Impact of age on glomerular filtration estimates.
Glomerular filtration decreases progressively with age in adults. Predictive equation should have proper modelling to adequately account for normal senescence. Corrected 24-h creatinine clearances (CCLs) were measured in a cohort of 773 outpatients from 18 to 90 years old. Multiple linear regression was used to model the effect of age on glomerular filtration. Comparisons were made with the simplified MDRD and the MAYO equations. Impact of the derived equation was tested in a second cohort of 7551 patients with normal serum creatinine. While all equations show declining function with age, our results suggest that the GFR reduction is progressive after the age of 30 and continue to decline steadily after the age of 60. This leads to a convex curve in the multiple regression analysis that is best fitted by an equation including the quadratic term (age(2)). In contrast, the MDRD equation produces a faster decrease in early adulthood and a flatter curve after the age of 60 while the MAYO equation produces a more linear effect. MDRD results in the normal range are lower than those estimated by the MAYO equation. These equations, as applied on an independent cohort of 7551 normal outpatients from 18 to 102 years, produce different profile of evolution of GFR with age. Inclusion of a quadratic term for age in the formula estimating GFR results in better modelling of the natural decline of renal function associated with ageing. Furthermore, as GFR steadily declines after the age of 30, a single cut-off value of GFR normality for all ages leads to underdiagnosis of young adults and over diagnosis of elderly individuals. Guidelines should take into account the observed reduction of kidney function with age in normal population for optimal evaluation of eGFR.


[The ways of the results improvement in surgical treatment of the right side colonic decompensated obstruction].
There were operated on 87 patients with an acute ileus, caused by stenosing tumor of the right colon. In 49 patients the shunting ileotransversoanastomosis was formed and in 30--the right-sided hemicolectomy with primary anastomosis and decompressive terminal ileostomy according to method of clinic was performed. After application of conventional method postoperative mortality was 22.4% and frequency of postoperative complications--36.7%, and after application of the proposed method--13.3 and 26.6% accordingly.


Evaluation of an isotope dilution liquid chromatography tandem mass spectrometry method for pharmaceuticals in fish.
An isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was successfully developed and applied for analysis of 15 pharmaceuticals and 2 pharmaceutically active metabolites in fish tissues. This method relied on electrospray ionization (ESI), for which the influence of sample matrix on analyte ionization efficiencies remains a persistent challenge to environmental analysis. Statistically derived method detection limits (MDLs) for most analytes ranged from 1 to 10 ng/g, independent of sample matrix, and were as low as 0.04 ng/g for the most sensitive compounds in fillet tissue. MDLs for fish fillets were determined for both 10 μL and 100 μL injection volumes; however, results showed that detection limits did not scale linearly with injection volume. Direct comparison of spike recoveries from fish liver demonstrated that isotope dilution was superior to matrix-matched calibration in compensating for matrix interference. Spike recoveries for the isotope dilution approach generally ranged from 91 to 112%, independent of tissue (i.e., fillet or liver). The developed method was applied to examine target analytes in brown trout (Salmo trutta), collected upstream and downstream from a municipal effluent discharge to East Canyon Creek, Park City, UT, USA. Though no pharmaceuticals were detected in fish samples from the upstream location, 3 and 10 compounds (out of 17 target analytes) were detected in fish fillet and liver samples, respectively, from the downstream sampling site. Pharmaceuticals in fish fillets were observed at concentrations ranging from 0.14 to 12 ng/g, while levels were markedly higher in liver tissues (range: 0.27-600 ng/g).


Cytosolic Quality Control of Mitochondrial Protein Precursors-The Early Stages of the Organelle Biogenesis.
With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.


Loneliness and depression dissociated on parietal-centered networks in cognitive and resting states.
Perceived loneliness, an increasingly prevalent social issue, is closely associated with major depressive disorder (MDD). However, the neural mechanisms previously implicated in key cognitive and affective processes in loneliness and MDD still remain unclear. Such understanding is critical for delineating the psychobiological basis of the relationship between loneliness and MDD. We isolated the unique and interactive cognitive and neural substrates of loneliness and MDD among 27 MDD patients (mean age = 51.85 years, 20 females), and 25 matched healthy controls (HCs; mean age = 48.72 years, 19 females). We assessed participants' behavioral performance and neural regional and network functions on a Stroop color-word task, and their resting-state neural connectivity. Behaviorally, we found greater incongruence-related accuracy cost in MDD patients, but reduced incongruence effect on reaction time in lonelier individuals. When performing the Stroop task, loneliness positively predicted prefrontal-anterior cingulate-parietal connectivity across all participants, whereas MDD patients showed a decrease in connectivity compared to controls. Furthermore, loneliness negatively predicted parietal and cerebellar activities in MDD patients, but positively predicted the same activities in HCs. During resting state, MDD patients showed reduced parietal-anterior cingulate connectivity, which again positively correlated with loneliness in this group. We speculate the distinct neurocognitive profile of loneliness might indicate increase in both bottom-up attention and top-down executive control functions. However, the upregulated cognitive control processes in lonely individuals may eventually become exhausted, which may in turn predispose to MDD onset.


Biogenesis of Afipia-containing phagosomes in non-professional phagocytes.
Afipia felis is a Gram-negative alpha-proteobacterium, a rare cause of human cat scratch disease (CSD), and likely a pathogen of amoeba. Here, we show that various members of the genus Afipia attach to and are taken up by various non-professional phagocytic mammalian cells (epithelial CHO, endothelial EA.hy926, epithelial HeLa, epithelial INT407 cells, endothelial HMEC-1, endothelial HUVEC, and fibroblast L929 cells). However, only A. felis was able to do this efficiently. Invasion depended on a functional actin cytoskeleton and much less on microtubule dynamics. Bacteria were slowly taken up into HMEC-1 (and HUVEC) via pocket-like structures and they resided within membrane-surrounded phagosomes. While A. felis was found in a non-canonical endocytic compartment in macrophage cells, Afipia-containing phagosomes in HMEC-1 were transiently positive for early endosomal EEA1 and then became and remained positive for lysosome-associated membrane protein-1 (LAMP1) and the proton-pumping ATPase, suggesting undisturbed, albeit slowed, phagosome biogenesis in these cells. Similarly, at 24h of infection, most phagosomes in HeLa, INT407, HUVEC and in EA.hy926 cells were positive for LAMP1. In summary, A. felis enters various non-professional phagocytes and its compartmentation differs between macrophages and non-professional phagocytes.


Review of pemetrexed in combination with cisplatin for the treatment of malignant pleural mesothelioma.
Malignant pleural mesothelioma is a resistant form of lung cancer, and its incidence continues to rise in Europe and Australia. Until recently, chemotherapy had not been shown to be effective in the treatment of this slowly progressive disease. In 2004, the combination of pemetrexed and cisplatin was shown to induce high response rates in MPM. This article reviews the published literature describing the development and testing of this therapeutic combination in mesothelioma, and examines in detail the key phase III clinical trial that led to the approval of pemetrexed by the US FDA. Ongoing research will further define the role of pemetrexed plus cisplatin in the treatment of MPM.


FGF21 Improves Glycolipid Metabolism in Rainbow Trout (Oncorhynchus mykiss) Fed a High-Carbohydrate Diet by Inhibiting Inflammatory Responses and Activating Autophagy.
In this study, the coding region of rainbow trout fgf21 was cloned and sequenced to synthesize a recombinant protein (rFGF21) and investigate its potential role in improving glycolipid metabolism. Acute injection of rFGF21 into rainbow trout effectively reduced serum glucose levels. To investigate the effect of rFGF21 on high-carbohydrate diet (HCD)-induced metabolic disorders in rainbow trout, a 31-day feeding experiment was conducted. At the end of the third week, fish were injected with either PBS or rFGF21. The results showed that the final body weight (FBW) significantly increased in rainbow trout on an HCD (P < 0.05), but there were potential risks including disturbances in glycolipid metabolism and increased inflammatory responses. However, these effects were altered by rFGF21 treatment. In addition, rFGF21 promotes glucose uptake by increasing the phosphorylation levels of AKT (protein kinase B) and GSK3β (glycogen synthase kinase 3β), increasing hepatic glycogen, thereby lowering serum glucose. Notably, the rFGF21 did not exacerbate the inflammatory response but downregulated the expression of inflammatory factors. Interestingly, the activation of autophagy and the AMPK pathway may contribute to the positive effect of rFGF21, where rFGF21 injection significantly increased the levels of LC3I/II protein and phosphorylate AMPKα (P < 0.05).


Atypical antipsychotic induced weight gain: pathophysiology and management.
There is compelling evidence that patients with schizophrenia are prone to gain weight. In addition, atypical antipsychotic (AAP) drugs also induce weight gain. All antipsychotic drugs produce weight gain but the potential varies. Many studies overwhelmingly confirm that AAP drugs produce substantially more weight gain in comparison to conventional antipsychotic drugs. Clozapine and olanzapine have the most weight inducing potential. Even ziprasidone, which is considered to be weight neutral, and aripiprazole a dopamine modulator produce weight gain in some. The pathophysiology of weight gain is complicated. Many neurohormones, neuropeptides, gut hormones, as well as adipose tissue and hair root derived hormones interact with environmental factors to produce weight gain. Management of weight gain is a difficult problem. Basic to treatment is an understanding of the etiology. Drug induced obesity provides a unique opportunity to psychiatrists to understand this clinically important problem. In the absence of this knowledge, prevention is the best hope. Education, diet control and simple behavioral measures may prevent excessive weight gain. In those with weight gain, treatment can be attempted with pharmacotherapy with careful monitoring of the side effects.


A SIRPαFc Fusion Protein Conjugated With the Collagen-Binding Domain for Targeted Immunotherapy of Non-Small Cell Lung Cancer.
The SIRPαFc fusion protein can block the immunosuppressive CD47-SIRPα signal between macrophages and tumor cells as a decoy receptor and has demonstrated its immunotherapeutic efficacy in various tumors. However, its clinical application was limited because of the potential hematologic toxicity. The heptapeptide "TKKTLRT" is a collagen-binding domain (CBD) which can bind collagen specifically. Herein, we aim to improve the tumor targeting of SIRPαFc and therefore avoid its unnecessary exposure to normal cells through synthesizing a TKKTLRT-SIRPαFc conjugate. Experiments at molecular and cellular levels indicate that the TKKTLRT-SIRPαFc conjugate-derived collagen-binding affinity and the introduction of CBD did not impact the CD47-binding affinity as well as its phagocytosis-promoting effect on NSCLC cells. In vivo distribution experiments showed that CBD-SIRPαFc accumulated in tumor tissue more effectively compared to unmodified SIRPαFc, probably due to the exposed collagen in the tumor vascular endothelium and stroma resulting from the abnormal vessel structure. On an A549 NSCLC nude mouse xenograft model, CBD-SIRPαFc presented more stable and effective antitumor efficacy than SIRPαFc, along with significantly increased CD11b+F4/80+ macrophages especially MHC II+ M1 macrophages within tumors. All of these results revealed that CBD brought a tumor-targeting ability to the SIRPαFc fusion protein, which contributed to the enhanced antitumor immune response. Altogether, the CBD-SIRPαFc conjugate may have the potential to be an effective tumor immunotherapy with improved antitumor efficacy but less non-tumor-targeted side effect.


RAD51 maintains chromosome integrity and mitochondrial distribution during porcine oocyte maturation in vitro.
DNA repair protein RAD51 homolog 1 (RAD51) plays a central role in homologous recombination (HR) repair of DNA breaks. HR depends on the formation of a RAD51 recombinase filament that facilitates strand invasion. However, the role of RAD51 during porcine oocyte maturation is unknown. The objective of this study was to investigate the expression and function of RAD51 during porcine oocyte maturation in vitro. RAD51 was mainly localized to the nucleus at the germinal vesicle (GV) stage, and was widely distributed in the cytoplasm between the GV breakdown (GVBD) and metaphase II stage. DNA damage induced by etoposide was accompanied by the formation of RAD51 foci that were colocalized with γH2AX. Inhibition of RAD51 increased DNA damage and induced metaphase I arrest along with spindle defects, chromosomal misalignment, and abnormal spindle assembly checkpoint (SAC) activity. Inhibition of RAD51 also increased ROS levels and led to an abnormal mitochondrial distribution. Our results indicate that RAD51 plays a critical role in maintaining chromosome integrity and mitochondrial activity during porcine oocyte maturation.


Experimental Evidence and Mechanistic Description of the Phenolic H-Transfer to the Cu2O2 Active Site of oxy-Tyrosinase.
Tyrosinase is a ubiquitous coupled binuclear copper enzyme that activates O2 toward the regioselective monooxygenation of monophenols to catechols via a mechanism that remains only partially defined. Here, we present new mechanistic insights into the initial steps of this monooxygenation reaction by employing a pre-steady-state, stopped-flow kinetics approach that allows for the direct measurement of the monooxygenation rates for a series of para-substituted monophenols by oxy-tyrosinase. The obtained biphasic Hammett plot and the associated solvent kinetic isotope effect values provide direct evidence for an initial H-transfer from the protonated phenolic substrate to the Cu2O2 core of oxy-tyrosinase. The correlation of these experimental results to quantum mechanics/molecular mechanics calculations provides a detailed mechanistic description of this H-transfer step. These new mechanistic insights revise and expand our fundamental understanding of Cu2O2 active sites in biology.


Mannose-binding lectin and infection risk in newborns: a systematic review.
The authors systematically reviewed the literature on mannose-binding lectin (MBL) and infections in newborns to determine whether infection risk is increased in MBL-deficient newborns. All original reports on MBL and infections in newborns were retrieved from Embase, Medline and CENTRAL from 1966 to December 2009. Information extracted from each article included study design, definitions of MBL deficiency and neonatal infection, follow-up period and risk factor analysis. The validity of each study was assessed. Eight prospective cohort studies, including 3166 (range 47-1832) premature or term neonates, were assessed. MBL levels were measured in five studies and MBL2 genotype in six studies. Definitions of MBL deficiency and infection varied. In three out of five phenotypic studies low MBL levels were statistically significantly associated with increased culture-confirmed sepsis rates, also after correction for gestational age or birth weight. In the first study, the median MBL level was decreased in newborns with confirmed sepsis (170 μg/l) compared with newborns without sepsis (1450 μg/l). In two other studies, culture-confirmed sepsis was associated with MBL levels ≤700 μg/l (OR 15.0, 95% CI 1.5 to 151.3) and ≤400 μg/l (OR 3.1), respectively. The remaining two studies investigated various non-culture-confirmed infections. Only one study included the timepoint of clinical suspicion of infection in multivariate analysis. Contradicting results were reported in six MBL2 genotypic studies. Newborns with low MBL levels appear to have culture-confirmed sepsis more frequently than MBL-sufficient newborns. However, the influence of confounding factors was analysed insufficiently. Variant MBL2 genotypes appear to have less influence.


DdrB protein, an alternative Deinococcus radiodurans SSB induced by ionizing radiation.
Deinococcus radiodurans exhibits an extraordinary resistance to the effects of exposure to ionizing radiation (IR). DdrB is one of five proteins induced to high levels in Deinococcus following extreme IR exposure and that play a demonstrable role in genome reconstitution. Although homology is limited, DdrB is a bacterial single-stranded DNA-binding protein. DdrB features a stable core with a putative OB-fold, and a C-terminal segment with properties consistent with other bacterial SSBs. In solution, the protein functions as a pentamer. The protein binds single-stranded DNA but not duplex DNA. Electron microscopy and assays with two RecA proteins provide further structural and functional identification with bacterial SSB. Overall, the results establish DdrB as the prototype of a new bacterial SSB family. Given the role of SSB as a mobilization scaffold for many processes in DNA metabolism, the induction of an alternative and quite novel SSB following irradiation has potentially broad significance for the organization of genome reconstitution functions.


Removal of endocrine disrupter compounds from municipal wastewater by an innovative biological technology.
The removal of selected endocrine disrupter compounds (EDCs), namely estrone(E1), 17beta-estradiol (E2), 17alpha-ethynylestradiol (EE2), bisphenol A (BPA) and 4-tert-octylphenol (4t-OP) from municipal wastewater was investigated using a sequencing batch biofilter granular reactor (SBBGR), a new system for biological treatment based on aerobic granular biomass. This new biological treatment is characterized by high biomass concentration (up to 40 g/L), high sludge retention times (up to 6 months) and low sludge production (i.e., an order of magnitude lower than commonly reported for conventional biological technologies). The investigation was carried out comparing a demonstration SBBGR system with a conventional full-scale activated sludge process. Results showed that the SBBGR performed better than a conventional activated sludge process in removing E1, E2, BPA and 4t-OP. In fact, the average removal percentages of the above mentioned EDCs, obtained during a four month operating period, were 62.2, 68, 91.8, 77.9% and 56.4, 36.3, 71.3, 64.6% for the demonstrative SBBGR system and the conventional activated sludge process of the municipal sewage treatment plant, respectively.


[Local structure of cytochrome c from horse heart in solution. Conformational analysis using data of two-dimensional nuclear Overhauser effect spectroscopy].
Using the earlier suggested method the calculation of the backbone conformations of horse heart cytochrome c in oxidized (ferricytochrome c) and reduced (ferrocytochrome c) states has been performed by the two-dimensional nuclear Overhauser effect spectroscopy data. For both protein forms the secondary structure elements have been revealed and the conformations of the irregular polypeptide chain segments have been analysed. The similarity of the secondary structures of ferri- and ferrocytochrome c in solution was established from the comparison of their conformations. Small differences between the conformations of two molecule forms are shown to be localized within the polypeptide chain fragments situated in the spatial structure near the heme crevice. The comparison of the dihedral phi and psi angles in the calculated conformations of horse cytochrome C with the corresponding characteristics of X-ray structures of tuna ferri- and ferrocytochrome c made for the oxidized and reduced protein forms using the quantitative criteria testifies the similarity of their conformations in solution and crystal. In is shown that the conformational changes of the separate amino acid residues which take place as the result of the "solution-to-crystal" transition occur on the surface fragments of protein globule and do not lead to essential alterations of the secondary molecule structure.


Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells.
The zinc finger protein ZPR1 is present in the cytoplasm of quiescent mammalian cells and translocates to the nucleus upon treatment with mitogens, including epidermal growth factor (EGF). Homologues of ZPR1 were identified in yeast and mammals. These ZPR1 proteins bind to eukaryotic translation elongation factor-1alpha (eEF-1alpha). Studies of mammalian cells demonstrated that EGF treatment induces the interaction of ZPR1 with eEF-1alpha and the redistribution of both proteins to the nucleus. In the yeast Saccharomyces cerevisiae, genetic analysis demonstrated that ZPR1 is an essential gene. Deletion analysis demonstrated that the NH2-terminal region of ZPR1 is required for normal growth and that the COOH-terminal region was essential for viability in S. cerevisiae. The yeast ZPR1 protein redistributes from the cytoplasm to the nucleus in response to nutrient stimulation. Disruption of the binding of ZPR1 to eEF-1alpha by mutational analysis resulted in an accumulation of cells in the G2/M phase of cell cycle and defective growth. Reconstitution of the ZPR1 interaction with eEF-1alpha restored normal growth. We conclude that ZPR1 is essential for cell viability and that its interaction with eEF-1alpha contributes to normal cellular proliferation.


[Comparative assessment of astemizole-pseudoephedrine and loratadine-pseudoephedrine in children with allergic rhinitis].
The purpose of the study was to evaluate the effectiveness and safety of astemizole-pseudoephedrine solution compared to loratadine-pseudoephedrine syrup in the treatment of allergic rhinitis. Fifty children (34 boys and 16 girls) ages between 2 and 7 years were enrolled and randomly assigned to each group. Patients were evaluated before treatment and on the third and seventh days of therapy. Children treated with astemizole-pseudoephedrine had better results with an average effectiveness of 84% compared to 64% for children treated with loratadine-pseudoephedrine. Differences were significant for eye symptoms by medical evaluation and for blocked nose, sneezing and itchy nose according to the patients diary. Both treatment groups started action within 30 minutes after drug intake. 4 hours later, 38% of the patients in the astemizole-pseudoephedrine group and 16% in the loratadine-pseudoephedrine groups had experienced improvement. One patient in the former and three in the latter showed adverse effects.


Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development.
The natural outcome of ultrasound-detected macronodules in cirrhosis is still poorly understood. In this study we assessed the incidence and predictors of malignant transformation in a prospective study of 90 consecutive ultrasound-detected macronodules in cirrhosis. Macronodules classification was based on recently proposed histological criteria. Extranodular large (LCC) and small cell changes were also evaluated. The follow-up included ultrasound and serum alfa-fetoprotein determination every 3 months. Independent predictors of hepatocellular carcinoma were evaluated by Cox proportional hazards regression analysis. During a mean follow-up of 33 months, 28 (31%) nodules transformed into hepatocellular carcinoma. The incidence of hepatocellular carcinoma per 100 person-years of follow-up was 11.3%, with a malignant transformation rate of 3.5, 15.5, 31 and 48.5% at 1, 2, 3, and 5 years respectively. High-grade dysplastic nodules (HGDN) (hazard risk=2.4; CI 95%=1.1-5.0) and LCC (hazard risk=3.1; CI 95%=1.2-7.8) were independent predictors of malignant transformation. Eight additional hepatocellular carcinomas developed outside the original lesions raising the overall malignant transformation rate to 40% while 15 macronodules (17%) became undetectable at ultrasound (US). Macronodules characterize a cirrhotic subpopulation with high risk of hepatocellular carcinoma. HGDN and LCC are strong predictors of malignant transformation; subjects with simultaneous presence of both these two conditions are at highest risk of cancer development. The management of cirrhotics with macronodules should be based on morphologic features detected on liver microsamples.


Discovering the complexities of adolescent compliance to treatment.
To explore the challenges faced in enhancing adolescent treatment compliance and to understand the roles of key players in this endeavor: the adolescent, parent and healthcare provider. Obtaining compliance from adolescents requires collaboration from the adolescent, caregiver and provider and depends on well-established relationships between each person in the triad: adolescent-provider, adolescent-caregiver, and caregiver-provider. Ensuring and improving adherence to treatment by adolescents is a challenging task but crucial to overall health outcomes. It requires the collaboration of the adolescent, parent and physician to create the optimal treatment plan, specifically tailored to the adolescent. For the clinician, maintaining good communication and relationships, active listening, as well as partnering with the adolescent and parent are keys to positive outcomes.


Evaluation of Subjective Appetite Assessment under Free-Living vs. Controlled Conditions: A Randomized Crossover Trial Comparing Whole-Grain Rye and Refined Wheat Diets (VASA-Home).
Accurate assessment of self-reported appetite under free-living conditions is warranted to conduct large-scale intervention studies measuring appetite at a feasible cost. However, the performance of visual analogue scales (VASs) for this purpose has not been widely examined. This randomized crossover trial was conducted to evaluate VASs in free-living vs. clinic-based settings and to assess appetite response following hypocaloric whole-grain rye and refined wheat diets. Twenty-nine healthy adults with overweight or obesity continuously answered VAS questions about their perceived appetite from morning to evening. No differences in whole-day VAS scores (primary outcome) between clinic-based and free-living settings were observed, whereas measures of total area under the curve (tAUC) showed increased fullness in clinic-based interventions of 7% (p < 0.008) for whole-day responses and 13% (p < 0.03) following a snack. Appetite responses for a whole day did not differ between diets whereas rye-based dinners induced 12% (p < 0.016) higher fullness and reduced hunger by 17% (p < 0.02) irrespective of setting. A reduction in hunger of 15% (p < 0.05) was also observed following rye-based vs. wheat-based lunches. The results suggest that the VAS is valid for evaluation of appetite responses between diets under free-living conditions. No difference in self-reported appetite over the whole day was found after whole-grain rye vs. refined wheat-based diets, but there were some suggested differences at certain postprandial periods, in individuals with overweight or obesity.


Integrating Multiple Data Sources for Combinatorial Marker Discovery: A Study in Tumorigenesis.
Identification of combinatorial markers from multiple data sources is a challenging task in bioinformatics. Here, we propose a novel computational framework for identifying significant combinatorial markers ( s) using both gene expression and methylation data. The gene expression and methylation data are integrated into a single continuous data as well as a (post-discretized) boolean data based on their intrinsic (i.e., inverse) relationship. A novel combined score of methylation and expression data (viz., ) is introduced which is computed on the integrated continuous data for identifying initial non-redundant set of genes. Thereafter, (maximal) frequent closed homogeneous genesets are identified using a well-known biclustering algorithm applied on the integrated boolean data of the determined non-redundant set of genes. A novel sample-based weighted support ( ) is then proposed that is consecutively calculated on the integrated boolean data of the determined non-redundant set of genes in order to identify the non-redundant significant genesets. The top few resulting genesets are identified as potential s. Since our proposed method generates a smaller number of significant non-redundant genesets than those by other popular methods, the method is much faster than the others. Application of the proposed technique on an expression and a methylation data for Uterine tumor or Prostate Carcinoma produces a set of significant combination of markers. We expect that such a combination of markers will produce lower false positives than individual markers.


ANMCO POSITION PAPER: Use of sacubitril/valsartan in hospitalized patients with acute heart failure.
Sacubitril/valsartan (S/V) has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in chronic heart failure with reduced ejection fraction compared with enalapril. After 7 years since the publication of the results of PARADIGM-HF, further insight has been gained with potential new indications. Two prospective randomized multicentre studies (PIONEER-HF and TRANSITION) in patients hospitalized for acute heart failure (AHF) have shown an improved clinical outcome and biomarker profile as compared with enalapril, and good tolerability, safety, and feasibility of initiating in-hospital administration of S/V. Furthermore, some studies have highlighted the favourable effects of S/V in attenuating adverse myocardial remodelling, supporting an early benefit after treatment. Observational data from non-randomized studies in AHF report that in-hospital and pre-discharge prescription of evidence-based drugs associated with better survival still remain suboptimal. Additionally, the COVID-19 pandemic has also negatively impacted on outpatient activities. Therefore, hospitalization, a real crossroad in the history of heart failure, must become a management and therapeutic opportunity for our patients. The objective of this ANMCO position paper is to encourage and facilitate early S/V administration in stabilized patients during hospitalization after an AHF episode, with the aim of improving care efficiency and clinical outcome.


Clinical implications of recent insights into the structural biology of beta2 adrenoceptors.
Analysis of the crystal structure of beta-2 adrenoceptors (β2ARs) is providing new insights into the functioning of this receptor and perhaps of G-protein coupled receptors (GPCRs) as a whole. This class of receptors represents the target of at least a third of the drugs on the market and plays an essential role in the study of therapetic drug-response. Among GPCRs, the β2AR is the best understood in terms of function, expression and activation. Regarding the interaction of β2ARs with a specific ligand, polymorphisms, conformational changes and stereoselectivity are important factors. Agonist affinity for β2ARs is influenced by the polymorphisms of these receptors, which in some cases appear to affect susceptibility to disorders. Conformational changes that take place upon the approach of a given ligand, as well as the stereoselectivity of this class of receptors can modify the intrinsic activity of β2ARs (and certainly of other receptors as well). Hence, a deepening understanding of these factors can provide new data on affinity and specifically the key residues involved in recognition of β2AR agonists. The deepening the understanding of the factors involved in ligand affinity for β2ARs will assist in the development of β2AR agonists that are more selective and potent, and that have longer term action. Not only are β2AR agonists employed as therapeutic agents, but also in diagnosis. Currently, the main clinical application of targeting human β2ARs is to treat asthma with bronchodilators. However, they are also used to treat other maladies in their acute or chronic forms, including heart conditions, metabolic disorders and muscle wasting. This review shows the scope and the possible future clinical implications of data from structures of β2ARs.


Towards p-type conductivity in SnO2 nanocrystals through Li doping.
This paper examines electrical transport properties and Li doping in SnO(2) synthesized by the sol-gel method. Solid-state (7)Li-NMR lineshapes reveal that Li ions occupy two distinct sites with differing dynamic mobilities. The chemical exchange rate between the two sites is, however, too slow for detection on the NMR timescale. Compressed nanoparticulate films of this doped semiconductor exhibit a positive Seebeck coefficient implying a p-type conductivity. A variable-temperature direct current conductivity, over a 25-350 degrees C temperature range, follows an Efros-Shklovskii variable range hopping (ES-VRH) conduction mechanism (ln(rho) versus T(-1/2)) at temperatures below 100 degrees C with a crossover to 2D Mott variable range hopping (M-VRH) (ln(rho) versus T(-1/3)) conduction at temperatures above 250 degrees C. In a transition region between these two limiting behaviors, the dc resistivity exhibits an anomalous temperature-independent plateau. We suggest that its origin may lie in a carrier inversion phenomenon wherein the majority carriers switch from holes to electrons due to Li ion expulsion from the crystalline core and creation of oxygen vacancies generated by loss of oxygen at elevated temperatures.


Long-Term Clinical Impact of Cardiogenic Shock and Heart Failure on Admission for Acute Myocardial Infarction.
Long-term clinical outcomes among patients with cardiogenic shock (CS) and heart failure (HF) who survive the early phase of acute myocardial infarction (AMI) remain uncertain. We investigated 3283 consecutive patients with AMI, selected from a prospective, nation-wide multicenter registry (J-MINUET) database comprising 28 institutions in Japan between July 2012 and March 2014. The 3263 eligible patients were divided into the following three groups: CS-/HF- group (n = 2467, 75.6%); CS-/HF+ group (n = 479, 14.7%); and CS+ group (n = 317, 9.7%). The thirty-day mortality rate in CS+ patients was 32.8%, significantly higher than in CS- patients. Among CS+ patients, multivariate logistic regression analysis identified statin use before admission (Odds ratio (OR) 0.32, 95% confidence interval (CI) 0.14-0.66, P = 0.002), renal deficiency (OR 8.72, 95%CI 2.81-38.67, P < 0.0001) and final thrombolysis in myocardial infarction flow grade (OR 0.42, 95%CI 0.18-0.99, P = 0.046) were associated with 30-day mortality. Landmark Kaplan-Meier analysis showed that mortality rates after 30 days were comparable between CS+ and CS-/HF+ groups but were lower in the CS-/HF- group. Multivariate Cox hazard analysis also showed that hazard risk of mortality after 30 days was comparable between the CS+ and CS-/HF+ groups (Hazard ratio (HR) 1.03, 95%CI 0.63-1.68, P = 0.90), and significantly lower in the CS-/HF- group (HR 0.44, 95%CI 0.32-059, P < 0.0001). In conclusion, AMI patients with CS who survived 30 days experienced worse long-term outcomes compared with those without CS up to 3 years. Attention is required for patients who show HF on admission without CS to improve long-term AMI outcomes.


Correlation of Arterial and Venous pH and Bicarbonate in Patients With Renal Failure.
Background and objective Blood gas analysis plays a pivotal role in the management of various respiratory and metabolic disorders. Both arterial and venous samples can be used for blood gas analysis. Arterial blood sampling is technically difficult and is associated with more complications as compared to venous sampling. Many studies have shown the correlation of arterial and venous pH and bicarbonate levels in sepsis, diabetic ketoacidosis (DKA), chronic obstructive pulmonary disease (COPD), and circulatory failure. But, there is a paucity of data, pertaining specifically to the correlation of arterial blood gas (ABG) analysis and venous blood gas (VBG) analysis in patients with renal failure. The objective of this study was to look for any possible correlation between arterial and venous pH and bicarbonate values in patients with renal failure. Methods This cross-sectional study was carried out at a large tertiary care hospital in Rawalpindi, Pakistan. Over a period of eight months, 101 patients with renal failure were enrolled after obtaining informed consent. Arterial and venous samples from the patients were obtained, analyzed, and compared. Results Out of the total 101 patients, 53 (52.5%) were male while 48 (47.5%) were female. The mean age of the patients was 46.23 ±15.54 years. Mean arterial pH and venous pH were 7.35 and 7.28 respectively. The Pearson correlation coefficient between arterial and venous pH was found to be 0.857 (p<0.001). The mean arterial and venous bicarbonate values were 14.47 mEq/L and 15.51 mEq/L respectively. And the Pearson correlation coefficient between arterial and venous bicarbonate was found to be 0.842 (p<0.001). Conclusion Venous pH and bicarbonate levels correlate strongly with arterial pH and bicarbonate levels, respectively, in patients with renal failure.


Competing realities, uncertain diagnoses of infectious disease: Mass self-testing for COVID-19 and liminal bio-citizenship.
Diagnoses of infectious diseases are being transformed as mass self-testing using rapid antigen tests (RATs) is increasingly integrated into public health. Widely used during the COVID-19 pandemic, RATs are claimed to have many advantages over 'gold-standard' polymerase chain reaction tests, especially their ease of use and production of quick results. Yet, while laboratory studies indicate the value of RATs in detecting the SARS-CoV-2 virus antigen, uncertainty surrounds their deployment and ultimate effectiveness in stemming infections. This article applies the analytic lens of biological citizenship (or bio-citizenship) to explore Australia's experience of implementing a RAT-based mass self-testing strategy to manage COVID-19. Drawing on Annemarie Mol's (1999, The Sociological Review, 47(1), 74-89) concept of ontological politics and analysing government statements, scientific articles and news media reporting published during a critical juncture of the strategy's implementation, we explore the kind of bio-citizenship implied by this strategy. Our analysis suggests the emergence of what we call liminal bio-citizenship, whereby citizens are made responsible for self-managing infection risk without the diagnostic certitude this demands. We discuss how the different realities of mass self-testing interact to reinforce this liminal citizenship and consider the implications for the sociology of diagnosis.


Influence of fiber on the phase transformations in the starch-water system.
High-sensitivity, temperature-controlled DSC measurements at a low heating rate and creation of differential DSC traces scaled with respect to the reference material (completely dehydrated starch or completely dehydrated fiber, or their respective blends) permitted investigation of the influence of fiber on phase transformations in the wheat-starch-water system in the course of thermal gelatinization. Thermal effects associated with water interactions over the temperature range from 283 to 384 K under atmospheric pressure were determined. These thermal effects and previous structural studies permit us to make the following observations: (1) The main endothermic transition associated with melting of the crystalline part of the starch granule followed by a helix-coil transition in amylopectin occurs over the temperature range 319-333 K independent of the water and fiber contents. Adding fiber causes that transition to disappear both in the native blends and in water suspensions at low water contents. After adding more water and heating, recrystallization is observed and the transition reappears. (2) The fiber content has practically no influence on the slow exothermic transformation, which follows melting and helix-coil transition in amylopectin, proving that the slow transformation has a specific chemical character. In this reaction, the free ends of the unwound helices of amylopectin reassociate with parts of amylopectin molecules other than their original helix duplex partner, forming physical junctions and creating more general amorphous hydrogen bonded associations. (3) The high-temperature transition and small, but reproducible, distortions on the peaks of the main endothermic transition for water contents near 70-80 wt % are associated with smectic and nematic transitions, respectively. These are significantly influenced by the fiber content; higher fiber content causes an almost complete disappearance of these transitions. (4) The slow exothermic effect appearing almost from the very beginning of the heating in the starch-water system, associated with softening and uptake of water in the amorphous growth rings of the starch granule, is significantly hindered by added fiber.


Personal profile: interview with Bill Andrews, Ph.D.
Dr. William H. Andrews has worked in the biotech industry for 31 years, focusing the last 19 years on finding ways to extend human life span through the intervention of telomere shortening in human cells. Dr. Andrews earned his Ph.D. in Molecular and Population Genetics at the University of Georgia. He was a Senior Scientist at Armos Corporation and Codon Corporation, Director of Molecular Biology at Codon and at Geron Corporation, and Director of Technology Development at EOS Biosciences. He is presently the founder, President, and CEO of Sierra Sciences, a biotechnology company focused exclusively on finding drugs that will transiently induce the expression of endogenous telomerase in human cells. Sierra Sciences has already identified more than 30 such drugs and is presently characterizing their mechanism of action. While Director of Molecular Biology at Geron Corporation, Dr. Andrews was one of the principal discoverers of both the RNA and protein components of human telomerase and was awarded second place as "National Inventor of the Year" in 1997 for this work. He is presently a named inventor on 43 U.S- issued telomerase patents.


Cancer physics: diagnostics based on damped cellular elastoelectrical vibrations in microtubules.
This paper describes a proposed biophysical mechanism of a novel diagnostic method for cancer detection developed recently by Vedruccio. The diagnostic method is based on frequency selective absorption of electromagnetic waves by malignant tumors. Cancer is connected with mitochondrial malfunction (the Warburg effect) suggesting disrupted physical mechanisms. In addition to decreased energy conversion and nonutilized energy efflux, mitochondrial malfunction is accompanied by other negative effects in the cell. Diminished proton space charge layer and the static electric field around the outer membrane result in a lowered ordering level of cellular water and increased damping of microtubule-based cellular elastoelectrical vibration states. These changes manifest themselves in a dip in the amplitude of the signal with the fundamental frequency of the nonlinear microwave oscillator-the core of the diagnostic device-when coupled to the investigated cancerous tissue via the near-field. The dip is not present in the case of healthy tissue.


Mice with Catalytically Inactive Cathepsin A Display Neurobehavioral Alterations.
The lysosomal carboxypeptidase A, Cathepsin A (CathA), is a serine protease with two distinct functions. CathA protects β-galactosidase and sialidase Neu1 against proteolytic degradation by forming a multienzyme complex and activates sialidase Neu1. CathA deficiency causes the lysosomal storage disease, galactosialidosis. These patients present with a broad range of clinical phenotypes, including growth retardation, and neurological deterioration along with the accumulation of the vasoactive peptide, endothelin-1, in the brain. Previous in vitro studies have shown that CathA has specific activity against vasoactive peptides and neuropeptides, including endothelin-1 and oxytocin. A mutant mouse with catalytically inactive CathA enzyme (CathAS190A ) shows increased levels of endothelin-1. In the present study, we elucidated the involvement of CathA in learning and long-term memory in 3-, 6-, and 12-month-old mice. Hippocampal endothelin-1 and oxytocin accumulated in CathAS190A mice, which showed learning impairments as well as long-term and spatial memory deficits compared with wild-type littermates, suggesting that CathA plays a significant role in learning and in memory consolidation through its regulatory role in vasoactive peptide processing.


Influence of distance between residence and health facilities on non-communicable diseases: An assessment over hypertension and diabetes in Bangladesh.
This paper reflected on the prevalence of hypertension and diabetes in Bangladesh, which is spreading rapidly in low-income countries. The rationale of constructing more health centers for addressing NCDs was assessed in this paper by determining the relationship between prevalence of NCDs, particularly hypertension and diabetes, and distance to health facilities. From BDHS (Bangladesh Health and Demographic Survey) 2011 data set, 7544 samples were analyzed to demonstrate association between Non-communicable diseases (NCD) and distance from respondents' home to health facilities like hospitals, community clinics, pharmacies or doctors' chambers, and community facilities like market, post office or cinema hall. Bivariate analysis was conducted between accessibility to health facilities and prevalence of the diseases. The causal relationship between the spatial effects and the prevalence of the diseases were analyzed by applying Generalized Linear Mixed Model (GLMM) was fitted. Fitting linear mixed effect models, we found that hypertension and diabetes react differently with various spatial effects. Distance from home to hospital had significant effect (P < 0.001) on hypertension showing people living further from the facilities or town centers seemed to be less hypertensive, whereas diabetes showed no such affiliation. Higher prevalence of diabetes (40.9%) over hypertension (26.5%) in people aging 35 or higher, have appeared to have caused the difference, which concluded that each non-communicable disease should be dealt to its own merit for policy making instead considering as a group of diseases.


Colonic electrolyte transport in health and in congenital chloride diarrhea.
Congenital chloride diarrhea (CCD) is a rare autosomal recessive disorder, characterized by watery stools with C1- concentration around 150 meq/liter. We have perfused the colon of three patients and their three healthy siblings with different salt solutions containing 36C1- to determine the nature of the colonic defect in CCD. In the controls, net absorption of Na+ and C1- occurred against steep concentration gradients. The influx (lumen-to-plasms flux) of C1- was twice the effux. Omission of HCO3- from the perfusate caused a clear decrease in C1- efflux which suggests a coupling of C1- effux to HCO3- influx. In CCD, net Na+ absorption occurred normally when HCO3- was present in the lumen. However, Na+ absorption was always impaired when the luminal contents were acid, a situation that prevails in CCD. Net K+ secretion was clearly increased. Both influx and efflux of C1- were practically absent. Only slight net secretion occurred along a steep gradient. Net appearance of HCO3- was not observed, in contrast to controls. These findings and earlier studies of ileal function in CCD are best explained by a defect in the C1-/HCO3- exchange mechanism, which operates in both directions in the normal ileum and colon.


Effects of chronic prenatal hypoxia on tyrosine hydroxylase and phenylethanolamine N-methyltransferase messenger RNA and protein levels in medulla oblongata of postnatal rat.
Catecholamines are a class of neurotransmitters involved in central nervous system autonomic control. Both acute and chronic hypoxia create alterations in ventilation and blood pressure via catecholamine release, although the mechanisms of these alterations are unknown. The enzymes tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) catalyze the rate-limiting step in the catecholamine pathway and production of epinephrine, respectively. Both have been colocalized with Fos protein in metabolic mapping studies of the O2-chemosensory pathway of adult and early postnatal rat. Thus, catecholamines are putative neurotransmitters in a subset of second and higher order respiratory neurons. To characterize the effects of prenatal hypoxia on subsequent TH and PNMT gene and protein expression, pregnant rats were placed in moderate hypoxia (10% O2) from gestational d 18 until birth. Northern and Western analyses of dorsal (catecholaminergic/adrenergic cell group 2) and ventral (catecholaminergic/adrenergic cell group 1) medullary tissue of postnatal (P) age P0, P3, P7, P10, and P14 pups were then done to examine changes in TH and PNMT mRNA and protein compared with normoxia-reared controls. Compared with controls, pups exposed to maternal hypoxia during pregnancy had lower levels of TH mRNA and protein at birth in dorsal medulla and higher levels of TH mRNA the first postnatal week in the ventral medulla. Pups that had been hypoxic in utero showed significantly lower levels of PNMT protein during the second postnatal week in dorsal medulla than did controls. Prenatal hypoxia-induced changes in levels of enzymes responsible for catecholamine synthesis may later be manifest as developmental deficiencies in neuronal function. This may compromise responses to acute hypoxic challenges during early postnatal life and contribute to autonomic nervous system disorders of the newborn such as apnea and sudden infant death syndrome.


Enlarged perivascular spaces are associated with cognitive function in healthy elderly men.
Increased white matter (WM) lesions on magnetic resonance imaging (MRI) are associated with worse cognitive function in older people. Enlarged perivascular spaces (EPVS) commonly coexist with and share some risk factors for WM lesions but are not quantified in published scales. It is not known whether the extent of EPVS is also associated with cognitive function. We tested the hypothesis that more EPVS would be associated with worse cognitive function. Ninety seven healthy men (65-70 years), not on medications, underwent MRI scanning and comprehensive cognitive testing. EPVS were quantified in both the basal ganglia/centrum semiovale and the hippocampus, and WM lesions were measured. Scores on published WM lesion rating scales intercorrelated highly significantly and positively (rho = 0.61 to 0.91, p<0.0001). A summary (WML) factor derived from principal components analysis of the WM scales correlated with EPVS in the basal ganglia/centrum semiovale (rho = 0.48, p<0.0001) but not in the hippocampus. EPVS scores in the basal ganglia/centrum semiovale correlated significantly and negatively with non-verbal reasoning (rho = -0.21, p = 0.038) and general visuospatial ability (rho = -0.22, p = 0.032), adjusted for prior intelligence. The WML factor correlated significantly and negatively with visuospatial ability, as previously reported, and showed an unexpected positive correlation with one test of verbal memory (list-learning). These findings suggest that increased EPVS are correlated with worse cognitive function. Future studies examining changes in WM with ageing should consider incorporating measures of EPVS and examine the sequence of EPVS and WM lesion development over time. More work is needed to develop valid and reliable measures of EPVS.


Wnts as essential growth factors for the adult small intestine and colon.
The study of physiologic functions of Wnt proteins has been complicated by the redundant nature of the families encoding the Wnt factors and their Frizzled receptors. Adenoviral expression of the secreted Wnt antagonist Dickkopf-1 (Dkk1) was used to achieve fully conditional inhibition of canonical Wnt signaling in adult mice. Systemic expression of Dkk1 resulted in rapid inhibition of Wnt target gene expression and of proliferation of the small intestine and colon, loss of proliferative crypts, and eventual inflammation and architectural degeneration. These studies indicate an essential requirement for extracellular Wnt signaling in the maintenance of adult small intestine and colon proliferation. The essential role of Wnt signaling in ongoing proliferation in the colon suggests potential clinical applications in mucosal repair for inflammatory bowel diseases and underscores the utility of adenoviral strategies for conditional ablation of gene function in adult organisms.


Effects of null mutations in the hexokinase genes of Saccharomyces cerevisiae on catabolite repression.
Saccharomyces cerevisiae has two homologous hexokinases, I and II; they are 78% identical at the amino acid level. Either enzyme allows yeast cells to ferment fructose. Mutant strains without any hexokinase can still grow on glucose by using a third enzyme, glucokinase. Hexokinase II has been implicated in the control of catabolite repression in yeasts. We constructed null mutations in both hexokinase genes, HXK1 and HXK2, and studied their effect on the fermentation of fructose and on catabolite repression of three different genes in yeasts: SUC2, CYC1, and GAL10. The results indicate that hxk1 or hxk2 single null mutants can ferment fructose but that hxk1 hxk2 double mutants cannot. The hxk2 single mutant, as well as the double mutant, failed to show catabolite repression in all three systems, while the hxk1 null mutation had little or no effect on catabolite repression.


Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.
Based on observational and interventional data for middle-aged cohorts (aged 40-64 years), serum cholesterol level is known to be an established major risk factor for coronary heart disease (CHD). However, findings for younger people are limited, and the value of detecting and treating hypercholesterolemia in younger adults is debated. To evaluate the long-term impact of unfavorable serum cholesterol levels on risk of death from CHD, cardiovascular disease (CVD), and all causes. Three prospective studies, from which were selected 3 cohorts of younger men with baseline serum cholesterol level measurements and no history of diabetes mellitus or myocardial infarction. A total of 11,017 men aged 18 through 39 years screened in 1967-1973 for the Chicago Heart Association Detection Project in Industry (CHA); 1266 men aged 25 through 39 years examined in 1959-1963 in the Peoples Gas Company Study (PG); and 69,205 men aged 35 through 39 years screened in 1973-1975 for the Multiple Risk Factor Intervention Trial (MRFIT). Cause-specific mortality during 25 (CHA), 34 (PG), and 16 (MRFIT) years of follow-up; mortality risks; and estimated life expectancy in relation to baseline serum cholesterol levels. Death due to CHD accounted for 26%, 34%, and 28% of all deaths in the CHA, PG, and MRFIT cohorts, respectively; and CVD death for 34%, 42%, and 39% of deaths in the same cohorts, respectively. Men in all 3 cohorts with unfavorable serum cholesterol levels (200-239 mg/dL [5.17-6.18 mmol/L] and >/=240 mg/dL [>/=6.21 mmol/L]) had strong gradients of relative mortality risk. For men with serum cholesterol levels of 240 mg/dL or greater (>/=6.21 mmol/L) vs favorable levels (<200 mg/dL [<5.17 mmol/L]), CHD mortality risk was 2.15 to 3.63 times greater; CVD disease mortality risk was 2.10 to 2.87 times greater; and all-cause mortality was 1.31 to 1.49 times greater. Hypercholesterolemic men had age-adjusted absolute risk of CHD death of 59 per 1000 men in 25 years (CHA cohort), 90 per 1000 men in 34 years (PG cohort), and 15 per 1000 men in 16 years (MRFIT cohort). Absolute excess risk was 43.6 per 1000 men (CHA), 81.4 per 1000 men (PG), and 12.1 per 1000 men (MRFIT). Men with favorable baseline serum cholesterol levels had an estimated greater life expectancy of 3.8 to 8.7 years. These results demonstrate a continuous, graded relationship of serum cholesterol level to long-term risk of CHD, CVD, and all-cause mortality, substantial absolute risk and absolute excess risk of CHD and CVD death for younger men with elevated serum cholesterol levels, and longer estimated life expectancy for younger men with favorable serum cholesterol levels. JAMA. 2000;284:311-318


[Contrast-induced nephropathy].
Iodine and gadolinium-based contrast induced nephropathy is the third leading cause of hospital-acquired acute kidney injury. It is essentially observed in patients with defined risk factors and is associated with increased morbidity and mortality. The prevention of contrast induced nephropathy consists in volume expansion through intravenous sodium chloride 0.9% or sodium bicarbonate 1.4%. Comparative randomized controlled trials appear to show a benefit in favor of sodium bicarbonate over saline fluids. According to last evidence, N-acetylcysteine does not provide additional benefit over intravenous fluids.


Filling the gaps: A mixed-methods study exploring the use of patient diaries in the critical care unit.
Survivors of critical illness often take time to recovery physically and psychologically from their critical care experience. There is tentative evidence suggesting that the use of a patient or family led diary with entries by nurses, doctors and allied health professionals may help the patient 'fill in the gaps' by making sense of a time they have forgotten. Many have confused or frightening memories and a diary can aid patients and their families in the recovery after critical illness. A mixed methods study including a qualitative exploration of the impact of diaries on critical care patients in order to describe the long-term effects of patient diaries. A two phase study including a prospective diary intervention and evaluation and subsequent in-depth interviews, using the principles of Grounded Theory. The instruments, Post Traumatic Stress Score-14 (PTSS-14) and EuroQol (EQ-5D-3L), were used to measured post-traumatic stress symptoms and quality of life in the year after diary. A questionnaire about diary use was completed by participants and content analysis of the diary was also undertaken, alongside basic demographics to explore patient characteristics. For the 50 patients receiving the diary intervention, those completing a diary evaluation, 95% found them helpful and 90% found it helped fill memory gaps. Mean scores for PTSS-14 (cumulative) at four months and 12 months: 30.5 (SD=10.8) and 25.7 (SD=11.7). Mean EuroQol visual analogue scores at four months and 12 months were 77.8 (SD=14.3) and 71.8 (SD=18.5) respectively. Themes from subsequent interviews with eight patients included: providing holistic care, emotional support and empathy and dealing with loss of control. Data confirmed that whilst diaries had broad value in making sense of the critical care experience and their subsequent recovery, not all were able to read them again. Integrated analysis of four data sources suggested the core themes of the diary revealed its value as: a dynamic communication tool integral to holistic care and person-centredness; a reflection of the impact of a critical care event and a resource that helped give a sense of meaning to what had happened. Diaries can offer a means of providing clarity for patients who struggle to come to terms with their critical care experience and subsequent recovery, but should be given to patients with forethought and support. It remains unclear which types of patients might benefit most from diaries.


[Acid-base equilibrium and spinal fluid enzyme activity in newborn infants with pathology of the nervous system].
The acid-base balance of the blood and cerebrospinal fluid was studied in 90 babies born in asphyxia in order to use these data in assessing the damage to the nervous system. Analysis revealed the hypoxic nature of the cerebral affection which was manifested by anaerobic glycolysis of the cerebral tissue and arterial hypoxemia. The degree of acidosis detected in the cerebrospinal fluid correlated with the severity of the nervous system damage. Children with the lethal outcome presented deeompensated respiratory acidosis, in the cerebrospinal fluid whereas children with severe neurological pathology had alkalosis. It is concluded that alkolosis is induced by an intensified catabolism of the nervous system proteins which leads to the accumulation of ammoniac compounds. The same children showed pulmonary hyperventilation leading to respiratory acidocis which was not related to pulmonary pathology. The latter points to the hypoxic impairment of the respiratory centre. At the same time, a considerable increase in the activity of the glycolytic enzymes was observed; the activity of glutamate oxalacetate transaminase increased 5-fold, the activity of lactate dehydrogenase rose two-fold.


Impact of diabetic retinopathy on quantitative retinal nerve fiber layer measurement and glaucoma screening.
To investigate the impact of diabetic retinopathy on quantitative retinal nerve fiber layer (RNFL) assessment and diagnostic power for glaucoma by scanning laser polarimetry (GDx-VCC) and optical coherence tomography (StratusOCT). The individual RNFL parameters of GDx and OCT were obtained for 170 eyes (one eye from each of 170 subjects [45 healthy, 47 glaucoma, 40 diabetes, and 38 glaucoma with diabetes]) and were compared among the four groups. Diabetic eyes had mild to moderate nonproliferative diabetic retinopathy (NPDR) without maculopathy. In glaucomatous eyes with or without diabetes, the ability to discriminate glaucoma was assessed by the areas under the receiver operating characteristic curves (AUROCs) and the sensitivities at more than 80% and 90% of specificities for each technique. Using GDx-VCC, significant differences (P < 0.05) in RNFL measurement parameters were found for all comparisons except those between glaucomatous eyes with diabetes and without diabetes. StratusOCT parameters did not detect significant differences between age-matched healthy and diabetic eyes. Among the parameters included, the nerve fiber indicator (NFI) of GDx-VCC and the inferior quadrant thickness (IQT) of StratusOCT had the largest AUROCs and sensitivities at specificities greater than 80%: NFI (0.912, 86%) and IQT (0.902, 85%) in glaucomatous eyes with diabetes; NFI (0.935, 92%) and IQT (0.921, 91%) in simple glaucomatous eyes. Mild to moderate NPDR causes a quantitative discrepancy in RNFL measurements between GDx-VCC and StratusOCT in simple diabetic eyes. However, mild to moderate glaucomatous optic neuropathy can be highly discriminated by the two imaging devices in eyes with diabetic retinopathy.


Complex oscillatory redox dynamics with signaling potential at the edge between normal and pathological mitochondrial function.
The time-keeping properties bestowed by oscillatory behavior on functional rhythms represent an evolutionarily conserved trait in living systems. Mitochondrial networks function as timekeepers maximizing energetic output while tuning reactive oxygen species (ROS) within physiological levels compatible with signaling. In this work, we explore the potential for timekeeping functions dependent on mitochondrial dynamics with the validated two-compartment mitochondrial energetic-redox (ME-R) computational model, that takes into account (a) four main redox couples [NADH, NADPH, GSH, Trx(SH)2], (b) scavenging systems (glutathione, thioredoxin, SOD, catalase) distributed in matrix and extra-matrix compartments, and (c) transport of ROS species between them. Herein, we describe that the ME-R model can exhibit highly complex oscillatory dynamics in energetic/redox variables and ROS species, consisting of at least five frequencies with modulated amplitudes and period according to power spectral analysis. By stability analysis we describe that the extent of steady state-as against complex oscillatory behavior-was dependent upon the abundance of Mn and Cu, Zn SODs, and their interplay with ROS production in the respiratory chain. Large parametric regions corresponding to oscillatory dynamics of increasingly complex waveforms were obtained at low Cu, Zn SOD concentration as a function of Mn SOD. This oscillatory domain was greatly reduced at higher levels of Cu, Zn SOD. Interestingly, the realm of complex oscillations was located at the edge between normal and pathological mitochondrial energetic behavior, and was characterized by oxidative stress. We conclude that complex oscillatory dynamics could represent a frequency- and amplitude-modulated H2O2 signaling mechanism that arises under intense oxidative stress. By modulating SOD, cells could have evolved an adaptive compromise between relative constancy and the flexibility required under stressful redox/energetic conditions.


Polyphenol intake from a Mediterranean diet decreases inflammatory biomarkers related to atherosclerosis: a substudy of the PREDIMED trial.
High dietary polyphenol intake is associated with reduced all-cause mortality and a lower incidence of cardiovascular events. However, the mechanisms involved are not fully understood. The aim of the present substudy of the PREvención con DIetaMEDiterránea (Prevention with Mediterranean diet; PREDIMED) trial was to analyse the relationship between polyphenol intake measured by total urinary polyphenol excretion (TPE), and circulating inflammatory biomarkers and cardiovascular risk factors in elderly individuals. A substudy of 1139 high-risk participants was carried out within the PREDIMED trial. The subjects were randomly assigned to a low-fat control diet or to two Mediterranean diets, supplemented with either extra-virgin olive oil or nuts. Dietary intake, anthropometric data, clinical and laboratory assessments, including inflammatory biomarkers, and urinary TPE were measured at baseline and after the one-year intervention. Participants in the highest tertile of changes in urinary TPE (T3) showed significantly lower plasma levels of inflammatory biomarkers [vascular cell adhesion molecule 1 (VCAM-1) (-9.47 ng ml-1 ), intercellular adhesion molecule 1 (-14.71 ng ml-1 ), interleukin 6 (-1.21 pg ml-1 ), tumour necrosis factor alpha (-7.05 pg ml-1 ) and monocyte chemotactic protein 1 (-3.36 pg ml-1 )] than those inthe lowest tertile (T1, P < 0.02; all). A significant inverse correlation existed between urinary TPE and the plasma concentration of\VCAM-1 (r = -0.301; P < 0.001). In addition, systolic and diastolic blood pressure (BP) decreased and plasma high-density lipoprotein cholesterol increased in parallel with increasing urinary TPE (T3 vs. T1) (P < 0.005 and P = 0.004, respectively). Increases in polyphenol intake measured as urinary TPE are associated with decreased inflammatory biomarkers, suggesting a dose-dependent anti-inflammatory effect of polyphenols. In addition, high polyphenol intake improves cardiovascular risk factors- mainly BP and the lipid profile.


Investigating the relationship between formal and informal care: An application using panel data for people living together.
There is limited evidence on the relationship between formal and informal care using panel data in a U.K. setting and focused specifically on people living together (co-residents). Using all 18 waves of the British Household Panel Survey (1991-2009), we analyse the effect of informal care given by co-residents on the use of formal home care and health care services more generally. To account for endogeneity, we estimate models using random effects instrumental variable regression using the number of daughters as a source of exogenous variation. We find that a 10% increase in the monthly provision of informal care hours decreases the probability of using home help (formal home care) by 1.02 percentage points (p < .05), equivalent to a 15.62% relative reduction. This effect was larger for home help provided by the state (β = -.117) compared with non-state home help (β = -.044). These results provide evidence that significant increases in the supply of informal care would reduce the demand for home-help provision.


Autologous bioscaffolds based on different concentrations of platelet rich plasma and synovial fluid as a vehicle for mesenchymal stem cells.
In the field of tissue engineering, diverse types of bioscaffolds are being developed currently for osteochondral defect applications. In this work, a novel scaffold based on platelet rich plasma (PRP) and hyaluronic acid with mesenchymal stem cells (MSCs) has been evaluated to observe its effect on immobilized cells. The bioscaffolds were prepared by mixing different volumes of synovial fluid (SF) with PRP from patients obtaining three formulations at PRP-SF ratios of 3:1, 1:1 and 1:3 (v/v). The live/dead staining revealed that although the cell number of each type of bioscaffold was different, these this constructs provide cells with a suitable environment for their viability and proliferation. Moreover, immobilized MSCs showed their ability to secrete fibrinolytic enzymes, which vary depending on the fibrin amount of the scaffold. Immunohistochemical analysis revealed the positive staining for collagen type II in all cases, proving the biologic action of SF derived MSCs together with the suitable characteristics of the bioscaffold for chondrogenic differentiation. Considering all these aspects, this study demonstrates that these cells-based constructs represent an attractive method for cell immobilization, achieving completely autologous and biocompatible scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 377-385, 2018.


Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines.
Eighty percent of human ovarian and endometrial cancers express receptors for luteinizing hormone-releasing hormone (LHRH). These receptors might be used for targeted chemotherapy with cytotoxic LHRH analogs such as AN-152, in which doxorubicin is linked to agonist carrier [D-Lys6]LHRH. The antiproliferative effects of doxorubicin and AN-152 were assessed in LHRH receptor-positive ovarian (EFO-21, EFO-27) and endometrial (HEC-1A, Ishikawa) cancer cell lines as well as in LHRH receptor negative ovarian SKOV-3 and endometrial MFE-296 lines. The mechanism of action of AN-152 was investigated by a blockage of receptors using an excess of the LHRH agonist [D-Trp6]LHRH. In some cases, confocal laser-scanning microscopy was used to visualize the accumulation of AN-152 or doxorubicin within the cells. In 3 of 4 LHRH receptor-positive cell lines (EFO-21, HEC-1A, Ishikawa) AN-152 was more effective than doxorubicin in inhibiting cell proliferation. The effect of AN-152 was shown to be receptor-mediated because it could be reduced by competitive blockade of the LHRH receptors with [D-Trp6]LHRH. In contrast, AN-152 was less active than doxorubicin in LHRH receptor-negative lines. Confocal laser-scanning microscopy showed an intranuclear accumulation of AN-152 and competitive inhibition thereof by [D-Trp6]LHRH in LHRH receptor-positive cell lines, but no intracellular accumulation of AN-152 could be detected in the receptor-negative SKOV-3 line. These results suggest a selective receptor-mediated action of AN-152 in receptor-positive cell lines.


Demographic and clinical factors associated with referrals and compliance to biopsy of oral and maxillofacial lesions.
The gold standard for diagnosing oral disease is tissue biopsy. Data regarding compliance with advised oral and maxillofacial (OMF) biopsy are scarce. To quantify compliance and evaluate the demographics and clinical factors associated with referrals and compliance with OMF biopsy procedures. Medical records of military personnel referred for a biopsy (RB; N = 669) of OMF lesions over a 4-year period were studied retrospectively. These patients were divided into performed the biopsy (PB; N = 386) and not perform biopsy (NPB; N = 283) groups. Demographic and clinical features were analyzed, and demographics were compared to a control group of general military personnel (N > 100,000). The RB group differed from the control group regarding age >21 (OR = 1.681, P < 0.001) and education >12 years of schooling (OR = 1.545, P < 0.001). Differences between the PB and NPB groups related to the clinical features of the lesion but not to demographic parameters. Exophytic and suspected potentially malignant/malignant lesions were positively associated with higher compliance to biopsy (OR = 1.75, P = 0.004 and OR = 2.18, P = 0.017, respectively). Referrals to biopsy of OMF lesions are significantly influenced by age and education, whereas compliance is influenced by clinical features or suspected malignancy. Clinicians and health authorities should be aware of non-compliance, enhance awareness to biopsy as the gold standard in the diagnostic workup of OMF lesions, and closely monitor compliance patterns of patients with clinical and demographic risk factors.


Solvothermal synthesis and controlled self-assembly of monodisperse titanium-based perovskite colloidal nanocrystals.
The rational design of monodisperse ferroelectric nanocrystals with controlled size and shape and their organization into hierarchical structures has been a critical step for understanding the polar ordering in nanoscale ferroelectrics, as well as the design of nanocrystal-based functional materials which harness the properties of individual nanoparticles and the collective interactions between them. We report here on the synthesis and self-assembly of aggregate-free, single-crystalline titanium-based perovskite nanoparticles with controlled morphology and surface composition by using a simple, easily scalable and highly versatile colloidal route. Single-crystalline, non-aggregated BaTiO3 colloidal nanocrystals, used as a model system, have been prepared under solvothermal conditions at temperatures as low as 180 °C. The shape of the nanocrystals was tuned from spheroidal to cubic upon changing the polarity of the solvent, whereas their size was varied from 16 to 30 nm for spheres and 5 to 78 nm for cubes by changing the concentration of the precursors and the reaction time, respectively. The hydrophobic, oleic acid-passivated nanoparticles exhibit very good solubility in non-polar solvents and can be rendered dispersible in polar solvents by a simple process involving the oxidative cleavage of the double bond upon treating the nanopowders with the Lemieux-von Rudloff reagent. Lattice dynamic analysis indicated that regardless of their size, BaTiO3 nanocrystals present local disorder within the perovskite unit cell, associated with the existence of polar ordering. We also demonstrate for the first time that, in addition to being used for fabricating large area, crack-free, highly uniform films, BaTiO3 nanocubes can serve as building blocks for the design of 2D and 3D mesoscale structures, such as superlattices and superparticles. Interestingly, the type of superlattice structure (simple cubic or face centered cubic) appears to be determined by the type of solvent in which the nanocrystals were dispersed. This approach provides an excellent platform for the synthesis of other titanium-based perovskite colloidal nanocrystals with controlled chemical composition, surface structure and morphology and for their assembly into complex architectures, therefore opening the door for the design of novel mesoscale functional materials/nanocomposites with potential applications in energy conversion, data storage and the biomedical field.


Genome wide analysis of TLR1/2- and TLR4-activated SZ95 sebocytes reveals a complex immune-competence and identifies serum amyloid A as a marker for activated sebaceous glands.
Toll-like receptors (TLR) 2 and 4 are active in sebaceous glands and play a central role in the development of acne. Still, there is only limited knowledge on their effect on sebocytes. In this work we performed global gene expression profile analysis with functional clustering of the differentially regulated genes of TLR1/2 (PAM3CSK4)- and TLR4 (lipopolysaccharide [LPS])-activated SZ95 sebocytes. Both TLR1/2- and 4-activation promoted inflammation in a similar manner already at an early time-point (6 hours), regulating genes involved in inflammation, wound healing and chemotaxis reflecting a more complex cytokine and chemokine regulation than previously known. Importantly, lipid metabolism, the primary feature of sebocytes, was affected at the level of gene expression only at a later time point (24 hours) indicating that sebocytes prioritize to exert a pro-inflammatory phenotype when confronted with a danger signal. Supporting the biological relevance of our results, a meta-analysis revealed that the genes showing the strongest up-regulation were also found up-regulated in acne. Of these genes, serum amyloid A 1/2 (SAA1/2) was confirmed to be a suitable protein marker for in vivo activated sebocytes, underlining their immune-competence, which is structurally defined within sebaceous glands of acne and rosacea skin samples. Altogether our findings demonstrate that sebocytes are not only positioned at the end point of inflammation but are actively involved in shaping the inflammatory response with putative diagnostic and therapeutic relevance.


Use of Amplatzer device for endobronchial closure of bronchopleural fistulas.
Bronchopulmonary fistula (BPF) is associated with high morbidity and mortality. It occurs as an uncommon but often severe complication of pneumonectomy. BPF may be treated by a range of surgical and medical techniques, including chest drain, Eloesser muscle flap, omental flap, transsternal bronchial closure, thoracoplasty, and prolonged therapy with antibiotic regimens. The use of bronchoscopy has been reported for the delivery of biological glue, coils, covered stents, and sealants. In this work, we describe a novel method of BPF closure using the Amplatzer device, which is commonly used for transcatheter closure of atrial septal defects.


Structure, dynamics, and substrate-induced conformational changes of the multidrug transporter EmrE in liposomes.
EmrE, a member of the small multidrug transporters superfamily, extrudes positively charged hydrophobic compounds out of Escherichia coli cytoplasm in exchange for inward movement of protons down their electrochemical gradient. Although its transport mechanism has been thoroughly characterized, the structural basis of energy coupling and the conformational cycle mediating transport have yet to be elucidated. In this study, EmrE structure in liposomes and the substrate-induced conformational changes were investigated by systematic spin labeling and EPR analysis. Spin label mobilities and accessibilities describe a highly dynamic ligand-free (apo) conformation. Dipolar coupling between spin labels across the dimer reveals at least two spin label populations arising from different packing interfaces of the EmrE dimer. One population is consistent with antiparallel arrangement of the monomers, although the EPR parameters suggest deviations from the crystal structure of substrate-bound EmrE. Resolving these discrepancies requires an unusual disposition of TM3 relative to the membrane-water interface and a kink in its backbone that enables bending of its C-terminal part. Binding of the substrate tetraphenylphosphonium changes the environment of spin labels and their proximity in three transmembrane helices. The underlying conformational transition involves repacking of TM1, tilting of TM2, and changes in the backbone configurations of TM3 and the adjacent loop connecting it to TM4. A dynamic apo conformation is necessary for the polyspecificity of EmrE allowing the binding of structurally diverse substrates. The flexibility of TM3 may play a critical role in movement of substrates across the membrane.


MAGEA10 expression is a predictive marker of early hepatic recurrence after curative gastrectomy for gastric and gastroesophageal junction cancer.
Resection for hepatic recurrence after gastrectomy in patients with gastric cancer may be curative; however, the prediction of hepatic recurrence remains intractable. Therefore, we aimed to explore predictive markers for hepatic recurrence in gastric and gastroesophageal junction cancer based on genetic information. This study recruited 154 patients who underwent curative gastrectomy for pathological stage II or III primary gastric and gastroesophageal junction adenocarcinoma. Genes associated with hepatic recurrence were comprehensively analyzed using whole-exome sequencing and gene expression profiling (GEP), followed by immunohistochemistry analysis for MAGEA10. The cumulative incidences of hepatic recurrence, relapse-free survival, and overall survival were evaluated. A total of 12 patients with early hepatic recurrences were found within 2 years of surgery. Although there were no distinct gene mutations in recurrent patients, upregulation of MAGEA10 was identified in patients with early hepatic recurrence using GEP analysis. Immunostaining for MAGEA10 stained the cell nuclei in 29 (18.8%) of 154 samples. Furthermore, protein expression of MAGEA10 on immunohistochemistry was significantly related to a high MAGEA10 mRNA expression, high cumulative incidences of hepatic recurrence, and poor relapse-free survival. Overall survival did not differ significantly between positive and negative immunohistochemical staining for MAGEA10. The sensitivity and specificity of MAGEA10 staining for early hepatic recurrence were 58.3% and 84.5%, respectively. MAGEA10 represents a promising predictive marker for early hepatic recurrence after curative gastrectomy for gastric and gastroesophageal junction cancer.


Extending Asia Pacific bioinformatics into new realms in the "-omics" era.
The 2009 annual conference of the Asia Pacific Bioinformatics Network (APBioNet), Asia's oldest bioinformatics organisation dating back to 1998, was organized as the 8th International Conference on Bioinformatics (InCoB), Sept. 7-11, 2009 at Biopolis, Singapore. Besides bringing together scientists from the field of bioinformatics in this region, InCoB has actively engaged clinicians and researchers from the area of systems biology, to facilitate greater synergy between these two groups. InCoB2009 followed on from a series of successful annual events in Bangkok (Thailand), Penang (Malaysia), Auckland (New Zealand), Busan (South Korea), New Delhi (India), Hong Kong and Taipei (Taiwan), with InCoB2010 scheduled to be held in Tokyo, Japan, Sept. 26-28, 2010. The Workshop on Education in Bioinformatics and Computational Biology (WEBCB) and symposia on Clinical Bioinformatics (CBAS), the Singapore Symposium on Computational Biology (SYMBIO) and training tutorials were scheduled prior to the scientific meeting, and provided ample opportunity for in-depth learning and special interest meetings for educators, clinicians and students. We provide a brief overview of the peer-reviewed bioinformatics manuscripts accepted for publication in this supplement, grouped into thematic areas. In order to facilitate scientific reproducibility and accountability, we have, for the first time, introduced minimum information criteria for our pubilcations, including compliance to a Minimum Information about a Bioinformatics Investigation (MIABi). As the regional research expertise in bioinformatics matures, we have delineated a minimum set of bioinformatics skills required for addressing the computational challenges of the "-omics" era.


Number skills are maintained in healthy ageing.
Numerical skills have been extensively studied in terms of their development and pathological decline, but whether they change in healthy ageing is not well known. Longer exposure to numbers and quantity-related problems may progressively refine numerical skills, similar to what happens to other cognitive abilities like verbal memory. Alternatively, number skills may be sensitive to ageing, reflecting either a decline of number processing itself or of more auxiliary cognitive abilities that are involved in number tasks. To distinguish between these possibilities we tested 30 older and 30 younger participants on an established numerosity discrimination task requiring to judge which of two sets of items is more numerous, and on arithmetical tasks. Older participants were remarkably accurate in performing arithmetical tasks although their numerosity discrimination (also known as 'number acuity') was impaired. Further analyses indicate that this impairment was limited to numerosity trials requiring inhibiting information incongruent to numerosity (e.g., fewer but larger items), and that this also correlated with poor inhibitory processes measured by standard tests. Therefore, rather than a numerical impairment, poor numerosity discrimination is likely to reflect elderly's impoverished inhibitory processes. This conclusion is supported by simulations with a recent neuro-computational model of numerosity perception, where only the specific degradation of inhibitory processes produced a pattern that closely resembled older participants' performance. Numeracy seems therefore resilient to ageing but it is influenced by the decline of inhibitory processes supporting number performance, consistent with the 'Inhibitory Deficit' Theory.


[Of Brazil and Quebec, food for thought: Brazilian community health workers bridge the gap between families and health professionals].
The Brazilian unified health system consists of 27,000 family health teams with a network of approximately 300,000 community health agents whose mandate is to link the families they visit every month with health professionals at the family health unit. Since 2003, Quebec has been implementing its health and social services reforms by emphasizing the integration of care and services (public, associative and private) in local networks which have a formal population health responsibility. This commentary aims to underline some similarities and differences between the program of the Brazilian 'units of family health' and that of integrated network clinics (CRI) or Groups of family medicine (GMF) in Quebec. In both cases, a major concern is to organize primary care services in as close proximity as possible to the population of a given territory, and to improve accessibility and adequacy of services. In addition, through these community health agents, Brazil enables the creation of a social security network that assures an effective follow-up of all members of the population with regard to health services.


Retrospective evaluation of potentially inappropriate prescribing in hospitalized patients with renal impairment.
Patients with chronic kidney disease require appropriate adjustment of nephrotoxic and renally cleared medications to ensure safe and effective pharmacotherapy. It is currently unclear how often appropriate medication selection and dosage adjustment occurs in practice. Therefore, this study aimed to evaluate the extent of potentially inappropriate prescribing (PIP) (the use of a contraindicated medication or inappropriately high dose according to the renal function) in patients with renal impairment from admission through to discharge from the Royal Hobart Hospital (RHH), Tasmania, Australia; to evaluate the medications most commonly implicated in PIP; and the factors associated with PIP in renal impairment. Medical records of 251 patients consecutively admitted to the RHH aged 40 years and above, with a creatinine clearance of ≤60 mL/min, and hypertension and/or diabetes mellitus in their medical history, were reviewed. PIP was assessed using the Australian Medicines Handbook and/or product information. Of the 251 patients, 81 (32.3%) were receiving a total of 116 potentially inappropriate medications (PIMs) at the time of admission. The number of patients receiving PIMs (81 vs. 44, p<0.001 chi-square test) as well as the total number of PIMs (116 vs. 63, p<0.001 Wilcoxon signed rank test) were significantly decreased at discharge. Metformin was the most common PIM at admission. However, PIP of metformin was reduced by approximately 50% by discharge. Logistic regression analysis revealed two significant independent risk factors for PIP: a higher number of medications at admission increased risk of PIP (OR 1.1, 95% CI 1.02-1.18, p=0.010), and higher initial estimated glomerular filtration rate (eGFR) decreased the risk of PIP (OR 0.9, 95% CI 0.96-0.99, p=0.011). Despite the limitations of lack of body weight documentation and lack of clear guidelines for dosage adjustment based on the eGFR, PIP in patients with renal impairment is common and admission to the hospital was associated with a significant reduction in PIP. More recognition of chronic kidney disease in the community and strategies to alert clinicians of the need for dosage adjustment in renal impairment are warranted.


Inhibition of USP10 induces degradation of oncogenic FLT3.
Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3. Because the relevant DUBs for FLT3 are not known, we assembled a focused library of most reported small-molecule DUB inhibitors and carried out a cellular phenotypic screen to identify compounds that could induce the degradation of oncogenic FLT3. Subsequent target deconvolution efforts allowed us to identify USP10 as the critical DUB required to stabilize FLT3. Targeting of USP10 showed efficacy in preclinical models of mutant-FLT3 AML, including cell lines, primary patient specimens and mouse models of oncogenic-FLT3-driven leukemia.


Interleukin-8: an important neutrophil chemotaxin in some cases of exudative pleural effusions.
It was hypothesized that IL-8, a neutrophil chemotaxin, contributes to the influx of neutrophils into the pleural cavity of patients with pleural effusions. Pleural fluids were collected from 57 patients including 13 with effusions due to congestive heart failure, 28 with pleural involvement by carcinoma, 5 with empyema, 4 with parapneumonic effusions complicating bacterial pneumonia, 3 with hemothorax, 3 with tuberculosis, and 1 with rheumatoid arthritis. All exudate groups had significantly higher IL-8 concentrations than the CHF group (p < .001). In 18 of the exudate fluids, the concentrations of IL-8 was equal to or in excess of the optimal concentration of IL-8 which causes neutrophil chemotaxis in vitro. Between 20 and 90% of the chemotactic activity in the fluids was removed by absorbing the IL-8 with an IL-8 affinity column. These data showed that IL-8 is a major chemotaxin in the fluid. The percentage of neutrophils in the fluids was not correlated with the IL-8 concentration. Although TNF alpha, a potent stimulator of IL-8 production, is present in some pleural effusions, no correlation was found between the concentrations of IL-8 and TNF alpha in the fluids. The data suggest that IL-8 contributes to the neutrophil influx into the pleural space of patients with pleural exudates in conjunction with other chemoattractants. It is unlikely that TNF alpha is the sole stimulus for the IL-8 production in pleural disease states.


Feasibility and Safety of Controlled Active Hypothermia Treatment During Transport in Neonates With Hypoxic-Ischemic Encephalopathy.
To evaluate the feasibility and safety of controlled active hypothermia versus standard intensive care during neonatal transport in patients with hypoxic-ischemic encephalopathy. Cohort study with a historic control group. All infants were transported by Neonatal Emergency & Transport Services to a Level-III neonatal ICU. Two hundred fourteen term newborns with moderate-to-severe hypoxic-ischemic encephalopathy. An actively cooled group of 136 newborns were compared with a control group of 78 newborns. Controlled active hypothermia during neonatal transport. Key measured variables were timing of hypothermia initiation, temperature profiles, and vital signs during neonatal transport. Hypothermia was initiated a median 2.58 hours earlier in the actively cooled group compared with the control group (median 1.42 [interquartile range, 0.83-2.07] vs 4.0 [interquartile range, 2.08-5.79] hours after birth, respectively; p < 0.0001), and target temperature was also achieved a median 1.83 hours earlier (median 2.42 [1.58-3.63] vs 4.25 [2.42-6.08] hours after birth, respectively; p < 0.0001). Blood gas values and vital signs were comparable between the two groups with the exception of heart rate, which was significantly lower in the actively cooled group. The number of infants in the target temperature range (33-34°C) on arrival was 79/136 (58.1%) and the rate of overcooling was 16/136 (11.8%) in the actively cooled group. In the overcooled infants, Apgar scores, pH, base deficit, and eventual death rate (7/16; 43.8%) indicated more severe asphyxia suggesting poor temperature control in this subgroup of patients. Adverse events leading to pulmonary or circulatory failure were not observed in either groups during the transport period. Therapeutic hypothermia during transport is feasible and safe, allowing for significantly earlier initiation and achievement of target temperature, possibly providing further benefit for neonates with hypoxic-ischemic encephalopathy.


Factors Affecting Microbial Contamination on the Back Surface of Worn Soft Contact Lenses.
The results of this study demonstrate that Smart Touch Technology packaging, which is designed to reduce and simplify contact lens handling before insertion, is effective in reducing the frequency of bacterial contamination of the back surface of contact lenses after short-term wear. The purpose of this study was to investigate the effect of lens packaging type, chelating agent, and finger contamination on microbial contamination on the back surface of worn soft contact lenses. Twenty-five subjects completed each contralateral lens wear comparison in this randomized study: Smart Touch Technology versus conventional blister packaging for (1) silicone hydrogel lenses with ethylenediaminetetraacetic acid (EDTA) and (2) hydrogel lenses without EDTA in the packaging, and (3) silicone hydrogel lenses without EDTA versus hydrogel lenses with EDTA both in Smart Touch Technology packaging. Participants washed hands, underwent finger swabs, and inserted the lenses. After 45 minutes, lenses were removed aseptically and the posterior lens surfaces cultured. Thirty-eight subjects (average age, 30.9 ± 12.5 years) participated in this study. Overall, the level of back surface contamination was low for both lens materials, ranging from 0 to 43 colony-forming unit (CFU)/lens for the silicone hydrogel and 0 to 17 CFU/lens for the hydrogel lenses. The proportion of lenses with zero back surface contamination ranged from 16 to 64% for silicone hydrogel lenses and 28 to 64% for hydrogel lenses. Contact lenses from conventional packaging containing EDTA had 3.38 times increased risk (95% confidence interval [CI], 1.02 to 11.11; P = .05) of contamination being present compared with lenses from Smart Touch packaging with EDTA. Contact lenses from conventional packaging without EDTA had 3.4 times increased risk (95% CI, 1.02 to 11.36; P = .05) of contamination being present compared with Smart Touch packaging without EDTA, and silicone hydrogel lenses had a 6.28 times increased risk (95% CI, 1.65 to 23.81; P = .007) of contamination being present compared with hydrogels. The median (interquartile range) number of bacteria isolated from fingers used to perform lens insertion after handwashing but before lens insertion was not significantly different between the silicone hydrogel and hydrogel lenses (63.7 [204.2] vs. 59 [84.5], P = .09). Finger contamination was not significantly associated with lens contamination in the presence or absence of EDTA. Smart Touch Technology packaging was effective in reducing the proportion of contaminated lenses. Although silicone hydrogel lenses were more likely to be contaminated, the presence of EDTA ameliorated this effect. Finger contamination was not associated with lens contamination.