Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism.
From viral binding to the hepatocyte surface to extracellular virion release, the replication cycle of the hepatitis C virus (HCV) intersects at various levels with lipid metabolism; this leads to a derangement of the lipid profile and to increased viral infectivity. Accumulating evidence supports the crucial regulatory role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism. Notably, a complex interaction between HCV and PCSK9 has been documented. Indeed, either increased or reduced circulating PCSK9 levels have been observed in HCV patients; this discrepancy might be related to several confounders, including HCV genotype, human immunodeficiency virus (HIV) coinfection and the ambiguous HCV-mediated influence on PCSK9 transcription factors. On the other hand, PCSK9 may itself influence HCV infectivity, inasmuch as the expression of different hepatocyte surface entry proteins and receptors is regulated by PCSK9. The aim of this review is to summarize the current evidence about the complex interaction between HCV and liver lipoprotein metabolism, with a specific focus on PCSK9. The underlying assumption of this review is that the interconnections between HCV and PCSK9 may be central to explain viral infectivity.


Gentisate and 3-oxoadipate pathways in the yeast Candida parapsilosis: identification and functional analysis of the genes coding for 3-hydroxybenzoate 6-hydroxylase and 4-hydroxybenzoate 1-hydroxylase.
The pathogenic yeast Candida parapsilosis degrades various hydroxy derivatives of benzenes and benzoates by the gentisate and 3-oxoadipate pathways. We identified the genes MNX1, MNX2, MNX3, GDX1, HDX1 and FPH1 that code for enzymes involved in these pathways in the complete genome sequence of C. parapsilosis. Next, we demonstrated that MNX1, MNX2, MNX3 and GDX1 are inducible and transcriptionally controlled by hydroxyaromatic substrates present in cultivation media. Our results indicate that MNX1 and MNX2 code for flavoprotein monooxygenases catalysing the first steps in the 3-oxoadipate and gentisate pathways, respectively (i.e. 4-hydroxybenzoate 1-hydroxylase and 3-hydroxybenzoate 6-hydroxylase). Moreover, we found that the two pathways differ by their intracellular localization. The enzymes of the 3-oxoadipate pathway, Mnx1p and Mnx3p, localize predominantly in the cytosol. In contrast, intracellular localization of the components of the gentisate pathway, Mnx2p and Gdx1p, depends on the substrate in the cultivation medium. In cells growing on glucose these proteins localize in the cytosol, whereas in media containing hydroxyaromatic compounds they associate with mitochondria. Finally, we showed that the overexpression of MNX1 or MNX2 increases the tolerance of C. parapsilosis cells to the antifungal drug terbinafine.


The 2 microm plasmid causes cell death in Saccharomyces cerevisiae with a mutation in Ulp1 protease.
The 2 microm circle plasmid confers no phenotype in wild-type Saccharomyces cerevisiae but in a nib1 mutant, an elevated plasmid copy number is associated with cell death. Complementation was used to identify nib1 as a mutant allele of the ULP1 gene that encodes a protease required for removal of a ubiquitin-like protein, Smt3/SUMO, from protein substrates. The nib1 mutation replaces conserved tryptophan 490 with leucine in the protease domain of Ulp1. Complete deletion of ULP1 is lethal, even in a strain that lacks the 2 microm circle. Partial deletion of ULP1, like the nib1 mutation, results in clonal variations in plasmid copy number. In addition, a subset of these mutant cells produces lineages in which all cells have reduced proliferative capacity, and this phenotype is dependent upon the presence of the 2 microm circle. Segregation of the 2 microm circle requires two plasmid-encoded proteins, Rep1 and Rep2, which were found to colocalize with Ulp1 protein in the nucleus and interact with Smt3 in a two-hybrid assay. These associations and the observation of missegregation of a fluorescently tagged 2 microm circle reporter plasmid in a subset of ulp1 mutant cells suggest that Smt3 modification plays a role in both plasmid copy number control and segregation.


Does hospital discharge policy influence sick-leave patterns in the case of female breast cancer?
The objective was to investigate how differences among hospitals in the shift from in-patient care to day surgery and a reduced hospital length of stay affect the sick-leave period for female patients surgically treated for breast cancer. All women aged 18-64 who were diagnosed with breast cancer in 2000 were selected from the National Cancer Register and combined with data from the sick-leave database of the National Social Insurance Board and the National Hospital Discharge Register (N = 1834). A multi-factorial model was fitted to the data to investigate how differences in hospital care practice affected the length of sick-leave. The main output measure was the number of sick-leave days after discharge during the year following surgery. The confounders used included age, type of primary surgical treatment, whether or not lymph node dissection was performed, labour-market status, county, and readmission. Women treated with breast-conserving surgery had a 54.7-day (-71.9 < or = CI(95%) < or = -37.5) shorter sick-leave period than those with more invasive surgery. The day-surgery cases had 24.3 (-47.5 < or = CI(95%) < or = -1.1) days shorter sick-leave than those who received overnight care. The effect of the hospital median length of stay (LOS) was U-shaped, suggesting that hospitals with a median LOS that is either short or long are associated with longer sick-leave. In the intermediate range, women treated in hospitals with a median LOS of 2 days had 22 days longer sick-leave than those treated in hospitals with a mean LOS of 3 days. This is possibly a sign of sub-optimising.


The prevalence and diversity of AmpC β-lactamase genes in plasmids from aquatic systems.
This study aimed to investigate the presence and diversity of AmpC β-lactamase and integrase genes among DNA (genomic and plasmid) from bacterial populations in selected aquatic systems. Following an enrichment step, DNA was isolated and subjected to polymerase chain reaction (PCR) and digital droplet PCR. The intI1 gene and AmpC β-lactamase genes were present in genomic and plasmid DNA from all sites in the Mooi, Crocodile and Marico Rivers, with the exception of intI1 in the Marico River. Digital droplet PCR demonstrated that copy numbers varied considerably (0.0 to 29.38 copies per picogram of DNA). Some samples in which ampC was not detected, intI1 was present. Amplicons of ampC genes were subjected to restriction digest using HindIII. Samples where the restriction markers were absent were purified by cloning followed by plasmid extraction, PCR amplification, and sequencing of individual AmpC gene fragments. Phylogenetic analysis identified all positive AmpC genes as Class C β-lactamases, comprising of ampC, CMY- and ACT-families. Detecting AmpC and intl1 genes on plasmids suggests a high risk of horizontal gene transfer and potential dissemination of these and other antibiotic resistance genes surrounding immediate aquatic environments. Consequences of β-lactamase diversity in aquatic ecosystems are relatively unexplored in South African aquatic ecosystems.


The Efficiency of Mental Health Integration in Primary Health Care: a Ten-year Study.
This study was conducted on the estimation of the efficiency of mental health program in primary health care in Chaharmahal and Bakhtyari province, situated in center of the Islamic Republic of Iran, from 1999 to 2009. One of the important objectives of mental health program is screening of mental health disorders and follow up. According to the prescription of mental health program, General Practitioners (GPs) were appointed to screen under-covered individuals, treat patients and also follow-up the patients with mental health disorders who needs referring to psychiatric clinics. Diagnostic criteria of mental disorders were based on American Psychiatry Association (DSM IV1994). Patients were categorized in four groups as follows: 1 - Severe mental disorders, such as major depression, schizophrenia, bipolar disorders, etc., 2 - Mild mental disorders, such as neurosis, anxiety, etc., 3 - Convulsive disorders and 4 - Behavioral disorders. The convulsive disorders and their types were diagnosed by physical examination and electroencephalography. In order to screen mental retardation, intelligence scale (IQ) score < 70 was considered as mental retardation. During the 10 years (1999 to 2009) of conducting program, all new diagnosed cases were confirmed by psychiatrists. All data was recorded in health files by trained GPs and they were assessed and justified by psychiatrists. During 10 years after conducting and stabilizing integrated mental health in primary health care, 13514 patients overall were newly detected and followed. Ten years incidence of total psychiatric disorders was estimated in about 15.9 per 1000 populations. Integrated mental health care offers the opportunity to increase access and develop efficiency of the mental health cares.


A comparison of Computed Tomography perfusion-guided and time-guided endovascular treatments for patients with acute ischemic stroke.
The role of CT perfusion (CT-P) imaging for the selection of patients with acute ischemic stroke who may benefit from endovascular treatment is not defined. The objective of this study was to determine whether CT-P-guided endovascular treatment improves clinical outcomes compared with standard endovascular treatment based on the time interval between symptom onset and presentation and noncontrast cranial CT imaging. A retrospective study was performed comparing the clinical characteristics, complications, and clinical outcomes of patients with acute ischemic stroke who were treated using endovascular modalities based on either CT-P imaging (CT-P-guided) or time interval between symptom onset and presentation and absence of intracerebral hemorrhage or extensive ischemic changes on noncontrast cranial CT scan (time-guided). The rates of partial and complete recanalization were similar between the CT-P- and time-guided treatment groups (n=61 [88%] versus n=103 [81%]; P=0.52) regardless of whether they received intravenous recombinant tissue plasminogen activator before endovascular treatment. Comparing the CT-P-guided with the time-guided patients, favorable discharge outcome (modified Rankin Scale 0 to 2) was observed in 23 (32%) versus 41 (33%) of the patients, respectively (P=0.9). In-hospital mortality was observed in 15 (21%) of CT-P- and 29 (23%) of time-guided patients (P=0.74). CT-P-guided endovascular treatment did not increase the rate of short-term favorable outcomes among patients with acute ischemic stroke. Prospective studies are required to validate the CT-P criteria and protocols currently in use before incorporating CT-P as a routine modality for patient selection for endovascular treatment.


[Percutaneous hydromechanical thrombectomy in acute and subacute lower limb ischemia].
A prospective study should evaluate the primary and 2-year results of treating acute and subacute lower-limb ischemia with hydromechanical thrombectomy (HTE). Consecutively 64 patients, 12 with viable and 52 with threatening limb ischemia and onset of symptoms within 8 +/- 9 days, were treated and controlled for 24 months. An 8 F hydromechanical thrombectomy device (HTK), was used. It sucks and shreds the thrombi. The shredded particles are transported to the outside. In 8 patients a total, in the others a partial restoration of the vessel lumen up to 70-50% was achieved in a mean time of 34 minutes. Residual thrombi, underlying atherosclerotic vessel disease and occluded arteries with a small diameter made adjunctive interventions (balloon angioplasty, percutaneous aspiration thrombectomy, lysis) necessary. Clinical symptoms and the ankle-brachial index improved significantly (p < 0.01). Primary patency was 72%, 70%, 67%, and 65%; the limb salvage rates were 81%, 78%, 75%, and 73% for one, 3, 12, and 24 months respectively. Device-induced complications did not occur. The HTK allowed a rapid reduction of fresh thrombotic material without complications. In 78% of the cases adjunctive therapies are required for wall-adherent thrombi and when tibial vessels with smaller lumina are included. Long-term results are comparable to literature data for fibrinolytic or operative regimens. The advantage, however of the HTK seems to be the reduction of intervention time and intra-arterial dosage of fibrinolytic drugs.


Hydrophobically-associating cationic polymers as micro-bubble surface modifiers in dissolved air flotation for cyanobacteria cell separation.
Dissolved air flotation (DAF), an effective treatment method for clarifying algae/cyanobacteria-laden water, is highly dependent on coagulation-flocculation. Treatment of algae can be problematic due to unpredictable coagulant demand during blooms. To eliminate the need for coagulation-flocculation, the use of commercial polymers or surfactants to alter bubble charge in DAF has shown potential, termed the PosiDAF process. When using surfactants, poor removal was obtained but good bubble adherence was observed. Conversely, when using polymers, effective cell removal was obtained, attributed to polymer bridging, but polymers did not adhere well to the bubble surface, resulting in a cationic clarified effluent that was indicative of high polymer concentrations. In order to combine the attributes of both polymers (bridging ability) and surfactants (hydrophobicity), in this study, a commercially-available cationic polymer, poly(dimethylaminoethyl methacrylate) (polyDMAEMA), was functionalised with hydrophobic pendant groups of various carbon chain lengths to improve adherence of polymer to a bubble surface. Its performance in PosiDAF was contrasted against commercially-available poly(diallyl dimethyl ammonium chloride) (polyDADMAC). All synthesised polymers used for bubble surface modification were found to produce positively charged bubbles. When applying these cationic micro-bubbles in PosiDAF, in the absence of coagulation-flocculation, cell removals in excess of 90% were obtained, reaching a maximum of 99% cell removal and thus demonstrating process viability. Of the synthesised polymers, the polymer containing the largest hydrophobic functionality resulted in highly anionic treated effluent, suggesting stronger adherence of polymers to bubble surfaces and reduced residual polymer concentrations.


The nurse labor market.
The national shortage of nurses, which grew to crisis proportions in many communities in the late 1970s, has subsided. Recent evidence suggests that hospital nurse vacancy and turnover rates have declined significantly since 1979. The recent swift reversal in the availability of nurses, from shortage to waiting lists in some hospitals, has taken many by surprise. It also raises the possibility that greater understanding of the factors that influence the market for nurses might make it possible to avert future shortages.


Electromyographic activity in deadlift exercise and its variants. A systematic review.
The main purpose of this review was to systematically analyze the literature concerning studies which have investigated muscle activation when performing the Deadlift exercise and its variants. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement (PRISMA). Original studies from inception until March 2019 were sourced from four electronic databases including PubMed, OVID, Scopus and Web of Science. Inclusion criteria were as follows: (a) a cross-sectional or longitudinal study design; (b) evaluation of neuromuscular activation during Deadlift exercise or variants; (c) inclusion of healthy and trained participants, with no injury issues at least for six months before measurements; and (d) analyzed "sEMG amplitude", "muscle activation" or "muscular activity" with surface electromyography (sEMG) devices. Major findings indicate that the biceps femoris is the most studied muscle, followed by gluteus maximus, vastus lateralis and erector spinae. Erector spinae and quadriceps muscles reported greater activation than gluteus maximus and biceps femoris muscles during Deadlift exercise and its variants. However, the Romanian Deadlift is associated with lower activation for erector spinae than for biceps femoris and semitendinosus. Deadlift also showed greater activation of the quadriceps muscles than the gluteus maximus and hamstring muscles. In general, semitendinosus muscle activation predominates over that of biceps femoris within hamstring muscles complex. In conclusion 1) Biceps femoris is the most evaluated muscle, followed by gluteus maximus, vastus lateralis and erector spinae during Deadlift exercises; 2) Erector spinae and quadriceps muscles are more activated than gluteus maximus and biceps femoris muscles within Deadlift exercises; 3) Within the hamstring muscles complex, semitendinosus elicits slightly greater muscle activation than biceps femoris during Deadlift exercises; and 4) A unified criterion upon methodology is necessary in order to report reliable outcomes when using surface electromyography recordings.


Microfluidic diafiltration-on-chip using an integrated magnetic peristaltic micropump.
Diafiltration is a membrane filtration technique that rapidly removes permeable molecules from a solution by controlling the tangential and orthogonal flows over a membrane and by replenishing the permeate with an equivalent amount of replacement buffer. However, its application to the purification of many key biomaterials and nanomaterials has been limited by the large dead volume (>10 mL) that is required to automate the process. To address this challenge, we have developed a diafiltration-on-a-chip device that can process low-volume samples (50 μL). The key innovation of this device is a magnetically-driven on-chip peristaltic pump that is able to continuously drive fluid flow at rates as high as 50 mL h-1 with minimal external instrumentation and a dead volume of <50 μL. To demonstrate the utility of this device, we purified microbeads from dye with >99% purity and >96% retention within two hours. We additionally showed that cells could be purified from microbeads with >97% purity and >97% retention in two hours. Because our approach requires minimal instrumentation, it is well suited for on-chip parallelization, which was demonstrated by incorporating four complete diafiltration systems onto a single credit card-sized chip.


Quantitative structure-activity relationships for cycloguanil analogs as PfDHFR inhibitors using mathematical molecular descriptors.
Computed molecular descriptors were used to develop quantitative structure-activity relationships (QSARs) for binding affinities (K(i)) for a set of 58 cycloguanil (2,4-diamino-1,6-dihydro-1,3,5-triazine) analogues for dihydrofolate reductase (DHFR) enzyme extracted from wild and A16V+S108T mutant type (a double mutation) malaria parasite Plasmodium falciparum (Pf). High-quality models were obtained in both cases. The results of statistical analyses show that ridge regression (RR) outperformed the two other modelling methods, principal component regression (PCR) and partial least squares (PLS). For both enzymes, recognition of the inhibitors was based on four broad categories of descriptors encoding information on: (1) the electronic character of the various atoms in the molecule, (2) the size and shape of the structure, (3) the degree of branching in the molecular skeleton, and (4) two to five atom molecular fragments with aliphatic carbon at one end and aliphatic or aromatic carbon or nitrogen at the other end. The subsets of influential descriptors underlying the QSARs for the wild versus the mutant DHFR are quite non-overlapping. This indicates that the two enzymes recognize the inhibitor molecules on the basis of mutually distinct structural attributes. Such differential QSARs can be useful in the design of novel drugs active against malaria parasites which are growing in resistant to existing chemotherapeutic agents.


Recent evolutionary diversification of a protist lineage.
Here, we have identified a protist (dinoflagellate) lineage that has diversified recently in evolutionary terms. The species members of this lineage inhabit cold-water marine and lacustrine habitats, which are distributed along a broad range of salinities (0-32) and geographic distances (0-18 000 km). Moreover, the species present different degrees of morphological and sometimes physiological variability. Altogether, we analysed 30 strains, generating 55 new DNA sequences. The nuclear ribosomal DNA (nrDNA) sequences (including rapidly evolving introns) were very similar or identical among all the analysed isolates. This very low nrDNA differentiation was contrasted by a relatively high cytochrome b (COB) mitochondrial DNA (mtDNA) polymorphism, even though the COB evolves very slowly in dinoflagellates. The 16 Maximum Likelihood and Bayesian phylogenies constructed using nr/mtDNA indicated that the studied cold-water dinoflagellates constitute a monophyletic group (supported also by the morphological analyses), which appears to be evolutionary related to marine-brackish and sometimes toxic Pfiesteria species. We conclude that the studied dinoflagellates belong to a lineage which has diversified recently and spread, sometimes over long distances, across low-temperature environments which differ markedly in ecology (marine versus lacustrine communities) and salinity. Probably, this evolutionary diversification was promoted by the variety of natural selection regimes encountered in the different environments.


How to Assess Data Availability, Accessibility and Format for Risk Analysis?
Risk assessments are mostly carried out based on available data, which do not reflect all data theoretically required by experts to answer them. This study aimed at developing a methodology to assess data availability, accessibility and format, based on a scoring system and focusing on two diseases: Venezuelan equine encephalomyelitis (VEE), still exotic to Europe, and alveolar echinococcosis, caused by Echinococcus multilocularis (EM), endemic in several Member States (MSs). After reviewing 36 opinions of the EFSA-AHAW Panel on risk assessment of animal health questions, a generic list of needed data was elaborated. The methodology consisted, first, in implementing a direct and an indirect survey to collect the data needed for both case studies: the direct survey consisted in a questionnaire sent to contact points of three European MSs (Belgium, France and the Netherlands), and the organization of a workshop gathering experts on both diseases. The indirect survey, focusing on the three MSs involved in the direct survey plus Spain, relied on web searches. Secondly, a scoring system with reference to data availability, accessibility and format was elaborated, to, finally, compare both diseases and data between MSs. The accessibility of data was generally related to their availability. Web searches resulted in more data available for VEE compared to EM, despite its current exotic status in the European Union. Hypertext markup language and portable document files were the main formats of available data. Data availability, accessibility and format should be improved for research scientists/assessors. The format of data plays a key role in the feasibility and rapidness of data management and analysis, through a prompt compilation, combination and aggregation in working databases. Harmonization of data collection process is encouraged, according to standardized procedures, to provide useful and reliable data, both at the national and the international levels for both animal and human health; it would allow assessing data gaps through comparative studies. The present methodology is a good way of assessing the relevance of data for risk assessment, as it allows integrating the uncertainty linked to the quality of data used. Such an approach could be described as transparent and traceable and should be performed systematically.


One-Pot Formal Dehydrogenative Ketone Synthesis from Aldehydes and Non-activated Hydrocarbons.
Ketones are a fundamental functionality found throughout a range of natural and synthetic compounds, making their synthesis essential throughout the chemical disciplines. Herein, we describe a one-pot synthesis of ketones via decatungstate-mediated formal dehydrogenative coupling between aldehydes and non-activated hydrocarbons. A variety of substituted benzaldehydes and cycloalkanes could be used in the optimized reaction to produce the desired ketones in moderate yields. The decatungstate photocatalyst functions in two reactions in this synthesis, catalyzing both the coupling and oxidation steps of the process. Notably, the reaction displays both high atom economy and sustainability, as it uses light and oxygen as key energy sources.


Optically controlled Fabry-Perot interferometer using a liquid crystal light valve.
We report an optically controlled Fabry-Perot interferometer which uses a liquid crystal light valve (LCLV) for one of the mirrors. The light valve rotates the plane of polarization for light incident on its read side through an angle dependent on the intensity of a write beam incident on its other side. The Fabry-Perot interferometer is constructed using a polarizing cube beam-splitter and a second mirror. The finesse of this Fabry-Perot varies sharply with the rotation angle introduced by the LCLV. The dependence of this rotation angle on the incident write beam intensity varies with the frequency of the voltage applied to the LCLV, the bias voltage, and the orientation angle of the LCLV. Experimental performance is examined using a single mode He-Ne laser beam and compares well with theoretical predictions: This device has potential uses in optical computing and optical neural networks.


Localized retinal electrophysiological and fundus autofluorescence imaging abnormalities in maternal inherited diabetes and deafness.
To investigate retinal function in patients with maternally inherited diabetes and deafness (MIDD) and to correlate the findings with fundus autofluorescence (FAF) imaging. FAF was imaged in five patients (age range, 49-60 years) confirmed to have the mitochondrial DNA nucleotide A3243G point mutation. Retinal function was measured by full-field (Ganzfeld) electroretinography (ERG) and pattern ERG, incorporating the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. Multifocal ERG (mfERG) was also performed. For analysis of the mfERG data, five regional ring groups of equal eccentricity were formed. For each ring, the peak amplitude (defined as the difference between P1 and N1) and the implicit time of P1 were determined and compared with normative values. Visual acuity in the patients was between 20/20 and 20/40 (Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Irregular increased FAF signals were observed adjacent to and between areas of atrophy of the retinal pigment epithelium (RPE). Ganzfeld ERGs were within normal limits in three patients. Pattern ERG was abnormal in five eyes of three patients. mfERG peak amplitude abnormalities were particularly present in rings 2 and 3 and were consistent with the distribution of FAF abnormalities. In all but one eye, no implicit times changes were present. Significant mfERG abnormalities with normal Ganzfeld ERG are consistent with nonuniform damage to the central retina in MIDD, in keeping with the FAF findings. Reduced peak amplitudes with normal implicit times in the mfERG suggest localized loss of function and may indicate damage to the cone photoreceptor outer segments or cone photoreceptor loss in MIDD.


On the solvation structure of dimethylsulfoxide/water around the phosphatidylcholine head group in solution.
The solution structure of the phosphocholine (PC) head group in 1,2-dipropionyl-sn-glycero-3-phosphocholine (C(3)-PC) in 30 mol. % dimethylsulfoxide (DMSO)-water solutions has been determined by using neutron diffraction enhanced with isotopic substitution in combination with computer simulation techniques. By investigating the atomic scale hydration structure around the PC head group, a unique description of the displacement of water molecules by DMSO molecules is detailed around various locations of the head group. Specifically, DMSO molecules were found to be the most prevalent around the onium portion of the head group, with the dipoles of the DMSO molecules being aligned where the negatively charged oxygen can interact strongly with the positively charged lipid group. The phosphate group is also partially dehydrated by the presence of the DMSO molecules. However, around this group the bulkier positive end of the DMSO dipole is interacting with negatively charged groups of the lipid head group, the DMSO layer shows no obvious ordering as it cannot form hydrogen bonds with the oxygen atoms in the PO(4) group such as water molecules can. Interestingly, DMSO-water contacts have also increased in the presence of the lipid molecule relative to DMSO-water contacts observed in pure DMSO/water solutions at similar concentrations.


Humanized Care From the Nurse-Patient Perspective in a Hospital Setting: A Systematic Review of Experiences Disclosed in Spanish and Portuguese Scientific Articles.
Nowadays, humanized care is an essential component in the field of health because the professional work of nursing seeks to provide quality services to patients who are suffering and fear illness or the dying process. Nurses recognize the need to incorporate humanized care into their daily work, as supported by Jean Watson, who states that caring entails establishing an adequate nurse-patient therapeutic relationship, where health education is a tool that promotes self-care in the patient, family, and community. The main objective of this work was to find scientific evidence on humanized care from the perspectives of nurses and hospitalized patients. To meet those research objectives, an exploratory systematic review of articles published in high-quality scientific journals from 2016 to 2020 using the PRISMA methodology in the Scopus and Scielo databases was conducted, yielding 26 studies that were analyzed. The findings show that nurses and patients perceive the need to remove the barriers that limit the advancement of humanized care in hospital institutions because they urgently demand that health professionals in all settings, especially critical ones, strengthen their humanizing role by sharing cordial, empathetic health experiences, and respecting their customs and beliefs during the hospitalization process. As a conclusion of the findings, the nurse-patient professionals agree that health personnel training is critical to providing humanized attention with quality in the hospital context, emphasizing that professional training should develop in practice soft skills, communication, safety environment, and human values.


Evidence for antigenic seniority in influenza A (H3N2) antibody responses in southern China.
A key observation about the human immune response to repeated exposure to influenza A is that the first strain infecting an individual apparently produces the strongest adaptive immune response. Although antibody titers measure that response, the interpretation of titers to multiple strains--from the same sera--in terms of infection history is clouded by age effects, cross reactivity and immune waning. From July to September 2009, we collected serum samples from 151 residents of Guangdong Province, China, 7 to 81 years of age. Neutralization tests were performed against strains representing six antigenic clusters of H3N2 influenza circulating between 1968 and 2008, and three recent locally circulating strains. Patterns of neutralization titers were compared based on age at time of testing and age at time of the first isolation of each virus. Neutralization titers were highest for H3N2 strains that circulated in an individual's first decade of life (peaking at 7 years). Further, across strains and ages at testing, statistical models strongly supported a pattern of titers declining smoothly with age at the time a strain was first isolated. Those born 10 or more years after a strain emerged generally had undetectable neutralization titers to that strain (<1:10). Among those over 60 at time of testing, titers tended to increase with age. The observed pattern in H3N2 neutralization titers can be characterized as one of antigenic seniority: repeated exposure and the immune response combine to produce antibody titers that are higher to more 'senior' strains encountered earlier in life.


Evaluation of serum anti-Müllerian hormone levels in women with Hashimoto thyroiditis in the reproductive age
Autoimmune thyroid disease in women is associated with subfertility and early pregnancy loss, and patients with primary ovarian insufficiency have a high prevalence of thyroid autoimmune disorders. The aim of this study was to investigate the association between Hashimoto thyroiditis (HT) and ovarian reserve. Levels of serum thyroid stimulating hormones, thyroid autoantibodies, and anti-Müllerian hormone (AMH) were measured in women with HT and a healthy control group between 2018 and 2019. Evaluation was made of 108 premenopausal women with HT, and a control group of 172 healthy females with normal antithyroid antibody levels and thyroid function. Serum AMH levels were determined to be significantly lower in the HT group compared to the control group. Ovarian reserve evaluated by serum AMH concentration is affected by thyroid autoimmunity independently of antithyroid antibodies type or titers.


Patient organisations and the reimbursement process for medicines: an exploratory study in eight European countries.
Little is known about the role European patient organisations play in the process of deciding on reimbursement for medicines. Therefore we explore the current role of patient organisations in the process of reimbursement for medicines in Western Europe. We focus in particular on collaboration between patient organisations and the pharmaceutical industry in this respect. Sixty-eight patient organisations representing seven medical conditions, from ten Western European countries, were asked to participate in the study. The participating organisations reported their experiences in a web-based questionnaire. Twenty-one patient organisations completed the questionnaire (response rate: 31%), of which ten (47.6%) demanded reimbursement for medicines. Organisations demanding reimbursement were larger than those not demanding reimbursement. The main aim of these organisations was to create better accessibility of medicines for patients. Most organisations limited themselves to single actions. Only two engaged in multiple actions. Almost all organisations had general policies on cooperation with the pharmaceutical industry, with autonomy as the key feature. The patient organisations said they were reasonably successful and almost always satisfied with their own role in the reimbursement process. Our study has found that the role of European patient organisations in the reimbursement process still seems limited, especially for small patient organisations.


Phylotranscriptomic analysis uncovers a wealth of tissue inhibitor of metalloproteinases variants in echinoderms.
Tissue inhibitors of metalloproteinases (TIMPs) help regulate the extracellular matrix (ECM) in animals, mostly by inhibiting matrix metalloproteinases (MMPs). They are important activators of mutable collagenous tissue (MCT), which have been extensively studied in echinoderms, and the four TIMP copies in humans have been studied for their role in cancer. To understand the evolution of TIMPs, we combined 405 TIMPs from an echinoderm transcriptome dataset built from 41 specimens representing all five classes of echinoderms with variants from protostomes and chordates. We used multiple sequence alignment with various stringencies of alignment quality to cull highly divergent sequences and then conducted phylogenetic analyses using both nucleotide and amino acid sequences. Phylogenetic hypotheses consistently recovered TIMPs as diversifying in the ancestral deuterostome and these early lineages continuing to diversify in echinoderms. The four vertebrate TIMPs diversified from a single copy in the ancestral chordate, all other copies being lost. Consistent with greater MCT needs owing to body wall liquefaction, evisceration, autotomy and reproduction by fission, holothuroids had significantly more TIMPs and higher read depths per contig. Ten cysteine residues, an HPQ binding site and several other residues were conserved in at least 70% of all TIMPs. The conservation of binding sites and the placement of echinoderm TIMPs involved in MCT modification suggest that ECM regulation remains the primary function of TIMP genes, although within this role there are a large number of specialized copies.


[Effect of food loading on the activity of the kallikrein-kinin system of the blood in an experiment].
The influence of some food loads on the blood kallikrein-kinin system was studied in an experiment on 30 Wistar male rats. Significant changes in the blood kallikrein-kinin system were recorded in the animals after starvation and after glucose injections. Increased alpha 2-macroglobulin and alpha 1-antitrypsin activities in these groups were considered as manifestations of the defensive-compensatory reactions of the body in response to the intensified synthesis of the kininogenase component. Diminution of kallikrein activity observed in the group of animals, that received meat load, was regarded as the result of compensatory adaptation to protein. It has been suggested that the influence of the alimentary factor on the kallikrein-kinin system should be considered in a direct association with other neurohumoral and neuromediator systems of the body.


Assessment of RV Function in Patients of (COPD).
Chronic Obstructive Pulmonary Disease (COPD) has considerable effects on cardiac functions primarily affecting the pulmonary vasculature and then right ventricle along with left ventricle. One of the important causes of increased morbidity and mortality associated with COPD is cor pulmonale. Echocardiography provides a rapid, non-invasive method to evaluate cardiac changes. Our aim was to evaluate RVfunction in COPD as per guidelines of American Society of Echocardiography with an aim to find a simpler way of predicting cardiac morbidity. A cross sectional observational study was conducted on 17 COPD patients attending Respiratory Medicine outdoor of R. G. KAR Medical College, Kolkata, India, through history taking, clinical examination, PFT (PFT) and Echocardiography. Statistical analysis was done by using Statistical Package for the Social Sciences (SPSS) version-17. Fractional area change of RV (FAC-%) was positively correlated with Forced Expiratory Volume in One Second (FEV1) (r = 0.4879), FEV1/ Forced Vital Capacity (FVC) ratio (r = 0.5048) and Peak Expiratory Flow Rate (PEFR) (r = 0.5361). There was strong negative correlation of Systolic Pulmonary Artery Pressure (SPAP) with FEV1/FVC ratio (r = -0.5553) and PEFR (r = - 0.4604). Right Index of Myocardial Performance (RIMP) of right ventricle was negatively correlated with FEV1/FVC ratio (r = - 0.598), PEFR (r = - 0.619), Forced Expiratory Flow (FEF) 25-75 (r = -0.515). Tricuspid annular plane systolic excursion (TAPSE) did not show any association with PFT parameters though it showed strong positive correlation with RV wall thickness. This study substantiates that FAC% and RIMP can be vital prognostic factors for RV function apart from SPAP, TAPSE to define RV dysfunction and predict morbidity in COPD.


Spouses' cortisol associations and moderators: testing physiological synchrony and connectedness in everyday life.
In this study, associations were examined between cortisol levels of wives and husbands in 47 heterosexual married couples. Both partners' salivary cortisol levels were measured at the same moments seven times a day on 2 typical weekdays. After accounting for the effects of the diurnal rhythm of cortisol and relevant control variables, dyadic hierarchical linear modeling indicated significant positive linkages between partners' cortisol levels, consistent with the hypothesized within-couple physiological synchrony. Variables reflecting more (spousal presence) or less connectedness (loneliness, being alone) were also collected at the time of each cortisol sample. Results indicated that husbands' cortisol levels were higher at moments they reported feeling lonelier and lower at moments they were in the presence of their spouse. Wives' cortisol levels were higher at moments they were alone. In addition, wife-husband cortisol synchrony was stronger for husbands who spent relatively more time with their spouse across the study period-even after accounting for time spent with others in general. These findings suggest that marital partners evidence positive within-couple cortisol associations, and that connectedness (particularly physical closeness) may underpin spouses' physiological synchrony.


Impact of depression on disablement in late middle aged and older persons: results from the Longitudinal Aging Study Amsterdam.
The main pathway of the disablement process consists of four consecutive phases: Pathology (presence of disease/injury), Impairments (dysfunctions/structural abnormalities), Functional Limitations (restrictions in basic physical/mental actions), and Disability (difficulty doing activities of daily life, ADL). This study determines the presence of the main pathway of disablement in a cohort aged 55 years and older and examines whether progression of the main pathway of disablement is accelerated in the presence of depression. Based on baseline (T1) and two three-year follow-up interviews (T2 and T3) from the Longitudinal Aging Study Amsterdam (LASA) in a population-based cohort of 1110 Dutch persons, we first analysed the intermediate effect of the different consecutive phases of the disablement process by means of multiple regression, adjusted for covariates. Then, depression was used as interaction term in multiple regression analyses linking the consecutive phases of the disablement process. We found that Impairments mediated the association between Pathology and Functional Limitations, and that Functional Limitations mediated the association between Impairments and Disability. Depression significantly modified the associations between Pathology and subsequent Impairments, and between Functional Limitations and subsequent Disability. In sum, the main pathway of the disablement process was identified in our sample. In addition, we found an accelerating effect of depression, particularly in the early and late stages of the model. Reduction of depression may help slow down the process of disablement for persons who find themselves in those stages of the model.


Structural Basis for the Peptidoglycan-Editing Activity of YfiH.
Bacterial cells are encased in peptidoglycan (PG), a polymer of disaccharide N-acetylglucosamine (GlcNAc) and N-acetyl-muramic acid (MurNAc) cross-linked by peptide stems. PG is synthesized in the cytoplasm as UDP-MurNAc-peptide precursors, of which the amino acid composition of the peptide is unique, with l-Ala added at the first position in most bacteria but with l-Ser or Gly in some bacteria. YfiH is a PG-editing factor whose absence causes misincorporation of l-Ser instead of l-Ala into peptide stems, but its mechanistic function is unknown. Here, we report the crystal structures of substrate-bound and product-bound YfiH, showing that YfiH is a cytoplasmic amidase that controls the incorporation of the correct amino acid to the nucleotide precursors by preferentially cleaving the nucleotide precursor by-product UDP-MurNAc-l-Ser. This work reveals an editing mechanism in the cytoplasmic steps of peptidoglycan biosynthesis. IMPORTANCE YfiH is a peptidoglycan (PG)-editing factor required for the maintenance of specific amino acid compositions of the stem peptides. However, the activity of YfiH has not been deciphered, and the editing mechanism involving YfiH has remained a mystery. Through X-ray crystallographic and biochemical analyses, we demonstrate that YfiH is a hydrolase with a previously unknown activity specific for the UDP-MurNAc-monopeptide, one of the nucleotide precursors from the cytoplasmic steps of the PG biosynthesis pathway. YfiH selectively hydrolyzes UDP-MurNAc-Ser, an incorrect by-product of the biosynthesis reaction, to ensure that only the correct PG precursor, UDP-MurNAc-Ala, is incorporated. Therefore, this work reveals coupled synthetic and editing reactions in the cytoplasmic steps of PG biosynthesis.


Antireflux catheter improves tumor targeting in liver radioembolization with resin microspheres.
We aimed to determine whether antireflux (ARC) catheter may result in better tumor targeting in liver radioembolization using 90Y-resin microspheres. Patients treated with resin microspheres for hepatocellular carcinoma (HCC) and secondary liver malignancies were retrospectively analyzed. All patients underwent a 99mTc-macroaggregated albumin (99mTc-MAA) single photon emission computed tomography (SPECT) following the planning arteriography with a conventional end-hole catheter. For 90Y-microspheres injection, two groups were defined depending on the type of catheter used: an ARC group (n=38) and a control group treated with a conventional end-hole catheter (n=23). 90Y positron emission tomography computed tomography (PET/CT) was performed after the therapeutic arteriography. The choice of the catheter was not randomized, but left to the choice of the interventional radiologist. 99mTc-MAA SPECT and 90Y PET/CT were co-registered with the baseline imaging to determine a tumor to normal liver ratio (T/NL[MAA or 90Y]) and tumor dose (TD[MAA or 90Y]) for the planning and therapy. Overall, 38 patients (115 lesions) and 23 patients (75 lesions) were analyzed in the ARC and control groups, respectively. In the ARC group, T/NL90Y and TD90Y were significantly higher than T/NLMAA and TDMAA. Median (IQR) T/NL90Y was 2.16 (2.15) versus 1.74 (1.43) for T/NLMAA (p < 0.001). Median (IQR) TD90Y was 90.96 Gy (98.31 Gy) versus 73.72 Gy (63.82 Gy) for TDMAA (p < 0.001). In this group, the differences were highly significant for neuroendocrine metastases (NEM) and HCC and less significant for colorectal metastases (CRM). In the control group, no significant differences were demonstrated. The use of an ARC significantly improves tumor deposition in liver radioembolization with resin microspheres.


Dimeric CRISPR RNA-Guided FokI-dCas9 Nucleases Directed by Truncated gRNAs for Highly Specific Genome Editing.
Monomeric clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated 9 (Cas9) nucleases have been widely adopted for simple and robust targeted genome editing but also have the potential to induce high-frequency off-target mutations. In principle, two orthogonal strategies for reducing off-target cleavage, truncated guide RNAs (tru-gRNAs) and dimerization-dependent RNA-guided FokI-dCas9 nucleases (RFNs), could be combined as tru-RFNs to further improve genome editing specificity. Here we identify a robust tru-RFN architecture that shows high activity in human cancer cell lines and embryonic stem cells. Additionally, we demonstrate that tru-gRNAs reduce the undesirable mutagenic effects of monomeric FokI-dCas9. Tru-RFNs combine the advantages of two orthogonal strategies for improving the specificity of CRISPR-Cas nucleases and therefore provide a highly specific platform for performing genome editing.


Effect of non-instructed instrumental contingency of monetary reward and positive affect in a cognitive control task.
In recent years, we observed a strong interest in the influence of motivation and emotion on cognitive control. Prior studies suggest that the instrumental contingency between a response and a rewarding or affective stimulus is particularly important in that context-which is resonating with observations in the associative learning literature. However, despite this overlap, and the relevance of non-instructed learning in real life, the vast majority of studies investigating motivation-cognition interactions use direct instructions to inform participants about the contingencies between responses and stimuli. Thus, there is little experimental insight regarding how humans detect non-instructed contingencies between their actions and motivational or affective outcomes, and how these learned contingencies come to influence cognitive control processes. In an attempt to close this gap, the goal of the present study was to test the effect of non-instructed contingent and non-contingent outcomes (i.e. monetary reward and positive affective stimuli) on cognitive control using the AX-continuous performance task (AX-CPT) paradigm. We found that entirely non-instructed contingencies between responses and positive outcomes (both monetary and affective ones) led to significant performance improvement. The present results open new perspectives for studying the influence of motivation and emotion on cognitive control at the insertion with associative learning.


Mitochondria in cancer stem cells: a target for therapy.
Complete knowledge about the evolution of the carcinogenic process has to include cancer stem cells (CSCs), which are essential to understand tumor occurrence, recurrence, and also its reduction rate after radio- and/or chemotherapeutic treatments. Understanding CSCs physiology and metabolism may be crucial for the development of novel effective therapies. Therefore, being mitochondria an undeniable target for cancer therapy and a central hub in metabolism and cell and death decisions, it is essential to take this organelle into account and explore its actions and involvements in the context of CSCs physiology. In this review, we focus on recent patents and discoveries about mitochondrial bioenergetics and physiology of CSCs. A full understanding of the role of mitochondrial activity in CSCs and the creation of new strategies, methods and discoveries to support actual treatments with novel ones are of pivotal importance in order to ultimately eradicate cancer.


Curved wavelet transform for image coding.
The conventional two-dimensional wavelet transform used in existing image coders is usually performed through one-dimensional (1-D) filtering in the vertical and horizontal directions, which cannot efficiently represent edges and lines in images. The curved wavelet transform presented in this paper is carried out by applying 1-D filters along curves, rather than being restricted to vertical and horizontal straight lines. The curves are determined based on image content and are usually parallel to edges and lines in the image to be coded. The pixels along these curves can be well represented by a small number of wavelet coefficients. The curved wavelet transform is used to construct a new image coder. The code-stream syntax of the new coder is the same as that of JPEG2000, except that a new marker segment is added to the tile headers. Results of image coding and subjective quality assessment show that the new image coder performs better than, or as well as, JPEG2000. It is particularly efficient for images that contain sharp edges and can provide a PSNR gain of up to 1.67 dB for natural images compared with JPEG2000.


Expanding the phenotypic spectrum in EP300-related Rubinstein-Taybi syndrome.
Rubinstein-Taybi syndrome (RSTS) can be caused by heterozygous mutations or deletions involving CREBBP or, less commonly, EP300. To date, only 15 patients with EP300 mutations have been clinically described. Frequently reported manifestations in these patients include characteristic facial and limb features, varying degrees of neurocognitive dysfunction, and maternal preeclampsia. Other congenital anomalies are less frequently reported. We describe a child found to have a de novo EP300 mutation (c.4933C>T, predicted to result in p.Arg1645X) through research-based whole-genome sequencing of the family trio. The child's presentation involved dysmorphic features as well as unilateral renal agenesis, a myelomeningocele, and minor genitourinary anomalies. The involvement of congenital anomalies in all 16 clinically described patients with EP300 mutations (25% of which have been identified by "hypothesis free" methods, including microarray, exome, and whole-genome sequencing) is reviewed. In summary, genitourinary anomalies have been identified in 38%, cardiovascular anomalies in 25%, spinal/vertebral anomalies in 19%, other skeletal anomalies in 19%, brain anomalies in 13%, and renal anomalies in 6%. Our patient expands the phenotypic spectrum in EP300-related RSTS; this case demonstrates the evolving practice of clinical genomics related to increasing availability of genomic sequencing methods.


Gender differences in fatigue: biopsychosocial factors relating to fatigue in men and women.
Fatigue is a common problem, which is found more frequently among women than men. To date, neither the etiology of fatigue nor the factors that explain the gender difference in its incidence are still fully understood. In a sample of men (n = 4,681) and women (n = 4,698) (age range, 15-64 years) in the Dutch National Survey of Morbidity and Interventions in General Practice, the gender differences in the underlying biological, psychological, and social factors of fatigue were analyzed. Both general and gender-specific factors were recognized. Men and women who experience complaints of fatigue appeared to be younger and more highly educated. They had more acute health complaints and more psychosocial problems and also showed a lower level of perceived health. Among women, only gender-specific biological complaints and psychosocial problems were related to fatigue. In addition, relevant sociodemographic variables included taking care of young children and being employed. Among men, fatigue was particularly related to having handicaps and severe chronic complaints. Taking care of young children did not make a difference in the male sample. Fatigue can only be adequately understood in a multicausal model with biomedical and psychosocial factors. Complaints of fatigue are too often ignored in general practice. By adopting a patient-centered style of communication, physicians can acquire a more complete picture of the patients' fatigue.


Catalytic hydrodechlorination of chloroaromatic gas streams promoted by Pd and Ni: the role of hydrogen spillover.
Catalytic hydrodechlorination (HDC) is an effective means of detoxifying chlorinated waste. Involvement of spillover hydrogen is examined in gas phase dechlorination of chlorobenzene (CB) and 1,3-dichlorobenzene (1,3-DCB) over Pd and Ni. The catalytic action of single component Pd and Ni, Pd/Al(2)O(3), Ni/Al(2)O(3) and physical mixtures with Al(2)O(3) has been considered. Catalyst activation is characterized in terms of temperature programmed reduction, the supported nano-scale metal phase by transmission electron microscopy and hydrogen/surface interactions by chemisorption/temperature programmed desorption. Pd/Al(2)O(3) generated significantly greater amounts of spillover hydrogen (by a factor of over 40) compared with Ni/Al(2)O(3). Hydrogen spillover on Pd/Al(2)O(3) far exceeded the chemisorbed component, whereas chemisorbed and spillover content was equivalent for Ni/Al(2)O(3). Inclusion of Al(2)O(3) with Ni and Ni/Al(2)O(3) increased spillover with an associated increase in specific HDC rate (up to a factor of 10) and enhanced selectivity to benzene from 1,3-DCB. HDC rate delivered by Pd and Pd/Al(2)O(3) was largely unaffected by the addition of Al(2)O(3). This can be attributed to the higher intrinsic HDC performance of Pd that results in appreciable HDC activity under conditions where Ni/Al(2)O(3) was inactive. Spillover was partially recovered (post TPD) for the Ni samples but the loss was irreversible in the case of Pd.


Measurement of Fall Injury With Health Care System Data and Assessment of Inclusiveness and Validity of Measurement Models.
National injury surveillance systems use administrative data to collect information about severe fall-related trauma and mortality. Measuring milder injuries in ambulatory clinics would improve comprehensive outcomes measurement across the care spectrum. To assess a flexible set of administrative data-only algorithms for health systems to capture a greater breadth of injuries than traditional fall injury surveillance algorithms and to quantify the algorithm inclusiveness and validity associated with expanding to milder injuries. In this longitudinal diagnostic study of 13 939 older adults (≥65 years) in the nationally representative Health and Retirement Study, a survey was conducted every 2 years and was linked to hospital, emergency department, postacute skilled nursing home, and outpatient Medicare claims (2000-2012). During each 2-year observation period, participants were considered to have sustained a fall-related injury (FRI) based on a composite reference standard of having either an external cause of injury (E-code) or confirmation by the Health and Retirement Study patient interview. A framework involving 3 algorithms with International Classification of Diseases, Ninth Revision codes that extend FRI identification with administrative data beyond the use of fall-related E-codes was developed: an acute care algorithm (head and face or limb, neck, and trunk injury reported at the hospital or emergency department), a balanced algorithm (all acute care algorithm injuries plus severe nonemergency outpatient injuries), and an inclusive algorithm (almost all injuries). Data were collected from January 1, 1998, through December 31, 2012, and statistical analysis was performed from August 1, 2016, to March 1, 2019. Validity, measured as the proportion of potential FRI diagnoses confirmed by the reference standard, and inclusiveness, measured as the proportion of reference-standard FRIs captured by the potential FRI diagnoses. Of 13 939 participants, 1672 (42.4%) were male, with a mean (SD) age of 77.56 (7.63) years. Among 50 310 observation periods, 9270 potential FRI diagnoses (18.4%) were identified; these were tested against 8621 reference-standard FRIs (17.1%). Compared with the commonly used method of E-coded-only FRIs (2-year incidence, 8.8% [95% CI, 8.6%-9.1%]; inclusion of 51.5% [95% CI, 50.4%-52.5%] of the reference-standard FRIs), FRI inclusion was increased with use of the study framework of algorithms. With the acute care algorithm (2-year incidence, 12.6% [95% CI, 12.4%-12.9%]), validity was prioritized (88.6% [95% CI, 87.4%-89.8%]) over inclusiveness (62.1% [95% CI, 61.1%-63.1%]). The balanced algorithm showed a 2-year incidence of 14.6% (95% CI, 14.3%-14.9%), inclusion of 65.3% (95% CI, 64.3%-66.3%), and validity of 83.2% (95% CI, 81.9%-84.6%). With the inclusive algorithm, the number of potential FRIs increased compared with the E-code-only method (2-year incidence, 17.4% [95% CI, 17.1%-17.8%]; inclusion, 68.4% [95% CI, 67.4%-69.3%]; validity, 75.2% [95% CI, 73.7%-76.6%]). The findings suggest that use of algorithms with International Classification of Diseases, Ninth Revision codes may increase inclusion of FRIs by health care systems compared with E-codes and that these algorithms may be used by health systems to evaluate interventions and quality improvement efforts.


3CAPS - a structural AP-site analogue as a tool to investigate DNA base excision repair.
Abasic sites (AP-sites) are frequent DNA lesions, arising by spontaneous base hydrolysis or as intermediates of base excision repair (BER). The hemiacetal at the anomeric centre renders them chemically reactive, which presents a challenge to biochemical and structural investigation. Chemically more stable AP-site analogues have been used to avoid spontaneous decay, but these do not fully recapitulate the features of natural AP-sites. With its 3'-phosphate replaced by methylene, the abasic site analogue 3CAPS was suggested to circumvent some of these limitations. Here, we evaluated the properties of 3CAPS in biochemical BER assays with mammalian proteins. 3CAPS-containing DNA substrates were processed by APE1, albeit with comparably poor efficiency. APE1-cleaved 3CAPS can be extended by DNA polymerase β but repaired only by strand displacement as the 5'-deoxyribophosphate (dRP) cannot be removed. DNA glycosylases physically and functionally interact with 3CAPS substrates, underlining its structural integrity and biochemical reactivity. The AP lyase activity of bifunctional DNA glycosylases (NTH1, NEIL1, FPG), however, was fully inhibited. Notably, 3CAPS-containing DNA also effectively inhibited the activity of bifunctional glycosylases on authentic substrates. Hence, the chemically stable 3CAPS with its preserved hemiacetal functionality is a potent tool for BER research and a potential inhibitor of bifunctional DNA glycosylases.


[Evidence-based patient information: the example of immunotherapy for patients with multiple sclerosis].
The article elucidates consideration of scientific criteria for the development and design of evidence-based patient information (EBPI). Immunotherapy of multiple sclerosis serves as an example. Since in EBPI lack of evidence or ambiguities in available evidence are explicitly communicated, processing of EBPI does not necessarily lead to certainty about benefit and harms of medical interventions. However, only if the information is comprehensive in this respect can the EBPI be regarded as a robust basis for an informed choice. EBPI requires substantial developmental efforts. Regarding the growing number of medical interventions and the half-life of information, the question of responsibility for provision of EBPI is crucial. A vision is drafted in which EBPI is driven by demand of the patients and the public and is provided according to a costs-by-cause principle by those who distribute usual information hitherto. Trained patient advocates can appraise quality of information by use of instruments that consider criteria of EBPI. Critical health literacy should evolve early in school and can later on enhance usefulness of EBPI for people concerned with health issues.


Ecological constraints coupled with deep-time habitat dynamics predict the latitudinal diversity gradient in reef fishes.
We develop a spatially explicit model of diversification based on palaeohabitat to explore the predictions of four major hypotheses potentially explaining the latitudinal diversity gradient (LDG), namely, the 'time-area', 'tropical niche conservatism', 'ecological limits' and 'evolutionary speed' hypotheses. We compare simulation outputs to observed diversity gradients in the global reef fish fauna. Our simulations show that these hypotheses are non-mutually exclusive and that their relative influence depends on the time scale considered. Simulations suggest that reef habitat dynamics produced the LDG during deep geological time, while ecological constraints shaped the modern LDG, with a strong influence of the reduction in the latitudinal extent of tropical reefs during the Neogene. Overall, this study illustrates how mechanistic models in ecology and evolution can provide a temporal and spatial understanding of the role of speciation, extinction and dispersal in generating biodiversity patterns.


The association between Trichomonas infection and incarceration in HIV-seropositive and at-risk HIV-seronegative women.
The prevalence of Trichomonas vaginalis is higher among incarcerated women than in the general community. We sought to determine whether a history of incarceration itself was independently associated with trichomoniasis. The HIV Epidemiology Research Study is a prospective cohort study of 871 HIV-seropositive and 439 high-risk seronegative women in 4 urban centers (Bronx, NY; Detroit, MI; Providence, RI; Baltimore, MD). All participants enrolled between April 1993 and January 1995, with interviews and physical examinations conducted at baseline and at follow-up visits every 6 months up to 7 years. Of 1310 subjects, 427 (33%) reported being incarcerated on at least one occasion. In addition, 724 (55%) were found to have a sexually transmitted infection on at least one occasion during the study; baseline rates were 21% for T. vaginalis, 4.3% for Chlamydia trachomatis, 0.6% for N. gonorrhea, and 8% for syphilis. Incarceration was associated with the detection of trichomonas infection (between-subject, odds ratio, 2.4; 95% confidence interval: 1.85-3.14; P < 0.01 and within-subject, odds ratio, 1.56; 95% confidence interval: 1.26-1.92; P < 0.01). The association with incarceration remained significant after adjusting for age, race, HIV status, enrollment risk group, number of sexual partners, marital status, education, bacterial vaginosis, vaginal candidiasis, drug use (crack, cocaine, heroin), alcohol use, health insurance, receipt of public assistance, employment status, visit number, and study site. A history of incarceration was independently associated with the detection of trichomonas infection in a cohort of high-risk women. These data have implications for increased sexually transmitted infection prevention, screening, and treatment upon entry to jail as well as in the communities most affected by incarceration.


Traditional measures of hospital utilization may not accurately reflect dynamic patient demand: findings from a children's hospital.
Hospital crowding adversely affects access to emergent and elective care, quality and safety, patient and staff satisfaction, and trainee education. Reliable and valid measurements are crucial to operational planning and improvement, but traditional measures of hospital utilization may not accurately describe dynamic demand at hospitals. The goal of this study was to determine how effectively traditional measures express demand for hospital services and to describe the dynamic nature of patient flow in children's hospitals compared with alternative measures. This was a retrospective administrative data review conducted at an urban, tertiary care children's hospital. A total of 28045 inpatients (22310 from fiscal year 2008 and 5735 from 2 months in the fall of 2009 during the H1N1 influenza surge [October 16, 2009-November 18, 2009]) were reviewed. Admission-discharge-transfer data were abstracted from a total of 14 months (1 fiscal year and a separate 2 months including an influenza surge). Hourly hospital census and occupancy were determined. Measures of mean and median length of stay (LOS) were compared. Turnover was calculated by summing admissions, discharges, and interunit transfers. Coefficient of variation (SD/mean) was used to describe variation. Midnight occupancy was generally closer to minimum occupancy than peak. Peak was usually between 10 AM and 12 PM and was a mean of 40/% points higher than midnight (but as large as 13% points). Median LOS was 58% shorter than average LOS. There was a high level of turnover, and patient-days did not express the wide variation in how demand was generated by day of week. Traditional metrics for hospital utilization do not accurately express the true extent and dynamic nature of patient flow and inpatient demand at a children's hospital. Hospitals and government regulatory agencies should consider additional means of measuring utilization to accurately determine demand, including its variation, and thus assist in budgeting, staffing, and capacity planning.


Impact of High Fat Diet-induced Obesity on the Plasma Levels of Monoamine Neurotransmitters in C57BL/6 Mice.
Obesity is one of the most serious health problems in developed countries. It negatively affects diverse aspects of human wellbeing. Of these, a relationship between obesity and depression is widely recognized but biomarkers for assessment of obesityassociated mood changes in animal obesity models are rarely known. Here we explored the link between obesity and the plasma levels of monoamine neurotransmitters involved in mood control using a sensitive UPLC/MSMS technique in high fat diet (HFD)- induced obesity model in male C57BL/6 mice to explore the potential utility of plasma tests for obesity-associated mood change. HFD (60% of total calories, 8 weeks) induced significantly higher weight gains in body (+37.8%) and fat tissue (+306%) in male C57BL/6 mice. Bioanalysis of serotonin, dopamine and norepinephrine in plasma at 8 weeks of HFD revealed that serotonin decreased significantly in the obese mice when compared to normal diet-fed mice (2.7 ± 0.6 vs 4.3 ± 2.0 ng/ml, N=8). Notably, a negative correlation was found between the levels of serotonin and body weight gains. Furthermore, principal component analysis (PCA) with the individual levels of neurotransmitters revealed that plasma levels of dopamine and serotonin could apparently differentiate the obese mice from lean ones. Our study demonstrated that blood plasma levels of neurotransmitters can be employed to evaluate the mood changes associated with obesity and more importantly, provided an important clue for understanding of the relationship between obesity and mood disorders.


[Distribution of macronutrients from the diet and regulation of weight and body composition: role of lipids intake in obesity].
The maintenance of a stable body weight and composition over time depends, amongst other factors, on the equilibrium in the balance between the intake and metabolic utilisation of the macronutrients in the diet. The organism appears to give greater priority to the adjustment of the oxidation of glucose and amino acids in relation to their ingestion than to the maintenance of the balance of fats. The system of homeostatic self-regulation of the lipid balance is not very efficient, besides which the capacity of storing of energy reserves in the adipose tissue is almost unlimited. Besides, fat appears to confer palatability and flavour on foodstuffs, which could lead to greater consumption. Excessive ingestion of fat is one of the factors that is most frequently associated with a high prevalence of obesity. Some studies indicate that some obese subjects show a reduced capacity for oxidising fatty acids. In this context, the reduction of lipid ingestion is one of the strategies most frequently recommended in the prevention of the epidemic of obesity. However, the role of the lipid intake of the diet in the prevalence and subsequent treatment of obesity is nowadays the subject of scientific controversy.


Isolation and characterization of a profenofos degrading bacterium.
Profenofos, a well known organophosphate pesticide, has been in agricultural use over the last two decades for controlling Lepidopteron pests of cotton and tobacco crops. In this study, a bacterial strain, OW, was isolated from a long term profenofos exposed soil by an enrichment technique, and its ability to degrade profenofos was determined using gas chromatography. The isolated strain OW was identified as Pseudomonas aeruginosa according to its physiological and biochemical properties, and the analysis of its 16S rRNA gene sequence. The strain grew well at pH 5.5-7.2 with a broad temperature profile. Bioremediation of profenofos-contaminated soil was examined using soil treated with 200 microg/g profenofos, which resulted in a higher degradation rate than control soils without inoculation. In a mineral salt medium (FTW), removal in the level of profenofos of 86.81% was obtained within 48 h of incubation. The intermediates of profenofos metabolism indicated that the degradation occurred through a hydrolysis mechanism, and one of the metabolites was found to be 4 bromo-2-cholorophenol (BCP) which in turn was also mineralized by the strain. The results of this study highlighted the potentiality of P aeruginosa as a biodegrader which could be used for the bioremediation of profenofos contaminated soil.


Long-term efficacy and safety of two doses of Norditropin® (somatropin) in Noonan syndrome: a 4-year randomized, double-blind, multicenter trial in Japanese patients.
This 4-year randomized, double-blind, multicenter trial (NCT01927861) investigated the long-term efficacy and safety of Norditropin® (NN-220; somatropin) in Japanese children with short stature due to Noonan syndrome. Pre-pubertal children with Noonan syndrome were randomized 1:1 to receive 0.033 mg/kg/day (n = 25, mean age 6.57 years) or 0.066 mg/kg/day (n = 26, mean age 6.06 years) GH. Height standard deviation score (SDS) change after 208 weeks from baseline was evaluated using an analysis of covariance model. Height SDS improved from -3.24 at baseline with a significantly greater increase (estimated mean [95% confidence interval]) with 0.066 vs. 0.033 mg/kg/day GH (1.84 [1.58; 2.10] vs. 0.85 [0.59; 1.12]; estimated mean difference 0.99 [0.62; 1.36]; p < 0.0001). The majority of treatment-emergent adverse events (TEAEs) were non-serious, mild and assessed as unlikely treatment-related. TEAE rates and frequencies of serious TEAEs were similar between groups. Three patients receiving 0.066 mg/kg/day were withdrawn; two due to TEAEs at days 1,041 and 1,289. Mean insulin-like growth factor-I SDS increased from -1.71 to -0.75 (0.033 mg/kg/day) and 0.57 (0.066 mg/kg/day) (statistically significant difference). In both groups, there were only minor glycosylated hemoglobin changes, similar oral glucose tolerance test insulin response increases and no clinically relevant changes in oral glucose tolerance test blood glucose, vital signs, electrocardiogram or transthoracic echocardiography. In conclusion, treatment with 0.033 and 0.066 mg/kg/day GH for 208 weeks improved height SDS in Japanese children with short stature due to Noonan syndrome with a significantly greater increase with 0.066 vs. 0.033 mg/kg/day GH and was well tolerated, with no new safety concerns.


X-linked adrenoleukodystrophy: correlation between Loes score and diffusion tensor imaging parameters.
The present study was aimed at evaluating the correlation between diffusion tensor imaging parameters and Loes score as well as whether those parameters could indicate early structural alterations. Diffusion tensor imaging measurements were obtained in 30 studies of 14 patients with X-linked adrenoleukodystrophy and were correlated with Loes scores. A control group including 28 male patients was created to establish agematched diffusion tensor imaging measurements. Inter- and intraobserver statistical analyses were undertaken. Diffusion tensor imaging measurements presented strong Pearson correlation coefficients (r) of -0.86, 0.89, 0.89 and 0.84 for fractional anisotropy and mean, radial and axial diffusivities (p < 0.01). Analysis of changes in diffusion tensor measurements at early stage of the disease indicates that mean and radial diffusivities might be useful to predict the disease progression. Measurements of diffusion tensor parameters can be used as an adjunct to the Loes score, aiding in the monitoring of the disease and alerting for possible Loes score progression in the range of interest for therapeutic decisions.


Cooperative binding of R17 coat protein to RNA.
The binding of the R17 coat protein to synthetic RNAs containing one or two coat protein binding sites was characterized by using nitrocellulose filter and gel-retention assays. RNAs with two available sites bound coat protein in a cooperative manner, resulting in a higher affinity and reduced sensitivity to pH, ionic strength, and temperature when compared with RNAs containing only a single site. The cooperativity can contribute up to -5 kcal/mol to the overall binding affinity with the greatest cooperativity found at low pH, high ionic strength, and high temperatures. Similar solution properties for the encapsidation of the related fr and f2 phage suggest that the cooperativity is due to favorable interactions between the two coat proteins bound to the RNA. This system therefore resembles an intermediate state of phage assembly. No cooperative binding was observed for RNAs containing a single site and a 5' or 3' extension of nonspecific sequence, indicating that R17 coat protein has a very low nonspecific binding affinity. Unexpectedly weak binding was observed for several RNAs due to the presence of alternative conformational states of the RNA.


An electrophoretic study of the low-molecular-weight components of myosin.
1. The low-molecular-weight components of myosin freshly prepared by the standard procedure from adult rabbit skeletal muscle migrated as four main bands Ml(1), Ml(2), Ml(3) and Ml(4) on polyacrylamide-gel electrophoresis in 8m-urea. 2. The number of bands increased on storage. This change was accelerated by increasing the temperature and pH. 3. None of the bands had electrophoretic mobilities identical with those of the well-characterized proteins of the myofibril or with the sarcoplasmic proteins. 4. By varying the ionic conditions and concentration of muscle mince used for the initial extraction it was possible to change the relative proportions of the two electrophoretic bands of intermediate mobility, Ml(2) and Ml(3). 5. The four-band picture similar to that obtained with rabbit was observed with myosin isolated from skeletal muscle of the rat, mouse, hamster, pigeon and chicken. 6. Rabbit cardiac myosin gave only two bands on electrophoresis. Myosin from rabbit red muscle gave a pattern intermediate between cardiac and white-skeletal-muscle myosin, i.e. the two fastest bands were present in decreased relative amounts. 7. It is suggested that the differences in the low-molecular-weight components of myosin from different types of muscle are a consequence of differences in the isoenzyme composition of the myosins.


Comparison of haematological indices between women of four ethnic groups and the effect of oral contraceptives.
Six-hundred-and-eighty-two women volunteers from four ethnic groups--Black, Indian, Oriental and White took part in a study to assess differences in haematological indices between the groups. This study was part of a broad investigation into the metabolic effects of oral contraceptives. The effect of the oral contraceptive (OC) on haematological indices was analysed but not found to be significant. The haemoglobin concentrations were lower than normal laboratory reference values for White subjects in 12.5% of Indian, 16.5% of Black and 4.3% of Oriental control groups respectively. All the White control group were within the normal range. These findings were considered in relation to age, weight, pregnancies, smoking, alcohol consumption, nutritional status, and disorders of haemoglobin synthesis. A deficient iron intake accounted for the high incidence of low haemoglobin in the Indian group in whom low transferrin saturation and serum ferritin were observed. With the possible exception of inherited disorders of haemoglobin synthesis, none of the factors we considered could account for the low haemoglobins found in the Black group. Separate reference values for haematological indices in different ethnic populations are considered.


Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.
The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension.


Fast-slow and slow-slow form of atrioventricular nodal reentrant tachycardia sustained by the same reentrant circuit: a case report.
It has been suggested that a reentrant circuit confined to the posterior extensions of the atrioventricular node underlies both fast-slow and slow-slow types of atrioventricular nodal reentrant tachycardia (AVNRT). According to this hypothesis the fast-slow reentrant circuit would be formed by two slow pathways, located in the rightward and leftward posterior extension of the atrioventricular node. Thus, the fast pathway would act as a bystander with respect to the reentrant circuit. We describe the case of a 40-year-old woman with several episodes of palpitations unresponsive to antiarrhythmic drugs. The ECG during symptoms showed a narrow QRS tachycardia with a long ventriculo-atrial interval and a negative P wave in the inferior leads. Electrophysiological study showed the inducibility of a slow-slow AVNRT which rapidly shifted to a fast-slow AVNRT without any change in the duration of the tachycardia cycle. Our observation is in agreement with the hypothesis that the fast-slow reentrant circuit consists of two slow pathways with the fast pathway acting as a bystander.


Favorable effect of short-term lifestyle intervention on human paraoxonase-1 activity and adipokine levels in childhood obesity.
The prevalence of obesity is increasing in adult and child populations throughout the world. Childhood obesity has a great impact on adult cardiovascular morbidity and mortality; treatment of this pathological state is important given the significant health consequences. We investigated the effect of short-term lifestyle changes on the alteration of human serum paraoxonase-1 (PON1) activities, leptin, adiponectin, E-selectin, and asymmetric dimethylarginine (ADMA) as atherogenic and antiatherogenic factors in obese children. PON1 protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low density lipoprotein (LDL) and therefore may protect against atherosclerosis. A total of 23 white obese and overweight children (age, 11.43 ± 1.78 years; 8 girls, 15 boys) participated in a 2-week-long lifestyle camp based on a diet and exercise program. Overweight and obesity were defined according to the national body mass index (BMI) reference tables for age and sex. After a 2-week-long supervised diet and aerobic exercise program, obese children had significantly lower leptin (55.02 ± 33.42 ng/ml vs 25.37 ± 19.07 ng/ml; p < 0.0001), ADMA (0.68 ± 0.15 μmol/l vs 0.55 ± 0.16 μmol/l; p < 0.01), and E-selectin levels (67.19 ± 30.35 ng/ml vs 46.51 ± 18.40 ng/ml; p < 0.0001), whereas they had significantly higher PON1 paraoxonase activity (110.48 ± 72.92 U/l vs 121.75 ± 93.48 U/l; p < 0.05) besides the antiatherogenic alteration of the lipid profile and significant weight change (70.32 ± 19.51 kg vs 67.01 ± 18.75 kg, p < 0.0001; BMI, 28.95 ± 5.05 kg/m(2) vs 27.43 ± 4.82 kg/m(2), p < 0.0001). Adiponectin and PON1 arylesterase activity did not change significantly. Our investigation suggests that modifications in dietary habits and physical activity induce antiatherogenic changes in childhood obesity. These findings emphasize the major role of primary prevention and nonpharmaceutical treatment of childhood obesity through lifestyle changes based on diet and increased physical activity.


Salmonella enteritis in children in Libya: role of antibiotic therapy.
In vivo sensitivity of salmonella has been studied in 38 children with acute gastroenteritis. They were treated for 7 days with gentamicin, to which the organisms were sensitive in vitro. Stool culture remained positive in 30 of the 38 cases. The children improved on supportive and symptomatic therapy. This study shows that antibiotics have no role to play in the management of acute salmonella gastro-enteritis in children.


Terpene Biosynthesis in Red Algae Is Catalyzed by Microbial Type But Not Typical Plant Terpene Synthases.
Red algae (Rhodophyta) and land plants belong to the monophyletic clade Archaeplastida, and taxa of both groups are rich producers of terpene secondary metabolites. The terpene carbon skeletons of land plants are made by two types of terpene synthases: typical plant terpene synthases and microbial-type terpene synthases (MTPSLs); however, terpene biosynthesis in red algae is poorly understood. By systematic sequence analysis of seven genomes and 34 transcriptomes of red algae, MTPSL homologs were identified within one genome and two transcriptomes, whereas no homolog of typical plant terpene synthase genes was found. Phylogenetic analysis showed that red algae MTPSLs group with bacterial terpene synthases. Analysis of the genome assembly and characterization of neighboring genes demonstrated red algal MTPSLs to be bona fide red algal genes and not microbial contaminants. MTPSL genes from Porphyridium purpureum and Erythrolobus australicus were characterized via heterologous expression in Escherichia coli and demonstrated to have sesquiterpene synthase activities. We detected a number of volatile sesquiterpenes in the headspace of P. purpureum and E. australicus cultures, most identical to the in vitro products of the respective MTPSLs. Expression of the MTPSL gene in P. purpureum was found to be induced by methyl jasmonate, suggesting a role for this gene in host defense. In summary, this study indicates that the formation of terpene carbon skeletons in red algae is carried out by MTPSLs that are phylogenetically unrelated to typical plant terpene synthases and most likely originated in Rhodophyta via horizontal gene transfer from bacteria.


Extraordinary multilocus genetic organization in mole crickets, Gryllotalpidae.
Allozymic diversity at 21 loci was analyzed in 470 individuals of three species of mole cricket superspecies, Gryllotalpa gryllotalpa (two new chromosomal species, G. tali and G. marismortui) and G. africana in Israel, which are distributed along a southward transect of increasing aridity. Two outstanding findings emerged in G. tali and G. marismortui: (1) genetic polymorphism was high but heterozygosity very low, indicating significant deviations from Hardy-Weinberg expectations; and (2) significant linkage disequilibria at an unprecedented level for outbreeders and remarkable intersite differences. The results may characterize subterranean gryllotalpids worldwide because a single sample of Neocurtilla hexadactyla from Tefé, Amazonia, shows the same features. Significant variation of heterozygote paucity among loci, combined with the biology of the species, rejects the simple explanation of inbreeding or any other single explanatory model. Likewise, direct selection against heterozygotes or specific multilocus associations can explain, but is not necessary nor likely to explain, the observed results in mole crickets. To explain these results, we developed a multiple-factor mathematical model combining niche viability selection, niche choice, and positive assortative mating. This model involves a special case of Wahlund effect and inbreeding. Simulations based on this model showed that a combination of these three mechanisms may produce the observed distribution of alleles, via selection on a few loci, to affect the entire genome organization.


The notch ligand Delta1 recruits Dlg1 at cell-cell contacts and regulates cell migration.
Delta1 acts as a membrane-bound ligand that interacts with the Notch receptor and plays a critical role in cell fate specification. By using peptide affinity chromatography followed by mass spectrometry, we have identified Dlg1 as a partner of the Delta1 C-terminal region. Dlg1 is a human homolog of the Drosophila Discs large tumor suppressor, a member of the membrane-associated guanylate kinase family of molecular scaffolds. We confirmed this interaction by co-immunoprecipitation experiments between endogenous Dlg1 and transduced Delta1 in a 3T3 cell line stably expressing Delta1. Moreover, we showed that deletion of a canonical C-terminal PDZ-binding motif (ATEV) in Delta1 abrogated this interaction. Delta4 also interacted with Dlg1, whereas Jagged1, another Notch ligand, did not. In HeLa cells, transfected Delta1 triggered the accumulation of endogenous Dlg1 at sites of cell-cell contact. Expression of Delta1 also reduced the motility of 3T3 cells. Finally, deletion of the ATEV motif totally abolished these effects but did not interfere with the ability of Delta1 to induce Notch signaling and T cell differentiation in co-culture experiments. These results point to a new, probably cell-autonomous function of Delta1, which is independent of its activity as a Notch ligand.


Examining guideline-concordant care for acute myocardial infarction (AMI): the case of hospitalized post-acute and long-term care (PAC/LTC) residents.
Previous studies have examined differences in care for acute myocardial infarction (AMI) according to patient characteristics such as age, gender, or insurance, but little attention has been given to whether admission source is related to guideline adherence. To investigate: (1) the use of aspirin and reperfusion in the care of post-acute/long-term care (PAC/LTC) patients who are hospitalized for AMI, and (2) 30-day mortality associated with these treatments. Secondary examination of data from the Cooperative Cardiovascular Project (CCP) national baseline data. A total of 4013 U.S. hospitals. Patients hospitalized with a confirmed AMI admitted from PAC/LTC (n = 8151) or community-dwelling (n = 120,032) settings. Early administration of aspirin and reperfusion via either thrombolysis or percutaneous intervention. PAC/LTC patients were less likely to receive treatment for AMI, even after adjustment for multiple variables associated with treatment choice. Differences persisted with additional econometric adjustment using seemingly-unrelated regression. Multivariable logistic regression results indicated that aspirin was related to improved 30-day survival for both PAC/LTC and community admissions (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.43-0.58 for PAC/LTC, and OR, 0.57; 95% CI, 0.54-0.60 for community). Reperfusion was associated with higher ORs for mortality for eligible patients admitted from community setting (OR, 1.24; 95% CI, 1.13-1.35), but ideally-eligible candidates had lower ORs for mortality (OR, 0.58; 95% CI, 0.35-0.95 for PAC/LTC, and OR, 0.74; 95% CI, 0.68-0.81 for community). Patients transferred from PAC/LTC settings were less likely to receive early treatment for AMI than other patients. Future trials should inform which guidelines are applicable to PAC/LTC patients.


Biomechanical evaluation of the motor function of the thumb.
An experimental apparatus was developed to measure force production of a digit at various points of force application along the digit and in any direction within the transverse plane of the longitudinal axis of the digit. Eight normal subjects with asymptomatic hands were tested. Maximum voluntary isometric contraction forces were measured at the interphalangeal joint of the thumb in 16 directions that were evenly distributed within 360 degrees. Peak forces measured in all directions were used to create polar plots and to construct force envelopes using cubic spline interpolation. The areas of the force envelope and force quadrants were then calculated. The force produced by the thumb was dependent on the direction of force application. The highest force, 104.8 +/- 14.2 N, was generated in flexion, while the lowest force was generated in extension. The forces in extension, abduction and adduction were 24.8%, 57.2%, and 46.2% of the flexion force, respectively. Relatively high forces were generated in the directions of flexion combined with abduction, and flexion combined with adduction. The area of the entire force envelope was found to be 12,142 +/- 3,149 N-N. The percentage quadrant areas, relative to the total force envelope area, for extension-adduction, extension-abduction, flexion-abduction, and flexion-adduction were 7.8%, 11.4%, 39.3%, and 41.4%, respectively. The percentage quadrant areas for extension, abduction, flexion, and adduction were 4.9%, 23.6%, 52.7%, and 18.8%, respectively. The current study provides a more advanced and comprehensive method for quantification and investigation of the motor function of the thumb, which has potential in clinical applications for diagnosis of hand disorders, evaluation of deterioration or improvement of hand motor function, and guidance of therapeutic and surgical intervention.


Dukes' A tumor.
Dukes' classification for colorectal cancer is easy to remember and accurate in estimating survival. The Japanese definition of early gastric cancer have some problems, since it includes node-positive cases showing a worse prognosis. The aim of this study was to clarify whether or not Dukes' A tumor can be used as new criteria for early gastric cancer. Using 217 patients who underwent radical gastrectomy and lymph node dissection for primary gastric adenocarcinoma, long-term results and cumulative survival rates after operation were examined. Patients consisted of three groups: Group 1, 20 patients with node-negative tumor invading down to the muscularis propria, Group 2, 175 patients with node-negative tumor limited to the mucosa or submucosa, and Group 3, 22 patients with node-positive tumor limited to the mucosa or submucosa. The 10-year survival rates for Group 1, Group 2, and Group 3 patients were 94.7%, 96.9%, and 85.1%, respectively. The survival rate of Group 3 patients was significantly lower than that of Group 1 and Group 2 patients (p<0.05). The prognosis of patients with Dukes' A tumor (Group 1 plus Group 2) was excellent, showing 10-year survival rate of 96.6%. Mucosal or submucosal cancer brought a poor prognosis when there was lymph node metastasis. Early gastric cancer would better be defined as a Dukes' A tumor which includes node-negative tumor not beyond the muscularis propria.


Crystal engineering yields crystals of cyclophilin D diffracting to 1.7 A resolution.
In the pharmaceutical industry, knowledge of the three-dimensional structure of a specific target facilitates the drug-discovery process. Despite possessing favoured analytical properties such as high purity and monodispersion in light scattering, some proteins are not capable of forming crystals suitable for X-ray analysis. Cyclophilin D, an isoform of cyclophilin that is expressed in the mitochondria, was selected as a drug target for the treatment of cardiac disorders. As the wild-type enzyme defied all attempts at crystallization, protein engineering on the enzyme surface was performed. The K133I mutant gave crystals that diffracted to 1.7 A resolution using in-house X-ray facilities and were suitable for soaking experiments. The crystals were very robust and diffraction was maintained after soaking in 25% DMSO solution: excellent conditions for the rapid analysis of complex structures including crystallographic fragment screening.


Time-resolved functional analysis of acute impairment of frataxin expression in an inducible cell model of Friedreich ataxia.
Friedreich ataxia is a neurodegenerative disease caused by a GAA triplet repeat expansion in the first intron of the frataxin gene, which results in reduced expression levels of the corresponding protein. Despite numerous animal and cellular models, therapeutic options that mechanistically address impaired frataxin expression are lacking. Here, we have developed a new mammalian cell model employing the Cre/loxP recombination system to induce a homozygous or heterozygous frataxin knockout in mouse embryonic fibroblasts. Induction of Cre-mediated disruption by tamoxifen was successfully tested on RNA and protein levels. After loss of frataxin protein, cell division, aconitase activity and oxygen consumption rates were found to be decreased, while ROS production was increased in the homozygous state. By contrast, in the heterozygous state no such changes were observed. A time-resolved analysis revealed the loss of aconitase activity as an initial event after induction of complete frataxin deficiency, followed by secondarily elevated ROS production and a late increase in iron content. Initial impairments of oxygen consumption and ATP production were found to be compensated in the late state and seemed to play a minor role in Friedreich ataxia pathophysiology. In conclusion and as predicted from its proposed role in iron sulfur cluster (ISC) biosynthesis, disruption of frataxin primarily causes impaired function of ISC-containing enzymes, whereas other consequences, including elevated ROS production and iron accumulation, appear secondary. These parameters and the robustness of the newly established system may additionally be used for a time-resolved study of pharmacological candidates in a HTS manner.