Iron therapy for preoperative anaemia.
Preoperative anaemia is common and occurs in 5% to 76% of patients preoperatively. It is associated with an increased risk of perioperative allogeneic blood transfusion, longer hospital stay, and increased morbidity and mortality. Iron deficiency is one of the most common causes of anaemia. Oral and intravenous iron therapy can be used to treat anaemia. Parenteral iron preparations have been shown to be more effective in conditions such as inflammatory bowel disease, chronic heart failure and postpartum haemorrhage due to rapid correction of iron stores. A limited number of studies has investigated iron therapy for the treatment of preoperative anaemia. The aim of this Cochrane Review is to summarise the evidence for iron supplementation, both enteral and parenteral, for the management of preoperative anaemia. To evaluate the effects of preoperative iron therapy (enteral or parenteral) in reducing the need for allogeneic blood transfusions in anaemic patients undergoing surgery. We ran the search on 30 July 2018. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic and Embase (Ovid), CINAHL Plus (EBSCO), PubMed, and clinical trials registries, and we screened reference lists. We ran a top-up search on 28 November 2019; one study is now awaiting classification. We included all randomised controlled trials (RCTs) that compared preoperative iron monotherapy to placebo, no treatment, standard care or another form of iron therapy for anaemic adults undergoing surgery. We defined anaemia as haemoglobin values less than 13 g/dL for males and 12 g/dL for non-pregnant females. Two review authors collected data and a third review author checked all collected data. Data were collected on the proportion of patients who receive a blood transfusion, the amount of blood transfused per patient (units), quality of life, ferritin levels and haemoglobin levels, measured as continuous variables at the following predetermined time points: pretreatment (baseline), preoperatively but postintervention, and postoperatively. We performed statistical analysis using the Cochrane software, Review Manager 5. We summarised outcome data in tables and forest plots. We used the GRADE approach to describe the quality of the body of evidence. Six RCTs, with a total of 372 participants, evaluated preoperative iron therapy to correct anaemia before planned surgery. Four studies compared iron therapy (either oral (one study) or intravenous (three studies)) with no treatment, placebo or usual care, and two studies compared intravenous iron therapy with oral iron therapy. Iron therapy was delivered over a range of periods that varied from 48 hours to three weeks prior to surgery. The 372 participants in our analysis fall far short of the 819 required - as calculated by our information size calculation - to detect a 30% reduction in blood transfusions. Five trials, involving 310 people, reported the proportion of participants who received allogeneic blood transfusions. Meta-analysis of iron therapy versus placebo or standard care showed no difference in the proportion of participants who received a blood transfusion (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.87 to 1.70; 4 studies, 200 participants; moderate-quality evidence). Only one study that compared oral versus intravenous iron therapy measured this outcome, and reported no difference in risk of transfusion between groups. There was no difference between the iron therapy and placebo/standard care groups for haemoglobin level preoperatively at the end of the intervention (mean difference (MD) 0.63 g/dL, 95% CI -0.07 to 1.34; 2 studies, 83 participants; low-quality evidence). However, intravenous iron therapy produced an increase in preoperative postintervention haemoglobin levels compared with oral iron (MD 1.23 g/dL, 95% CI 0.80 to 1.65; 2 studies, 172 participants; low-quality evidence). Ferritin levels were increased by intravenous iron, both when compared to standard care ((MD 149.00, 95% CI 25.84 to 272.16; 1 study, 63 participants; low-quality evidence) or to oral iron (MD 395.03 ng/mL, 95% CI 227.72 to 562.35; 2 studies, 151 participants; low-quality evidence). Not all studies measured quality of life, short-term mortality or postoperative morbidity. Some measured the outcomes, but did not report the data, and the studies which did report the data were underpowered. Therefore, uncertainty remains regarding these outcomes. The inclusion of new research in the future is very likely to change these results. The use of iron therapy for preoperative anaemia does not show a clinically significant reduction in the proportion of trial participants who received an allogeneic blood transfusion compared to no iron therapy. Results for intravenous iron are consistent with a greater increase in haemoglobin and ferritin when compared to oral iron, but do not provide reliable evidence. These conclusions are drawn from six studies, three of which included very small numbers of participants. Further, well-designed, adequately powered, RCTs are required to determine the true effectiveness of iron therapy for preoperative anaemia. Two studies are currently in progress, and will include 1500 randomised participants.


Meeting report from the first meetings of the Computational Modeling in Biology Network (COMBINE).
The Computational Modeling in Biology Network (COMBINE), is an initiative to coordinate the development of the various community standards and formats in computational systems biology and related fields. This report summarizes the activities pursued at the first annual COMBINE meeting held in Edinburgh on October 6-9 2010 and the first HARMONY hackathon, held in New York on April 18-22 2011. The first of those meetings hosted 81 attendees. Discussions covered both official COMBINE standards-(BioPAX, SBGN and SBML), as well as emerging efforts and interoperability between different formats. The second meeting, oriented towards software developers, welcomed 59 participants and witnessed many technical discussions, development of improved standards support in community software systems and conversion between the standards. Both meetings were resounding successes and showed that the field is now mature enough to develop representation formats and related standards in a coordinated manner.


Variable carbon catabolism among Salmonella enterica serovar Typhi isolates.
Salmonella enterica serovar Typhi (S. Typhi) is strictly a human intracellular pathogen. It causes acute systemic (typhoid fever) and chronic infections that result in long-term asymptomatic human carriage. S. Typhi displays diverse disease manifestations in human infection and exhibits high clonality. The principal factors underlying the unique lifestyle of S. Typhi in its human host during acute and chronic infections remain largely unknown and are therefore the main objective of this study. To obtain insight into the intracellular lifestyle of S. Typhi, a high-throughput phenotypic microarray was employed to characterise the catabolic capacity of 190 carbon sources in S. Typhi strains. The success of this study lies in the carefully selected library of S. Typhi strains, including strains from two geographically distinct areas of typhoid endemicity, an asymptomatic human carrier, clinical stools and blood samples and sewage-contaminated rivers. An extremely low carbon catabolic capacity (27% of 190 carbon substrates) was observed among the strains. The carbon catabolic profiles appeared to suggest that S. Typhi strains survived well on carbon subtrates that are found abundantly in the human body but not in others. The strains could not utilise plant-associated carbon substrates. In addition, α-glycerolphosphate, glycerol, L-serine, pyruvate and lactate served as better carbon sources to monosaccharides in the S. Typhi strains tested. The carbon catabolic profiles suggest that S. Typhi could survive and persist well in the nutrient depleted metabolic niches in the human host but not in the environment outside of the host. These findings serve as caveats for future studies to understand how carbon catabolism relates to the pathogenesis and transmission of this pathogen.


Emergence of Majorana and Dirac particles in ultracold fermions via tunable interactions, spin-orbit effects, and Zeeman fields.
We discuss the emergence of rings of zero-energy excitations in momentum space for superfluid phases of ultracold fermions when spin-orbit effects, Zeeman fields, and interactions are varied. We show that phases containing rings of nodes possess nontrivial topological invariants, and that phase transitions between distinct topological phases belong to the Lifshitz class. Upon crossing phase boundaries, existing massless Dirac fermions in the gapless phase annihilate to produce bulk zero-mode Majorana fermions at phase boundaries, and then become massive Dirac fermions in the gapped phase. We characterize these tunable topological phase transitions via several spectroscopic properties, including excitation spectrum, spectral function, and momentum distribution.


High temperature (30 degrees C) blocks aerosol but not contact transmission of influenza virus.
Influenza causes significant morbidity in tropical regions; however, unlike in temperate zones, influenza in the tropics is not strongly associated with a given season. We have recently shown that influenza virus transmission in the guinea pig model is most efficient under cold, dry conditions, which are rare in the tropics. Herein, we report the lack of aerosol transmission at 30 degrees C and at all humidities tested. Conversely, transmission via the contact route was equally efficient at 30 degrees C and 20 degrees C. Our data imply that contact or short-range spread predominates in the tropics and offer an explanation for the lack of a well-defined, recurrent influenza season affecting tropical and subtropical regions of the world.


Propensity score matched analysis comparing the clinical outcome of Klebsiella pneumoniae and Escherichia coli causing community-onset monomicrobial bacteremia.
Bacteremia is a life-threatening condition that is associated with substantial healthcare costs. Escherichia coli and Klebsiella pneumoniae are the leading causes of community-onset gram-negative bacteremia. However, a comprehensive comparison between these pathogens involved in bacteremia episodes has yet to be reported.In this retrospective cohort study, adults with community-onset monomicrobial bacteremia caused by E coli or K pneumoniae were recruited in the emergency department of a medical center during a 6-year period, and the clinical variables were collected retrospectively from medical records. The complicated abscess occurrence was determined through imaging studies, according to the opinion of an infectious disease consultant. According to the independent predictors of 28-day mortality identified through multivariate regression analyses, patients in the E coli group were propensity score matched (PSM) in a 1:1 ratio to those in the K pneumoniae group.A total of 274 and 823 adults with K pneumoniae and E coli bacteremia were included in the present study. The K pneumoniae group had more patients with fatal comorbidities (McCabe classification), critical illness (Pitt bacteremia score ≥ 4) at bacteremia onset, and initial syndrome (e.g., severe sepsis and septic shock) as well as a higher crude mortality rate than did the E coli group. After appropriate matching, no significant differences were observed in the critical illness at bacteremia onset, initial syndrome, major comorbidities, and comorbidity severity of the 2 groups (E coli, n = 242; K pneumoniae, n = 242). Furthermore, despite similar 14- and 28-day crude mortality rates between the 2 PSM groups, more frequent abscess occurrences and a longer length of hospitalization were observed in the K pneumoniae group than in the E coli group.Conclusively, numerous clinical features at initial presentations varied between the E coli and K pneumoniae groups. Despite conducting a PSM analysis to control the differences in the baseline characteristics, a longer length of hospitalization and more frequent abscess occurrences were observed in the K pneumoniae group than in the E coli group.


Myofascial pain syndromes and their evaluation.
Myofascial pain refers to a specific form of soft-tissue rheumatism that results from irritable foci (trigger points) within skeletal muscles and their ligamentous junctions. It must be distinguished from bursitis, tendonitis, hypermobility syndromes, fibromyalgia and fasciitis. On the other hand it often exists as part of a clinical complex that includes these other soft-tissue conditions, i.e., it is not a diagnosis of exclusion. The clinical science of trigger points can be traced to the pioneering work of Kellgren in the 1930s, with his mapping of myotomal referral patterns of pain resulting from the injection of hypertonic saline into muscle and ligaments. Most muscles have characteristic myotomal patterns of referred pain; this feature forms the basis of the clinical recognition of myofascial trigger points in the form of a tender locus within a taut band of muscle which restricts the full range of motion and refers pain centrifugally when stimulated. Although myofascial pain syndromes have been described in the medical literature for about the last 100 years, it is only recently that scientific studies have revealed objective abnormalities.


Optimal timing for intravascular administration set replacement.
The tubing (administration set) attached to both venous and arterial catheters may contribute to bacteraemia and other infections. The rate of infection may be increased or decreased by routine replacement of administration sets. This review was originally published in 2005 and was updated in 2012. The objective of this review was to identify any relationship between the frequency with which administration sets are replaced and rates of microbial colonization, infection and death. We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (1950 to June 2012), CINAHL (1982 to June 2012), EMBASE (1980 to June 2012), reference lists of identified trials and bibliographies of published reviews. The original search was performed in February 2004. We also contacted researchers in the field. We applied no language restriction. We included all randomized or controlled clinical trials on the frequency of venous or arterial catheter administration set replacement in hospitalized participants. Two review authors assessed all potentially relevant studies. We resolved disagreements between the two review authors by discussion with a third review author. We collected data for seven outcomes: catheter-related infection; infusate-related infection; infusate microbial colonization; catheter microbial colonization; all-cause bloodstream infection; mortality; and cost. We pooled results from studies that compared different frequencies of administration set replacement, for instance, we pooled studies that compared replacement ≥ every 96 hours versus every 72 hours with studies that compared replacement ≥ every 48 hours versus every 24 hours. We identified 26 studies for this updated review, 10 of which we excluded; six did not fulfil the inclusion criteria and four did not report usable data. We extracted data from the remaining 18 references (16 studies) with 5001 participants: study designs included neonate and adult populations, arterial and venous administration sets, parenteral nutrition, lipid emulsions and crystalloid infusions. Most studies were at moderate to high risk of bias or did not adequately describe the methods that they used to minimize bias. All included trials were unable to blind personnel because of the nature of the intervention.No evidence was found for differences in catheter-related or infusate-related bacteraemia or fungaemia with more frequent administration set replacement overall or at any time interval comparison (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.67 to 1.69; RR 0.67, 95% CI 0.27 to 1.70). Infrequent administration set replacement reduced the rate of bloodstream infection (RR 0.73, 95% CI 0.54 to 0.98). No evidence revealed differences in catheter colonization or infusate colonization with more frequent administration set replacement (RR 1.08, 95% CI 0.94 to 1.24; RR 1.15, 95% CI 0.70 to 1.86, respectively). Borderline evidence suggested that infrequent administration set replacement increased the mortality rate only within the neonatal population (RR 1.84, 95% CI 1.00 to 3.36). No evidence revealed interactions between the (lack of) effects of frequency of administration set replacement and the subgroups analysed: parenteral nutrition and/or fat emulsions versus infusates not involving parenteral nutrition or fat emulsions; adult versus neonatal participants; and arterial versus venous catheters. Some evidence indicates that administration sets that do not contain lipids, blood or blood products may be left in place for intervals of up to 96 hours without increasing the risk of infection. Other evidence suggests that mortality increased within the neonatal population with infrequent administration set replacement. However, much the evidence obtained was derived from studies of low to moderate quality.


The hippocampal formation: morphological changes induced by thyroid, gonadal and adrenal hormones.
The hippocampal formation is of considerable interest due to its proposed role in a number of important functions, including learning and memory processes. Manipulations of thyroid, gonadal and adrenal hormones have been shown to influence hippocampal physiology as well as learning and memory. The cellular events which underlie these hormone-induced functional changes are largely unexplored. However, studies suggest that hormonal manipulations during development and in adulthood result in dramatic morphological changes within the hippocampal formation. Because neuronal physiology has been suggested to depend upon neuronal morphology, we have been determining the morphologic sensitivity of hippocampal neurons to thyroid and steroid hormones in an effort to elucidate possible structural mechanisms to account for differences in hippocampal function. In this review, hormone-induced structural changes in the developing and adult hippocampal formation are discussed, with particular emphasis on their functional relevance. Sex differences, as well as the developmental effects of thyroid hormone and glucocorticoids, are described. Moreover, the effects of ovarian steroids, thyroid hormone and glucocorticoids on neuronal morphology in the hippocampal formation of the adult rat are reviewed. These hormone-induced structural changes may account, at least in part, for previously reported hormone-induced changes in hippocampal function.


Can treatment trial samples be representative?
A catchment area-based sample of patients recruited for an eating disorder treatment trial was compared with patients from the same geographical area seen in the 12 months before and after the trial. The three samples were very similar. The research sample was representative of the usual clinic sample from which it had been selected and thus the results could be extrapolated with some confidence to other similar clinical settings. It is concluded that whilst treatment trials, by their very nature, have explicit and implicit inclusion and exclusion criteria with appropriate designs they can be usefully representative.


Accelerated robotic discovery of type II porous liquids.
Porous liquids are an emerging class of materials and to date little is known about how to best design their properties. For example, bulky solvents are required that are size-excluded from the pores in the liquid, along with high concentrations of the porous component, but both of these factors may also contribute to higher viscosities, which are undesirable. Hence, the inherent multivariate nature of porous liquids makes them amenable to high-throughput optimisation strategies. Here we develop a high-throughput robotic workflow, encompassing the synthesis, characterisation and property testing of highly-soluble, vertex-disordered porous organic cages dissolved in a range of cavity-excluded solvents. As a result, we identified 29 cage-solvent combinations that combine both higher cage-cavity concentrations and more acceptable carrier solvents than the best previous examples. The most soluble materials gave three times the pore concentration of the best previously reported scrambled cage porous liquid, as demonstrated by increased gas uptake. We were also able to explore alternative methods for gas capture and release, including liberation of the gas by increasing the temperature. We also found that porous liquids can form gels at higher concentrations, trapping the gas in the pores, which could have potential applications in gas storage and transportation.


Comparison of a human neuronal model proteome upon Japanese encephalitis or West Nile Virus infection and potential role of mosquito saliva in neuropathogenesis.
Neurotropic flavivirus Japanese encephalitis virus (JEV) and West Nile virus (WNV) are amongst the leading causes of encephalitis. Using label-free quantitative proteomics, we identified proteins differentially expressed upon JEV (gp-3, RP9) or WNV (IS98) infection of human neuroblastoma cells. Data are available via ProteomeXchange with identifier PXD016805. Both viruses were associated with the up-regulation of immune response (IFIT1/3/5, ISG15, OAS, STAT1, IRF9) and the down-regulation of SSBP2 and PAM, involved in gene expression and in neuropeptide amidation respectively. Proteins associated to membranes, involved in extracellular matrix organization and collagen metabolism represented major clusters down-regulated by JEV and WNV. Moreover, transcription regulation and mRNA processing clusters were also heavily regulated by both viruses. The proteome of neuroblastoma cells infected by JEV or WNV was significantly modulated in the presence of mosquito saliva, but distinct patterns were associated to each virus. Mosquito saliva favored modulation of proteins associated with gene regulation in JEV infected neuroblastoma cells while modulation of proteins associated with protein maturation, signal transduction and ion transporters was found in WNV infected neuroblastoma cells.


ECM-based microchannel for culturing in vitro vascular tissues with simultaneous perfusion and stretch.
We present an extracellular matrix (ECM)-based stretchable microfluidic system for culturing in vitro three-dimensional (3D) vascular tissues, which mimics in vivo blood vessels. Human umbilical vein endothelial cells (HUVECs) can be cultured under perfusion and stretch simultaneously with real-time imaging by our proposed system. Our ECM (transglutaminase (TG) cross-linked gelatin)-based microchannel was fabricated by dissolving water-soluble sacrificial polyvinyl alcohol (PVA) molds printed with a 3D printer. Flows in the microchannel were analyzed under perfusion and stretch. We demonstrated simultaneous perfusion and stretch of TG gelatin-based microchannels culturing HUVECs. We suggest that our TG gelatin-based stretchable microfluidic system proves to be a useful tool for understanding the mechanisms of vascular tissue formation and mechanotransduction.


Isoform-specific biotransformation of glyceryl trinitrate by rat aortic glutathione S-transferases.
The objective of this study was to purify and characterize rat aortic glutathione S-transferases (GSTs) and to assess their role in the biotransformation of the nitrovasodilator, glyceryl trinitrate (GTN). Two class alpha GSTs (Ya and Yc) a class mu GST (Yb2) and a class pi GST (Yp) were identified in rat aortic cytosol. Partial purification of three of these (Yb2, Yc and Yp) was achieved by affinity chromatography with S-hexylglutathione agarose. Further purification by cation- and anion-exchange chromatography resulted in the purification of GST Yc and GST Yb2/Yp to apparent homogeneity, a purification of 200- and 110-fold, respectively. Purified GST Yc and Yb2/Yp mediated GTN biotransformation with similar rates. GST activity and GTN biotransformation by rat aortic cytosol and affinity-purified GSTs were highly sensitive to inhibition by the class mu selective inhibitors Basilen Blue and bromosulfophthalein. Removal of GST Yb2 from rat aortic cytosol by immunoprecipitation resulted in marked inhibition of GST activity and GTN biotransformation. We conclude that the GSTs account for the major portion of GTN biotransformation in rat aortic cytosol, and that this is primarily attributable to the GST Yb2 isoform.


Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acid metabolism by retinoids and dietary vitamin A in liver of mice and rats.
Retinoic acid (RA), through nuclear retinoid receptors, regulates the expression of numerous genes. However, little is known of the biochemical mechanisms that regulate RA concentration in vivo. CYP26 (P450RAI), a novel cytochrome P450, is expressed during embryonic development, induced by all-trans RA, and capable of catalyzing the oxidation of [3H]RA to polar retinoids including 4-oxo-RA. Here we report that CYP26 expression in adult liver is regulated by all-trans RA and dietary vitamin A, and is correlated with the metabolism of all-trans RA to polar metabolites. In normal mouse and rat liver, CYP26 mRNA was barely detectable; however, after acute treatment with all-trans RA CYP26 mRNA and RA metabolism by liver microsomes were significantly induced. Aqueous-soluble RA metabolites were detected, but their formation was not induced. The expression of retinoid receptors, RAR-gamma and RXR-alpha, was not changed after RA treatment in vivo. In a model of chronic vitamin A ingestion during aging, CYP26 mRNA expression, determined by Northern blot and RT-PCR analysis, increased progressively with dietary vitamin A (P<0.0001; marginal < control < supplemented) and age (P<0.003). The relative expression of CYP26 mRNA was positively correlated with liver total retinol (log10), ranging from undetectable CYP26 expression at liver retinol concentrations below approximately 20 nmol/g to a three- to fourfold elevation at concentrations >10,000 nmol/g (r=0.90, P<0.0001). We conclude that CYP26 expression and RA metabolism are regulated in adult liver not only acutely by RA administration, as may be relevant to retinoid therapy, but under chronic dietary conditions relevant to vitamin A nutrition in humans.


[Immunosuppression in kidney donors with rapamycin and tacrolimus. Proinflammatory cytokine expression].
The ischemia-reperfusion injury (IRI) remains a major problem in transplantation. The objective of this study was to evaluate the effects of preconditioning a donor group with rapamycin and another donor group with tacrolimus to prevent IRI. Twelve hours before nephrectomy, donor Wistar rats received immunosuppressive drugs. The sample was divided into four experimental groups: a sham group, an untreated control group, a group treated with rapamycin (2 mg/kg) and a group treated with tacrolimus (0.3 mg/kg). Left kidneys were removed and, after three hours of cold ischemia, grafts were transplanted. Twenty-four hours later, the transplanted organs were recovered for histological analysis and evaluation of cytokine expression. The pre-conditioning treatment with rapamycin or tacrolimus significantly reduced donor blood urea nitrogen and creatinine levels compared with control group (BUN: p < 0.001 vs. control and creatinine: p < 0.001 vs. control). Acute tubular necrosis was significantly lower in donors treated with immunosuppressant drugs compared with the control group (p < 0.001). Finally, inflammatory cytokines such as TNF-a, IL-6 and rIL-21 showed lower levels in the graft of pre-treated animals. This exploratory experimental study shows that preconditioning donors with rapamycin and tacrolimus in different groups improves clinical outcome and pathology in recipients and reduces in situ pro-inflammatory cytokines associated with Th17 differentiation, creating a favorable environment for the differentiation of regulatory T cells (Tregs).


Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: implications to mitochondria-targeted antioxidant therapeutics.
Synaptic pathology and mitochondrial oxidative damage are early events in Alzheimer's disease (AD) progression. Loss of synapses and synaptic damage are the best correlates of cognitive deficits found in AD patients. Recent research on amyloid beta (Aβ) and mitochondria in AD revealed that Aβ accumulates in synapses and synaptic mitochondria, leading to abnormal mitochondrial dynamics and synaptic degeneration in AD neurons. Further, recent studies using live-cell imaging and primary neurons from amyloid beta precursor protein (AβPP) transgenic mice revealed reduced mitochondrial mass, defective axonal transport of mitochondria and synaptic degeneration, indicating that Aβ is responsible for mitochondrial and synaptic deficiencies. Tremendous progress has been made in studying antioxidant approaches in mouse models of AD and clinical trials of AD patients. This article highlights the recent developments made in Aβ-induced abnormal mitochondrial dynamics, defective mitochondrial biogenesis, impaired axonal transport and synaptic deficiencies in AD. This article also focuses on mitochondrial approaches in treating AD, and also discusses latest research on mitochondria-targeted antioxidants in AD. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.


Requirement for myeloid growth factors in the differentiation of acute promyelocytic leukaemia.
It is well known that the differentiation of acute promyelocytic leukaemia (APL) cells by all-trans-retinoic acid (ATRA) may be enhanced by myeloid growth factors, but the requirement for growth factors in this process is unclear. Our previous studies in multiple myeloma and non-APL acute myeloid leukaemia demonstrated that lineage-specific growth factors are required for the maximal activity of many pharmacologic differentiating agents in vitro. Thus, we studied whether the differentiation of APL is similarly dependent on growth factors. We found that the myeloid growth factors granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor markedly increased the differentiation of NB4 cells or APL blasts from clinical samples treated with ATRA, arsenic trioxide (ATO), or bryostatin-1 as evidenced by the enhanced expression of myeloid surface antigens and the inhibition of clonogenic growth. Furthermore, myeloid growth factors were necessary for the differentiation of APL cells since the activity of each pharmacologic agent could be blocked by specific growth factor-neutralizing antibodies. Each differentiating agent was active only at concentrations that inhibited cell cycling, suggesting that this property is also required for differentiation. These data demonstrate that both pharmacologic differentiating agents and myeloid growth factors are required, but neither sufficient, for the differentiation of APL cells. The combined use of pharmacologic differentiating agents and growth factors may improve the clinical efficacy of differentiation therapy in APL.


Integration of movement competency training to optimize behavioral interventions for child obesity: Comment on Wilfley et al. (2018).
Wilfley, Hayes, Balantekin, Van Buren, and Epstein (2018) provided an important review of behavioral interventions for obesity in children and adults. Although behavioral change interventions are effective in increasing the frequency of exercise behaviors, behavioral treatment providers may not be experts regarding how fundamental movement/motor skills (FMS) deficits (e.g., ability to run, skip, balance, leap, kick, throw, catch, bounce) may hinder obese children from achieving physical activity goals. Prerequisite knowledge and skills are necessary to perform new target behaviors such as increasing physical activity, and exercise physiologists are best positioned to provide individualized exercise prescriptions to improve movement competence. Similar to psychologists and other behavioral treatment providers, exercise physiologists conduct their exercise interventions using an individualized, skills-building approach; by working collaboratively, behavioral health providers and exercise physiologists can develop integrative behavioral treatment plans to improve skills (both cognitive-behavioral and FMS) that may increase physical activity and improve health outcomes in children with obesity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations.
Regular aspirin use is associated with reduced risk of colorectal cancer (CRC). Variation in aspirin's chemoprevention efficacy has been attributed to the presence of single nucleotide polymorphisms (SNPs). We conducted a meta-analysis using two large population-based case-control datasets, the UK-Leeds Colorectal Cancer Study Group and the NIH-Colon Cancer Family Registry, having a combined total of 3325 cases and 2262 controls. The aim was to assess 42 candidate SNPs in 15 genes whose association with colorectal cancer risk was putatively modified by aspirin use, in the literature. Log odds ratios (ORs) and standard errors were estimated for each dataset separately using logistic regression adjusting for age, sex and study site, and dataset-specific results were combined using random effects meta-analysis. Meta-analysis showed association between SNPs rs6983267, rs11694911 and rs2302615 with CRC risk reduction (All P<0.05). Association for SNP rs6983267 in the CCAT2 gene only was noteworthy after multiple test correction (P = 0.001). Site-specific analysis showed association between SNPs rs1799853 and rs2302615 with reduced colon cancer risk only (P = 0.01 and P = 0.004, respectively), however neither reached significance threshold following multiple test correction. Meta-analysis of SNPs rs2070959 and rs1105879 in UGT1A6 gene showed interaction between aspirin use and CRC risk (Pinteraction = 0.01 and 0.02, respectively); stratification by aspirin use showed an association for decreased CRC risk for aspirin users having a wild-type genotype (rs2070959 OR = 0.77, 95% CI = 0.68-0.86; rs1105879 OR = 0.77 95% CI = 0.69-0.86) compared to variant allele cariers. The direction of the interaction however is in contrast to that published in studies on colorectal adenomas. Both SNPs showed potential site-specific interaction with aspirin use and colon cancer risk only (Pinteraction = 0.006 and 0.008, respectively), with the direction of association similar to that observed for CRC. Additionally, they showed interaction between any non-steroidal anti-inflammatory drugs (including aspirin) use and CRC risk (Pinteraction = 0.01 for both). All gene x environment (GxE) interactions however were not significant after multiple test correction. Candidate gene investigation indicated no evidence of GxE interaction between genetic variants in genes involved in aspirin pathways, regular aspirin use and colorectal cancer risk.


Picky eating and child weight status development: a longitudinal study.
Children's picky eating behaviour has been linked both to being overweight and underweight. However, the role of parenting practices in this relationship has rarely been investigated. The present study aimed to clarify the direction of the association between picky eating and weight status and to examine the moderating role of food parenting practices. The present study comprised a longitudinal study on the effects of picky eating on child weight status within the KOALA Birth Cohort Study, the Netherlands. Mothers and their children were included in the analyses. Children's picky eating behaviour and food parenting practices were assessed at baseline (child age 5 years). Their weight status was assessed repeatedly until age 9 years. Mixed effects linear and logistic regressions were used to compare picky eaters (n = 403) and non-picky eaters (n = 621) on changes in weight status over the years. At baseline of age 5 years, picky eaters were slightly shorter, more often underweight and less often overweight than non-picky eaters, whereas energy intake in relation to body weight (kJ kg(-1)) was similar. Picky eaters with a normal weight at baseline had no increased risk of becoming underweight during follow-up until age 9 years, and were less likely to become overweight compared to non-picky eaters. There were no interactions with food parenting practices. The parents of picky eaters more often reported pressuring their child to eat and restrict unhealthy food intake compared to parents of non-picky eaters. The association between picky eating and child weight status was not influenced by parenting practices.


The first haramiyoid mammal from Asia.
A lower molar of a haramiyoid mammal is described from the Toutunhe Formation of Liuhuanggou near Urumqi in the southern Junggar Basin, Xinjiang, China. It is referred to Eleutherodon sp., otherwise exclusively known from the Upper Bathonian of England. It is the first record of the order Haramiyida from Asia and the first Mesozoic mammal described from the southern Junggar Basin. Apart from the English specimens of Eleutherodon and Staffia from the Upper Jurassic of East Africa, it is the geologically youngest haramiyoid known. It is the first vertebrate taxon from the Toutunhe Formation that is probably not endemic and lends some support to the dating of the Formation as late Middle Jurassic, probably Bathonian.


Individual-subject Functional Localization Increases Univariate Activation but Not Multivariate Pattern Discriminability in the "Multiple-demand" Frontoparietal Network.
The frontoparietal "multiple-demand" (MD) control network plays a key role in goal-directed behavior. Recent developments of multivoxel pattern analysis (MVPA) for fMRI data allow for more fine-grained investigations into the functionality and properties of brain systems. In particular, MVPA in the MD network was used to gain better understanding of control processes such as attentional effects, adaptive coding, and representation of multiple task-relevant features, but overall low decoding levels have limited its use for this network. A common practice of applying MVPA is by investigating pattern discriminability within a ROI using a template mask, thus ensuring that the same brain areas are studied in all participants. This approach offers high sensitivity but does not take into account differences between individuals in the spatial organization of brain regions. An alternative approach uses independent localizer data for each subject to select the most responsive voxels and define individual ROIs within the boundaries of a group template. Such an approach allows for a refined and targeted localization based on the unique pattern of activity of individual subjects while ensuring that functionally similar brain regions are studied for all subjects. In the current study, we tested whether using individual ROIs leads to changes in decodability of task-related neural representations as well as univariate activity across the MD network compared with when using a group template. We used three localizer tasks to separately define subject-specific ROIs: spatial working memory, verbal working memory, and a Stroop task. We then systematically assessed univariate and multivariate results in a separate rule-based criterion task. All the localizer tasks robustly recruited the MD network and evoked highly reliable activity patterns in individual subjects. Consistent with previous studies, we found a clear benefit of the subject-specific ROIs for univariate results from the criterion task, with increased activity in the individual ROIs based on the localizers' data, compared with the activity observed when using the group template. In contrast, there was no benefit of the subject-specific ROIs for the multivariate results in the form of increased discriminability, as well as no cost of reduced discriminability. Both univariate and multivariate results were similar in the subject-specific ROIs defined by each of the three localizers. Our results provide important empirical evidence for researchers in the field of cognitive control for the use of individual ROIs in the frontoparietal network for both univariate and multivariate analysis of fMRI data and serve as another step toward standardization and increased comparability across studies.


Other important applications for beta-blockers in high-risk patients.
Beta-blockers suppress the adverse effects of chronic activation of the sympathetic nervous system-which plays an important role in the progression of cardiovascular disease- and the drugs are also recommended as primary therapy in other diverse medical conditions that present treatment problems. For many patients with atrial fibrillation, a common condition that poses a high risk of stroke, heart rate control with beta-blockers is increasingly seen as a critical therapeutic component. Similarly, perioperative beta-blocker use provides clinical benefits in patients undergoing noncardiac surgery who are at risk of cardiac events. In migraine therapy, beta-blockers are well established as effective agents for prophylaxis, and beta-blockers may reduce levels of C-reactive protein, a sensitive marker of inflammation in cardiovascular disease. Reviewing the role of beta-blockers in several ancillary conditions should help illuminate various aspects of the complex progression of cardiovascular disease and clarify the drugs' various therapeutic benefits.


Perspectives of older adults on co-management of low back pain by doctors of chiropractic and family medicine physicians: a focus group study.
While older adults may seek care for low back pain (LBP) from both medical doctors (MDs) and doctors of chiropractic (DCs), co-management between these providers is uncommon. The purposes of this study were to describe the preferences of older adults for LBP co-management by MDs and DCs and to identify their concerns for receiving care under such a treatment model. We conducted 10 focus groups with 48 older adults who received LBP care in the past year. Interviews explored participants' care seeking experiences, co-management preferences, and perceived challenges to successful implementation of a MD-DC co-management model. We analyzed the qualitative data using thematic content analysis. Older adults considered LBP co-management by MDs and DCs a positive approach as the professions have complementary strengths. Participants wanted providers who worked in a co-management model to talk openly and honestly about LBP, offer clear and consistent recommendations about treatment, and provide individualized care. Facilitators of MD-DC co-management included collegial relationships between providers, arrangements between doctors to support interdisciplinary referral, computer systems that allowed exchange of health information between clinics, and practice settings where providers worked in one location. Perceived barriers to the co-management of LBP included the financial costs associated with receiving care from multiple providers concurrently, duplication of tests or imaging, scheduling and transportation problems, and potential side effects of medication and chiropractic care. A few participants expressed concern that some providers would not support a patient-preferred co-managed care model. Older adults are interested in receiving LBP treatment co-managed by MDs and DCs. Older adults considered patient-centered communication, collegial interdisciplinary interactions between these providers, and administrative supports such as scheduling systems and health record sharing as key components for successful LBP co-management.


Individualization of mycophenolate mofetil dose in renal transplant recipients.
The immunosuppressive agent mycophenolate mofetil has been successfully used over the past 10 years to prevent acute allograft rejection after renal transplantation. It has mainly been administered as a fixed dose of mycophenolate mofetil 1000 mg b.i.d. The pharmacokinetics of mycophenolic acid, the active moiety of the prodrug mycophenolate mofetil, show large between-patient variability, and exposure to mycophenolic acid correlates with the risk for acute rejection. This suggests that already excellent clinical results can be further improved by mycophenolate mofetil dose individualization. This review discusses different arguments in favour of individualization of mycophenolate mofetil dose, as well as strategies for managing mycophenolate mofetil therapy individualization, including pharmacokinetic and pharmacodynamic monitoring and dose individualization based on pharmacogenetic information. It is expected that pharmacokinetic monitoring of mycophenolic acid will offer the most effective and feasible tool for mycophenolate mofetil dose individualization.


Enterococcus faecalis 3-hydroxy-3-methylglutaryl coenzyme A synthase, an enzyme of isopentenyl diphosphate biosynthesis.
Biosynthesis of the isoprenoid precursor isopentenyl diphosphate (IPP) proceeds via two distinct pathways. Sequence comparisons and microbiological data suggest that multidrug-resistant strains of gram-positive cocci employ exclusively the mevalonate pathway for IPP biosynthesis. Bacterial mevalonate pathway enzymes therefore offer potential targets for development of active site-directed inhibitors for use as antibiotics. We used the PCR and Enterococcus faecalis genomic DNA to isolate the mvaS gene that encodes 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, the second enzyme of the mevalonate pathway. mvaS was expressed in Escherichia coli from a pET28 vector with an attached N-terminal histidine tag. The expressed enzyme was purified by affinity chromatography on Ni(2+)-agarose to apparent homogeneity and a specific activity of 10 micromol/min/mg. Analytical ultracentrifugation showed that the enzyme is a dimer (mass, 83.9 kDa; s(20,w), 5.3). Optimal activity occurred in 2.0 mM MgCl(2) at 37(o)C. The DeltaH(a) was 6,000 cal. The pH activity profile, optimum activity at pH 9.8, yielded a pK(a) of 8.8 for a dissociating group, presumably Glu78. The stoichiometry per monomer of acetyl-CoA binding was 1.2 +/- 0.2 and that of covalent acetylation was 0.60 +/- 0.02. The K(m) for the hydrolysis of acetyl-CoA was 10 microM. Coupled conversion of acetyl-CoA to mevalonate was demonstrated by using HMG-CoA synthase and acetoacetyl-CoA thiolase/HMG-CoA reductase from E. faecalis.


Physical characterization of a low-charge glycoform of the MUC5B mucin comprising the gel-phase of an asthmatic respiratory mucous plug.
We have previously noted that sequential extraction of an asthmatic mucous exudate with 6 M guanidinium chloride yielded a fraction of the mucins that were most resistant to solubilization and of high Mr [Sheehan, Richardson, Fung, Howard and Thornton (1995) Am. J. Respir. Cell Mol. Biol. 13, 748-756]. Here we show that this mucin fraction is dominated (at least 96% of the total) by the low-charge glycoform of the MUC5B gene product. Seen in the electron microscope the mucins appeared mainly as compact 'island' structures composed of linear threads often emanating from globular 'nodes' rather than the discrete linear threads more typical of mucins that we have previously described. The effect of reducing agents was as expected for other gel-forming mucins, i.e. reduced subunits or monomers of Mr 3x10(6)) were produced within 15 min of treatment. Kinetic experiments on the cleavage of the intact mucins with the proteinase trypsin indicated two clear regimes of fragmentation. An initial rapid cleavage generated mucins ranging from Mr=4x10(6) to 30x10(6) that in the electron microscope appeared as polydisperse threads (500-3000 nm in length), similar to normal and other respiratory mucins that we have previously characterized. A subsequent slower fragmentation over many hours yielded a major fragment of Mr 3x10(6) and length 200-600 nm, very similar in size and Mr to the subunits obtained by reduction. The results suggest that the MUC5B mucin is assembled, first into polydisperse linear threads, which are then linked together via a protein-mediated process. This might involve part of the mucin polypeptide or an as yet unidentified protein(s). The high proteinase susceptibility of the linkage suggests that it might be a point of control for mucin size and thus mucus rheology.


University clinic and private practice treatment outcomes in Class I extraction and nonextraction patients: A comparative study with the American Board of Orthodontics Objective Grading System.
The aim of this study was to compare treatment outcomes in university vs private practice settings with Class I patients using the American Board of Orthodontics Objective Grading System. A parent sample of 580 Class I patients treated with and without extractions of 4 first premolars was subjected to discriminant analysis to identify a borderline spectrum of 66 patients regarding the extraction modality. Of these patients, 34 were treated in private orthodontic practices, and 32 were treated in a university graduate orthodontic clinic. The treatment outcomes were evaluated using the 8 variables of the American Board of Orthodontics Objective Grading System. The total scores ranged from 10 to 47 (mean, 25.44; SD, 9.8) for the university group and from 14 to 45 (mean, 25.94; SD, 7.7) for the private practice group. The university group achieved better scores for the variables of buccolingual inclination (mean difference, 2.28; 95% confidence interval [CI], 0.59, 3.98; P = 0.01) and marginal ridges (mean difference, 1.32; 95% CI, 0.28, 2.36; P = 0.01), and the private practice group achieved a better score for the variable of root angulation (mean difference, -0.65; 95% CI, -1.26, -0.03; P = 0.04). However, no statistically intergroup differences were found between the total American Board of Orthodontics Objective Grading System scores (mean difference, -0.5; 95% CI, -3.82, 4.82; P = 0.82). Patients can receive similar quality of orthodontic treatment in a private practice and a university clinic. The orthodontists in the private practices were more successful in angulating the roots properly, whereas the orthodontic residents accomplished better torque control of the posterior segments and better marginal ridges.


Response of Methanogens in Arctic Sediments to Temperature and Methanogenic Substrate Availability.
Although cold environments are major contributors to global biogeochemical cycles, comparatively little is known about their microbial community function, structure, and limits of activity. In this study a microcosm based approach was used to investigate the effects of temperature, and methanogenic substrate amendment, (acetate, methanol and H2/CO2) on methanogen activity and methanogen community structure in high Arctic wetlands (Solvatnet and Stuphallet, Svalbard). Methane production was not detected in Stuphallet sediment microcosms (over a 150 day period) and occurred within Solvatnet sediments microcosms (within 24 hours) at temperatures from 5 to 40°C, the maximum temperature being at far higher than in situ maximum temperatures (which range from air temperatures of -1.4 to 14.1°C during summer months). Distinct responses were observed in the Solvatnet methanogen community under different short term incubation conditions. Specifically, different communities were selected at higher and lower temperatures. At lower temperatures (5°C) addition of exogenous substrates (acetate, methanol or H2/CO2) had no stimulatory effect on the rate of methanogenesis or on methanogen community structure. The community in these incubations was dominated by members of the Methanoregulaceae/WCHA2-08 family-level group, which were most similar to the psychrotolerant hydrogenotrophic methanogen Methanosphaerula palustris strain E1-9c. In contrast, at higher temperatures, substrate amendment enhanced methane production in H2/CO2 amended microcosms, and played a clear role in structuring methanogen communities. Specifically, at 30°C members of the Methanoregulaceae/WCHA2-08 predominated following incubation with H2/CO2, and Methanosarcinaceaeand Methanosaetaceae were enriched in response to acetate addition. These results may indicate that in transiently cold environments, methanogen communities can rapidly respond to moderate short term increases in temperature, but not necessarily to the seasonal release of previously frozen organic carbon from thawing permafrost soils. However, as temperatures increase such inputs of carbon will likely have a greater influence on methane production and methanogen community structure. Understanding the action and limitations of anaerobic microorganisms within cold environments may provide information which can be used in defining region-specific differences in the microbial processes; which ultimately control methane flux to the atmosphere.


In vitro and in vivo targeting of different folate receptor-positive cancer cell lines with a novel 99mTc-radiofolate tracer.
For the assessment of folate-based radiopharmaceuticals, human nasopharyngeal KB carcinoma cells are traditionally used although nasopharyngeal cancer is rare. On the other hand, the folate receptor (FR) is frequently overexpressed on diverse cancer types, the highest frequency (>90%) being on ovarian carcinomas. The goal of our study was the in vitro and in vivo assessment of different FR-positive human carcinoma cells. In addition, a murine sarcoma cell line was assessed as a pre-clinical alternative to human xenograft models. FR-positive human nasopharyngeal, cervical, ovarian and colorectal cancer cell lines and the transgenic mouse sarcoma (24JK-FBP) cell line were targeted with a novel 99mTc-tricarbonyl folate derivative 2. Comparative in vitro cell binding studies were carried out under standardised folate-deficient conditions. In vivo studies were performed in nude mice and C6 black mice. The in vitro cell experiments revealed only FR-specific binding (unspecific <0.02%), ranging from 3.5% to 52% of complex 2 owing to variable levels of FR expression of the cell lines. In vivo tumour uptake of radiotracer 2 varied less than in vitro. It ranged from 0.66+/-0.17% ID/g (LoVo) through 1.16+/-0.64% ID/g (IGROV-1) and 1.55+/-0.43% ID/g (24JK-FBP) to 2.33+/-0.36% ID/g (KB) 4 h p.i. These pre-clinical studies indicate that in vitro data obtained in FR-positive cancer cells do not necessarily correspond with or predict in vivo radiofolate uptake in corresponding (xeno)grafts. In addition, the murine 24JK-FBP cell line proved to be a valuable pre-clinical alternative to human tumour models.


[Catecholamines in salivary gland and oral mucosal tissue and in the saliva in acute inflammation of the oral soft tissues].
Catecholamine contents in non-stimulated and pilocarpine-stimulated submaxillary salivary gland tissue (SGT), oral mucosa (OM) and stimulated saliva in acute staphylococcal inflammation of soft oral cavity tissue were determined in rats using the standard HPLC method. It was shown that 2 hrs after toxin injection NA contents decreased in non-stimulated SGT. After 24 hrs A contents decreased too as well as HA contents in OM. After 2 and 24 hrs HA contents increased in stimulated SGT, in OM HA contents did not change but A contents after 24 hrs decreased. In saliva, after 24 hrs these levers were normalized. The authors concluded that the inflammatory process in the soft oral cavity tissue was the cause of basal and stimulated salivary secretion disturbance.


Validation of the Spanish version of the WOMAC questionnaire for patients with hip or knee osteoarthritis. Western Ontario and McMaster Universities Osteoarthritis Index.
The aim of this study was to validate a translated version of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire in Spanish patients with hip or knee osteoarthritis (OA). The WOMAC questionnaire and the SF-36 were administered to a sample of 269 patients on the waiting list for hip or knee replacement. We studied the convergent validity and the item-scale correlation using Pearson's correlation coefficient and Spearman's pi. For the reliability study we used another sample of 58 patients who received the WOMAC twice within 15 days. The Pearson's, Spearman's pi, and intraclass correlation coefficients were calculated. Internal consistency was measured by Cronbach's alpha. The responsiveness study was carried out by resending the two questionnaires to all patients 6 months after surgical intervention; responsiveness was measured by means of the paired t-test, the effect size I and the standardised response mean. The Pearson's coefficients for the convergent validity ranged from -0.52 to -0.63. The coefficients obtained for the item-scale correlation of the pain area were 0.74 or higher, 0.91 or higher for stiffness, and 0.61 or higher for function. When measuring the test-retest reliability, the coefficients ranged from 0.66 to 0.81. Internal consistency yielded a Cronbach's alpha ranging from 0.81 to 0.93. The responsiveness showed an effect size I ranging from 1.5 to 2.2 in patients who underwent hip replacement; for those who underwent knee replacement the range was 1 to 1.8. The standardised response mean ranged from 1.3 to 1.9 for patients with hip OA; those with knee OA ranged from 0.8 to 1.5. The Spanish version of WOMAC is a valid, reliable and responsive instrument in patients with hip or knee OA.


A gateway for phylogenetic analysis powered by grid computing featuring GARLI 2.0.
We introduce molecularevolution.org, a publicly available gateway for high-throughput, maximum-likelihood phylogenetic analysis powered by grid computing. The gateway features a garli 2.0 web service that enables a user to quickly and easily submit thousands of maximum likelihood tree searches or bootstrap searches that are executed in parallel on distributed computing resources. The garli web service allows one to easily specify partitioned substitution models using a graphical interface, and it performs sophisticated post-processing of phylogenetic results. Although the garli web service has been used by the research community for over three years, here we formally announce the availability of the service, describe its capabilities, highlight new features and recent improvements, and provide details about how the grid system efficiently delivers high-quality phylogenetic results.


Ambulatory diagnosis and treatment of nonmalignant pain in the United States, 2000-2010.
Escalating rates of prescription opioid use and abuse have occurred in the context of efforts to improve the treatment of nonmalignant pain. The aim of the study was to characterize the diagnosis and management of nonmalignant pain in ambulatory, office-based settings in the United States between 2000 and 2010. Serial cross-sectional and multivariate regression analyses of the National Ambulatory Medical Care Survey (NAMCS), a nationally representative audit of office-based physician visits, were conducted. (1) Annual visit volume among adults with primary pain symptom or diagnosis; (2) receipt of any pain treatment; and (3) receipt of prescription opioid or nonopioid pharmacologic therapy in visits for new musculoskeletal pain. Primary symptoms or diagnoses of pain consistently represented one-fifth of visits, varying little from 2000 to 2010. Among all pain visits, opioid prescribing nearly doubled from 11.3% to 19.6%, whereas nonopioid analgesic prescribing remained unchanged (26%-29% of visits). One-half of new musculoskeletal pain visits resulted in pharmacologic treatment, although the prescribing of nonopioid pharmacotherapies decreased from 38% of visits (2000) to 29% of visits (2010). After adjusting for potentially confounding covariates, few patient, physician, or practice characteristics were associated with a prescription opioid rather than a nonopioid analgesic for new musculoskeletal pain, and increases in opioid prescribing generally occurred nonselectively over time. Increased opioid prescribing has not been accompanied by similar increases in nonopioid analgesics or the proportion of ambulatory pain patients receiving pharmacologic treatment. Clinical alternatives to prescription opioids may be underutilized as a means of treating ambulatory nonmalignant pain.


Structural and functional classes of multipolar cells in the ventral cochlear nucleus.
Multipolar cells in the ventral cochlear nucleus (VCN) are a structurally and functionally diverse group of projection neurons. Understanding their role in the ascending pathway involves partitioning multipolar cells into distinct populations and determining where in the brain each sends its coded messages. In this study, we used retrograde labeling techniques in rats to identify multipolar neurons that project their axons to the ipsilateral dorsal cochlear nucleus (DCN), the contralateral CN, or both structures. Three rats received injections of biotinylated dextran amine in the ipsilateral DCN and diamidino yellow in the contralateral CN. Several radiate multipolar neurons (defined by their axonal projections to the ipsilateral DCN and their dendrites that traverse VCN isofrequency sheets) were double-labeled but over 70% were not. This result suggests two distinct populations: (1) radiate-commissural (RC) multipolar cells that project to the ipsilateral DCN and the contralateral CN, and (2) radiate multipolar cells that project exclusively (in this context) to the ipsilateral DCN. In a different group of animals, we retrogradely labeled multipolar neurons that project their axons to the contralateral CN and measured the size of their cell bodies. The mean size of this population (266 +/- 156 microm2) was significantly smaller than those of RC-multipolar cells (418 +/- 140 microm2). We conclude that the CN commissural pathway is composed of at least two components: (1) RC multipolar cells and (2) commissural multipolar cells that are small- and medium-sized neurons that project exclusively (in this context) to the contralateral CN. These results identify separate structural groups of multipolar cells that may correspond to physiological unit types described in the literature. They also provide protocols for isolating and studying different populations of multipolar cells to determine the neural mechanisms that govern their responses to sound.


Influence of the LOV domain on low-lying excited states of flavin: a combined quantum-mechanics/molecular-mechanics investigation.
The ground and low-lying excited states of flavin mononucleotide (FMN) in the light, oxygen, and voltage sensitive (LOV) domain of the blue-light photosensor YtvA of Bacillus subtilis were studied by means of combined quantum-mechanical/molecular-mechanical (QM/MM) methods. The FMN cofactor (without the side chain) was treated with density functional theory (DFT) for the geometry optimizations and a combination of DFT and multireference configuration interaction (MRCI) for the determination of the excitation energies, while the protein environment was represented by the CHARMM force field. In addition, several important amino acid side chains, including the reactive cysteine residue, were included in the QM region in order to probe their influence on the spectral properties of the cofactor in two protein conformations. Spin-orbit coupling was taken into account employing an efficient, nonempirical spin-orbit mean-field Hamiltonian. Our results reveal that the protein environment of YtvA-LOV induces spectral shifts for the (pi pi*) states that are similar to those in aqueous solution. In contrast, the blue shifts of the (n pi*) states are smaller in the protein environment, enabling a participation of these states in the decay processes of the optically bright S(1) state. Increased spin-orbit coupling between the initially populated S(1) state and the T(1) and T(2) states is found in YtvA-LOV as compared to free lumiflavine in water. The enhanced singlet-triplet coupling is brought about partially by configuration interaction with (n pi*) states at the slightly out-of-plane distorted minimum geometry. In addition, an external heavy-atom effect is observed when the sulfur atom of the nearby cysteine residue is included in the QM region, in line with experimental findings.


The role of the complement system in cancer.
In addition to being a component of innate immunity and an ancient defense mechanism against invading pathogens, complement activation also participates in the adaptive immune response, inflammation, hemostasis, embryogenesis, and organ repair and development. Activation of the complement system via classical, lectin, or alternative pathways generates anaphylatoxins (C3a and C5a) and membrane attack complex (C5b-9) and opsonizes targeted cells. Complement activation end products and their receptors mediate cell-cell interactions that regulate several biological functions in the extravascular tissue. Signaling of anaphylatoxin receptors or assembly of membrane attack complex promotes cell dedifferentiation, proliferation, and migration in addition to reducing apoptosis. As a result, complement activation in the tumor microenvironment enhances tumor growth and increases metastasis. In this Review, I discuss immune and nonimmune functions of complement proteins and the tumor-promoting effect of complement activation.


Complexes of CO₂ with the Azoles: Tetrel Bonds, Hydrogen Bonds and Other Secondary Interactions.
Ab initio MP2/aug'-cc-pVTZ calculations have been performed to investigate the complexes of CO₂ with the azoles pyrrole, pyrazole, imidazole, 1,2,3- and 1,2,4-triazole, tetrazole and pentazole. Three types of complexes have been found on the CO₂:azole potential surfaces. These include ten complexes stabilized by tetrel bonds that have the azole molecule in the symmetry plane of the complex; seven tetrel-bonded complexes in which the CO₂ molecule is perpendicular to the symmetry plane; and four hydrogen-bonded complexes. Eight of the planar complexes are stabilized by Nx···C tetrel bonds and by a secondary interaction involving an adjacent Ny-H bond and an O atom of CO₂. The seven perpendicular CO₂:azole complexes form between CO₂ and two adjacent N atoms of the ring, both of which are electron-pair donors. In three of the four hydrogen-bonded complexes, the proton-donor Nz-H bond of the ring is bonded to two C-H bonds, thereby precluding the planar and perpendicular complexes. The fourth hydrogen-bonded complex forms with the strongest acid pentazole. Binding energies, charge-transfer energies and changes in CO₂ stretching and bending frequencies upon complex formation provide consistent descriptions of these complexes. Coupling constants across tetrel bonds are negligibly small, but 2hJ(Ny-C) across Nz-H···C hydrogen bonds are larger and increase as the number of N atoms in the ring increases.


Enhancement in spatial and recognition memory functions following long term oral administration of ginger extract in rats.
Ginger (Zingiber Officinale) is known over the centuries for its medicinal properties and has been used worldwide as health supplement and for treatment of several diseases. The purpose of this study was to evaluate the effects of whole ginger extract administration on spatial and recognition memory using experimental animal models. The antimicrobial properties of ginger extract against various pathogenic fungal and bacterial species were also examined. Aqueous extract of ginger at a dose of 500 mg/kg was orally administered to test rats and water was orally given to control rats for 6 weeks. Water Maze task (WM) was used to assess spatial memory and recognition memory of rats was evaluated by the Novel Object Recognition (NOR) task. Time spent with novel object was significantly increased in ginger treated rats as compared to control animals in novel object recognition task exhibiting enhanced recognition memory in ginger treated rats. Ginger treated rats exhibited significantly enhanced both short term memory and long term memory as evidenced by decrease in time to reach the hidden platform 1h and 24 h after training as compared to control rats. Short term memory functions of ginger treated rats were more enhanced than long term memory functions. Our findings suggest that ginger consumption may lead to an improvement in spatial and recognition memory. Significant activity of aqueous ginger extract was observed against pathogenic bacteria as well as fungal species. It is therefore suggested in this study that ginger extract can be used in microbial infections and as a memory enhancing drug in various memory disorders.


Occult malformations of the skull base.
Occult malformations of the skull base are rare anomalies. They are often not detected until they give rise to complications such as meningitis or cerebrospinal fluid rhinorrhea. We used high-resolution computed tomography, fluorescein endoscopy, cisternography, magnetic resonance imaging, and duraplasty to diagnose occult malformations of the skull base in 4 patients. The four patients had had between 4 and 6 attacks of meningitis. Cerebrospinal fluid rhinorrhea was confirmed in 3 cases. The following occult malformations were found: (1) an encephalocele of the glabella/cribriform plate and a meningocele at the petrous bone apex, (2) a meningoencephalocele at the petrous bone apex, (3) dural lesions in the regions foramen rotundum/sphenoid sinus and frontal sinus/cribriform plate, and (4) a dural lesion of the sphenoid sinus. In patients presenting with recurrent meningitis, meningitis with isolation of upper airway pathogens, or cerebrospinal fluid rhinorrhea, modern diagnostic methods should be used to search for dural lesions. Diagnosis of an occult malformation makes it possible to perform the necessary surgical repair and thus prevent the further occurrence of potentially fatal episodes of meningitis.


Geometry-dependent scattering through quantum billiards: experiment and theory.
We present experimental studies of geometry-specific quantum scattering in microwave billiards of a given shape. We perform full quantum-mechanical scattering calculations and find excellent agreement with experimental results. We also carry out semiclassical calculations where the conductance is given as a sum over all classical trajectories between the leads, each of the trajectories carrying a quantum-mechanical phase. We unambiguously demonstrate that the characteristic frequencies of the oscillations in the transmission and reflection amplitudes t and r are related to the length distribution of the classical trajectories between the leads, whereas the frequencies of the probabilities T=/t/(2) and R=/r/(2) can be understood in terms of the length difference distribution in the pairs of classical trajectories. We also discuss the effect of nonclassical "ghost" trajectories, i.e., trajectories that include classically forbidden reflection off the lead mouths.


Antibody-mediated trapping of helminth larvae requires CD11b and Fcγ receptor I.
Infections with intestinal helminths severely impact on human and veterinary health, particularly through the damage that these large parasites inflict when migrating through host tissues. Host immunity often targets the motility of tissue-migrating helminth larvae, which ideally should be mimicked by anti-helminth vaccines. However, the mechanisms of larval trapping are still poorly defined. We have recently reported an important role for Abs in the rapid trapping of tissue-migrating larvae of the murine parasite Heligmosomoides polygyrus bakeri. Trapping was mediated by macrophages (MΦ) and involved complement, activating FcRs, and Arginase-1 (Arg1) activity. However, the receptors and Ab isotypes responsible for MΦ adherence and Arg1 induction remained unclear. Using an in vitro coculture assay of H. polygyrus bakeri larvae and bone marrow-derived MΦ, we now identify CD11b as the major complement receptor mediating MΦ adherence to the larval surface. However, larval immobilization was largely independent of CD11b and instead required the activating IgG receptor FcγRI (CD64) both in vitro and during challenge H. polygyrus bakeri infection in vivo. FcγRI signaling also contributed to the upregulation of MΦ Arg1 expression in vitro and in vivo. Finally, IgG2a/c was the major IgG subtype from early immune serum bound by FcγRI on the MΦ surface, and purified IgG2c could trigger larval immobilization and Arg1 expression in MΦ in vitro. Our findings reveal a novel role for IgG2a/c-FcγRI-driven MΦ activation in the efficient trapping of tissue-migrating helminth larvae and thus provide important mechanistic insights vital for anti-helminth vaccine development.


Third molar maturity index by measurements of open apices in a Libyan sample of living subjects.
In most countries, forensic age estimation in living subjects has become increasingly important in the last few years. In addition, as the age of legal majority ranges from 14 to 18 in many countries, and in Libya it is 18 years, radiographic assessment of the degree of third molar development is essential for forensic age estimation of adolescents and young adults. The aim of this paper is to assess the accuracy of the cut-off value of 0.08, by measurements of third molar index (I3M), in determining if a subject is adult or not in Libyan population. Digital panoramic radiographs of 307 healthy subjects (163 girls, 144 boys), aged between 14 and 22, were analysed. The I3M, the age and the sex of the subjects were used as predictive variable for age estimation. Using a cut-off of 0.08, the sensitivity of the test for boys was 90.9% and the specificity 100%. The proportion of correctly classified individuals was 95.1% (95% CI: 91.5-98.7%). The sensitivity for girls was 90.6% and the specificity 100%. The proportion of correctly classified individuals was 94.5% (95% CI: 90.9-98.1%). Estimated post-test probability in boys and girls was 100%. Further analyses, performed using a cut-off of 0.09, do not affect the specificity (100%) while they improve the sensitivity for both boys and girls.


Polymorphisms in CYP2D6 may predict methamphetamine related heart failure.
Methamphetamine (METH) has been associated with a dilated cardiomyopathy. The first and rate-limiting step of metabolism is dependent on the polymorphic enzyme CYP2D6. To evaluate if polymorphisms in CYP2D6 can be associated with the development of a methamphetamine-induced cardiomyopathy. We performed a prospective case-control pilot study. Cases were defined by a urinary drug screen positive for amphetamine and evidence of heart failure by beta natriuretic peptide (BNP) greater than 300 pg/ml and symptoms of heart failure. Controls were defined with urinary drug screens positive for amphetamines but without evidence of heart failure defined by a BNP lesser than 300 pg/ml or symptoms of heart failure. Exclusion criteria were less than 18 years or greater than 60 years of age, urinary toxicology screen positive for additional stimulants, known coronary artery disease (CAD) defined by greater than 50% stenosis on catheterization or previous myocardial infarction, known cardiomyopathy of alternative etiology or inability to provide consent. Patients underwent gas chromatography confirmation-mass spectroscopy for methamphetamine, genotyping of CYP2D6, limited echocardiography, and participated in a modified 2007 National Survey of Drug Use and Health Stimulant Survey. Genotype results were analyzed with traditional classifications and "Activity Scores". Fifty-six patients completed the study with 19 cases and 37 controls. There was no statistically significant difference in days of use in a month, age, gender, or ethnicity between cases and controls. While not statistically significant, age and days of use did trend higher in cases. CYP2D6 genotype demonstrated that the lower the activity score/poor metabolizer group had less heart failure than extensive metabolizers/higher activity score. However, it did not reach statistical significance. When adjusting for higher days of use, extensive metabolizers had the highest odds of developing a dilated cardiomyopathy. (OR: 2.33, 95% CI: 0.54-10.13). Echo findings in all cases showed reduced ejection fractions with a mean of 18.6% (range: 10-35%) and 70% had a dilated cardiomyopathy. No cardiomyopathies were seen in the controls. Mean ejection fraction was 56.75% (range: 45-70%). The odds ratio of having a dilated cardiomyopathy in extensive metabolizers was 1.62 (95% CI: 0.47-5.5). Our study demonstrates a trend that individuals with decreased metabolic activity were less likely to develop heart failure. While not statistically significant, a signal is present that extensive metabolizers may be at increased risk for the development of a cardiomyopathy.


High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma.
Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as the main cause of inactivation of the p16 gene. More recently, it has been suggested that the human ras association domain family (RASSF) 1 gene, cloned from the lung tumor-suppressor locus 3p21.3, also may be inactivated by methylation. It consists of two major alternative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A was observed in several carcinomas and tumor cell lines. In this study, promoter hypermethylation of RASSF1A and p16 was investigated in 83 hepatocellular carcinoma (HCC) tissue samples from Taiwan and in two HCC cell lines (Hep3B and HepG2). High frequencies (85% and 47%, respectively) of methylation of the CpG island promoters of RASSF1A and p16 were found in the HCC tissues. The methylation of RASSF1A also was detected in Hep3B cells but not in HepG2 cells; p16 was not methylated in either cell line. Methylation status was determined in 12 normal control liver tissues and 10 adjacent nontumor tissues. No methylation was found in normal liver control tissues for both RASSF1A and p16; methylation was detected in one of 10 and seven of 10 adjacent nontumor tissue sampless for p16 and RASSF1A, respectively, in subjects with positive tumors. These data indicate that aberrant methylation of the CpG island promoters of both genes is a frequent occurrence in hepatocarcinogenesis. The high frequency of RASSF1A methylation in adjacent tissues suggests that this may be an early event. The relationship between methylation status and clinical parameters and tumor markers, including DNA damage resulting from aflatoxin B(1) (AFB(1)), an environmental carcinogen, and p53 status, also was analyzed. A statistically significant association was found between RASSF1A methylation status and the level of AFB(1)-DNA adducts in tumor tissues. No association was found between methylation status and p53 status. These results suggest the hypothesis that exposure to environmental carcinogens may be involved in altered methylation of genes involved in cancer development.


Assessing intrarater, interrater and test-retest reliability of continuous measurements.
In this paper we review the problem of defining and estimating intrarater, interrater and test-retest reliability of continuous measurements. We argue that the usual notion of product-moment correlation is well adapted in a test-retest situation, whereas the concept of intraclass correlation should be used for intrarater and interrater reliability. The key difference between these two approaches is the treatment of systematic error, which is often due to a learning effect for test-retest data. We also consider the reliability of a sum and a difference of variables and illustrate the effects on components. Further, we compare these approaches of reliability with the concept of limits of agreement proposed by Bland and Altman (for evaluating the agreement between two methods of clinical measurements) and show how product-moment correlation is related to it. We then propose new kinds of limits of agreement which are related to intraclass correlation. A test battery to study the development of neuro-motor functions in children and adolescents illustrates our purpose throughout the paper.


A monoclonal antibody to common acute lymphoblastic leukemia antigen (neutral endopeptidase) immunostains senile plaques in the brains of patients with Alzheimer's disease.
We immunostained brain tissues of patients with Alzheimer's disease (AD) together with non-demented aged and younger controls with a battery of anti-human hemopoietic cell monoclonal antibodies (OK series, Ortho Diagnostics Co., Ltd. and some others) by the avidin-biotin-peroxidase complex (ABC) method to see if any epitopes are shared with the nervous system or might contribute to the neurodegenerative changes in this disease. One out of 29 monoclonal antibodies, OKBcALLa, which recognizes common acute lymphocytic leukemia antigen (CALLA, CD10), immunostained senile plaques in the brains of patients with AD. The pattern and intensity of this staining, using cryopreserved samples, was almost identical to that obtained with anti beta-protein. Thus, senile plaques in the Alzheimer's brain share an epitope with CALLA.


Transition state analysis of an enantioselective Michael addition by a bifunctional thiourea organocatalyst.
The mechanism of the enantioselective Michael addition of diethyl malonate to trans-β-nitrostyrene catalyzed by a tertiary amine thiourea organocatalyst is explored using experimental 13C kinetic isotope effects and density functional theory calculations. Large primary 13C KIEs on the bond-forming carbon atoms of both reactants suggest that carbon-carbon bond formation is the rate-determining step in the catalytic cycle. This work resolves conflicting mechanistic pictures that have emerged from prior experimental and computational studies.


Motor learning and the use of videotape feedback after stroke.
Efforts have been made to apply motor learning theories to the rehabilitation of individuals following stroke. Motor learning poststroke has not been well investigated in the literature. This research attempted to fill the gap regarding motor learning applied to practice. This two-group research study attempted to determine the effectiveness of an experimental therapy combining videotape feedback with occupational therapy compared to only occupational therapy in learning the motor skill of donning socks and shoes after stroke. Ten participants were randomly assigned to one of the two groups and all participants were videotaped during pretest and up to 10 treatment sessions aimed at donning socks and shoes. Only one group viewed their videotape replay. The acquisition of donning socks and shoes was measured using the socks and shoes subtests of the Klein-Bell Activities of Daily Living Scale and their scores on the Canadian Occupational Performance Measure. There was no significant difference between the two groups and both groups improved. However, the group that received videotape feedback thought they performed better and were more satisfied with their ability to don shoes, lending support for the use of videotape feedback poststroke to improve satisfaction with performance.


A prescribed Chinese herbal medicine improves glucose profile and ameliorates oxidative stress in Goto-Kakisaki rats fed with high fat diet.
Oxidative stress (OS) plays a role in hyperglycemia induced islet β cell dysfunction, however, studies on classic anti-oxidants didn't show positive results in treating diabetes. We previously demonstrated that the prescribed Chinese herbal medicine preparation "Qing Huo Yi Hao" (QHYH) improved endothelial function in type 2 diabetic patients. QHYH protected endothelial cells from high glucose-induced damages by scavenging superoxide anion and reducing production of reactive oxygen species. Its active component protected C2C12 myotubes against palmitate-induced oxidative damage and mitochondrial dysfunction. In the present study, we investigated whether QHYH protected islet β cell function exacerbated by high fat diet (HFD) in hyperglycemic GK rats. 4-week-old male rats were randomly divided into high HFD feeding group (n = 20) and chow diet feeding group (n = 10). Each gram of HFD contained 4.8 kcal of energy, 52% of which from fat. Rats on HFD were further divided into 2 groups given either QHYH (3 ml/Kg/d) or saline through gastric tube. After intervention, serum glucose concentrations were monitored; IPGTTs were performed without anesthesia on 5 fasting rats randomly chosen from each group on week 4 and 16. Serum malondialdehyde (MDA) concentrations and activities of serum antioxidant enzymes were measured on week 4 and 16. Islet β cell mass and OS marker staining was done by immunohistochemistry on week 16. QHYH prevented the exacerbation of hyperglycemia in HFD feeding GK rats for 12 weeks. On week 16, it improved the exacerbated glucose tolerance and prevented the further loss of islet β cell mass induced by HFD. QHYH markedly decreased serum MDA concentration, increased serum catalase (CAT) and SOD activities on week 4. However, no differences of serum glucose concentration or OS were observed on week 16. We concluded that QHYH decreased hyperglycemia exacerbated by HFD in GK rats by improving β cell function partly via its antioxidant effect.


Prevalence and related risk factors of chronic kidney disease among adults in Luxembourg: evidence from the observation of cardiovascular risk factors (ORISCAV-LUX) study.
Evidence on stages of renal impairment and related risk factors in Luxembourg is lacking. This study aimed to assess the prevalence of chronic kidney disease (CKD) and identify potential correlates among the general population, using the recent definition suggested by the Kidney Disease Improving Global Outcomes guidelines. Data analysed from 1361 participants aged 18-69 years, enrolled in the Observation of Cardiovascular Risk Factors in Luxembourg (ORISCAV-LUX) study, 2007-08. Descriptive and multivariable logistic regression analyses were performed to identify demographic, socio-economic, behavioural, and clinical factors associated with CKD, defined as a single estimated glomerular filtration rate (eGFR) measure <60 ml/min/1.73m2 and/or urinary albumin: creatinine ratio (ACR) > 30 mg/g. Overall, 6.3% had CKD, including 4.4% and 0.7% with moderate and severe macroalbuminuria respectively. 0.1% had kidney failure (eGFR < 15 ml/min/1.73 m2). CKD was higher among subjects with primary education and risk increased significantly with age; the odd ratio was more than 2-fold higher among participants aged 50-69 years. Hypertension and diabetes were associated with more than 3-fold and 4-fold higher risks of CKD [adjusted odd ratio (AOR 3.46 (95%CI 1.92, 6.24), P < 0.001] and [AOR 4.45 (2.18, 9.07), P < 0.001] respectively. Increased physical activity measured as total MET-hour/week was independently associated with a lower odds of CKD (P = 0.035). The national baseline prevalence estimate of CKD, a neglected public health problem, stresses the benefit of early detection particularly in high-risk subjects with associated cardiovascular pathologies (e.g. hypertension, diabetes), to prevent and defray costs related to eventual complications.


Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution.
Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology.


A White-Box Machine Learning Approach for Revealing Antibiotic Mechanisms of Action.
Current machine learning techniques enable robust association of biological signals with measured phenotypes, but these approaches are incapable of identifying causal relationships. Here, we develop an integrated "white-box" biochemical screening, network modeling, and machine learning approach for revealing causal mechanisms and apply this approach to understanding antibiotic efficacy. We counter-screen diverse metabolites against bactericidal antibiotics in Escherichia coli and simulate their corresponding metabolic states using a genome-scale metabolic network model. Regression of the measured screening data on model simulations reveals that purine biosynthesis participates in antibiotic lethality, which we validate experimentally. We show that antibiotic-induced adenine limitation increases ATP demand, which elevates central carbon metabolism activity and oxygen consumption, enhancing the killing effects of antibiotics. This work demonstrates how prospective network modeling can couple with machine learning to identify complex causal mechanisms underlying drug efficacy.


Ruthenium(II) complexes containing 8-(dimethylphosphino)quinoline (Me(2)Pqn): preparation, crystal structures, and electrochemical and spectroscopic properties of [Ru(bpy or phen)(3)(-)(n)(Me(2)Pqn)(n)](PF(6))(2) (bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline; n = 1, 2, or 3).
Several new ruthenium(II) complexes containing 8-(dimethylphosphino)quinoline (Me(2)Pqn) were synthesized, and their structures and electrochemical/spectroscopic properties have been investigated. In addition to the mono(Me(2)Pqn) complex [Ru(bpy or phen)(2)(Me(2)Pqn)](PF(6))(2) (1 or 1'; bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline), the geometrical isomers trans(P)- and C(1)-[Ru(bpy)(Me(2)Pqn)(2)](PF(6))(2) (tP-2 and C(1)-2) and mer- and fac-[Ru(Me(2)Pqn)(3)](PF(6))(2) (m-3 and f-3) were also selectively synthesized and isolated. It was found that complexes tP-2 and m-3 were converted quantitatively to the corresponding C(1)-2 and f-3 isomers, respectively, by irradiation of light corresponding to the MLCT transition energy. The strong trans influence of the Me(2)P- donor group of Me(2)Pqn was confirmed by the X-ray structural analyses for 1, tP-2, m-3, and f-3. Cyclic voltammetry of a series of complexes, [Ru(bpy)(3)](PF(6))(2), 1, C(1)-2, and f-3, exhibited a reversible one-electron oxidation wave and two or three one-electron reduction waves. The oxidation potentials of the complexes gave a large positive shift with increasing number of coordinated Me(2)Pqn molecules, indicating a larger pi-acceptability of the Me(2)P- group compared with bpy or qn. Complex f-3 in EtOH/MeOH (4:1) glass at 77 K exhibited an intense long-lived (tau = 920 microseconds) emission arising from the quinoline-based (3)(pi-pi) excited state. In contrast, the mixed-ligand complexes 1, 1', and C(1)-2 showed a characteristic dual emission, giving a double-exponential emission decay, and the dual emission originates from both the bpy-based (3)MLCT and the quinoline-based (3)(pi-pi) emitting states.


Directing the differentiation of human dental follicle cells into cementoblasts and/or osteoblasts by a combination of HERS and pulp cells.
It is known that the dental follicle (DF) consists of progenitor cells that give rise to the cementum, periodontal ligament, and alveolar bone; but little information is available about the regulation of DF cell differentiation into either cementogenic or osteogenic cell lineages for the regeneration of diseased periodontal tissue. Here, we investigated the roles of DF, Hertwig's epithelial root sheath (HERS), and pulp cells in the cementum and during alveolar bone formation. We cultured these cells; transplanted them alone or in combination into immunocompromised mice; and observed their effects at 6 and 12 weeks. Histological and immunohistochemical results revealed that DF cells formed cementum-like tissues with immunoreactivity to cementum-derived attached protein, bone sialoprotein, type I collagen, and alkaline phosphatase. In addition, HERS cells played a role in the induction and maturation of cementum-like tissues formed by DF cells. In contrast, implants of DF cells in the presence of pulp cells led to the formation of bone-like tissues. Interestingly, in the presence of both HERS and pulp cells, DF cells formed both cementum-like and bone-like tissues. We demonstrated that while HERS cells are able to induce DF cell differentiation into cementoblasts and promote cementum formation, pulp cells could direct DF cell differentiation into osteoblasts and enhance alveolar bone formation. These results suggest that the combined use of DF, HERS, and pulp cells could direct DF cell differentiation into cementoblasts and/or osteoblasts in vivo, thus providing a novel strategy for the successful repair and regeneration of diseased periodontal tissue.


Synthesis and structural and magnetic characterization of {[(phen)(2)Ni](2)(micro-P(2)O(7))} . 27H(2)O and {[(phen)(2)Mn](2)(micro-P(2)O(7))} . 13H(2)O: rare examples of coordination complexes with the pyrophosphate ligand.
The reaction in water of M(II) [M = Ni or Mn] with 1,10-phenanthroline (phen) and sodium pyrophosphate (Na4P2O7) in a 2:4:1 stoichiometry resulted in the crystallization of dinuclear complexes featuring the heretofore rare bridging pyrophosphate. Single-crystal X-ray diffraction studies revealed the complexes to be {[(phen)2Ni]2(micro-P2O7)} . 27H2O (1) and {[(phen)2Mn]2(micro-P2O7)} . 13H2O (2) where the asymmetric M(phen)2 units are bridged by bis-bidentate pyrophosphate, each metal ion exhibiting a distorted octahedral geometry. The bridging pyrophosphate places adjacent metal centers at 5.031 A in 1 and 4.700 A in 2, and its conformation also gives rise to an intramolecular pi-pi interaction between two adjacent phen ligands. Intermolecular pi-pi interactions between phen ligands from adjacent dinuclear complexes create an ornate 3D network in 1, whereas a 2D sheet results in 2. The hydrophilic nature of the pyrophosphate ligand leads to heavy hydration with the potential solvent-accessible area for 1 and 2 accounting for 45.7% and 26.4% of their unit cell volumes, respectively. Variable-temperature magnetic susceptibility measurements on polycrystalline samples of 1 and 2 revealed net weak intramolecular antiferromagnetic coupling between metal centers in both compounds with J = -3.77 cm(-1) in 1 and J = -0.88 cm(-1) in 2, the Hamiltonian being defined as H = -JSA.SB. The ability of the bis-bidentate pyrophosphate to mediate magnetic interactions between divalent first row transition metal ions is discussed bearing in mind the number and nature of the interacting magnetic orbitals.


Personalized Integrated Network Modeling of the Cancer Proteome Atlas.
Personalized (patient-specific) approaches have recently emerged with a precision medicine paradigm that acknowledges the fact that molecular pathway structures and activity might be considerably different within and across tumors. The functional cancer genome and proteome provide rich sources of information to identify patient-specific variations in signaling pathways and activities within and across tumors; however, current analytic methods lack the ability to exploit the diverse and multi-layered architecture of these complex biological networks. We assessed pan-cancer pathway activities for >7700 patients across 32 tumor types from The Cancer Proteome Atlas by developing a personalized cancer-specific integrated network estimation (PRECISE) model. PRECISE is a general Bayesian framework for integrating existing interaction databases, data-driven de novo causal structures, and upstream molecular profiling data to estimate cancer-specific integrated networks, infer patient-specific networks and elicit interpretable pathway-level signatures. PRECISE-based pathway signatures, can delineate pan-cancer commonalities and differences in proteomic network biology within and across tumors, demonstrates robust tumor stratification that is both biologically and clinically informative and superior prognostic power compared to existing approaches. Towards establishing the translational relevance of the functional proteome in research and clinical settings, we provide an online, publicly available, comprehensive database and visualization repository of our findings ( https://mjha.shinyapps.io/PRECISE/ ).