The effectiveness of complementary manual therapies for pregnancy-related back and pelvic pain: A systematic review with meta-analysis.
Low back pain and pelvic girth pain are common in pregnancy and women commonly utilize complementary manual therapies such as massage, spinal manipulation, chiropractic, and osteopathy to manage their symptoms. The aim of this systematically review was to critically appraise and synthesize the best available evidence regarding the effectiveness of manual therapies for managing pregnancy-related low back and pelvic pain. Seven databases were searched from their inception until April 2015 for randomized controlled trials. Studies investigating the effectiveness of massage and chiropractic and osteopathic therapies were included. The study population was pregnant women of any age and at any time during the antenatal period. Study selection, data extraction, and assessment of risk of bias were conducted by 2 reviewers independently, using the Cochrane tool. Separate meta-analyses were conducted to compare manual therapies to different control interventions. Out of 348 nonduplicate records, 11 articles reporting on 10 studies on a total of 1198 pregnant women were included in this meta-analysis. The therapeutic interventions predominantly involved massage and osteopathic manipulative therapy. Meta-analyses found positive effects for manual therapy on pain intensity when compared to usual care and relaxation but not when compared to sham interventions. Acceptability did not differ between manual therapy and usual care or sham interventions. There is currently limited evidence to support the use of complementary manual therapies as an option for managing low back and pelvic pain during pregnancy. Considering the lack of effect compared to sham interventions, further high-quality research is needed to determine causal effects, the influence of the therapist on the perceived effectiveness of treatments, and adequate dose-response of complementary manual therapies on low back and pelvic pain outcomes during pregnancy.


Morphological and Functional Modifications of Optical Thin Films for Space Applications Irradiated with Low-Energy Helium Ions.
Future space missions will operate in increasingly hostile environments, such as those in low-perihelion solar orbits and Jovian magnetosphere. This exploration involves the selection of optical materials and components resistant to the environmental agents. The conditions in space are reproduced on ground through the use of ion accelerators. The effects of He particles coming from the solar wind impinging on a gold thin film have been systematically investigated, considering absorbed doses compatible with the duration of the European Space Agency Solar Orbiter mission. Structural and morphological changes have been proved to be dependent not only on the dose but also on the irradiation flux. A predictive model of the variation of thin film reflectance has been developed for the case of lower flux irradiation. The results are discussed regarding reliability and limitations of laboratory testing. The outcomes are important to address the procedures for the space qualification tests of optical coatings.


Induction of IL-22-Producing CD4+ T Cells by Segmented Filamentous Bacteria Independent of Classical Th17 Cells.
The intestinal microbiota modulates IL-22 production in the intestine, including the induction of IL-22-producing CD4+ T helper cells. Which specific bacteria are responsible for the induction of these cells is less well understood. Here, we demonstrate through the use of novel gnotobiotic knock-in reporter mice that segmented filamentous bacteria (SFB), which are known for their ability to induce Th17 cells, also induce distinct IL-17A negative CD4+ T cell populations in the intestine. A subset of these cells instead produces IL-22 upon restimulation ex vivo and also during enteric infections. Furthermore, they produce a distinct set of cytokines compared to Th17 cells including the differential expression of IL-17F and IFN-γ. Importantly, genetic models demonstrate that these cells, presumably Th22 cells, develop independently of intestinal Th17 cells. Together, our data identifies that besides Th17, SFB also induces CD4+ T cell populations, which serve as immediate source of IL-22 during intestinal inflammation.


Life expectancy of rigid gas permeable and high water content contact lenses.
The purpose of this study was to evaluate the life expectancy of various rigid gas permeable (RGP) lens materials used on a daily wear basis and to compare these results with the life expectancy of a matched group of soft lens wearers. We retrospectively analyzed the records of 600 contact lens wearing patients (300 soft contact lens users and 300 RGP lens users fit between September 1987 and September 1994. None of the subjects wore lenses on a planned replacement system. For the purpose of the study, RGP lenses were divided into three groups: < or = 40 Dk were considered low-Dk; 41-89 Dk were considered mid-Dk; and > or = 90 Dk were considered high-Dk. All soft lenses were high water content lenses (> or = 60% water content). Lenses were included if they were replaced due to loss, breakage, deposition, or poor wettability but not if replaced because of changes in fit or prescription. The mean (+/- SD) life-spans of each lens type in months were 19.9 +/- 17 for low-Dk RGP lenses, 15.9 +/- 13.3 for mid-Dk RGP lenses, 9.0 +/- 8.2 for high-Dk RGP lenses, and 6.4 +/- 5.2 for high water content soft lenses. Statistical analysis using a one-way ANOVA on ranks indicated that these results were statistically significant (P < 0.0001). Patients should be informed that high-Dk lenses (RGP and soft) provide substantial clinical benefits and that they should except to replace high-Dk RGP lenses after approximately 6 months. This lends further credence to the use of high-Dk lenses on a planned replacement basis.


Obsidian hydration dates glacial loading?
Three different groups of hydration rinds have been measured on thin sections of obsidian from Obsidian Cliff, Yellowstone National Park, Wyoming. The average thickness of the thickest (oldest) group of hydration rinds is 16.3 micrometers and can be related to the original emplacement of the flow 176,000 years ago (potassium-argon age). In addition to these original surfaces, most thin sections show cracks and surfaces which have average hydration rind thicknesses of 14.5 and 7.9 micrometers. These later two hydration rinds compare closely in thickness with those on obsidian pebbles in the Bull Lake and Pinedale terminal moraines in the West Yellowstone Basin, which are 14 to 15 and 7 to 8 micrometers thick, respectively. The later cracks are thought to have been formed by glacial loading during the Bull Lake and Pinedale glaciations, when an estimated 800 meters of ice covered the Obsidian Cliff flow.


Recent advances in the surgical treatment of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The treatment of HCC is complex and complicated by the severity of associated chronic liver disease, the stage of HCC, and the clinical condition of the patient. Liver resection (LR) is one of the most efficient treatments for patients with HCC, with an expected 5-year survival of 38%-61% depending on the stage of the disease. Improved liver function assessment, increased understanding of segmental liver anatomy from advanced imaging studies, and surgical technical progress are important factors that have led to reduced mortality in patients with HCC. The indication for LR may be expanded due to emerging evidences from laparoscopic hepatectomies and combined treatments with newly developed chemotherapies. Liver transplantation (LT) is considered as an ideal treatment for removal of existing tumors and the injured/preneoplastic underlying liver tissue with impaired liver function and the risk of multicentric carcinogenesis that results from chronically injured liver. However, LT is restricted to patients with minimal risk of tumor recurrence under immunosuppression. The expansion of criteria for LT in HCC patients is still under trial and discussion. Limited availability of grafts, as well as the risk and the cost of transplantation have led to considerable interest in expansion of the donor pool, living donor-related transplantation, and combined treatment involving LR and LT. This highlight presents evidence concerning recent studies evaluating LR and LT in HCC patients. In addition, alternative therapies for the treatment of early stage tumors and the management of patients on transplant waiting lists are discussed.


Is the performance of cancer services influenced more by hospital factors or by specialization?
The Cancer Plan for England, introduced in 2000, has promoted cancer service specialization. We have investigated how far specialization and general hospital factors each contributed to service performance for four common cancers-breast, colorectal, lung and prostate-at the time of the Cancer Plan. Performance measures of service standards, waiting time to treatment, satisfaction with care, in-hospital mortality and population-level survival were identified from secondary data sets for 167 acute hospitals and 34 cancer networks in England. We correlated rankings of networks and hospitals between the data sets using non-parametric statistics. At cancer network level, peer-review service standards were associated (P < 0.05) with 1-year survival for colorectal and lung cancers, and waiting times for lung cancer. At hospital level, standards were associated (P < 0.01) with waiting time to treatment for breast and colorectal cancers. However, there were stronger associations between specializations within hospitals: rankings of breast, colorectal and prostate cancers were highly associated (P < 0.001) for 5-year survival, patient satisfaction, standards and in-hospital mortality. Hospital-level differences appear to contribute more to variations in cancer performance than specialization differences within hospitals. The findings may be used for planning and commissioning better cancer services.


Stereopsis and color vision impairment in patients with right extrastriate cerebral lesions.
The extrastriate cortex is a visual processing structure beyond the striate cortex. This region contains cells that differ in selectivity for different features of stimuli such as color, motion and stereopsis. We studied stereopsis and color vision in patients with right extrastriate cerebral lesions. Patients with right extrastriate cerebral lesions determined by MRI were recruited among consecutive inpatients. Patients with cognitive impairment (Mini Mental Status Examination score <24) were excluded. An ophthalmologist performed cortical visual testing: visual acuity, stereopsis, color vision and strabismus within 1 week after the insult. Cortical visual testing was performed in 12 patients. Among the patients studied, 11 demonstrated abnormalities: reduced stereoacuity (8/12), color vision abnormalities (7/12). Seven patients showed complex cortical visual abnormalities. However, only 2 patients complained of subjective clinical symptoms. The MRI lesions in patients with disturbance of stereopsis were located in the dorsal occipitoparietal area and the ventral occipitotemporal area. Color vision abnormalities corresponded to lesions in the ventral occipitotemporal area. Patients with lesions in the right extrastriate cortex tend to have disturbance of stereopsis and color vision abnormalities, even in the absence of visual complaints.


MGcV: the microbial genomic context viewer for comparative genome analysis.
Conserved gene context is used in many types of comparative genome analyses. It is used to provide leads on gene function, to guide the discovery of regulatory sequences, but also to aid in the reconstruction of metabolic networks. We present the Microbial Genomic context Viewer (MGcV), an interactive, web-based application tailored to strengthen the practice of manual comparative genome context analysis for bacteria. MGcV is a versatile, easy-to-use tool that renders a visualization of the genomic context of any set of selected genes, genes within a phylogenetic tree, genomic segments, or regulatory elements. It is tailored to facilitate laborious tasks such as the interactive annotation of gene function, the discovery of regulatory elements, or the sequence-based reconstruction of gene regulatory networks. We illustrate that MGcV can be used in gene function annotation by visually integrating information on prokaryotic genes, like their annotation as available from NCBI with other annotation data such as Pfam domains, sub-cellular location predictions and gene-sequence characteristics such as GC content. We also illustrate the usefulness of the interactive features that allow the graphical selection of genes to facilitate data gathering (e.g. upstream regions, ID's or annotation), in the analysis and reconstruction of transcription regulation. Moreover, putative regulatory elements and their corresponding scores or data from RNA-seq and microarray experiments can be uploaded, visualized and interpreted in (ranked-) comparative context maps. The ranked maps allow the interpretation of predicted regulatory elements and experimental data in light of each other. MGcV advances the manual comparative analysis of genes and regulatory elements by providing fast and flexible integration of gene related data combined with straightforward data retrieval. MGcV is available at http://mgcv.cmbi.ru.nl.


An inhibitor of angiotensin converting enzyme (enalapril) augments endotoxin-induced hypotension in the pig.
Septic shock causes an extensive inflammatory reaction including increased capillary leakage and a decrease in systemic blood pressure. Human septic shock can be replicated in the endotoxaemic pig. Angiotensin converting enzyme (ACE) is involved in the degradation of bradykinin, an inflammatory mediator, and in the regulation of blood pressure. Inhibition of ACE is a common approach to reduce hypertension as well as left ventricular insufficiency. Fifteen anaesthetised pigs received a continuous 3 h endotoxin infusion. The animals were randomly given an inhibitor of ACE (enalpril) [at a dose (0.5 mg x kg-1) that did not per se reduce mean arterial blood pressure (MAP); (n = 7)], or the corresponding volume of saline (n = 8). Another seven pigs were randomised for treatment with enalapril (0.5 mg x kg-1) + saline (n = 3). Four pigs were randomised to serve as untreated controls (saline + saline). Basic physiologic variables were registered. Endotoxaemia progressively reduced MAP. This decrease was significantly augmented by enalapril. Hypovolemia caused by increased permeability or salt/water excretion did not seem to explain this effect as neither blood haemoglobin nor plasma sodium differed between the two groups of endotoxaemic pigs. Inhibitors of ACE are known to potentiate the cardio-depressant effect of bradykinin. This may explain the reduction in MAP by enalapril during porcine endotoxaemia.


Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei.
Leptin has profound effects on feeding, metabolism, and neuroendocrine status. Evidence indicates that the hypothalamus coordinates these responses, though the specific brain pathways engaged by leptin remain obscure. The paraventricular nucleus of the hypothalamus (PVH) regulates pituitary gland function and feeding, and innervates autonomic preganglionic neurons, making it a candidate to regulate many of the responses to leptin. The subparaventricular zone, an anterior hypothalamic region receiving dense innervation from the suprachiasmatic nucleus, is thought to integrate circadian and metabolic information. We investigated the distribution of neurons in the rat brain activated by leptin administration that also project to the PVH or the subparaventricular zone by coupling immunohistochemistry for Fos with retrograde transport of cholera toxin-b. Intravenous leptin characteristically activated several cell groups including the ventromedial hypothalamic nucleus, the dorsomedial hypothalamic nucleus (DMH), and the PVH. When tracer injections were centered in the subparaventricular zone, many double-labeled cells were observed in the dorsomedial subdivision of the ventromedial hypothalamic nucleus. This projection may provide an anatomic substrate for integration of metabolic and circadian information to regulate the hypothalamo-pituitary axis. When cholera toxin-b injections were centered in the PVH, many double-labeled cells were found within the caudal DMH. Hence, activation of specific neuroendocrine and autonomic elements of the PVH may be triggered by leptin-activated afferents arising in the DMH. Our results demonstrate that a discrete set of hypothalamic pathways may underlie leptin's autonomic, endocrine, and behavioral effects.


A tissue-specific protein in rat osteogenic tissues.
A tissue-specific protein fraction has been detected in rat osteogenic tissue. Dissociative extraction of adult rat bone matrix with 4 M guanidinium chloride solution was followed sequentially by gel chromatography and polyacrylamide gel electrophoresis. By the latter procedure a prominent protein component of molecular weight 19,000 was isolated from the low molecular weight fraction, and antibodies directed against this protein were raised in rabbits. The antibodies were mainly against antigenic sites on this protein, as shown by protein blotting techniques. By embedding rat tissues in hydrophilic plastic and by using immunohistochemical procedures the presence of this protein was demonstrated specifically in bone matrix in vivo, in osteogenic tissue developing in diffusion chamber culture, and in a malignant osteoblast cell line (UMR 106). Soft tissues (liver, kidney, spleen, gut, skin, thymus, eye) showed no reactivity with the antiserum and in vitro a further malignant osteoblast cell line (ROS 17/2.8) did not synthesize the 19,000 molecular weight protein. This protein appears to be expressed solely by osteogenic tissue and may be used as a biochemical criterion of osteogenic differentiation.


Single metal nanoparticle spectroscopy: optical characterization of individual nanosystems for biomedical applications.
The last decade has witnessed the development of a variety of single nanoparticle spectroscopy methods. This has facilitated unprecedented growth of knowledge and understanding of fascinating optical properties of individual metal nanoparticles. This has opened up exciting possibilities of single nanoparticles for applications in many areas including advanced photonics, biomedical imaging and sensing. The field of single nanoparticles detection and characterization is still growing. This paper reviews recent advances in single nanoparticles spectroscopy using both near-field and far-field optics. It covers spectroscopy methods for extremely small (approximately 1 nm) to relatively large nanoparticles (approximately 200 nm) and their optical properties. Different optical techniques are described. Finally, a perspective on possible practical applications of single nanoparticle spectroscopy focusing on biomedical fields is given.


Consent: an event or a memory in lumbar spinal surgery? A multi-centre, multi-specialty prospective study of documentation and patient recall of consent content.
Prospective, multi-centre, multi-specialty medical notes review and patient interview. The consenting process is an important communication tool which also carries medico-legal implications. While written consent is a pre-requisite before spinal surgery in the UK, the standard and effectiveness of the process have not been assessed previously. This study assesses standard of written consent for elective lumbar decompressive surgery for degenerative disc disease across different regions and specialties in the UK; level of patient recall of the consent content; and identifies factors which affect patient recall. Consent forms of 153 in-patients from 4 centres a, b, c, d were reviewed. Written documentation of intended benefits, alternative treatments and operative risks was assessed. Of them, 108 patients were interviewed within 24 h before or after surgeries to assess recall. The written documentation rates of the operative risks showed significant inter-centre variations in haemorrhage and sphincter disturbance (P = 0.000), but not for others. Analysis of pooled data showed variations in written documentation of risks (P < 0.0005), highest in infection (96.1%) and lowest in recurrence (52.3%). For patient recall of these risks, there was no inter-centre variation. Patients' recall of paralysis as a risk was highest (50.9%) and that of recurrence was lowest (6.5%). Patients <65 years old recalled risks better than those ≥65, significantly so for infection (29.9 vs 9.7%, P = 0.027). Patients consented >14 days compared to <2 days before their surgeries had higher recall for paralysis (65.2 vs 43.7%) and recurrence (17.4 vs 2.8%). Patient recall was independent of consenter grade. Overall, the standard of written consent for elective lumbar spinal decompressive surgery was sub-optimal, which was partly reflected in the poor patient recall. While consenter seniority did not affect patient recall, younger age and longer consent-to-surgery time improved it.


Obesity increases histone H3 lysine 9 and 18 acetylation at Tnfa and Ccl2 genes in mouse liver.
Obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD), which is characterized by the upregulated expression of two key inflammatory mediators: tumor necrosis factor (Tnfa) and monocyte chemotactic protein 1 (Mcp1; also known as Ccl2). However, the chromatin make-up at these genes in the liver in obese individuals has not been explored. In this study, to identify obesity-mediated epigenetic changes at Tnfa and Ccl2, we used a murine model of obesity induced by a high-fat diet (HFD) and hyperphagic (ob/ob) mice. Chromatin immunoprecipitation (ChIP) assay was used to determine the abundance of permissive histone marks, namely histone H3 lysine 9 and 18 acetylation (H3K9/K18Ac), H3 lysine 4 trimethylation (H3K4me3) and H3 lysine 36 trimethylation (H3K36me3), in conjunction with polymerase 2 RNA (Pol2) and nuclear factor (Nf)-κB recruitment in the liver. Additionally, to correlate the liver tissue-derived ChIP measurements with a robust in vitro transcriptional response at the Tnfa and Ccl2 genes, we used lipopolysaccharide (LPS) treatment to induce an inflammatory response in Hepa1-6 cells, a cell line derived from murine hepatocytes. ChIP revealed increased H3K9/K18Ac at Tnfa and Ccl2 in the obese mice, although the differences were only statistically significant for Tnfa (p<0.05). Unexpectedly, the levels of H3K4me3 and H3K36me3 marks, as well as Pol2 and Nf-κB recruitment, did not correspond with the increased expression of these two genes in the obese mice. By contrast, the acute treatment of Hepa1-6 cells with LPS significantly increased the H3K9/K18Ac marks, as well as Pol2 and Nf-κB recruitment at both genes, while the levels of H3K4me3 and H3K36me3 marks remained unaltered. These results demonstrate that increased Tnfa and Ccl2 expression in fatty liver at the chromatin level corresponds to changes in the level of histone H3 acetylation.


Two types of phosphofructokinase-1 differentially regulate the glycolytic pathway in insulin-stimulated chicken skeletal muscle.
To elucidate the precise regulation of glucose homeostasis in chicken skeletal muscle, expression of muscle- and liver-type phosphofructokinase-1 (EC:220.127.116.11, PFK-M, PFK-L) was characterized in the insulin-stimulated state by Real-Time PCR. Firstly, chicken PFK-M and PFK-L full-length cDNA sequences were identified. The deduced amino acid sequences were 81.6% and 86.5% identical with human PFK-M and PFK-L, respectively. In pectoralis superficialis (PS) muscle and extensor digitorum longus (EDL), PFK-M mRNA levels were unchanged following insulin stimulation. Surprisingly, although mammalian PFK-L has been reported to be expressed in liver, kidney and brain, chicken PFK-L was not detected in liver and kidney, however, strong expression was detected in skeletal muscle and brain by Northern blot analysis. However, using PCR, PFK-L mRNA was detected in liver. Taken together, chicken PFK-L mRNA expression was at a very low level, below the detection limit of Northern blot analysis. Chicken PFK-L mRNA levels were increased 200% in PS muscle but decreased by 40% in EDL following insulin stimulation. These results suggest that two types of PFK regulate the glycolytic pathway in the insulin-stimulated state and, therefore, that glucose metabolism in chicken skeletal muscle may be regulated in a very different manner compared to mammals.


Temporal transcriptional profiling of somatic and germ cells reveals biased lineage priming of sexual fate in the fetal mouse gonad.
The divergence of distinct cell populations from multipotent progenitors is poorly understood, particularly in vivo. The gonad is an ideal place to study this process, because it originates as a bipotential primordium where multiple distinct lineages acquire sex-specific fates as the organ differentiates as a testis or an ovary. To gain a more detailed understanding of the process of gonadal differentiation at the level of the individual cell populations, we conducted microarrays on sorted cells from XX and XY mouse gonads at three time points spanning the period when the gonadal cells transition from sexually undifferentiated progenitors to their respective sex-specific fates. We analyzed supporting cells, interstitial/stromal cells, germ cells, and endothelial cells. This work identified genes specifically depleted and enriched in each lineage as it underwent sex-specific differentiation. We determined that the sexually undifferentiated germ cell and supporting cell progenitors showed lineage priming. We found that germ cell progenitors were primed with a bias toward the male fate. In contrast, supporting cells were primed with a female bias, indicative of the robust repression program involved in the commitment to XY supporting cell fate. This study provides a molecular explanation reconciling the female default and balanced models of sex determination and represents a rich resource for the field. More importantly, it yields new insights into the mechanisms by which different cell types in a single organ adopt their respective fates.


Molecular characterization of the CRa gene conferring clubroot resistance in Brassica rapa.
Clubroot disease is one of the major diseases affecting Brassicaceae crops, and a number of these crops grown commercially, such as Chinese cabbage (Brassica rapa L. ssp. pekinensis), are known to be highly susceptible to clubroot disease. To provide protection from this disease, plant breeders have introduced genes for resistance to clubroot from the European turnip into susceptible lines. The CRa gene confers specific resistance to the clubroot pathogen Plasmodiophora brassicae isolate M85. Fine mapping of the CRa locus using synteny to the Arabidopsis thaliana genome and partial genome sequences of B. rapa revealed a candidate gene encoding a TIR-NBS-LRR protein. Several structural differences in this candidate gene were found between susceptible and resistant lines, and CRa expression was observed only in the resistant line. Four mutant lines lacking clubroot resistance were obtained by the UV irradiation of pollen from a resistant line, and all of these mutant lines carried independent mutations in the candidate TIR-NBS-LRR gene. This genetic and molecular evidence strongly suggests that the identified gene is CRa. This is the first report on the molecular characterization of a clubroot Resistance gene in Brassicaceae and of the disease resistance gene in B. rapa.


The impact of religious fasting on human health.
The past two decades have seen a rise in the number of investigations examining the health-related effects of religiously motivated fasts. Islamic Ramadan is a 28 - 30 day fast in which food and drink are prohibited during the daylight hours. The majority of health-specific findings related to Ramadan fasting are mixed. The likely causes for these heterogeneous findings are the differences between studies in the following: 1) the amount of daily fasting time; 2) the percentage of subjects who smoke, take oral medications, and/or receive intravenous fluids; and 3) the subjects' typical food choices and eating habits. Greek Orthodox Christians fast for a total of 180 - 200 days each year, and their main fasting periods are the Nativity Fast (40 days prior to Christmas), Lent (48 days prior to Easter), and the Assumption (15 days in August). The fasting periods are more similar than dissimilar, and they can each be described as a variant of vegetarianism. Some of the more favorable effects of these fasts include the lowering of body mass, total cholesterol, LDL-C, and the LDL-C/HDL-C ratio. The Biblical-based Daniel Fast prohibits the consumption of animal products, refined carbohydrates, food additives, preservatives, sweeteners, flavorings, caffeine, and alcohol. It is most commonly partaken for 21 days, although fasts of 10 and 40 days have been observed. Our initial investigation of the Daniel Fast noted favorable effects on several health-related outcomes, including: blood pressure, blood lipids, insulin sensitivity, and biomarkers of oxidative stress. This review summarizes the health-specific effects of these fasts and provides suggestions for future research.


Immunocytochemical labelling of aerobic and hypoxic mammalian cells using a platinated derivative of EF5.
The monoclonal antibody ELK3-51 was previously developed to detect adducts of the 2-nitroimidazole EF5. Direct immunofluorescence was used to detect adducts of EF5 or of a platinated derivative cis-[PtCl2(NH3)EF5] in SCCVII cells treated under aerobic or hypoxic conditions. Fluorescence measurements of these cells using both image and flow cytometric methods were compared, giving similar profiles. Platination significantly decreased immunofluorescence levels (approximately 4-fold less than EF5) after 3 h in hypoxia, but also increased levels after exposure in air (approximately 1.5 x) such that the hypoxic ratio decreased from approximately 50 to approximately 13. Platinated EF5 also showed significantly greater cytotoxicity than its parent in both aerobic and hypoxic cells. These results are consistent with targeting of EF5 to DNA, which was confirmed qualitatively by confocal microscopy.


Duration of abstinence from cannabis is positively associated with verbal learning performance: A systematic review and meta-analysis.
Although there is a consensus that cannabis intoxication will have deleterious effects on a wide spectrum of cognitive skills, there is no consensus regarding the duration of time from last use necessary to ameliorate these effects. A systematic review and series of meta-analyses were undertaken to assess anticipated gains in verbal learning with longer periods of cannabis abstinence. Studies assessing verbal learning performance in abstinent regular cannabis users and nonusing control participants; studies reporting length of cannabis abstinence at the time of neuropsychological assessment; and studies implementing one of three highly comparable measures of verbal learning and memory were included in the analyses. The included tasks have demonstrated some of the most robust declines associated with cannabis use and are prevalent in the clinical practice of neuropsychology. We assessed associations between cannabis abstinence and verbal learning scores via mixed effects subgroup analyses. Twenty-three studies (k = 28; N = 1,711) met all inclusion criteria. Cannabis users abstinent for 7 days or fewer performed worse than controls on verbal learning tasks, whereas cannabis users abstinent for longer periods showed no average significant difference in verbal learning performance compared with controls. Based on available evidence, some amelioration of verbal learning limitations presumed to result from cannabis appear to resolve between 7 and 28 days of sustained abstinence. However, in the reviewed studies, years of regular use were inversely related to longer periods of abstinence and verbal learning performance, undermining a confident inference that abstinence alone has direct benefits to verbal learning and memory. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Renal cancer resistance to antiangiogenic therapy is delayed by restoration of angiostatic signaling.
Treatment of metastatic renal cell cancer (RCC) with antiangiogenic agents that block vascular endothelial growth factor (VEGF) receptor 2 signaling produces tumor regression in a substantial fraction of patients; however, resistance typically develops within 6 to 12 months. The purpose of this study was to identify molecular pathways involved in resistance. Treatment of mice bearing either 786-0 or A498 human RCC xenografts with sorafenib or sunitinib produced tumor growth stabilization followed by regrowth despite continued drug administration analogous to the clinical experience. Tumors and plasma were harvested at day 3 of therapy and at the time of resistance to assess pathways that may be involved in resistance. Serial perfusion imaging, and plasma and tumor collections were obtained in mice treated with either placebo or sunitinib alone or in combination with intratumoral injections of the angiostatic chemokine CXCL9. Sunitinib administration led to an early downmodulation of IFNγ levels as well as reduction of IFNγ receptor and downstream angiostatic chemokines CXCL9 to 11 within the tumor. Intratumoral injection of CXCL9, although producing minimal effects by itself, when combined with sunitinib resulted in delayed resistance in vivo accompanied by a prolonged reduction of microvascular density and tumor perfusion as measured by perfusion imaging relative to sunitinib alone. These results provide evidence that resistance to VEGF receptor therapy is due at least in part to resumption of angiogenesis in association with reduction of IFNγ-related angiostatic chemokines, and that this resistance can be delayed by concomitant administration of CXCL9.


Fortification and health: challenges and opportunities.
Fortification is the process of adding nutrients or non-nutrient bioactive components to edible products (e.g., food, food constituents, or supplements). Fortification can be used to correct or prevent widespread nutrient intake shortfalls and associated deficiencies, to balance the total nutrient profile of a diet, to restore nutrients lost in processing, or to appeal to consumers looking to supplement their diet. Food fortification could be considered as a public health strategy to enhance nutrient intakes of a population. Over the past century, fortification has been effective at reducing the risk of nutrient deficiency diseases such as beriberi, goiter, pellagra, and rickets. However, the world today is very different from when fortification emerged in the 1920s. Although early fortification programs were designed to eliminate deficiency diseases, current fortification programs are based on low dietary intakes rather than a diagnosable condition. Moving forward, we must be diligent in our approach to achieving effective and responsible fortification practices and policies, including responsible marketing of fortified products. Fortification must be applied prudently, its effects monitored diligently, and the public informed effectively about its benefits through consumer education efforts. Clear lines of authority for establishing fortification guidelines should be developed and should take into account changing population demographics, changes in the food supply, and advances in technology. This article is a summary of a symposium presented at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 on current issues involving fortification focusing primarily on the United States and Canada and recommendations for the development of responsible fortification practices to ensure their safety and effectiveness.


Cocoa procyanidins suppress transformation by inhibiting mitogen-activated protein kinase kinase.
Cocoa was shown to inhibit chemically induced carcinogenesis in animals and exert antioxidant activity in humans. However, the molecular mechanisms of the chemopreventive potential of cocoa and its active ingredient(s) remain unknown. Here we report that cocoa procyanidins inhibit neoplastic cell transformation by suppressing the kinase activity of mitogen-activated protein kinase kinase (MEK). A cocoa procyanidin fraction (CPF) and procyanidin B2 at 5 mug/ml and 40 mum, respectively, inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ mouse epidermal (JB6 P+) cells by 47 and 93%, respectively. The TPA-induced promoter activity and expression of cyclooxygenase-2, which is involved in tumor promotion and inflammation, were dose-dependently inhibited by CPF or procyanidin B2. The activation of activator protein-1 and nuclear factor-kappaB induced by TPA was also attenuated by CPF or procyanidin B2. The TPA-induced phosphorylation of MEK, extracellular signal-regulated kinase, and p90 ribosomal s6 kinase was suppressed by CPF or procyanidin B2. In vitro and ex vivo kinase assay data demonstrated that CPF or procyanidin B2 inhibited the kinase activity of MEK1 and directly bound with MEK1. CPF or procyanidin B2 suppressed JB6 P+ cell transformation induced by epidermal growth factor or H-Ras, both of which are known to be involved in MEK/ERK signal activation. In contrast, theobromine (up to 80 mum) had no effect on TPA-induced transformation, cyclooxygenase-2 expression, the transactivation of activator protein-1 or nuclear factor-kappaB, or MEK. Notably, procyanidin B2 exerted stronger inhibitory effects compared with PD098059 (a well known pharmacological inhibitor of MEK) on MEK1 activity and neoplastic cell transformation.


Compartmentalization of beta-adrenergic signals in cardiomyocytes.
Activation of adrenergic receptors (AR) represents the primary mechanism to increase cardiac performance under stress. Activated βAR couple to Gs protein, leading to adenylyl cyclase-dependent increases in secondary-messenger cyclic adenosine monophosphate (cAMP) to activate protein kinase A. The increased protein kinase A activities promote phosphorylation of diversified substrates, ranging from the receptor and its associated partners to proteins involved in increases in contractility and heart rate. Recent progress with live-cell imaging has drastically advanced our understanding of the βAR-induced cAMP and protein kinase A activities that are precisely regulated in a spatiotemporal fashion in highly differentiated myocytes. Several features stand out: membrane location of βAR and its associated complexes dictates the cellular compartmentalization of signaling; βAR agonist dose-dependent equilibrium between cAMP production and cAMP degradation shapes persistent increases in cAMP signals for sustained cardiac contraction response; and arrestin acts as an agonist dose-dependent master switch to promote cAMP diffusion and propagation into intracellular compartments by sequestrating phosphodiesterase isoforms associated with the βAR signaling cascades. These features and the underlying molecular mechanisms of dynamic regulation of βAR complexes with adenylyl cyclase and phosphodiesterase enzymes and the implication in heart failure are discussed.


Multiple Endocrine Neoplasia Type 1: Latest Insights.
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.


Treatment After Anterior Cruciate Ligament Injury: Panther Symposium ACL Treatment Consensus Group.
Treatment strategies for anterior cruciate ligament (ACL) injuries continue to evolve. Evidence supporting best-practice guidelines for the management of ACL injury is to a large extent based on studies with low-level evidence. An international consensus group of experts was convened to collaboratively advance toward consensus opinions regarding the best available evidence on operative versus nonoperative treatment for ACL injury. The purpose of this study was to report the consensus statements on operative versus nonoperative treatment of ACL injuries developed at the ACL Consensus Meeting Panther Symposium 2019. There were 66 international experts on the management of ACL injuries, representing 18 countries, who were convened and participated in a process based on the Delphi method of achieving consensus. Proposed consensus statements were drafted by the scientific organizing committee and session chairs for the 3 working groups. Panel participants reviewed preliminary statements before the meeting and provided initial agreement and comments on the statement via online survey. During the meeting, discussion and debate occurred for each statement, after which a final vote was then held. Ultimately, 80% agreement was defined a priori as consensus. A total of 11 of 13 statements on operative versus nonoperative treatment of ACL injury reached consensus during the symposium. Overall, 9 statements achieved unanimous support, 2 reached strong consensus, 1 did not achieve consensus, and 1 was removed because of redundancy in the information provided. In highly active patients engaged in jumping, cutting, and pivoting sports, early anatomic ACL reconstruction is recommended because of the high risk of secondary meniscal and cartilage injuries with delayed surgery, although a period of progressive rehabilitation to resolve impairments and improve neuromuscular function is recommended. For patients who seek to return to straight-plane activities, nonoperative treatment with structured, progressive rehabilitation is an acceptable treatment option. However, with persistent functional instability, or when episodes of giving way occur, anatomic ACL reconstruction is indicated. The consensus statements derived from international leaders in the field will assist clinicians in deciding between operative and nonoperative treatment with patients after an ACL injury.


Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study.
The combination of bortezomib, lenalidomide, and dexamethasone is a highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an investigational, oral, proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma. We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. In phase 1, we gave patients escalating doses of ixazomib (1·68-3·95 mg/m(2)) to establish the recommended dose for phase 2. The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial response or better for phase 2. Safety analyses were done in all patients who received at least one dose of study drug; efficacy analyses were done in all patients who received at least one dose of study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-baseline response assessment. This study is registered at ClinicalTrials.gov, number NCT01217957. Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: one at a dose of ixazomib of 2·97 mg/m(2) and three at 3·95 mg/m(2). The maximum tolerated dose of ixazomib was established as 2·97 mg/m(2) and the recommended phase 2 dose was 2·23 mg/m(2), which was converted to a 4·0 mg fixed dose based on population pharmacokinetic results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 response-evaluable patients, 37 (58%, 95% CI 45-70) had a very good partial response or better. The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple myeloma. These results support the phase 3 trial development of this combination for multiple myeloma. Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.


Climate Change, Drought and Human Health in Canada.
Droughts have been recorded all across Canada and have had significant impacts on individuals and communities. With climate change, projections suggest an increasing risk of drought in Canada, particularly in the south and interior. However, there has been little research on the impacts of drought on human health and the implications of a changing climate. A review of the Canadian, U.S. and international literature relevant to the Canadian context was conducted to better define these impacts and adaptations available to protect health. Drought can impact respiratory health, mental health, illnesses related to exposure to toxins, food/water security, rates of injury and infectious diseases (including food-, water- and vector-borne diseases). A range of direct and indirect adaptation (e.g., agricultural adaptation) options exist to cope with drought. Many have already been employed by public health officials, such as communicable disease monitoring and surveillance and public education and outreach. However, gaps exist in our understanding of the impacts of short-term vs. prolonged drought on the health of Canadians, projections of drought and its characteristics at the regional level and the effectiveness of current adaptations. Further research will be critical to inform adaptation planning to reduce future drought-related risks to health.


Impact of home and community-based services on hospitalisation and institutionalisation among individuals eligible for long-term care insurance in Japan.
This population-based retrospective cohort study aimed to clarify the impact of home and community-based services on the hospitalisation and institutionalisation of individuals certified as eligible for long-term care insurance (LTCI) benefits. Health insurance data and LTCI data were combined into a database of 1,020 individuals in two farming communities in Hokkaido who were enrolled in Citizen's Health Insurance. They had not received long-term care services prior to April 1, 2000 and were newly certified as eligible for Long-Term Care Insurance benefits between April 1, 2000 and February 29, 2008. The analysis covered 565 subjects who had not been hospitalised or institutionalised at the time of first certification of LTCI benefits. The adjusted hazard ratios (HRs) of hospitalisation or institutionalisation or death after the initial certification were calculated using the Cox proportional hazard model. The predictors were age, sex, eligibility level, area of residence, income, year of initial certification and average monthly outpatient medical expenditures, in addition to average monthly total home and community-based services expenditures (analysis 1), the use or no use of each type of service (analysis 2), and average monthly expenditures for home-visit and day-care types of services, the use or no use of respite care, and the use or no use of rental services for assistive devices (analysis 3). Users of home and community-based services were less likely than non-users to be hospitalised or institutionalised. Among the types of services, users of respite care (HR: 0.71, 95% confidence interval [CI]: 0.55-0.93) and rental services for assistive devices (HR: 0.70, 95% CI: 0.54-0.92) were less likely to be hospitalised or institutionalised than non-users. For those with relatively light needs, users of day care were also less likely to be hospitalised or institutionalized than non-users (HR: 0.77, 95% CI: 0.61-0.98). Respite care, rental services for assistive devices and day care are effective in preventing hospitalisation and institutionalisation. Our results suggest that home and community-based services contribute to the goal of the LTCI system of encouraging individuals certified as needing long-term care to live independently at home for as long as possible.


Postural control in elderly subjects participating in balance training.
The changes in postural control in elderly people after an 8-week training course were characterized. Static postural stability was measured during standing on a single force platform first with the eyes open and then with the eyes closed. Body sway was analysed on a force plate in groups of elderly and of young subjects. Half of the elderly subjects then took part in the training course. The posturographic measurements were repeated after the course. The sway in anteroposterior (AP) and mediolateral (ML) directions was subjected to spectral analysis. The frequency spectrum of the platform oscillations was calculated by fast Fourier transformation in the intervals 0.1-0.3, 0.3-1 and 1-3 Hz. It was found that the sway path was longer and the frequency power was higher in the elderly group. The training caused a significant improvement in functional performance, but a significantly longer sway path was observed after the training in the ML direction. The frequency analysis revealed a significantly higher power after 8 weeks without visual control in the ML direction in the training group in the low and the middle frequency bands. The results suggest that the participants' balance confidence and the control of ML balance improved in response to the training. The higher ML frequency power exhibited after the training may be indicative of a better balance performance. Thus, the increase in the sway path in this age group did not mean a further impairment of the postural control.


Risks worth taking: safety agreements among discordant gay couples.
As HIV research and prevention efforts increasingly target gay men in relationships, situational factors such as couple serostatus and agreements about sex become central to examinations of risk. Discordant gay couples are of particular interest because the risk of HIV infection is seemingly near-at-hand. Yet, little is known about their sexual behaviors, agreements about sex, and safer sex efforts. The present study utilized longitudinal semi-structured, qualitative interviews to explore these issues among 12 discordant couples. Findings show that nearly every couple had agreements about reducing the likelihood of HIV transmission from one partner to the other. Negotiating these agreements involved establishing a level of acceptable risk, determining condom use, and employing other risk-reduction techniques, such as seropositioning and withdrawal. For half of the couples, these agreements did not involve using condoms; only two couples reported consistent condom use. Despite forgoing condoms, however, none reported seroconversion over the course of data collection. Additional issues are raised where long-term HIV prevention is concerned. Future prevention efforts with discordant couples should work with, rather than fight against, the couple's decision to use condoms and endeavor to complement and accentuate their other safer sex efforts.


Phenotypic Variability Correlates with Clinical Outcome in Cryptococcus Isolates Obtained from Botswanan HIV/AIDS Patients.
Pathogenic species of Cryptococcus cause hundreds of thousands of deaths annually. Considerable phenotypic variation is exhibited during infection, including increased capsule size, capsule shedding, giant cells (≥15 μm), and micro cells (≤1 μm). We examined 70 clinical isolates of Cryptococcus neoformans and Cryptococcus tetragattii from HIV/AIDS patients in Botswana to determine whether the capacity to produce morphological variants was associated with clinical parameters. Isolates were cultured under conditions designed to simulate in vivo stresses. Substantial variation was seen across morphological and clinical data. Giant cells were more common in C. tetragattii, while micro cells and shed capsule occurred in C. neoformans only. Phenotypic variables fell into two groups associated with differing symptoms. The production of "large" phenotypes (greater cell and capsule size and giant cells) was associated with higher CD4 count and was negatively correlated with intracranial pressure indicators, suggesting that these are induced in early stage infection. "Small" phenotypes (micro cells and shed capsule) were associated with lower CD4 counts, negatively correlated with meningeal inflammation indicators, and positively correlated with intracranial pressure indicators, suggesting that they are produced later during infection and may contribute to immune suppression and promote proliferation and dissemination. These trends persisted at the species level, indicating that they were not driven by association with particular Cryptococcus species. Isolates possessing giant cells, micro cells, and shed capsule were rare, but strikingly, they were associated with patient death (P = 0.0165). Our data indicate that pleomorphism is an important driver in Cryptococcus infection.IMPORTANCE Cryptococcosis results in hundreds of thousands of deaths annually, predominantly in sub-Saharan Africa. Cryptococcus is an encapsulated yeast, and during infection, cells have the capacity for substantial morphological changes, including capsule enlargement and shedding and variations in cell shape and size. In this study, we examined 70 Cryptococcus isolates causing meningitis in HIV/AIDS patients in Botswana in order to look for associations between phenotypic variation and clinical symptoms. Four variant phenotypes were seen across strains: giant cells of ≥15 µm, micro cells of ≤1 µm, shed extracellular capsule, and irregularly shaped cells. We found that "large" and "small" phenotypes were associated with differing disease symptoms, indicating that their production may be important during the disease process. Overall, our study indicates that Cryptococcus strains that can switch on cell types under different situations may be more able to sustain infection and resist the host response.


ICA and me--a subjective review.
ICA - instrumentation, control and automation - is a hidden technology. It is ubiquitous in all industrial processes, including water and wastewater treatment systems. Still, as long as everything works fine, it is not noted but when things go wrong it will be observed. ICA has now about forty years of history in water and wastewater systems and is well recognized. One early attitude was that ICA will be a necessary burden to be added to a plant in order to correct for a poor design. However, the key reason for ICA is the fact that all processes are subject to disturbances, externally via the wastewater influent, from the customers in a water supply system, or from operations in one unit process that will propagate as a disturbance to another unit within a plant. This paper is an attempt to describe the development of ICA in water and wastewater systems. Most of it is based on personal experiences with all their limitations. No single paper can fairly describe the development that is documented in thousands of research papers, practiced by so many operators and process engineers and implemented in so many treatment systems. Still, the hope is that the paper can give a flavour of the most important ingredients of this fascinating development.


Amyloidogenic peptides of yeast cell wall glucantransferase Bgl2p as a model for the investigation of its pH-dependent fibril formation.
The pH-dependence of the ability of Bgl2p to form fibrils was studied using synthetic peptides with potential amyloidogenic determinants (PADs) predicted in the Bgl2p sequence. Three PADs, FTIFVGV, SWNVLVA and NAFS, were selected on the basis of combination of computational algorithms. Peptides AEGFTIFVGV, VDSWNVLVAG and VMANAFSYWQ, containing these PADs, were synthesized. It was demonstrated that these peptides had an ability to fibrillate at pH values from 3.2 to 5.0. The PAD-containing peptides, except for VDSWNVLVAG, could fibrillate also at pH values from pH 5.0 to 7.6. We supposed that the ability of Bgl2p to form fibrils most likely depended on the coordination of fibrillation activity of the PAD-containing areas and Bgl2p could fibrillate at mild acid and neutral pH values and lose the ability to fibrillate with the increasing of pH values. It was demonstrated that Bgl2p was able to fibrillate at pH value 5.0, to form fibrils of various morphology at neutral pH values and lost the fibrillation ability at pH value 7.6. The results obtained allowed us to suggest a new simple approach for the isolation of Bgl2p from Saccharomyces cerevisiae cell wall.


Clinical relevance of sirolimus drug interactions in transplant patients.
Sirolimus, a new immunosuppressant drug; is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of the P-glycoprotein drug efflux pump. The CYP3A4/P-glycoprotein system is mainly localized in the liver and intestine. It is responsible for the severe first pass metabolism of sirolimus with a low bioavailability. Drugs like voriconazole, itraconazole, fluconazole, and erytrhomycin may decrease the metabolic activity of this enzymatic system. This report documents in five patients that coadministration of these antimicrobials with sirolimus increases the blood concentrations of the immunosuppressant. The dose-normalized trough blood concentration showed a mean increase of sevenfold with the coadministration of these drugs. It is essential to monitor the blood sirolimus concentrations and to adjust the sirolimus doses before and after coadministration of these drugs.


Clinical relevance of serum antibodies to extracellular N-methyl-D-aspartate receptor epitopes.
There are now a large number of requests for N-methyl-D-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as 'Low Positive'. The clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as 'Definite', 'Possible' or 'Unlikely'. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated. Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases. Using live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.


[Investigation of microbial community involved in fermentation of Massa Medicata Fermentata].
This study aimed to clarify the microbial diversity, dominant species and the change of community structures in the fermentation of Liushenqu(Massa Medicata Fermentata), and explore the material foundation of its pharmacodynamics effect. On the basis of standardizing the fermentation process, Massa Medicata Fermentata was prepared by screening and optimizing the recipes and the standard formula issued by the Ministry. The community structure and growth process of fungi and bacteria in the samples at five time points(0, 17, 41, 48, 65 h) in the fermentation process of Massa Medicata Fermentata were analyzed by using isolation and culture of eight different media and high-throughput DNA sequencing technology. The results indicated that the samples of the two recipes pre-sented high microbial diversity at the initial fermentation stage, with Aspergillus spp. as the dominant species. As the fermentation process goes forward, Saccharomycopsis fibuligera and Rhizopus oryzae soon became dominant species from 17 h after fermentation commencement point to the fermentation end, while the other species were inhibited at a lower level from 17 h. The species diversity of bacteria in the initial fermentation samples was also high, and Enterobacter was the dominant species. Enterobacter cloacae, Pediococcus pentosaceus and Cronobacter sakazakii became dominant bacterial species 17 h after fermentation commencement, while the species diversity was decreased. Our results will be a scientific basis for promoting the fermentation process of Massa Medicata Fermentata by using pure microbial cultures.


Prevalence and correlates of shoplifting in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).
This study presented nationally representative data on the lifetime prevalence, correlates, and comorbidity of shoplifting among adults in the United States. Data were derived from a large national sample of the United States population. Face-to-face surveys of more than 43,000 adults ages 18 years and older residing in households were conducted during the 2001-2002 period. Diagnoses of mood, anxiety, and drug disorders as well as personality disorders were based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version. The prevalence of lifetime shoplifting in the U.S. population was 11.3%. Associations between shoplifting and all antisocial behaviors were positive and significant. Besides stealing, the behaviors more strongly associated with shoplifting were making money illegally and scamming someone for money. Strong associations between shoplifting and all 12-month and lifetime comorbid psychiatric disorders were also found. The strongest associations with shoplifting were with disorders often associated with deficits in impulse control, such as antisocial personality disorder, substance use disorders, pathological gambling, and bipolar disorder. High rates of mental health service use were also identified in this population. Shoplifting is a relatively common behavior. A history of shoplifting is associated with substantial rates of comorbid disorders, psychosocial impairment, and mental health service use. Future research should identify the biological and environmental underpinnings of shoplifting and develop effective screening tools and interventions for individuals with shoplifting problems.


Conservative treatment of Charcot artroparthy in a series of spina bifida patients: the experience of one center and review of the literature.
The present study was performed to evaluate the use of patellar tendon-bearing ankle foot orthesis for the treatment of Charcot arthropathy in a series of patients with spina bifida. A cohort of 350 spina bifida patients, ages ranging between 12 months and 22 years were evaluated in our clinic between June 1993 and March 2004. Charcot arthropathy was seen in five of these children. Treatment was initiated with nonsteroidal anti-inflammatory drugs, oral bisphosphonates and immobilization. No change was observed in the patients' symptoms after a month of treatment. At this time, a patellar tendon-bearing ankle foot orthesis was prescribed and used for a period of 6 to 24 months. All patients improved within 2 months. At the end of 2 years of follow-up, three patients are still using the brace without any complaints. One patient still has symptoms, although she is wearing her brace, but she has had significant improvement compared with the initiation of therapy. Non-weight-bearing, immobilization and surgery are the known treatment choices in Charcot arthropathy. Little experience exists about this entity and its treatment. Our experience reveals that the patellar tendon-bearing ankle foot orthesis leads to significant improvement in children with Charcot arthropathy without surgery and immobilization.


Narrowband high-reflection filters with wide and low-reflection sidebands.
Narrowband high-reflection filters with the structure sub|H(LH)(m1)alpha L(HL)(m2)Cr(beta)M|air are proposed. The effects of the Cr layer and the matching stack consisting of dielectric multilayer on the reflection characteristics of the filters are analyzed. The distribution of the internal electric field and the optical absorption is also calculated. The analysis indicates that the improvement of the sidebands could be reached by applying the matching stack without impairing the maximal reflectance and half-width of the reflection band. Wide and flat reflection sidebands could be realized by applying a relatively thicker metal layer. However, lowering the sideband reflection could only be achieved by adding appropriate matching stacks. Large m(1)-m(2) could increase the maximal reflectance, while large m(2) or n(H)/n(L) would reduce the width of the reflection band. In the Cr layer, the least average intense electric field occurred at the central wavelength, the relatively high electric field intensity exists at the wavelengths outside the central wavelength region. The optical absorption of the filter depends strongly on the electric field intensity inside the Cr layer.


Expression of caveolin-1 in human adipose tissue is upregulated in obesity and obesity-associated type 2 diabetes mellitus and related to inflammation.
Caveolin-1 (CAV-1) plays important roles in many aspects of cellular biology, including vesicular transport, cholesterol homeostasis and signal transduction. The aim of the present study was to explore gene expression levels of CAV-1 in human adipose tissue in obesity and obesity-associated type 2 diabetes mellitus (T2DM) and to analyse its potential implication in the inflammatory state associated with obesity. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) obtained from 15 females were used in the study. Patients were classified as lean (BMI 20.8 +/- 1.0 kg/m(2)) or obese (BMI 50.5 +/- 2.6 kg/m(2)). The obese group was further subclassified as normoglycaemic (NG) or patients with T2DM. Anthropometric measurements as well as circulating metabolites, hormones and adipokines were determined. Real-time polymerase chain reaction (PCR) analyses were performed to quantify transcript levels of CAV-1 and monocyte chemoattractant protein (MCP-1). The presence of CAV-1 protein was detected in VAT and SAT by immunohistochemistry. Both obese NG and with T2DM patients exhibited significantly higher CAV-1 expression levels in VAT and SAT compared with lean subjects (P < 0.05). No differences between obese NG and T2DM patients were observed in VAT. However, obese T2DM patients were found to have higher CAV-1 expression levels in SAT (P < 0.05) compared with obese NG patients. A significant correlation was found between CAV-1 mRNA expression levels in VAT and different circulating inflammatory markers such as sialic acid (SA) (P < 0.001) and fibrinogen (P < 0.001) as well as with MCP1 mRNA expression (P < 0.05). Our findings show for the first time the upregulation of mRNA CAV-1 expression levels in VAT and SAT of obese NG and obese T2DM patients compared with lean controls, suggesting a role for CAV-1 in obesity and T2DM development. The association with different inflammatory markers further suggests an implication of CAV-1 in the low-grade inflammation accompanying obesity.


Functional consequences of a rod outer segment membrane guanylate cyclase (ROS-GC1) gene mutation linked with Leber's congenital amaurosis.
ROS-GC1 is the original member of the subfamily of membrane guanylate cyclases with two Ca2+ switches, which have been defined as CRM1 and CRM2. These are separately located within the intracellular domain of the cyclase. CRM1 switches on the enzyme at nanomolar concentrations of Ca2+ and is linked with phototransduction; the other stimulates at micromolar Ca2+ concentrations and is predicted to be linked with retinal synaptic activity. Ca2+ acts indirectly via Ca2+-binding proteins, GCAP1 and CD-GCAP. GCAP1 is a modulator of the CRM1 switch, and CD-GCAP turns on the CRM2 switch. A Leber's congenital amaurosis, termed LCA1, involves F514S point mutation in ROS-GC1. The present study shows that the mutation severely damages its intrinsic cyclase activity and inactivates its CRM1 switch but does not affect the CRM2 switch. In addition, on the basis of the established modulatory features of ROS-GC1, it is predicted that, in two other forms of LCA1 involving deletion of nt 460C or 693C, there is a frameshift in ROS-GC1 gene, which results in the nonexpression of the cyclase. For the first time, the findings define the linkage of distinct molecular forms of LCA to ROS-GC1 in precise biochemical terms; they also explain the reasons for the insufficient production of cyclic GMP in photoreceptors to sustain phototransduction, which ultimately leads to the degeneration of the photoreceptors.


Conjugation of lentivirus to paramagnetic particles via nonviral proteins allows efficient concentration and infection of primary acute myeloid leukemia cells.
Nonviral producer cell proteins incorporated into retroviral vector surfaces profoundly influence infectivity and in vivo half-life. We report the purification and concentration of lentiviral vectors using these surface proteins as an efficient gene transduction strategy. Biotinylation of these proteins and streptavidin paramagnetic particle concentration enhances titer 400- to 2,500-fold (to 10(9) CFU/ml for vesicular stomatitis virus G protein and 5 x 10(8) for amphotropic murine leukemia virus envelope). This method also uses newly introduced membrane proteins (B7.1 and DeltaLNGFR) directed to lentiviral surfaces, allowing up to 17,000-fold concentrations. Particle conjugation of lentivirus allows facile manipulation in vitro, resulting in the transduction of 48 to 94% of human acute myeloid leukemia blasts.


Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse origins. PAH is now further subclassified as idiopathic PAH, familial PAH, and associated PAH varieties. Heterozygous mutations in BMPR2 can be detected in 50% to 70% of patients with familial PAH and 10% to 40% of patients with idiopathic PAH. Although endothelial cells have been suspected as the cellular origin of PAH pathogenesis, no direct in vivo evidence has been clearly presented. The present study was designed to investigate whether endothelial Bmpr2 deletion can predispose to PAH. The Bmpr2 gene was deleted in pulmonary endothelial cells using Bmpr2 conditional knockout mice and a novel endothelial Cre transgenic mouse line. Wide ranges of right ventricular systolic pressure were observed in mice with heterozygous (21.7 to 44.1 mm Hg; median, 23.7 mm Hg) and homozygous (20.7 to 56.3 mm Hg; median, 27 mm Hg) conditional deletion of Bmpr2 in pulmonary endothelial cells compared with control mice (19.9 to 26.7 mm Hg; median, 23 mm Hg) at 2 to 7 months of age. A subset of mice with right ventricular systolic pressure >30 mm Hg exhibited right ventricular hypertrophy and an increase in the number and wall thickness of muscularized distal pulmonary arteries. In the lungs of these mice with high right ventricular systolic pressure, the expression of proteins involved in the pathogenesis of PAH such as serotonin transporter and tenascin-C was elevated in distal arteries and had a high incidence of perivascular leukocyte infiltration and in situ thrombosis. Conditional heterozygous or homozygous Bmpr2 deletion in pulmonary endothelial cells predisposes mice to develop PAH.


Consumer perspectives on physical activity interventions within assertive community treatment programs.
The purpose of this study was to identify strategies for encouraging greater levels of physical activity among community-dwelling individuals living with serious mental illness participating in assertive community treatment (ACT). Eighteen individuals living with serious mental illness participated in focus group interviews. Participants were recruited from an ACT provider located in the Midwestern United States. A semistructured interview protocol was developed specifically for this study. Participants responded to a series of questions on ACT physical activity programming, providing (a) information about their personal experiences with physical activity-related interventions and (b) suggestions for intervention strategies that may enhance physical activity participation in this population. Consensual qualitative research conventions, a qualitative methodology used in social sciences, were followed for organizing, coding, quantifying, and interpreting participant responses. Several unique themes emerged from the data. Participants identified a variety of strategies used by their ACT provider to encourage physical activity, such as group physical activities and incentive programs. A number of recommendations related to skills training, intervention characteristics, and motivational strategies were identified by the participants as well. Physical activity is an important part of successful treatment for individuals with serious mental illness. In this study, participants identified a variety of strategies that may be useful for incorporating within the ACT treatment paradigm. Participant responses were frequently consistent with the tenets of popular health behavior theory (e.g., self-determination theory). Future research should focus on the efficacy of the recommended intervention strategies and their implementation within ACT treatment settings. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Factors associated with Taenia solium cysticercosis: analysis of nine hundred forty-six Peruvian neurologic patients. Cysticercosis Working Group in Peru (CWG).
In most developing countries, 10% of acute neurologic cases are patients with neurocysticercosis (NCC). Determining specific factors associated with contracting NCC will facilitate its diagnosis and prevention. We examined multiple socioeconomic, demographic, environmental, medical, and behavioral characteristics of 946 Peruvian neurologic patients for a correlation with NCC, which was diagnosed by the highly specific and sensitive electroimmunotransfer blot (EITB) or immunoblot assay. Eighteen percent (172 of 932) of serum samples and 28% (101 of 362) of cerebrospinal fluid samples were EITB-positive. The proportion of EITB-positive persons was similar for all socioeconomic levels. Significant factors associated with NCC were: 1) being born outside Lima, 2) having raised pigs, 3) more than 20 years of age, 4) a history of seizures, and 5) a history of taeniasis. Of these factors, raising pigs is the only one that is amenable to intervention, via improvements in animal husbandry.


Efficacy of anti-osteoporotic medications in patients with type 1 and 2 diabetes mellitus: a systematic review.
Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with bone fragility and increased fracture risk. However, little is known regarding the effect of anti-osteoporotic treatment on bone mineral density (BMD) and/or fracture risk in these patients. We aimed to systematically investigate the efficacy of anti-osteoporotic medications in patients with diabetes in comparison with non-diabetic subjects. MEDLINE and Scopus databases were searched (up to 31st October 2017). Nine studies fulfilled the pre-defined inclusion criteria [patients with T2DM (n = 8) or either T1DM or T2DM (n = 1)]. Regarding fracture risk, five studies were identified. Alendronate demonstrated comparable vertebral anti-fracture efficacy in patients with and without diabetes (n = 2), whereas non-vertebral fracture risk was either the same (n = 1) or higher in diabetic patients (n = 1). Raloxifene also demonstrated comparable vertebral anti-fracture efficacy in both groups (n = 2), without any effect on non-vertebral fractures in either group. In one study, diabetic patients exposed to raloxifene demonstrated the same vertebral and non-vertebral fracture risk with non-diabetic patients. Teriparatide (n = 1) demonstrated the same non-vertebral fracture rates in both patients with and without T2DM. Regarding BMD, equal increases in spine BMD were observed with alendronate (n = 4), risedronate (n = 1), and teriparatide (n = 1). With respect to hip BMD, similar increases were observed with teriparatide (n = 1), whereas data regarding alendronate were controversial (n = 3). No eligible study was found for zoledronic acid, ibandronate, strontium ranelate, denosumab, or bazedoxifene. The presence of diabetes does not alter anti-osteoporotic treatment response, regarding BMD increase and vertebral fracture risk reduction.


Effective gene therapy for pancreatic cancer by cytokines mediated by restricted replication-competent adenovirus.
Pancreatic cancer has a poor prognosis even when surgical treatment can be accomplished. Studies have demonstrated that pancreatic cancer is associated with various genetic abnormalities in oncogenes and tumor suppressor genes including p53. New therapeutic approaches for pancreatic cancer can be developed by targeting these genetic alterations. Adenovirus (Adv) lacking the 55-kDa E1B protein (E1B55K) replicates preferentially in p53-deficient cancer cells. We constructed E1B55K-deleted Adv (AxE1AdB), and studied its replication and cytopathic effect on pancreatic cancer cells. AxE1AdB replicated in and caused cell death of the p53-deficient pancreatic cancer cell lines tested (e.g., PANC-1, MIAPaCa-2, SU.86.86, BxPC-3, and PK-1). To enhance its therapeutic effect, we examined the combination of coinfecting this restricted replication-competent adenovirus (RRCA) with other Adv. Coinfection of E1-deficient Adv expressing the reporter lacZ gene (AxCAlacZ) together with AxE1AdB resulted in the replication of both viruses and a marked increase in reporter gene expression. PANC-1 cells coinfected with AxE1AdB and the Adv for human IL-2 (AxCAhIL2), produced 110 times more IL-2 than those infected with AxCAhIL2 alone. Similarly, coinfection of AxE1AdB and Adv for human IL-12 augmented the IL-12 production by 370-fold. Injecting AxE1AdB into the PANC-1 tumor of severe combined immunodeficient mice (SCID mice) resulted in marked reduction of the volume of the tumor. Moreover, injecting AxE1AdB with AxCAhIL2 into the PANC-1 tumor resulted in complete regression of the established tumors. These data suggest that RRCA, which augments the antitumor effect of a viral transgene (i.e., cytokines), may be a powerful tool for treating p53-deficient pancreatic cancer.


Toward Constitutive Models for Momentum, Species, and Energy Transport in Gas-Particle Flows.
As multiscale structures are inherent in multiphase flows, constitutive models employed in conjunction with transport equations for momentum, species, and energy are scale dependent. We suggest that this scale dependency can be better quantified through deep learning techniques and formulation of transport equations for additional quantities such as drift velocity and analogies for species, energy, and momentum transfer. How one should incorporate interparticle forces, which arise through van der Waals interaction, dynamic liquid bridges between wet particles, and tribocharging, in multiscale models warrants further study. Development of multiscale models that account for all the known interactions would improve confidence in the use of simulations to explore design options, decrease the number of pilot-scale experiments, and accelerate commercialization of new technologies.


Clinic based biopsy vs. theatre biopsy of bone and soft tissue extremity tumours: comparable diagnostic modalities.
To compare the diagnostic accuracy of clinic-based biopsy versus theatre biopsy against final histopathology in patients presenting with extremity tumours. The retrospective study was conducted at Aga Khan University Hospital, Karachi, and comprised record of patients who underwent biopsy procedure of extremity tumours from January 2008 to December 2011. Data regarding socio-demographic status, disease-related and procedure-related variables were collected from the files. Histopathology report of biopsy was compared with the final histopathology after definite procedure of the tumour for concordance. Of the 87 patients whose records were reviewed, 42(48%) had undergone biopsy in theatre and 45(52%) in clinic. The overall median age was 29 years (Inter-quartile range: 18-58 years). As compared to final histopathology after the definite procedure, diagnostic accuracy of theatre and clinic-based biopsy was 97.7% vs. 95.5% respectively. Surgical site infection was observed in 2(5%) in theatre and in 1(2.2%) in clinic. Clinic-based biopsy was accurate and safe with diagnostic accuracy comparable to theatre-based biopsy. Clinic-based biopsy, being cost-efficient along with low morbidity, should be preferred in patients with extremity tumours.


Antibiofilm Activity of Three Different Irrigation Techniques: An in Vitro Study.
The microbial infection of the endodontic space occurs in a necrotic tooth as a result of dental caries, trauma, periodontal disease, or previous root canal therapy. The disruption of the biofilms and the reduction of the bacterial load inside root canals are crucial for the success of root canal therapy. The aim of this study was to compare, in vitro, the antibiofilm efficacy of a novel passive sonic irrigation (PSI) device with passive ultrasonic irrigation (PUI) and conventional needle irrigation (CNI). Forty-four single-rooted human teeth were inoculated with a culture of E. faecalis for 28 days. The specimens were randomly divided into three groups: PUI, CNI, and PSI (n = 12). The activation protocols were performed using both 17% EDTA and 5.25% NaOCl. Residual bacterial biofilm was taken by means of a canal brush and colony-forming unit (CFU) were counted. The data were analyzed using one-way ANOVA and Games-Howell's post hoc tests. A major reduction in CFU was observed in the PSI and PUI groups, in comparison with the CNI group. No difference was found (p > 0.05) in terms of CFU reduction between PSI and PUI. PSI could be as effective as PUI in the removal of bacterial biofilms from straight root canals.


Pharmacokinetics of exogenous GIP(1-42) in C57Bl/6 mice; Extremely rapid degradation but marked variation between available assays.
Like other peptide hormones, glucose-dependent insulinotropic polypeptide (GIP) is rapidly cleared from the circulation. Dipeptidyl peptidase-4 (DPP-4) is known to be involved. Information on the overall pharmacokinetics of GIP in rodents is, however, lacking. We investigated the pharmacokinetics of exogenous GIP after intravenous, subcutaneous and intraperitoneal injection with and without DPP-4 inhibition in conscious female C57Bl/6 mice. Secondly, we compared total and intact GIP levels measured by an in-house RIA and commercially available ELISA kits to determine the suitability of these methods for in vivo and in vitro measurements. GIP half-life following intravenous injection amounted to 93 ± 2 s, which was extended to 5 ± 0.6 min by inhibition of DPP-4. Intact GIP levels following subcutaneous and intraperitoneal GIP administration were approximately 15 % of total GIP. The area under the curve of intact GIP (GIP exposure) following GIP injection was significantly increased by DPP-4 inhibition, whereas total GIP levels remained unchanged. We found significant variation between measurements of total, but not intact GIP performed with our in-house RIA and ELISAs in samples obtained after in vivo administration of GIP. Different preanalytical sample preparation (EDTA plasma, heparin plasma, assay buffer and PBS) significantly influenced results for all ELISA kits used. Thus, in experiments involving exogenous GIP(1-42) administration in mice, it is important to consider that this will result in a very low ratio of intact:total peptide but co-administration of a DPP-4 inhibitor greatly elevates this ratio. Furthermore, for comparison of GIP levels, it is essential to maintain uniformity concerning assay methodology and sample preparation.


Long-term exposure to particulate matter in relation to mortality and incidence of cardiovascular disease: the JPHC Study.
Associations between long-term exposure to particulate matter (PM) and increased cardiovascular mortality have been reported, but few studies have investigated the associated incidence of cardiovascular disease, and none involved men. We used data on 78,057 participants (37,121 men, 40,936 women) to examine the associations of long-term exposure to PM with mortality and the incidence of cardiovascular diseases. Average PM levels in the relevant area during the study period were used as an index of individual exposure to each subject. Cox models adjusted for age, sex, smoking, environmental smoking, body mass index, and alcohol consumption were used, with further adjustments for nitrogen dioxide and sulfur dioxide exposure, systolic blood pressure, total cholesterol, and diabetes mellitus. Increased PM levels were associated with an increased risk of incident coronary heart disease (CHD) and myocardial infarction (MI), particularly among smokers (adjusted hazard ratio (HR) per 10 µg/m(3) increase in PM for CHD: 1.39, 95% confidence interval (CI) 1.01-1.93; for MI: 1.52, 1.08-2.13) and among women (for CHD: 1.63, 0.91-2.92; for MI: 1.99, 1.07-3.70); however, the observed positive association of PM exposure with the incidence of CHD and MI was not robust, and the association disappeared when one of the areas (Akita) was excluded. The association with CHD mortality was not statistically significant (adjusted HR per 10 µg/m(3) increase in PM: 1.11, 0.92-1.33). There was an inverse association of long-term PM exposure with stroke mortality and incidence. There was no clear association between PM levels and lung cancer mortality and incidence. Long-term exposure to PM might increase the risk of incident CHD in middle-aged Japanese men and women. Our findings also suggest that women and smokers are especially vulnerable to PM exposure.


Managing fluid and electrolyte disorders in renal failure.
Because of the role of the kidneys in maintaining homeostasis in the body, kidney failure leads to derangements of fluid, electrolyte, and acid-base balance. The most effective therapy of a uremic crisis is careful management of fluid balance, which involves thoughtful assessment of hydration, a fluid treatment plan personalized for the specific patient, repeated and frequent reassessment of fluid and electrolyte balance, and appropriate changes in the treatment plan in response to the rapidly changing clinical situation of the patient that has renal failure. Disorders of sodium, chloride, potassium, calcium, and phosphorus are commonly encountered in renal failure and may be life threatening. Treatment of metabolic acidosis and nutritional support are frequently needed.


Complete response in multiple myeloma: clinical trial E9486, an Eastern Cooperative Oncology Group study not involving stem cell transplantation.
The importance of obtaining a complete response (CR) in multiple myeloma (MM) treated with chemotherapy is unclear. The Eastern Cooperative Oncology Group evaluated 653 previously untreated patients with active MM randomized to vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP), to VBMCP and recombinant interferon alfa-2 (INFalpha-2), or to VBMCP and high-dose cyclophosphamide. Objective response was achieved in 420 (67%) of the 628 eligible patients, and 85 (14%) achieved a CR. Patients receiving VBMCP and recombinant INFalpha-2 had a significantly higher CR (18%) than those receiving VBMCP alone (10%) (P = .02). The CR rate for VBMCP and high-dose cyclophosphamide was 12%. Median duration of survival was 3.5 years for all eligible patients, and the estimated 5-year survival rate was 31%. The median duration of survival from the date of objective response was 5.1 years for those who achieved a CR and 3.3 years for those with a partial response (P < .0001). The median postresponse survival was 6.6 years in the 21 patients in CR with nonclonal disease and 4.4 years in the 11 patients in CR who had persistent clonal disease. All patients with negative immunofixation results and nonclonal plasma cells in whom polymerase chain reaction was performed had a positive result (presence of tumor DNA). Patients in whom a CR was achieved had a longer survival than those who had a partial response.


Theoretical and experimental basis for the development of a dynamic airway stent.
Three major problems are currently associated with airway stents: mucostasis, formation of granulation tissue, and migration. We wanted to determine whether these problems could be solved by a different stent design. Based on theoretical considerations of an idealized trachea, we developed a dynamic bifurcation stent made of silicone which incorporates horseshoe-shaped steel struts. A flexible posterior membrane enables dynamic compression during cough, whilst the clasps maintain the airway lumen in the face of external compression. The design of the stent cast was based upon computed tomographic (CT)-scan studies of the central airways. Its complex shape provides a smoother distribution of pressure on the mucosa; thereby, lowering the stimulus for granulation formation. The bronchial limbs saddle on the carina, preventing displacement. The mechanical behaviours of the new stent and two commercially available stents were compared in an ex-vivo model, utilizing freshly excised tracheae and new visualization techniques. Dynamic (artificial coughs) and static loads (simulating tumour compression or pleural pressures) were applied on excised human tracheae with different stents. Our dynamic stent preserved effective compression of the posterior membrane in response to cough, and also provided lumen stability against extrinsic compression. In comparison, the two commercially available stents did not provide both functions equally well. In conclusion, our newly designed dynamic bifurcation stent shows characteristics which should prove useful in avoiding problems currently associated with airway stents.


The art and science of chart review.
Explicit chart review was an integral part of an ongoing national cooperative project, "Using Achievable Benchmarks of Care to Improve Quality of Care for Outpatients with Depression," conducted by a large managed care organization (MCO) and an academic medical center. Many investigators overlook the complexities involved in obtaining high-quality data. Given a scarcity of advice in the quality improvement (QI) literature on how to conduct chart review, the process of chart review was examined and specific techniques for improving data quality were proposed. The abstraction tool was developed and tested in a prepilot phase; perhaps the greatest problem detected was abstractor assumption and interpretation. The need for a clear distinction between symptoms of depression or anxiety and physician diagnosis of major depression or anxiety disorder also became apparent. In designing the variables for the chart review module, four key aspects were considered: classification, format, definition, and presentation. For example, issues in format include use of free-text versus numeric variables, categoric variables, and medication variables (which can be especially challenging for abstraction projects). Quantitative measures of reliability and validity were used to improve and maintain the quality of chart review data. Measuring reliability and validity offers assistance with development of the chart review tool, continuous maintenance of data quality throughout the production phase of chart review, and final documentation of data quality. For projects that require ongoing abstraction of large numbers of clinical records, data quality may be monitored with control charts and the principles of statistical process control. The chart review module, which contained 140 variables, was built using MedQuest software, a suite of tools designed for customized data collection. The overall interrater reliability increased from 80% in the prepilot phase to greater than 96% in the final phase (which included three abstractors and 465 unique charts). The mean time per chart was calculated for each abstractor, and the maximum value was 13.7 +/- 13 minutes. In general, chart review is more difficult than it appears on the surface. It is also project specific, making a "cookbook" approach difficult. Many factors, such as imprecisely worded research questions, vague specification of variables, poorly designed abstraction tools, inappropriate interpretation by abstractors, and poor or missing recording of data in the chart, may compromise data quality.


DRAGON: Determining Regulatory Associations using Graphical models on multi-Omic Networks.
The increasing quantity of multi-omic data, such as methylomic and transcriptomic profiles collected on the same specimen or even on the same cell, provides a unique opportunity to explore the complex interactions that define cell phenotype and govern cellular responses to perturbations. We propose a network approach based on Gaussian Graphical Models (GGMs) that facilitates the joint analysis of paired omics data. This method, called DRAGON (Determining Regulatory Associations using Graphical models on multi-Omic Networks), calibrates its parameters to achieve an optimal trade-off between the network's complexity and estimation accuracy, while explicitly accounting for the characteristics of each of the assessed omics 'layers.' In simulation studies, we show that DRAGON adapts to edge density and feature size differences between omics layers, improving model inference and edge recovery compared to state-of-the-art methods. We further demonstrate in an analysis of joint transcriptome - methylome data from TCGA breast cancer specimens that DRAGON can identify key molecular mechanisms such as gene regulation via promoter methylation. In particular, we identify Transcription Factor AP-2 Beta (TFAP2B) as a potential multi-omic biomarker for basal-type breast cancer. DRAGON is available as open-source code in Python through the Network Zoo package (netZooPy v0.8; netzoo.github.io).


Culture-Related and Individual Differences in Regional Brain Volumes: A Cross-Cultural Voxel-Based Morphometry Study.
Converging behavioral and functional neuroimaging evidence indicates that East Asian and Western individuals have different orientations for processing information that may stem from contrasting cultural values. In this cross-cultural magnetic resonance imaging (MRI) study, we used voxel-based morphometry (VBM) approach to investigate culture-related and individual differences of independent-interdependent orientation in structural brain volume between 57 Taiwanese and 56 Western participants. Each participant's degree of endorsement of independent and interdependent cultural value was assessed by their self-report on the Singelis Self-Construal Scale (SCS). Behaviorally, Taiwanese rated higher SCS scores than Westerners in interdependent value and Westerners rated higher SCS scores than Taiwanese in independent value. The VBM results demonstrated that Western participants showed greater gray matter (GM) volume in the fronto-parietal network, whereas Taiwanese participants showed greater regional volume in temporal and occipital regions. Our findings provide supportive evidence that socio-cultural experiences of learned independent-interdependent orientations may play a role in regional brain volumes. However, strategic differences in cognition, genetic variation, and/or modulations of other environmental factors should also be considered to interpret such culture-related effects and potential individual differences.