 which regulate lactate intake and export respectively, are both expressed in RA synovial tissue and are upregulated upon inflammation. SLC16A3 is more highly expressed by macrophages, while SLC16A1 was expressed by both cell types. ii) This expression is maintained in distinct synovial compartments at mRNA and protein level. iii) Lactate, at the concentration found in RA joints (10 mM), has opposite effects on the effector functions of these two cell types. In fibroblasts, lactate promotes cell migration, IL-6 production and increases glycolysis. In contrast macrophages respond to increases in lactate by reducing glycolysis, migration, and IL-6 secretion. In this study, we provide the first evidence of distinct functions of fibroblasts and macrophages in presence of high lactate levels, opening new insights in understanding the pathogenesis of RA and offering novel potential therapeutic targets.


Comorbidities according to airflow limitation severity: data from comprehensive health examination in Japan.
The present study aimed to investigate the relationship between airflow limitation (AL) severity and comorbidities in comprehensive health examination. This cross-sectional study included 6661 men and 6044 women aged 40-89 who underwent a lung function test during medical checkups. AL was defined as forced expiratory volume in 1 s/forced vital capacity of < 0.7. Logistic regression analysis was used to assess the association between AL severity and the presence of comorbidities. When compared with the normal lung function group, subjects with AL had a higher prevalence of lung cancer (odd ratio (OR) 9.88, 95% confidence interval (CI) 3.88-25.14) in men, hypertension (OR 1.63, 95% CI 1.26-2.10) in women, diabetes and hyperglycemia (OR 1.23, 95% CI 1.02-1.49 in men, OR 1.61, 95% CI 1.18-2.20 in women) in men and women after adjusting for potential confounders. In men, lung cancer and MetS (the Joint Interim Statement: JIS) were significantly associated with moderate-to-very severe AL after adjustment. In women, hypertension, diabetes and hyperglycemia, MetS (JIS), and MetS (the Japanese Committee of the Criteria for MetS: JCCMS) were significantly associated with mild AL after adjustment. Hypertension was significantly associated with moderate-to-very severe AL after adjustment in women. Significant relationships were found between AL severity and the presence of comorbid lung cancer in men, hypertension in women, diabetes and hyperglycemia, and MetS in men and women. Knowledge of comorbidities associated with AL should be widely publicized to raise the awareness of chronic obstructive pulmonary disease (COPD).


Subacute measles encephalitis in the young immunocompromised host: report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature.
Two young patients with subacute measles encephalitis are described: a 20-year-old male hemophiliac infected with human immunodeficiency virus (HIV) and a 4-year-old girl with acute leukemia. Both patients were afebrile and had persistent focal seizures and slurred speech beginning 2 and 7 months, respectively, after the onset of uncomplicated acute measles. The diagnosis of subacute measles encephalitis was established by demonstration of paramyxovirus nucleocapsid on electron microscopy of brain tissue in one case and by detection of measles virus genome with the polymerase chain reaction in both. Treatment of the HIV-infected man with intravenous ribavirin was begun when the patient lost consciousness after several weeks of seizures; he died. The girl with leukemia was treated early after the onset of symptoms and recovered after a 15-week course. Review of 31 previously published cases revealed a typical clinical presentation. Cerebrospinal fluid (CSF) analysis, electroencephalography, measurement of measles antibody in serum and CSF, and computed tomography of the brain were not helpful in the diagnosis of subacute measles encephalitis. In contrast, histologic examination of brain tissue proved useful in establishing the diagnosis. On the basis of our experience and our literature review, we conclude that histologic and polymerase chain reaction studies of brain tissue are required for the early diagnosis of subacute measles encephalitis and that therapy with intravenous ribavirin is effective when administered early.


Mitigation of occult lung injury by pneumonectomy via minithoracotomy in mice.
The systemic and pulmonary inflammatory response associated with pneumonectomy performed via minithoracotomy versus that after open posterolateral thoracotomy is uncertain. Groups consisting of 7 randomly assigned mice underwent a) minithoracotomy (with 5-mm long incisions and sparing of the muscles) alone, b) posterolateral thoracotomy (with 20-mm long incisions) alone, c) pneumonectomy via minithoracotomy, or d) pneumonectomy via posterolateral thoracotomy. The animals' daily food intake, body weight changes and spontaneous activity were monitored for 10 days, and lung water accumulation and vascular hyperpermeability in the remaining right lung were measured at 24 h after surgery. Concentrations of high mobility group box 1 protein (HMGB1), a mediator of inflammation and shock, were measured in the bronchoalveolar lavage fluid. Compared with posterolateral thoracotomy, pneumonectomy via minithoracotomy was associated with significantly less weight loss (p < 0.05), despite a similar daily food intake among the groups. Spontaneous activity after pneumonectomy via minithoracotomy returned earlier than after posterolateral thoracotomy. Pulmonary vascular hyperpermeability and water retention in the residual lung were significantly less prominent after pneumonectomy performed via minithoracotomy than after pneumonectomy via posterolateral thoracotomy (both comparisons p < 0.05). HMGB1 concentrations in the bronchoalveolar lavage fluid collected from the residual lung were significantly lower (p < 0.05) after minithoracotomy than after posterolateral thoracotomy. Based on postoperative weight loss, spontaneous activity, and the degree of pulmonary capillary injury in the residual lung, pneumonectomy via minithoracotomy was less invasive than posterolateral thoracotomy. The lower increase in HMGB1 associated with minithoracotomy might result in lower pulmonary vascular hyperpermeability and reflect less surgical invasiveness.


High adjuvant activity of layered double hydroxide nanoparticles and nanosheets in anti-tumour vaccine formulations.
Effective adjuvants in anti-tumour vaccine formulations are very important in the development of new-generation vaccines. In this study, two layered double hydroxide (LDH) nanomaterial forms, i.e. nanoparticles (NPs) and nanosheets (NSs), were synthesised and examined as adjuvants to provoke the immune responses for anti-tumour purpose. Immunogen ovalbumin (OVA) delivered by both nanomaterials induced much stronger humoral and cell-medicated immune responses, together with an immune stimulant (TLR9 ligand CpG), as evidenced by higher levels of IgG1, IgG2a and interferon-γ. By comparison, LDH NSs showed higher activity to promote specific antibody responses than LDH NPs but with a similar cell-mediated immune response. The mice immunised with OVA-CpG vaccines formulated with both nanomaterials showed stronger inhibition of the inoculated tumour growth and had a longer survival. Altogether, these data indicate that LDH NPs and NSs can be used as potential nanoadjuvants for efficient protein-based anti-tumour vaccines.


Evidence for interlaminar inhibitory circuits in the striate cortex of the cat.
An interlaminar, ascending, and GABAergic projection is demonstrated in the striate cortex of the cat. We have examined a basket cell, with soma and smooth dendrites in layers V and VI, that was injected intracellularly with HRP in the kitten. Three-dimensional reconstruction of its axon revealed a horizontal plexus in layer V and upper VI, extending about 1.8 mm anteroposteriorly and 0.8 mm mediolaterally; a dense termination in the vicinity of the soma in layers V and VI; and an ascending tuft terminating in layers II and III in register above the soma and about 250 microns in diameter. Many boutons of this cell contacted neuronal somata and apical dendrites of pyramidal cells and subsequent electron microscopy showed that these boutons formed type II synaptic contacts with these structures. A random sample of postsynaptic targets (n = 199) in layers III, V, and VI showed that somata (20.1%), dendritic shafts (38.2%), and dendritic spines (41.2%) were contacted. The fine structural characteristics of postsynaptic elements indicated that the majority originated from pyramidal cells. Direct identification of postsynaptic neurons was achieved by Golgi impregnation of four large pyramidal cells in layer V, which were contacted on their somata and apical dendrites by between three and 34 boutons of the HRP-filled basket cell. Layer IV neurons were not contacted. Golgi-impregnated neurons similar to the HRP-filled basket cell were also found in the deep layers. The axonal boutons of one of them were studied; it also formed type II synapses with somata and apical dendrites of pyramidal cells. Boutons of the HRP-filled neuron were shown to be GABA-immunoreactive by the immunogold method. This is direct evidence in favour of the GABAergic nature of deep layer basket cells with ascending projections. The existence of an ascending GABAergic pathway was also demonstrated by injecting [3H]GABA into layers II and III. The labelled amino acid was transported retrogradely by a subpopulation of GABA-immunoreactive cells in layers V and VI, in addition to cells around the injection site. The axonal pattern and mode of termination of deep basket cells make them a candidate for producing or enhancing directional selectivity, a characteristic of layer V cells.(ABSTRACT TRUNCATED AT 400 WORDS)


Anterior cruciate ligament reconstruction with fresh-frozen patellar tendon allografts: sixty cases with 2 years' minimum follow-up.
A prospective study was performed on 101 patients who underwent an arthroscopic anterior cruciate ligament (ACL) reconstruction with fresh-frozen patellar tendon allograft (bone-patellar tendon-bone). We present the results of the first 60 patients with a minimum follow-up of 2 years. Thirty-four were men and 26 women with a mean age of 23. In 45 patients, a postoperative arthroscopy was performed, and tissue biopsies of the reconstructed ACL were obtained. Patients were evaluated according to the International Knee Documentation Committee evaluation form. After a mean follow-up of 47 months, the overall results were normal or nearly normal in 85%. Under postoperative arthroscopy, the macroscopic appearance of the implant was similar to that of a normal ligament. The ACL allograft was covered with a normal, well-vascularized synovium. There were no cases of infection, disease transmission or tissue rejection. We conclude that the use of fresh-frozen patellar tendon allografts is a good method of ACL reconstruction.


Immunogenicity, safety and efficacy of tetravalent rhesus-human, reassortant rotavirus vaccine in Belém, Brazil.
A tetravalent rhesus-human reassortant rotavirus (RRV-TV) vaccine (4 x 10(4) plaque-forming units/dose) was evaluated for safety, immunogenicity and efficacy in a prospective, randomized, double-blind, placebo-controlled trial involving 540 Brazilian infants. Doses of vaccine or placebo were given at ages 1, 3 and 5 months. No significant differences were noted in the occurrence of diarrhoea or vomiting in vaccine and placebo recipients following each dose. Low-grade fever occurred on days 3-5 in 2-3% of vaccinees after the first dose, but not after the second or third doses of vaccine. An IgA antibody response to rhesus rotavirus (RRV) occurred in 58% of vaccinees and 33% of placebo recipients. Neutralizing antibody responses to individual serotypes did not exceed 20% when measured by fluorescent focus reduction, but exceeded 40% when assayed by plaque reduction neutralization. There were 91 cases of rotavirus diarrhoea among the 3-dose (vaccine or placebo) recipients during two years of follow-up, 36 of them among children given the vaccine. Overall vaccine efficacy was 8% (P = 0.005) against any diarrhoea and 35% (P = 0.03) against any rotavirus diarrhoea. Protection during the first year of follow-up, when G serotype 1 rotavirus predominated, was 57% (P = 0.008), but fell to 12% in the second year. Similar results were obtained when analysis was restricted to episodes in which rotavirus was the only identified pathogen. There was a tendency for enhanced protection by vaccine against illness associated with an average of 6 or more stools per day. These results are sufficiently encouraging to warrant further studies of this vaccine in developing countries using a higher dosage in an attempt to improve its immunogenicity and efficacy.


The benefits of community-based participatory arts activities for people living with dementia: a thematic scoping review.
The drive towards living well with dementia has resulted in a growing recognition of the value of community-based participatory arts activities. This review aimed to explore their overall impact and holistic benefits for people with early to moderate stages of dementia. Using a scoping review methodology and thematic analysis, this review explored relevant literature published between 2008 and 2019. 26 published papers were identified, comprising visual arts, literary arts, comedy, music and dance. The key themes included person-centred, in-the-moment approaches; participation and communication; attention and cognition; social cohesion and relationships; and the role of space, place and objects. There is strong evidence in support of using participatory arts for dementia, regardless of art form. In-the-moment and person-centred approaches were deemed impactful. Further research is needed to explore the importance of setting, material culture and the methodological or theoretical perspectives in participatory arts and dementia research.


Perioperative anaemia management: consensus statement on the role of intravenous iron.
A multidisciplinary panel of physicians was convened by Network for Advancement of Transfusion Alternatives to review the evidence on the efficacy and safety of i.v. iron administration to increase haemoglobin levels and reduce blood transfusion in patients undergoing surgery, and to develop a consensus statement on perioperative use of i.v. iron as a transfusion alternative. After conducting a systematic literature search to identify the relevant studies, critical evaluation of the evidence was performed and recommendations formulated using the Grades of Recommendation Assessment, Development and Evaluation Working Group methodology. Two randomized controlled trials (RCTs) and six observational studies in orthopaedic and cardiac surgery were evaluated. Overall, there was little benefit found for the use of i.v. iron. At best, i.v. iron supplementation was found to reduce the proportion of patients requiring transfusions and the number of transfused units in observational studies in orthopaedic surgery but not in cardiac surgery. The two RCTs had serious limitations and the six observational limited by the selection of the control groups. Thus, the quality of the available evidence is considered moderate to very low. For patients undergoing orthopaedic surgery and expected to develop severe postoperative anaemia, the panel suggests i.v. iron administration during the perioperative period (weak recommendation based on moderate/low-quality evidence). For all other types of surgery, no evidence-based recommendation can be made. The panel recommends that large, prospective, RCTs be undertaken to evaluate the efficacy and safety of i.v. iron administration in surgical patients. The implementation of some general good practice points is suggested.


The role of tax exemption in a competitive health care market.
The Federal Trade Commission and Department of Justice 2004 report on competition in health care raises the issue of nonprofit versus for-profit form in several contexts, including their relative financial performance, pricing behavior, and role in caring for the uninsured poor. The report, however, does not discuss in detail the connection between tax exemption and the nonprofit/for-profit debate. Is tax exemption, for example, "buying" charity care for the poor, and would withdrawal of exemption negatively impact health care for the uninsured poor? Or is tax exemption justified on the grounds of other nonprofit behavior outside the financial realm and thus not considered by the report? If nonprofit status does not result in differential financial behavior (as the report concludes) and if competition will end the ability of hospitals to cross subsidize free care for the poor (as the report speculates), is there any reason to retain tax exemption for nonprofit hospitals? This article summarizes the debate on these issues and offers some alternatives to the current structure of tax exemption for nonprofit health care providers.


One Health: Children, Waterfowl, and Lead Exposure in Northwestern Nigeria.
The One Health concept focuses on the interrelationship between the health of humans, animals, and the environment. There is a delicate balance among these relationships, and when an imbalance exists, the effects can be catastrophic. Such an imbalance occurred in 2010, when elevated lead exposure in rural communities in northwestern Nigeria resulted in the deaths of an estimated 400 children younger than 5 years in a 12-month period. Before the children became ill, waterfowl began to die in great numbers, a connection that would not be realized until much later. This review covers toxicodynamics and the neurotoxic effects of lead in the developing central nervous system, the role that animals can play in recognizing lead exposure and contamination, and environmental sources of lead exposure. The experiences in Nigeria may be especially pertinent to the emerging problems associated with lead exposure and poisoning in the United States.


Robust Estimation of Transition Matrices in High Dimensional Heavy-tailed Vector Autoregressive Processes.
Gaussian vector autoregressive (VAR) processes have been extensively studied in the literature. However, Gaussian assumptions are stringent for heavy-tailed time series that frequently arises in finance and economics. In this paper, we develop a unified framework for modeling and estimating heavy-tailed VAR processes. In particular, we generalize the Gaussian VAR model by an elliptical VAR model that naturally accommodates heavy-tailed time series. Under this model, we develop a quantile-based robust estimator for the transition matrix of the VAR process. We show that the proposed estimator achieves parametric rates of convergence in high dimensions. This is the first work in analyzing heavy-tailed high dimensional VAR processes. As an application of the proposed framework, we investigate Granger causality in the elliptical VAR process, and show that the robust transition matrix estimator induces sign-consistent estimators of Granger causality. The empirical performance of the proposed methodology is demonstrated by both synthetic and real data. We show that the proposed estimator is robust to heavy tails, and exhibit superior performance in stock price prediction.


Unilateral caudal zona incerta deep brain stimulation for Parkinsonian tremor.
The subthalamic nucleus is currently the target of choice in deep brain stimulation (DBS) for Parkinson's disease (PD), while thalamic DBS is used in some cases of tremor-dominant PD. Recently, a number of studies have presented promising results from DBS in the posterior subthalamic area, including the caudal zona incerta (cZi). The aim of the current study was to evaluate cZi DBS in tremor-dominant Parkinson's disease. 14 patients with predominately unilateral tremor-dominant PD and insufficient relief from pharmacologic therapy were included and evaluated according to the motor part of the Unified Parkinson Disease Rating Scale (UPDRS). The mean age was 65 ± 6.1 years and the disease duration 7 ± 5.7 years. Thirteen patients were operated on with unilateral cZi DBS and 1 patient with a bilateral staged procedure. Five patients had non-L-dopa responsive symptoms. The patients were evaluated on/off medication before surgery and on/off medication and stimulation after a minimum of 12 months after surgery. At the follow-up after a mean of 18.1 months stimulation in the off-medication state improved the contralateral UPDRS III score by 47.7%. Contralateral tremor, rigidity, and bradykinesia were improved by 82.2%, 34.3%, and 26.7%, respectively. Stimulation alone abolished tremor at rest in 10 (66.7%) and action tremor in 8 (53.3%) of the patients. Unilateral cZi DBS seems to be safe and effective for patients with severe Parkinsonian tremor. The effects on rigidity and bradykinesia were, however, not as profound as in previous reports of DBS in this area.


Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin's lymphoma.
Radioimmunotherapy (RIT) with yttrium-90 ((90)Y)-labeled anti-CD20 antibody ((90)Y ibritumomab tiuxetan; Zevalin, IDEC Pharmaceuticals Corporation, San Diego, CA) has a high rate of tumor response in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). This study presents the safety data from 349 patients in five studies of outpatient treatment with (90)Y ibritumomab tiuxetan. Patients received rituximab 250 mg/m(2) on days 1 and 8, and either 0.4 mCi/kg (15 MBq/kg) or 0.3 mCi/kg (11 MBq/kg) of (90)Y ibritumomab tiuxetan on day 8 (maximum dose, 32 mCi). Patients were observed for up to 4 years after therapy or until progressive disease. Infusion-related toxicities were typically grade 1 or 2 and were associated with rituximab. No significant organ toxicity was noted. Toxicity was primarily hematologic, with nadir counts occurring at 7 to 9 weeks and lasting approximately 1 to 4 weeks depending on the method of calculation. After the 0.4-mCi/kg dose, grade 4 neutropenia, thrombocytopenia, and anemia occurred in 30%, 10%, and 3% of patients, respectively, and after the 0.3-mCi/kg dose, these grade 4 toxicities occurred in 35%, 14%, and 8% of patients, respectively. The risk of hematologic toxicity increased with degree of baseline bone marrow involvement with NHL. Seven percent of patients were hospitalized with infection (3% with neutropenia) and 2% had grade 3 or 4 bleeding events. Myelodysplasia or acute myelogenous leukemia was reported in five patients (1%) 8 to 34 months after treatment. Single-dose (90)Y ibritumomab tiuxetan RIT has an acceptable safety profile in relapsed NHL patients with less than 25% lymphoma marrow involvement, adequate marrow reserve, platelets greater than 100,000 cells/ micro L, and neutrophils greater than 1,500 cells/ micro L.


Acetylcholine and GABA mediate opposing actions on neuronal chloride channels in crayfish.
A central principle of neural integration is that excitatory and inhibitory neurotransmitters effect the opening of distinct classes of membrane ionic channels and that integration consists of the summation of the opposing ionic currents on the postsynaptic membrane. In tangential cells of crayfish optic lobes, a hyperpolarizing, biphasic synaptic potential is produced by the concurrent action of acetylcholine and gamma aminobutyric acid (GABA). Acetylcholine hyperpolarizes the cell and increases chlorine conductance. GABA depolarizes the cell by closing some of the same chloride channels. Therefore, in this case integration is achieved by the antagonistic actions of two transmitters on the same ionic channel.


Nephrogenic Systemic Fibrosis Manifesting a Decade After Exposure to Gadolinium.
Nephrogenic systemic fibrosis (NSF) is a fibrosing skin disorder that develops in patients with kidney failure and has been linked to exposure to gadolinium-containing contrast agents. The time between exposure to gadolinium and the initial presentation of NSF is typically weeks to months but has been documented to be as long as 3½ years. We report a case of NSF developing 10 years after exposure to gadolinium. A long-term hemodialysis patient was exposed to gadolinium several times between 1998 and 2004 during magnetic resonance angiography of his abdominal vessels and arteriovenous fistula. In 2014, he was seen at our clinic with new dermal papules and plaques. Biopsy of affected skin showed thickening of collagen, CD34+ spindle cells, and increased mucin in the dermis, supporting the diagnosis of NSF. The clinical history and histopathological features of this case support the diagnosis of NSF 10 years after exposure to gadolinium. Although the use of gadolinium contrast agents in patients with kidney failure has markedly decreased, patients with exposure to gadolinium years to decades previously may manifest the disease.


Fiber optic distributed temperature and strain sensing system based on Brillouin light scattering.
We present an original method to improve the spatial resolution of a Brillouin distributed temperature and strain sensing system (DTSS). This method is shown to substantially improve the spatial resolution, while simultaneously strengthening the Brillouin backscattered light, which is based on the combination of an internal modulation of the laser source and an external modulator to generate two separate light pulses with different central wavelengths and pulse widths. Moreover, a novel Brillouin signal detection method, which we called isogenous heterodyne detection, is introduced, which is equivalent to a heterodyne detection scheme but is only with Rayleigh and Brillouin backscattered light without the need of an extra reference light. These new technical approaches have been incorporated into a fiber optic DTSS with 13 km single-mode fiber, which clearly successfully demonstrated all the advantages over conventional DTSS approaches in theory and the feasibility in experiment.


The role of habitat disturbance and recovery in metapopulation persistence.
Classical metapopulation theory assumes a static landscape. However, empirical evidence indicates many metapopulations are driven by habitat succession and disturbance. We develop a stochastic metapopulation model, incorporating habitat disturbance and recovery, coupled with patch colonization and extinction, to investigate the effect of habitat dynamics on persistence. We discover that habitat dynamics play a fundamental role in metapopulation dynamics. The mean number of suitable habitat patches is not adequate for characterizing the dynamics of the metapopulation. For a fixed mean number of suitable patches, we discover that the details of how disturbance affects patches and how patches recover influences metapopulation dynamics in a fundamental way. Moreover, metapopulation persistence is dependent not only on the average lifetime of a patch, but also on the variance in patch lifetime and the synchrony in patch dynamics that results from disturbance. Finally, there is an interaction between the habitat and metapopulation dynamics, for instance declining metapopulations react differently to habitat dynamics than expanding metapopulations. We close, emphasizing the importance of using performance measures appropriate to stochastic systems when evaluating their behavior, such as the probability distribution of the state of the metapopulation, conditional on it being extant (i.e., the quasistationary distribution).


Neighborhood income and health outcomes in infants: how do those with complex chronic conditions fare?
To quantify the effect of socioeconomic status (SES) on health outcomes during the first year after newborn discharge among infants with complex chronic conditions (CCCs) insured through a universal health plan. Longitudinal, population-based cohort study. Ontario, Canada. Infants born in hospitals from April 1, 1996, through March 31, 2000. Infants with CCCs were identified from their newborn discharge records. Neighborhood income quintiles were obtained by linking participants' postal codes to census data. Mortality and hospital admissions in the first year after newborn discharge. Logistic and Poisson regression analyses were used to examine the relationship between neighborhood income quintiles and outcomes, adjusting for important covariates such as low birth weight and rural residence. A total of 512 768 infants were included, of whom 2.3% had CCCs at newborn discharge. Infants with CCCs accounted for 37.8% of deaths and 11.0% of hospitalizations during the first year after the newborn discharge. Infants with CCCs living in the lowest-income neighborhoods had a 1.26-fold higher mortality risk (95% confidence interval, 0.83-1.90; P = .28) and a 1.24-fold higher hospitalization rate (1.09-1.40; P < .001) compared with those living in the highest-income neighborhoods. Although the income gradients associated with mortality and hospitalization were less pronounced among infants with CCCs compared with infants without CCCs, the absolute interquintile risk differences attributable to SES were higher among infants with CCCs. Despite universal health insurance, SES-related inequality affects hospitalization and, possibly, mortality rates among medically vulnerable infants.


Describing the clinical reasoning process: application of a model of enablement to a pediatric case.
Clinical reasoning is a core tenet of physical therapy practice leading to optimal patient care. The purpose of this case was to describe the outcomes, subjective experience, and reflective clinical reasoning process for a child with cerebral palsy using the International Classification of Functioning, Disability, and Health (ICF) model. Application of the ICF framework to a 9-year-old boy with spastic triplegic cerebral palsy was utilized to capture the interwoven factors present in this case. Interventions in the pool occurred twice weekly for 1 h over a 10-week period. Immediately post and 4 months post-intervention, the child made functional and meaningful gains. The family unit also developed an enjoyment of exercising together. Each individual family member described psychological, emotional, or physical health improvements. Reflection using the ICF model as a framework to discuss clinical reasoning can highlight important factors contributing to effective patient management.


Electrochemical CO2 Reduction over Compressively Strained CuAg Surface Alloys with Enhanced Multi-Carbon Oxygenate Selectivity.
The electrochemical reduction of carbon dioxide using renewably generated electricity offers a potential means for producing fuels and chemicals in a sustainable manner. To date, copper has been found to be the most effective catalyst for electrochemically reducing carbon dioxide to products such as methane, ethene, and ethanol. Unfortunately, the current efficiency of the process is limited by competition with the relatively facile hydrogen evolution reaction. Since multi-carbon products are more valuable precursors to chemicals and fuels than methane, there is considerable interest in modifying copper to enhance the multi-carbon product selectivity. Here, we report our investigations of electrochemical carbon dioxide reduction over CuAg bimetallic electrodes and surface alloys, which we find to be more selective for the formation of multi-carbon products than pure copper. This selectivity enhancement is a result of the selective suppression of hydrogen evolution, which occurs due to compressive strain induced by the formation of a CuAg surface alloy. Furthermore, we report that these bimetallic electrocatalysts exhibit an unusually high selectivity for the formation of multi-carbon carbonyl-containing products, which we hypothesize to be the consequence of a reduced coverage of adsorbed hydrogen and the reduced oxophilicity of the compressively strained copper. Thus, we show that promoting copper surface with small amounts of Ag is a promising means for improving the multi-carbon oxygenated product selectivity of copper during electrochemical CO2 reduction.


Predictors of Postpartum Exercise According to Prepregnancy Body Mass Index and Gestational Weight Gain.
The study purposes were to examine (1) differences in postpartum exercise (EX) and related personal/psychological correlates in women according to prepregnancy weight and pregnancy gestational weight gain (GWG) status and (2) predictors of EX at 2 weeks, 2 months, and 6 months postpartum. Participants (N = 891) were recruited at maternity hospitalization and completed interviews to assess EX (Leisure-Time Exercise Questionnaire) and personal correlates (demographics, anxiety/depressive symptoms) before/during pregnancy. Telephone interviews were conducted to assess postpartum EX/psychological correlates. Women were categorized according to prepregnancy weight (normal and overweight) and pregnancy GWG status (above or within weight gain guidelines): normal-above, normal-within, overweight-above, and overweight-within. Low levels of EX minutes were observed in all women with significant differences for strenuous EX minutes (overweight-within women had the lowest strenuous EX; normal-weight women had more strenuous EX than overweight women regardless of GWG). Correlates explained 14%-37% of the variance in postpartum EX; prepregnancy EX and pregnancy EX were strong determinants of early postpartum EX, and early postpartum EX predicted 6-month postpartum EX. Unique predictors of EX also emerged (eg, depressive symptoms for women with GWG above guidelines). These study findings highlight the benefits of EX before/during pregnancy for promoting postpartum EX and suggest tailoring postpartum EX interventions based on personal/psychological correlates to maximize effectiveness.