Chiroptically Active Metallic Nanohelices with Helical Anisotropy.
Manipulation of circular polarization states of light in the ultraviolet-visible-near infrared range, which cannot be operated using natural materials, is of fundamental interest derived from a wide range of chirality-associated optical, chemical and biological applications. To achieve this objective, chiral metamaterials made of metallic nanohelices (NHs) have been artificially designed and generated. The circular polarization manipulation is as a result of helical anisotropy and localized surface plasmon resonance of metallic NHs, and engineering helical structures and metallic composition gives rise to flexible tailoring of the circular polarization manipulation. Herein, we review the latest development of metallic NHs in terms of fabrication, fundamentally optical and magnetic properties, and chiroptical applications, followed by envisioning prospective applications closely related to molecular chirality. We strongly believe that the helicity-induced anisotropy of metallic NHs will provide us a wide range of opportunities to tackle some prominent problems and challenges intrinsically associated with the natural homochirality.


Preventing mother-to-child HIV transmission in a developing country: the Dominican Republic experience.
Transmission of HIV in the Dominican Republic occurs primarily through heterosexual contact. As part of a continuing strategy to prevent and contain the spread of HIV infection, the Ministry of Health of the Dominican Republic established an integrated package of interventions to reduce HIV mother-to-child transmission that was initiated on May 15, 2000. The program was designed to be implemented in 3 phases. The 1st phase included 4 mother and child hospitals; the 2nd phase included 8 mother and child health institutions in Santo Domingo, the capital of the Dominican Republic, and 7 additional mother and child hospitals. The 3rd phase will include the remaining 12 mother and child health care institutions of the Dominican Republic. Evaluation of the 1st year of this program, involving 8 hospitals and >40000 pregnant women, identified specific benefits and limitations. Low numbers of voluntary counseling sessions (6528/42666 = 28%) and inadequate number of HIV rapid tests (23067/42666 = 54%) were the 2 main obstacles encountered. From the 23067 pregnant women tested, 581 (2.5%) were HIV positive. Advantageous aspects included the successful administration of antiretroviral treatment to 89% (164/185) of the mothers and 98% (183/186) of the children. Cesarean section was performed in 67% (124/185) of the HIV-positive pregnant women, and infant formula was dispensed to 47% (87/186) of all cases. These findings demonstrate the feasibility of implementing a large-scale program to prevent mother-to-child transmission in a developing country.


Genome-Wide Identification and Low Temperature Responsive Pattern of Actin Depolymerizing Factor (ADF) Gene Family in Wheat (Triticum aestivum L.).
The actin depolymerizing factor (ADF) gene family, which is conserved in eukaryotes, is important for plant development, growth, and stress responses. Cold stress restricts wheat growth, development, and distribution. However, genome-wide identification and functional analysis of the ADF family in wheat is limited. Further, because of the promising role of ADF genes in cold response, there is need for an understanding of the function of this family on wheat under cold stress. In this study, 25 ADF genes (TaADFs) were identified in the wheat genome and they are distributed on 15 chromosomes. The TaADF gene structures, duplication events, encoded conversed motifs, and cis-acting elements were investigated. Expression profiles derived from RNA-seq data and real-time quantitative PCR analysis revealed the tissue- and temporal-specific TaADF expression patterns. In addition, the expression levels of TaADF13/16/17/18/20/21/22 were significantly affected by cold acclimation or freezing conditions. Overexpression of TaADF16 increased the freezing tolerance of transgenic Arabidopsis, possibly because of enhanced ROS scavenging and changes to the osmotic regulation in cells. The expression levels of seven cold-responsive genes were up-regulated in the transgenic Arabidopsis plants, regardless of whether the plants were exposed to low temperature. These findings provide fundamental information about the wheat ADF genes and may help to elucidate the regulatory effects of the encoded proteins on plant development and responses to low-temperature stress.


Analysis of bovine gamma delta T cell interactions with E-, P-, and L-selectin. Characterization of lymphocyte on lymphocyte rolling and the effects of O-glycoprotease.
In earlier studies, we found that bovine gamma delta T cells avidly bind and roll under physiologic flow on E- and P-selection. In this study, we have extended our analyses of shear interactions of gamma delta T cells and have found that once gamma delta T cells permanently bind to endothelial cell monolayers they can support continued rolling of newly arriving gamma delta T cells. Anti-L-selection Abs blocked gamma delta T cell rolling on immobilized gamma delta T cells, and it was L-selection on the rolling cell, not the bound cell, that mediated the interaction. We propose, as we have for neutrophils, that lymphocyte/lymphocyte rolling represents a mechanism for amplification of the extravasation process. Having defined P-, E-, and L-selectin interactions with gamma delta T cells, we tested the susceptibility of the ligands for these selectins to treatment with O-glycoprotease, a compound that selectively cleaves mucin-like selectin ligands. O-glycoprotease treatment of gamma delta T cells blocked their interaction with P-selectin, but not E-selectin. Rolling of O-glycoprotease-treated cells on bound untreated gamma delta T cells was unaffected; however, O-glycoprotease treatment of the bound gamma delta T cells blocked their capacity to support rolling interactions. These results define a new lymphocyte/selectin interaction that may be important in amplifying lymphocyte extravasation and suggest that gamma delta T cell ligands for P- and E-selectin are distinct, whereas ligands for P- and L-selectin may be similar.


A SIEVE M-THEOREM FOR BUNDLED PARAMETERS IN SEMIPARAMETRIC MODELS, WITH APPLICATION TO THE EFFICIENT ESTIMATION IN A LINEAR MODEL FOR CENSORED DATA.
In many semiparametric models that are parameterized by two types of parameters - a Euclidean parameter of interest and an infinite-dimensional nuisance parameter, the two parameters are bundled together, i.e., the nuisance parameter is an unknown function that contains the parameter of interest as part of its argument. For example, in a linear regression model for censored survival data, the unspecified error distribution function involves the regression coefficients. Motivated by developing an efficient estimating method for the regression parameters, we propose a general sieve M-theorem for bundled parameters and apply the theorem to deriving the asymptotic theory for the sieve maximum likelihood estimation in the linear regression model for censored survival data. The numerical implementation of the proposed estimating method can be achieved through the conventional gradient-based search algorithms such as the Newton-Raphson algorithm. We show that the proposed estimator is consistent and asymptotically normal and achieves the semiparametric efficiency bound. Simulation studies demonstrate that the proposed method performs well in practical settings and yields more efficient estimates than existing estimating equation based methods. Illustration with a real data example is also provided.


E-cadherin expression in endometrial malignancies: comparison between endometrioid and non-endometrioid carcinomas.
This study examined the frequency of E-cadherin expression in endometrial biopsy or hysterectomy specimens from patients diagnosed with endometrial adenocarcinoma and in normal endometrial tissue specimens. E-cadherin expression was detected by immunohistochemistry using monoclonal antibody to E-cadherin. Specimens were classified as positive when >or= 5% of the tumour cells showed staining for E-cadherin, irrespective of the pattern of staining. Twenty-three endometrioid carcinomas and nine non-endometrioid (four papillary serous and five clear cell) carcinomas were studied, along with 10 normal endometrial tissue specimens as controls. E-cadherin expression was significantly less frequent in non-endometrioid carcinomas compared with endometrioid carcinomas and controls. There was no statistically significant difference in the frequency of E-cadherin expression between endometrioid carcinomas and controls. In conclusion, this study demonstrated that uterine non-endometrioid (papillary serous and clear cell) carcinomas were less likely to express E-cadherin compared with endometrioid carcinomas and normal endometrial tissue. This may help to explain the more aggressive behaviour of non-endometrioid carcinomas.


Protocol: a simple method for extracting next-generation sequencing quality genomic DNA from recalcitrant plant species.
Next-generation sequencing technologies rely on high quality DNA that is suitable for library preparation followed by sequencing. Some plant species store large amounts of phenolics and polysaccharides within their leaf tissue making genomic DNA extraction difficult. While many DNA extraction methods exist that contend with the presence of phenolics and polysaccharides, these methods rely on long incubations, multiple precipitations or commercially available kits to produce high molecular weight and contaminant-free DNA. In this protocol, we describe simple modifications to the established CTAB- based extraction method that allows for reliable isolation of high molecular weight genomic DNA from difficult to isolate plant species Corymbia (a eucalypt) and Coffea (coffee). The simplified protocol does not require multiple clean up steps or commercial based kits, and the isolated DNA passed stringent quality control standards for whole genome sequencing on Illumina HiSeq and TruSeq sequencing platforms.


Accuracy and reproducibility of quantitation of left ventricular function by real-time three-dimensional echocardiography versus cardiac magnetic resonance.
The aim of this study was to investigate the accuracy and reproducibility of the quantification of left ventricular (LV) function by real-time 3-dimensional echocardiography (RT3DE) using current state-of-the-art hardware and software. Compared with cardiac magnetic resonance (CMR), previous generations of hardware and software for RT3DE significantly underestimated LV volumes partly because of inherent factors such as limited spatial and temporal resolution. Also, RT3DE volumes were compared with short-axis CMR data, whereas a combined short-axis and long-axis analysis is known to be superior. Twenty-four subjects (mean age 51 +/- 12 years, 17 men) in sinus rhythm and with good to excellent 2-dimensional image quality underwent RT3DE and CMR within 1 day. The acquisition of RT3DE data was done with current state-of-the-art hardware and software. Two blinded experts performed off-line LV volume analysis. Global LV volumes were determined from semiautomated border detection on the basis of endocardial speckle tracking with biplane projections using QLAB version 6.0. Volumes derived by magnetic resonance imaging were quantified from combined short-axis and long-axis series. The volume-rate on RT3DE was 33 +/- 8 Hz (range 19 to 42). Excellent correlations were found (R2 > or = 0.97) between CMR and RT3DE for global LV end-diastolic volume, LV end-systolic volume, the LV ejection fraction, and LV phase volumes (24 phases/cardiac cycle). Bland-Altman analyses showed mean differences of -7.1 ml, -4.2 ml, 0.2%, and -5.8 ml and 95% limits of agreement of +/-19.7 ml, +/-8.3 ml, +/-6.2%, and +/-15.4 ml for global LV end-diastolic volume, LV end-systolic volume, the LV ejection fraction, and LV phase volumes, respectively. Interobserver variability was 5.2% for global LV end-diastolic volume, 6.4% for LV end-systolic volume, and 7.6% for the LV ejection fraction. In conclusion, in patients with good acoustic windows, RT3DE using state-of-the-art technology provides accurate and reproducible measurements of global LV volumes, LV volume changes over time, and the LV ejection fraction.


14-3-3 proteins are required for the inhibition of Ras by exoenzyme S.
14-3-3 proteins play a regulatory role and participate in both signal transduction and checkpoint control pathways. 14-3-3 proteins bind phosphoserine ligands, such as Raf-1 kinase and Bad, by recognizing the phosphorylated consensus motif, Arg-Ser-Xaa-pSer-Xaa-Pro (where 'Xaa' represents 'any residue', and 'pSer' is 'phosphoserine'). However, 14-3-3 proteins must bind unphosphorylated ligands, such as glycoprotein Ibalpha and Pseudomonas aeruginosa exoenzyme S (ExoS), since it has been suggested that specific residues of 14-3-3 proteins are required for activation of ExoS. Furthermore, an unphosphorylated peptide derived from a phage display library inhibited the binding of both ExoS and Raf-1 to 14-3-3, and bound within the same conserved amphipathic groove on the surface of 14-3-3 as the Raf-derived phosphopeptide (pS-Raf-259). In the present study we identify the interaction site on ExoS for 14-3-3, and show that ExoS and 14-3-3 do indeed interact in vivo. In addition, we show that this interaction is critical for the ADP-ribosylation of Ras by ExoS, both in vitro and in vivo. Loss of the 14-3-3 binding site on ExoS results in an ExoS molecule that is unable to efficiently inactivate Ras, and displays reduced killing activity.


How Do People Experience Early Intervention Services for Psychosis? A Meta-Synthesis.
We conducted a study to explore how people diagnosed with first-episode psychosis experienced their contact with early intervention services for psychosis and the way these experiences relate to their recovery processes. Our aim was to integrate and describe the service users' experiences in a rigorous and comprehensive way. A broad literature search was performed in June and July 2016. After screening, 17 qualitative studies were included. We analyzed the findings in two main steps: (a) translating studies into one another and (b) synthesizing the findings from the studies. Through these interpretative processes, we found five new and overarching themes: (a) something is wrong, (b) do for myself, (c) it's about people, (d) a price to pay, and (e) ongoing vulnerability. We describe these themes as a process that service users' maneuver through in their contact with the services. Our findings are discussed in light of relevant research.


LyF-1, a transcriptional regulator that interacts with a novel class of promoters for lymphocyte-specific genes.
We have studied transcriptional control of the murine terminal deoxynucleotidyltransferase (TdT) gene, which is activated specifically in immature B and T lymphocytes. This analysis has led to the identification and purification of a 50-kDa sequence-specific DNA-binding protein, LyF-1, that interacts with the approximate consensus sequence PyPyTGGGAGPu and is enriched in cells at most stages of B- and T-cell differentiation. LyF-1 binds tightly to an element in the TdT promoter that we show is required for transcription in lymphocytes. LyF-1 also interacts with an element in the immunoglobulin mu enhancer, called microB, that was recently shown to be important for lymphocyte-specific enhancer activity. Moreover, LyF-1 binds to the promoters for the lymphocyte-specific genes lambda 5, VpreB, and lck, all of which we speculate have additional features in common with the TdT promoter. Thus, LyF-1 may be a general transcriptional activator for genes whose expression is restricted to the B- and/or T-lymphocyte lineages.


The toxicity of opiates and their metabolites in HepG2 cells.
The toxicity of codeine (C), codeinone (CO), morphine (M), oxycodone (OC), pholcodine (P) and pholcodine-N-oxide (P-NOX) was assessed in HepG2 cells by determining cell viability via the measurement of lactate dehydrogenase (LDH) leakage through the membrane, depletion of reduced glutathione (GSH) and measurement of total protein content. Incubation of C, M, OC, P or P-NOX with HepG2 cells resulted in no significant loss of cell viability, depletion of GSH or decreased total protein content. In contrast, with CO there was a marked depletion of GSH with significant differences from control cells (P<0.05) being detected after as little as 5 min. This effect preceded the loss of cell viability and the decrease in total protein content. To identify the cause of GSH depletion during incubations with CO, the incubation solutions were analysed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Analysis showed that a codeinone-glutathione conjugate (CO-SG) had been formed. This adduct was synthesised and characterised by LC/MS/MS and by nuclear magnetic resonance spectroscopy (NMR). CO-SG was quantified in the incubation solutions using the synthesised standard substance. Results obtained in this study support the hypothesis that the toxicity of CO may be partly due to GSH depletion. The absence of LDH leakage and GSH depletion in the incubations containing C or OC suggests, that the presence of both a double bond at Delta 7 and an adjoining keto-group in the 6-position are necessary to elicit the toxicity of M analogues with regard to GSH depletion.


Extramammary Paget disease is characterized by the consistent lack of estrogen and progesterone receptors but frequently expresses androgen receptor.
Extramammary Paget disease (EPD) is an uncommon cutaneous malignant neoplasm that arises in areas rich in apocrine glands (perineum, vulva, and axilla). Apocrine gland origin or apocrine differentiation of cells of EPD has been suggested. Estrongen, progesterone, and androgen hormone receptors have been reported to exhibit a characteristic pattern of expression in mammary apocrine type carcinomas; however, their expression in EPD has not been elucidated fully. By using immunohistochemical methods, we studied the expression of steroid receptors in EPD on formalin-fixed paraffin-embedded tissue samples from 28 patients with EPD without associated visceral malignant neoplasms or adnexal carcinoma. Androgen receptor (AR) was identified in 15 of 28 cases. The proportion of AR-positive cells varied from 1% to more than 75%; 8 cases expressed AR in more than 10% of cells. Strong AR expression also was seen in the invasive carcinoma arising from 1 case of EPD. All cases lacked immunohistochemically detectable estrogen and progesterone receptors. The immunophenotype characteristic of apocrine carcinomas (AR-positive, estrogen receptor-negative, progesterone receptor-negative) was seen in a substantial proportion of EPD cases. Results suggest that AR expression is a factor in pathogenesis of EPD. This may be important for the therapy of recurrent or invasive disease.


[Social participation as a central strategy of community nutrition to face the challenges associated with the nutritional transition].
In last decades modern societies are undergoing a rapid nutrition transition process that reinforces, at international level, the emergence of nutritional problems of contradictory nature, such as malnutrition and obesity. This represents a considerable challenge for contemporary Public Health leaders, who have been gradually developing a set of strategies which overwhelmingly adopt a population perspective. Nevertheless, the collective nature of these strategies could neglect the particular individual and family needs. We consider social participation as an approach to simultaneously reinforce both individual and population perspectives during the divers phases of development of Community Nutrition programs which tackle the paradoxical nature of this problematic. However in relation to some contextual factors, we find a growing trend to develop a more technocratic dimension of participatory practices, which distorts the emancipator and transformative potential of social participation. In order to avoid this tendency, we propose the use of the five intervention axes of the Ottawa Chart for Health Promotion as a guide for a systemic integration of social participation in planning, implementation and evaluation processes of Community Nutrition programs. We therefore take into account the integration of social participation in the efforts made in developing individual capacity-building, reinforcing collective action, creating enabling environments, health care reorganization, and finally, implementing nutritional and public health policies.


Acute and subacute encephalopathies: deficiency states (nutritional).
Optimal functioning of the central and peripheral nervous system is dependent on a constant supply of essential nutrients. Nutritional deficiencies of thiamine and niacin, rarely vitamin B (12), and possibly folate can cause a wide range of neuropsychiatric manifestations. Neurologic manifestations associated with these deficiency states are the focus of this review. The preventable and potentially treatable nature of these disorders makes this an important subject. Prognosis depends on prompt recognition and institution of appropriate therapy.


Alpha-macroglobulin from Limulus polyphemus exhibits proteinase inhibitory activity and participates in a hemolytic system.
Significant primary sequence homology between the alpha-macroglobulin family of proteinase inhibitors and the complement components C3, C4, and C5 implies that these proteins arose from a common ancestor. Hemolymph from the ancient invertebrate Limulus polyphemus contains both complement-like and proteinase inhibitory activity. In this report, we present evidence that L. polyphemus alpha-macroglobulin not only possesses proteinase inhibitory activity, but it also participates in the lytic system of the horseshoe crab. The protein is a disulfide-linked dimer of subunits of molecular mass 185 kDa. Upon reaction with proteinase or methylamine, L. polyphemus alpha-macroglobulin underwent a major conformational change and no proteinase-associated multimerization was detected. L. polyphemus alpha-macroglobulin is the only detectable inhibitor of a number of proteinases in L. polyphemus hemolymph. Proteinase inhibition follows the general "trapping" mechanism shared by most alpha-macroglobulins; however, no covalent linking of proteinases to the inhibitor was detected despite the presence of a functional thiolester. Moreover, the inhibitor demonstrated thiolester-mediated binding to sheep erythrocytes, a property also observed with complement components such as C3. Depletion of functional protein by treatment of hemolymph with methylamine destroyed the proteinase inhibitory capacity and the lytic activity of the hemolymph. Both activities were restored by adding purified protein to depleted hemolymph. Studies with purified L. polyphemus alpha-macroglobulin demonstrated that the thiolester incorporates glycerol as well as methylamine, a property shared by human C3. The data support the hypothesis that L. polyphemus alpha-macroglobulin is both a proteinase inhibitor and part of a lytic system, providing a link between the two distinct sides of the alpha-macroglobulin family. Because both properties are contained in one molecule, we propose the name "limac" to describe this Limulus alpha-macroglobulin complement-like protein.


Transitioning disopyramide to mavacamten in obstructive hypertrophic cardiomyopathy: A case series and clinical guide.
Hypertrophic cardiomyopathy (HCM) is a genetic disorder for which first-line treatments for obstructive HCM (oHCM) include beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide for refractory cases. Mavacamten, a selective cardiac myosin inhibitor, is indicated for symptomatic oHCM to improve functional capacity and symptoms. Use of disopyramide and mavacamten together is not recommended due to concerns of additive negative inotropic effects. Transitioning from disopyramide to mavacamten may be preferred to avoid adverse effects and frequent administration, however, the best approach for making the transition has not been established. We present a series of seven patients with oHCM who transitioned from disopyramide to mavacamten and underwent echocardiograms mandated by a Risk Evaluation and Mitigations Strategies program. Two methods were employed. The first approach, involving washout of disopyramide before starting mavacamten, resulted in worsening of heart failure symptoms in the first two cases. The second approach, involving tapering disopyramide when starting mavacamten, was successfully implemented in the last five cases, with no adverse effects or worsening of systolic dysfunction. Our method of tapering disopyramide when starting mavacamten using a stepwise approach is feasible and safe. Our report fulfills an unmet need by serving as a guide for other clinicians who seek to transition their patients from disopyramide to mavacamten.


Snapshots of a Y-family DNA polymerase in replication: substrate-induced conformational transitions and implications for fidelity of Dpo4.
Y-family DNA polymerases catalyze translesion DNA synthesis over damaged DNA. Each Y-family polymerase has a polymerase core consisting of a palm, finger and thumb domain in addition to a fourth domain known as a little finger domain. It is unclear how each domain moves during nucleotide incorporation and what type of conformational changes corresponds to the rate-limiting step previously reported in kinetic studies. Here, we present three crystal structures of the prototype Y-family polymerase: apo-Dpo4 at 1.9 A resolution, Dpo4-DNA binary complex and Dpo4-DNA-dTMP ternary complex at 2.2 A resolution. Dpo4 undergoes dramatic conformational changes from the apo to the binary structures with a 131 degrees rotation of the little finger domain relative to the polymerase core upon DNA binding. This DNA-induced conformational change is verified in solution by our tryptophan fluorescence studies. In contrast, the polymerase core retains the same conformation in all three conformationally distinct states. Particularly, the finger domain which is responsible for checking base pairing between the template base and an incoming nucleotide retains a rigid conformation. The inflexibility of the polymerase core likely contributes to the low fidelity of Dpo4, in addition to its loose and solvent-accessible active site. Interestingly, while the binary and ternary complexes of Dpo4 retain an identical global conformation, the aromatic side chains of two conserved tyrosines at the nucleotide-binding site change orientations between the binary and ternary structures. Such local conformational changes may correspond to the rate-limiting step in the mechanism of nucleotide incorporation. Together, the global and local conformational transitions observed in our study provide a structural basis for the distinct kinetic steps of a catalytic cycle of DNA polymerization performed by a Y-family polymerase.


Single nucleotide polymorphism C677T in the methylenetetrahydrofolate reductase gene might be a genetic risk factor for infertility for Chinese men with azoospermia or severe oligozoospermia.
To analyze the distribution of the single nucleotide polymorphism (SNP) C677T in the methylenetetrahydrofolate reductase (MTHFR) gene in 355 infertile Chinese patients with idiopathic azoospermia or severe oligozoospermia and 252 fertile Chinese men as controls to explore the possible association of the SNP and male infertility. Using the polymerase chain reaction (PCR)-restriction fragment length polymorphism technique, the allele and genotype distribution of SNP C677T in the MTHFR gene were investigated in both patients and controls. The frequencies of allele T (40.9% vs 30.4%, P = 0.002, odds ration [OR] = 1.58, 95% confidence interval [CI]: 1.24-2.02) and mutant homozygote (TT) (18.3% vs. 11.5%, P=0.023, OR=1.72, 95% CI: 1.07-2.76) as well as carrier with allele (TT + CT) (63.4% vs. 49.2%, P = 0.0005, OR = 1.79, 95% CI: 1.29-2.48) in infertile patients were significantly higher than those in controls. After patient stratification, the significant differences in distribution of the SNP between each patient subgroup and control group still remained. Our findings indicate that there is an association of SNP C677T in the MTHFR gene with male infertility, suggesting that this polymorphism might be a genetic risk factor for male infertility in Chinese men.


Polymer-stabilized liquid crystal microlens array with large dynamic range and fast response time.
We report a polymer-stabilized liquid crystal (LC) microlens array with a large dynamic range and fast response time. The top substrate has a planar indium-tin oxide (ITO) electrode, while the bottom substrate has two patterned ITO electrodes for generating a fringing field and uniform longitudinal field. The fringing field is utilized to create the desired gradient refractive index profile in the LC/monomer layer, which is later stabilized by UV curing to form polymer networks. To tune the focal length, we apply a longitudinal field to change the lens shape. This microlens array offers several attractive features, such as large dynamic range, fast response time, and good mechanical stability.


Pattern analysis of electromyographic linear envelopes exhibited by subjects with uninjured and injured knees during free and fast speed walking.
We wished to determine whether anterior cruciate ligament (ACL) injury caused changes in patterns of activity of individual or groups of muscles that control the knee joint. The electromyographic (EMG) patterns of six muscles in 26 individuals with uninjured knees and 20 individuals with ruptured ACL were studied during free and fast speed walking. A previously developed clustering technique was used for analysis. This technique involves making the Fourier transform of the average linear envelope (LE) of each muscle for each subject and using the amplitude and phase angles of the lower frequency harmonics as features to describe a pattern. These features are then grouped to subdivide the population of EMG patterns into different types. The results of analyses on single muscles showed that there exists a typical or "normal" pattern for each muscle which most uninjured and some injured subjects exhibit as well as several atypical patterns which mostly injured subjects exhibit, and that the atypical patterns are much more evident at fast walking speed. The characteristics of atypical patterns with respect to normal include time shifts in the peak of major phases of activity, the absence of a second phase of activity, and the existence of additional phases of activity. Synergy analysis showed that if one muscle has an atypical pattern, then several do; i.e., ACL injury induces major changes in the control strategy of the knee. The implications are that for rehabilitation programs one must focus on the training and strengthening of more than one muscle, and that for reconstructive procedures the changes in mechanics of the joint can possibly induce a significant change in its control strategy.


Point-of-care ultrasonography for diagnosing thoracoabdominal injuries in patients with blunt trauma.
Point-of-care sonography (POCS) has emerged as the screening modality of choice for suspected body trauma in many emergency departments worldwide. Its best known application is FAST (focused abdominal sonography for trauma). The technology is almost ubiquitously available, can be performed during resuscitation, and does not expose patients or staff to radiation. While many authors have stressed the high specificity of POCS, its sensitivity varied markedly across studies. This review aimed to compile the current best evidence about the diagnostic accuracy of POCS imaging protocols in the setting of blunt thoracoabdominal trauma. To determine the diagnostic accuracy of POCS for detecting and excluding free fluid, organ injuries, vascular lesions, and other injuries (e.g. pneumothorax) compared to a diagnostic reference standard (i.e. computed tomography (CT), magnetic resonance imaging (MRI), thoracoscopy or thoracotomy, laparoscopy or laparotomy, autopsy, or any combination of these) in patients with blunt trauma. We searched Ovid MEDLINE (1946 to July 2017) and Ovid Embase (1974 to July 2017), as well as PubMed (1947 to July 2017), employing a prospectively defined literature and data retrieval strategy. We also screened the Cochrane Library, Google Scholar, and BIOSIS for potentially relevant citations, and scanned the reference lists of full-text papers for articles missed by the electronic search. We performed a top-up search on 6 December 2018, and identified eight new studies which may be incorporated into the first update of this review. We assessed studies for eligibility using predefined inclusion and exclusion criteria. We included either prospective or retrospective diagnostic cohort studies that enrolled patients of any age and gender who sustained any type of blunt injury in a civilian scenario. Eligible studies had to provide sufficient information to construct a 2 x 2 table of diagnostic accuracy to allow for calculating sensitivity, specificity, and other indices of diagnostic test accuracy. Two review authors independently screened titles, abstracts, and full texts of reports using a prespecified data extraction form. Methodological quality of individual studies was rated by the QUADAS-2 instrument (the revised and updated version of the original Quality Assessment of Diagnostic Accuracy Studies list of items). We calculated sensitivity and specificity with 95% confidence intervals (CI), tabulated the pairs of sensitivity and specificity with CI, and depicted these estimates by coupled forest plots using Review Manager 5 (RevMan 5). For pooling summary estimates of sensitivity and specificity, and investigating heterogeneity across studies, we fitted a bivariate model using Stata 14.0. We included 34 studies with 8635 participants in this review. Summary estimates of sensitivity and specificity were 0.74 (95% CI 0.65 to 0.81) and 0.96 (95% CI 0.94 to 0.98). Pooled positive and negative likelihood ratios were estimated at 18.5 (95% CI 10.8 to 40.5) and 0.27 (95% CI 0.19 to 0.37), respectively. There was substantial heterogeneity across studies, and the reported accuracy of POCS strongly depended on the population and affected body area. In children, pooled sensitivity of POCS was 0.63 (95% CI 0.46 to 0.77), as compared to 0.78 (95% CI 0.69 to 0.84) in an adult or mixed population. Associated specificity in children was 0.91 (95% CI 0.81 to 0.96) and in an adult or mixed population 0.97 (95% CI 0.96 to 0.99). For abdominal trauma, POCS had a sensitivity of 0.68 (95% CI 0.59 to 0.75) and a specificity of 0.95 (95% CI 0.92 to 0.97). For chest injuries, sensitivity and specificity were calculated at 0.96 (95% CI 0.88 to 0.99) and 0.99 (95% CI 0.97 to 1.00). If we consider the results of all 34 included studies in a virtual population of 1000 patients, based on the observed median prevalence (pretest probability) of thoracoabdominal trauma of 28%, POCS would miss 73 patients with injuries and falsely suggest the presence of injuries in another 29 patients. Furthermore, in a virtual population of 1000 children, based on the observed median prevalence (pretest probability) of thoracoabdominal trauma of 31%, POCS would miss 118 children with injuries and falsely suggest the presence of injuries in another 62 children. In patients with suspected blunt thoracoabdominal trauma, positive POCS findings are helpful for guiding treatment decisions. However, with regard to abdominal trauma, a negative POCS exam does not rule out injuries and must be verified by a reference test such as CT. This is of particular importance in paediatric trauma, where the sensitivity of POCS is poor. Based on a small number of studies in a mixed population, POCS may have a higher sensitivity in chest injuries. This warrants larger, confirmatory trials to affirm the accuracy of POCS for diagnosing thoracic trauma.


Outcomes on quality of life, weight loss, and comorbidities after Roux-en-Y gastric bypass.
Bariatric surgery has become the most effective method for producing weight loss in obese patients. The evaluation of improvement of comorbidities and changes in the quality of life are important outcome factors; however, it is necessary to investigate whether they persist over the long term. A cross-sectional study was conducted on 143 obese patients from our institution from February 2007 to February 2008. These patients were divided into five independent groups, one being a control group, plus four other groups with 1, 2, 3, 4 or more years following surgical Roux-en-Y gastric bypass with a silicon ring banded. quality of life forms and anthropometric measurements were performed and its scores correlated with social factors, weight loss success, and status of obesity-related conditions. For the group that was 1 year postoperative, a significant percentage of excess body weight loss (EBWL%) of 81.7% was observed. The groups with 2, 3, 4 or more years of post-surgical follow-up showed a EBWL decline, but without significant difference. The main comorbidity percentages in all patients who had the surgery was as follows: 69.7% for hypertension; 88.2% for diabetes mellitus; and 27.5% for arthropathy. There was a significant decrease in the rate for diabetes resolution (P = 0.035) observed by evolutionary assessment of the comorbidity resolution. The results obtained by BAROS were good, very good, or excellent in more than 96% of patients in all evaluations that were performed. The use of the Moorehead-Ardelt Questionnaire (M/A) demonstrated improvement in the quality of life. Moreover, the quality of life, when evaluated through SF-36, also showed improvement in all related areas after 1 year; however, after 4 years, improvement remained elevated only in the areas of general state of health and functional capacity. The Roux-en-Y gastric bypass procedure was able to achieve EBWL of 81.7% after 1 year following surgery, remaining steady with little decline after this period. Important resolution of comorbidities, such as hypertension and diabetes, was also seen. Immediate surgical outcomes assessed by SF-36 and M/A in the area of quality of life were satisfactory, but the general state of health and functional capacity areas were sustained satisfactory at a later time only.


A novel putative interactor for the low density lipoprotein receptor cytoplasmic domain.
Familial hypercholesterolemia (FH) is a genetic disease mainly caused by mutations in the low density lipoprotein receptor (LDL-R) gene. However, FH-like phenotypes may also arise from mutations occurring in other genes, the products of which normally interact with the LDL receptor. Although several FH-associated proteins have been discovered, many FH-like phenotypes cannot be linked to mutations in already characterized genes, suggesting the existence of other genes still to be identified, the mutations of which may be directly linked to the FH disorder. In order to identify new putative LDLr interactors possibly involved in its internalization and/or sorting, the cytoplasmic tail of the receptor was used as 'bait' in a two-hybrid assay. We identified an 85-amino acid protein able to bind the LDLr intracellular domain through the last 14 C-terminal amino acids. The novel protein is probably derived from the translation of an alternative open reading frame of the human MT2A gene.


Short-term Changes on Follow-up Chest X-rays of Familial Cluster of COVID-19 Cases.
In this study, we report a familial cluster of cases which included five patients and two close contacts who were confirmed to have coronavirus disease 2019 (COVID-19). These participants had received real-time reverse transcription-polymerase chain reaction (RT-PCR) and chest X-rays (CXRs) before diagnosis. The follow-up CXRs of three patients in the family showed significant progression, with COVID-19 pneumonia, clinically worsening in a short period of time. Therefore, the results of follow-up CXRs in the short-term may be an adjunctive diagnostic method for COVID-19 disease diagnosis and its progression. Key Words: Chest X-ray, COVID-19, RT-PCR, Familial clustering.


Prevalence of enteropathogens in suckling and weaned piglets with diarrhoea in southern Germany.
Faecal samples from suckling (n = 205) and weaned piglets (n = 82) with diarrhoea from 24 farms in Southern Germany were examined for shedding of important metazoic parasitic, viral and bacterial pathogens using culture, microscopic and electronmicroscopic methods. Escherichia coli isolates were tested further for the enterotoxin genes est-Ia and elt-I by colony blot hybridization. Isospora suis was diagnosed in 26.9% and Cryptosporidium parvum in 1.4% of the piglets investigated. The proportion of coronavirus-positive animals was 13.4% and 4% were positive for rotavirus. It was found that 17.6% of the animals were infected with enterotoxigenic E. coli (ETEC; 10.1% ETEC-ST-Ia and 8.6% ETEC-LT-I, respectively). The occurrence of the pathogens was significantly associated with the age of the animals examined (P < 0.001). Isospora suis was predominantly isolated from suckling piglets (in the second and third week of life), while in weaned piglets (fourth week of life) rotavirus and ETEC were most prevalent. On 22 of the 24 piglet production farms examined at least one of the investigated pathogens was detected. Coronavirus was diagnosed in 66.7%, I. suis in 62.5%, rotavirus in 20.8% and C. parvum in 8.3% of the farms. These results underline the fact that despite the hygienic, technical and immune preventive efforts during the last years, enteropathogens are still common in German piglet production units.


Apollo 12 seismic signal: indication of a deep layer of powder.
The seismic signal caused by the Apollo 12 lunar module is interpreted in terms of propagation between source and receiver through a layer of powder in which sound velocity increases with depth. This increase, which is due to compaction, extends over several kilometers and leads to a concentration of seismic waves toward the surface. Computer simulations with the use of ray acoustics and on the assumption of a randomly undulating lunar surface approximate well the observed signal. Seismic amplitudes are greatly enhanced in such a medium compared to solid rock, so that the observed signal requires less power to be transmitted than previously estimated.


Single-cell topological RNA-seq analysis reveals insights into cellular differentiation and development.
Transcriptional programs control cellular lineage commitment and differentiation during development. Understanding of cell fate has been advanced by studying single-cell RNA-sequencing (RNA-seq) but is limited by the assumptions of current analytic methods regarding the structure of data. We present single-cell topological data analysis (scTDA), an algorithm for topology-based computational analyses to study temporal, unbiased transcriptional regulation. Unlike other methods, scTDA is a nonlinear, model-independent, unsupervised statistical framework that can characterize transient cellular states. We applied scTDA to the analysis of murine embryonic stem cell (mESC) differentiation in vitro in response to inducers of motor neuron differentiation. scTDA resolved asynchrony and continuity in cellular identity over time and identified four transient states (pluripotent, precursor, progenitor, and fully differentiated cells) based on changes in stage-dependent combinations of transcription factors, RNA-binding proteins, and long noncoding RNAs (lncRNAs). scTDA can be applied to study asynchronous cellular responses to either developmental cues or environmental perturbations.


Male adolescent exposure to endocrine-disrupting pesticides: vinclozolin exposure in peripubertal rabbits.
Adolescence is a time of dramatic neuroendocrine changes that are required for sexual maturation. Hormonal mimicking or inhibiting chemicals can cause significant impairment during this critical period. Vinclozolin (Vin) has been shown to be an anti-androgen affecting male offspring in rats in utero, and its mechanism of action may be mediated by inhibition of androgenic receptor action. The majority of teenagers working on farms are male, and therefore a systemic fungicide, vinclozolin, was selected for study. The rabbit has proved to be an excellent species for modelling reproductive toxicant effects in the male and was selected as the test species. The peripubertal phase for the rabbit was determined to be between the 3rd and 4th months. A 2-month dosing period was therefore initiated at 3 months of age and carried through to the 4th month. Vin was administered by dermal application (100 mg kg(-1) in 100 microl of dimethylsulphoxide) daily. Body weights were determined weekly. The rabbits were then held until fully mature (6 months of age). Semen was collected and evaluated from sexually mature males on a weekly schedule for 5 weeks to maximize sperm output. An automated solid phase extraction procedure for monitoring exposures through isolation and quantification of Vin and its metabolic products was developed. Increased plasma levels of Vin and M2 were found throughout the experimental period. The exposed rabbits had a smaller weight gain during pubertal growth (approaching significance; P=0.059). At maturity, the accessory sex glands of the exposed animals weighed less than those of the controls (P=0.016). Surprisingly, the pooled sperm count of the exposed animals was significantly higher (P=0.017) than that of the unexposed animals. The anti-androgenic effects of Vin may have blocked the negative feedback mechanism of testosterone on the hypothalamus or pituitary gland, allowing for an increase in gonadotrophin release, and consequently increasing sperm production at puberty.


Monoamine metabolites in cerebrospinal fluid in multiple sclerosis.
The concentrations of homovanillic acid (HVA), 5-hydroxyindolylacetic acid (5-HIAA), and 4-hydroxy, 3-methoxyphenylethylene glycol (MHPG) were estimated in the lumbar cerebrospinal fluid (CSF) of control subjects and in some patients who probably, and others who definitely, suffered from multiple sclerosis (MS). In the control group, the concentration of HVA was lower in people who underwent lumbar puncture having fasted and been recumbent for 12 hours before the procedure than in those from whom CSF was obtained under non-standardised conditions. These studies demonstrate that a standardised procedure for lumbar puncture is required in order to obtain meaningful results. In patients suffering from MS the CSF 5-HIAA concentrations were significantly lower than in comparable controls but the HVA concentrations did not differ. There was no relationship between metabolite concentrations, site of lesion, the duration of the disease, gamma-globulin levels nor the occurrence of relapse within the previous month.


Linoleic and α-linolenic acid as precursor and inhibitor for the synthesis of long-chain polyunsaturated fatty acids in liver and brain of growing pigs.
Studies suggested that in human adults, linoleic acid (LA) inhibits the biosynthesis of n-3 long-chain polyunsaturated fatty acids (LC-PUFA), but their effects in growing subjects are largely unknown. We used growing pigs as a model to investigate whether high LA intake affects the conversion of n-3 LC-PUFA by determining fatty acid composition and mRNA levels of Δ5- and Δ6 desaturase and elongase 2 and -5 in liver and brain. In a 2 × 2 factorial arrangement, 32 gilts from eight litters were assigned to one of the four dietary treatments, varying in LA and α-linolenic acid (ALA) intakes. Low ALA and LA intakes were 0.15 and 1.31, and high ALA and LA intakes were 1.48 and 2.65 g/kg BW0.75 per day, respectively. LA intake increased arachidonic acid (ARA) in liver. ALA intake increased eicosapentaenoic acid (EPA) concentrations, but decreased docosahexaenoic acid (DHA) (all P < 0.01) in liver. Competition between the n-3 and n-6 LC-PUFA biosynthetic pathways was evidenced by reductions of ARA (>40%) at high ALA intakes. Concentration of EPA (>35%) and DHA (>20%) was decreased by high LA intake (all P < 0.001). Liver mRNA levels of Δ5- and Δ6 desaturase were increased by LA, and that of elongase 2 by both ALA and LA intakes. In contrast, brain DHA was virtually unaffected by dietary LA and ALA. Generally, dietary LA inhibited the biosynthesis of n-3 LC-PUFA in liver. ALA strongly affects the conversion of both hepatic n-3 and n-6 LC-PUFA. DHA levels in brain were irresponsive to these diets. Apart from Δ6 desaturase, elongase 2 may be a rate-limiting enzyme in the formation of DHA.


Cost-effectiveness of physiologic pacing: results of the Canadian Health Economic Assessment of Physiologic Pacing.
The purpose of this study was to determine the cost-effectiveness of physiologic pacemakers. The Canadian Trial of Physiologic Pacing (CTOPP) was a large randomized trial that evaluated the efficacy of physiologic pacing compared with ventricular pacing. CTOPP also included a prospective cost-effectiveness substudy. Resource usage and costs were collected from a subset of 472 patients (of 1,094) who received a physiologic pacemaker and 586 (of 1,474) who received a ventricular pacemaker. Costs included initial pacemaker implantation and all health care follow-up costs over a follow-up of 5.2 years. Costs are reported in 2004 Canadian dollars (1 Canadian dollar = 0.76 US dollars), with adjustments for censoring. Incremental cost-effectiveness was estimated as the ratio of the difference (treatment-control) in mean cost to the difference in life expectancy (mean survival), with costs and effects discounted at 3% per year. Over a mean follow-up of 3.1 years, physiologic pacing was associated with a gain of 0.01 life-years. This benefit increases to 0.25 life-years in the subgroup of patients with an intrinsic (unpaced) heart rate < or =60 bpm. Physiologic pacing was more expensive than ventricular (16,833 Canadian dollars vs 13,857 US dollars), largely because of the increased cost of dual-chamber devices. Among all substudy patients, the incremental cost-effectiveness of physiologic pacing is 297,600 Canadian dollars per life-year gained; however, this value falls to 16,343 Canadian dollars in patients with an intrinsic heart rate >60. In the short term, a strategy of routine implantation of physiologic pacemakers is not cost-effective by currently accepted standards. The selective use of these devices in patients likely to be pacemaker dependent appears to be cost-effective. Further studies with longer follow-up and which consider the benefit of reducing nonfatal cardiac events would be valuable.


Structural basis for dolichylphosphate mannose biosynthesis.
Protein glycosylation is a critical protein modification. In biogenic membranes of eukaryotes and archaea, these reactions require activated mannose in the form of the lipid conjugate dolichylphosphate mannose (Dol-P-Man). The membrane protein dolichylphosphate mannose synthase (DPMS) catalyzes the reaction whereby mannose is transferred from GDP-mannose to the dolichol carrier Dol-P, to yield Dol-P-Man. Failure to produce or utilize Dol-P-Man compromises organism viability, and in humans, several mutations in the human dpm1 gene lead to congenital disorders of glycosylation (CDG). Here, we report three high-resolution crystal structures of archaeal DPMS from Pyrococcus furiosus, in complex with nucleotide, donor, and glycolipid product. The structures offer snapshots along the catalytic cycle, and reveal how lipid binding couples to movements of interface helices, metal binding, and acceptor loop dynamics to control critical events leading to Dol-P-Man synthesis. The structures also rationalize the loss of dolichylphosphate mannose synthase function in dpm1-associated CDG.The generation of glycolipid dolichylphosphate mannose (Dol-P-Man) is a critical step for protein glycosylation and GPI anchor synthesis. Here the authors report the structure of dolichylphosphate mannose synthase in complex with bound nucleotide and donor to provide insight into the mechanism of Dol-P-Man synthesis.


A preliminary checklist of the ants (Hymenoptera, Formicidae) of Andorra.
Within the last decade, checklists of the ant fauna of several European countries have been published or updated. Nevertheless, no ant checklists have hitherto been published for the principality of Andorra, a small landlocked country located in the eastern part of the Pyrenees. This work presents a critical list of the ant species of Andorra based on a review of the literature and on the biological material we collected during several field campaigns conducted in Andorra since the year 2005. Seventy-five species belonging to 21 genera of Formicidae were recorded. Nine species were recorded for the first time in Andorra: Aphaenogaster gibbosa (Latreille, 1798), Camponotus lateralis (Olivier, 1792), Camponotus piceus (Leach, 1825), Formica exsecta Nylander, 1846, Lasius piliferus Seifert, 1992, Tapinoma madeirense Forel, 1895, Temnothorax lichtensteini (Bondroit, 1918), Temnothorax niger (Forel, 1894), Temnothorax nigriceps (Mayr, 1855). The most speciose genera were Formica Linnaeus, 1758 and Temnothorax Forel, 1890 with 14 and 12 species, respectively. The ant fauna of Andorra is mostly dominated by Central European species (some are typical cold climate specialists); however species belonging to the Mediterranean ant fauna were also found. This can be explained by the particular geographic situation of Andorra which is characterized by a high mountain Mediterranean climate.


Haemagglutinin of influenza A virus is a target for the antiviral effect of Norakin.
The anticholinergic anti-parkinsonism drug Norakin is an inhibitor of influenza virus multiplication. By crossing a Norakin-resistant variant of fowl plague virus (FPV) strain Weybridge with the sensitive FPV/Rostock/34 wild-type virus, Norakin-resistant recombinants were obtained. Analyses of the gene composition showed that all Norakin-resistant recombinants had inherited their haemagglutinin gene from the Norakin-resistant parent strain. The majority of the recombinants had received all the other gene segments from the sensitive parent strain. Norakin was shown to inhibit red blood cell lysis induced either by purified virions or by the haemagglutinin of a sensitive FPV strain at low pH, but failed to affect the Norakin-resistant FPV variant. No aggregation of autoliposomes containing the haemagglutinin of a sensitive FPV strain or digestion of the HA1 subunit of haemagglutinin by trypsin occurred in the presence of Norakin at acid pH. The data suggest that the haemagglutinin of FPV is the target for the antiviral activity of Norakin, which acts by inhibiting the conformational change in the haemagglutinin at acid pH important for lysis.


Genomic signatures of adaptation to Sahelian and Soudanian climates in sorghum landraces of Senegal.
Uncovering the genomic basis of climate adaptation in traditional crop varieties can provide insight into plant evolution and facilitate breeding for climate resilience. In the African cereal sorghum (Sorghum bicolor L. [Moench]), the genomic basis of adaptation to the semiarid Sahelian zone versus the subhumid Soudanian zone is largely unknown. To address this issue, we characterized a large panel of 421 georeferenced sorghum landrace accessions from Senegal and adjacent locations at 213,916 single-nucleotide polymorphisms (SNPs) using genotyping-by-sequencing. Seven subpopulations distributed along the north-south precipitation gradient were identified. Redundancy analysis found that climate variables explained up to 8% of SNP variation, with climate collinear with space explaining most of this variation (6%). Genome scans of nucleotide diversity suggest positive selection on chromosome 2, 4, 5, 7, and 10 in durra sorghums, with successive adaptation during diffusion along the Sahel. Putative selective sweeps were identified, several of which colocalize with stay-green drought tolerance (Stg) loci, and a priori candidate genes for photoperiodic flowering and inflorescence morphology. Genome-wide association studies of photoperiod sensitivity and panicle compactness identified 35 and 13 associations that colocalize with a priori candidate genes, respectively. Climate-associated SNPs colocalize with Stg3a, Stg1, Stg2, and Ma6 and have allelic distribution consistent with adaptation across Sahelian and Soudanian zones. Taken together, the findings suggest an oligogenic basis of adaptation to Sahelian versus Soudanian climates, underpinned by variation in conserved floral regulatory pathways and other systems that are less understood in cereals.


[Evaluation on Malaria Hotspots in Yingjiang County of the China-Myanmar Border Area in 2015].
To understand the control status of malaria at hotspots in Yingjiang County and provide measures for malaria elimination in the China-Myanmar border areas of Yunnan Province. A survey was made in 4 villages with indigenous malaria cases or imported cases in Nabang and Tongbiguan of Yingjiang County in Yunnan Province in June and July 2015. Peripheral blood samples were collected from the neighboring residents around patients and examined by malaria rapid diagnostic test (RDT). The results were further verified by nested-PCR. Mosquitoes were collected by overnight trapping with light traps in Jingpo, Lilisu, Jiema, and Mengxiangyang villages or by human landing catches in Jingpo and Lisu villages. Nested-PCR was performed on part of the captured Anopheles minimus to detect the malaria parasites. One hundred and ninety-four filter blood samples were collected from 11 malaria cases in two sites. All were detected to be negative for Plasmodium by RDT. In contrast, two samples originated from Jingpo and Lisu villages with indigenous cases were detected to be positive for Plasmodium vivax by nested-PCR. A total of 2 374 mosquitoes were captured, belonging to 22 species of 4 genera: Anopheles, Culex, Aedes and Armigeres. The mosquitoes were predominated by genus Culex, followed by genus Anopheles(11.33%, 269/2 374) which was dominated by A. minimus(49.07%, 132/269), then was A. sinensis(4.09%, 11/269), A. maculatus(2.23%, 6/269), A. jeyporiensis(0.74%, 2/269)and so on. The mean indoor man-biting rate of mosquitoes was 5.78 and 3.20 per person per hour for Jingpo and Lisu villages, and the mean outdoor man-biting rate of mosquitoes was 2.30 per person per hour for Lisu Village. The 14 A. minimus were negative for sporozoite infection as detected by nested-PCR. Nested-PCR showed that there are asymptomatic Plasmodium carriers in Yingjiang's border area of Yunnan Province. Four major mosquito species as malaria vectors exist with A. minimus as the dominant one.


Hepatitis C virus-like particle budding: role of the core protein and importance of its Asp111.
In the absence of a hepatitis C virus (HCV) culture system, the use of a Semliki Forest virus replicon expressing genes encoding HCV structural proteins that assemble into HCV-like particles provides an opportunity to study HCV morphogenesis. Using this system, we showed that the HCV core protein constitutes the budding apparatus of the virus and that its targeting to the endoplasmic reticulum by means of the signal sequence of E1 protein is essential for budding. In addition, the aspartic acid at position 111 in the HCV core protein sequence was found to be crucial for virus assembly, demonstrating the usefulness of this system for mapping amino acids critical to HCV morphogenesis.


Globality and constructions of world health.
Explorations of the social construction of health and illness reveal that popular and professional discourses on health and disease implicitly contain underlying images of how societies can or should be structured. Globality, which is a notion that refers to the consciousness of the world as a single place, suggests that these images of world structure are now salient. This article describes four current discourses of "work health" and discusses them in terms of their underlying ideal images of world order. The four images of the world are defined in terms of four elemental points of reference: individuals, societies, the system of societies, and humankind. These ideal images have either a gemeinschaft (community) or gesellschaft (society) orientation. An anthropology of globality can refine and extend our understandings of discourses of world health. Sensitivity to these discourses and their world-oriented ideological roots should help to demystify the notion of world health.


The Impact of Body Mass Index on Abdominal Wall Reconstruction Outcomes: A Comparative Study.
Obesity and higher body mass index may be associated with higher rates of wound healing complications and hernia recurrence rates following complex abdominal wall reconstruction. The authors hypothesized that higher body mass indexes result in higher rates of postoperative wound healing complications but similar rates of hernia recurrence in abdominal wall reconstruction patients. The authors included 511 consecutive patients who underwent abdominal wall reconstruction with underlay mesh. Patients were divided into three groups on the basis of preoperative body mass index: less than 30 kg/m (nonobese), 30 to 34.9 kg/m (class I obesity), and 35 kg/m or greater (class II/III obesity). The authors compared postoperative outcomes among these groups. Class I and class II/III obesity patients had higher surgical-site occurrence rates than nonobese patients (26.4 percent versus 14.9 percent, p = 0.006; and 36.8 percent versus 14.9 percent, p < 0.001, respectively) and higher overall complication rates (37.9 percent versus 24.7 percent, p = 0.007; and 43.4 percent versus 24.7 percent, p < 0.001, respectively). Similarly, obese patients had significantly higher skin dehiscence (19.3 percent versus 7.2 percent, p < 0.001; and 26.5 percent versus 7.2 percent, p < 0.001, respectively) and fat necrosis rates (10.0 percent versus 2.1 percent, p = 0.001; and 11.8 percent versus 2.1 percent, p < 0.001, respectively) than nonobese patients. Obesity class II/III patients had higher infection and seroma rates than nonobese patients (9.6 percent versus 4.3 percent, p = 0.041; and 8.1 percent versus 2.1 percent, p = 0.006, respectively). However, class I and class II/III obesity patients experienced hernia recurrence rates (11.4 percent versus 7.7 percent, p = 0.204; and 10.3 percent versus 7.7 percent, p = 0.381, respectively) and freedom from hernia recurrence (overall log-rank, p = 0.41) similar to those of nonobese patients. Hernia recurrence rates do not appear to be affected by obesity on long-term follow-up in abdominal wall reconstruction. Risk, II.


Relationship between Sarcopenia and Mortality in Elderly Inpatients.
Sarcopenia, a geriatric syndrome, is an indicator of poor prognosis in elderly inpatients. In this study, we aimed to determine the effect of sarcopenia on mortality in elderly patients. Mobile/immobile geriatric inpatients, treated in the internal medicine ward between February and November 2018, were included in the study between Days 2 and 7 of hospitalization. The patients' fat-free mass (FFM) was measured by bioimpedance. The FFM index (FFMI) (kg/m2) was determined by dividing fat-free mass by body surface area (FFM/BSA). Sarcopenia was defined as a FFMI value at least two standard deviations below the gender-specific mean of normal young adults. The study included 200 geriatric inpatients; 96 (48.0%) were men, and the mean age was 74.49±6.32 years. Sarcopenia was detected in 28 (14%) of the patients. Diabetes mellitus was associated with a significantly lower sarcopenia prevalence (p=0.006). The risk of sarcopenia was 9.046 times higher in malnourished patients. The sarcopenia group had more deaths (p=0.012). Sarcopenia in geriatric inpatients increased the length of hospital stay and mortality. Our findings may guide future studies examining the relationship between sarcopenia and mortality among elderly inpatients in other hospitals.


Undifferentiated embryonal sarcoma of the liver in an adult patient: case report.
Undifferentiated embryonal sarcoma of the liver is a rare and aggressive tumor in adults, with an unfavorable prognosis. We present a 33-year-old female patient who was admitted with fatigue, weight loss and right upper abdominal pain. Magnetic resonance imaging of the liver revealed a bulky malignant mass with necrotic and cystic center, which nearly occupied the left lobe and invaded the middle-left hepatic vein and left portal vein. The patient was evaluated as inoperable, and in order to determine the histologic diagnosis, a Tru-cut biopsy was performed. Both histopathologic features and the immunocytochemical stainings revealed the diagnosis of hepatic embryonal sarcoma. Since the patient had no chance of surgery due to the advanced stage of the tumor and progressive hepatic failure, a combination chemotherapy was applied. Unfortunately, the patient did not respond to treatment at all and died in the second post-therapy week. Undifferentiated embryonal sarcoma of the liver is a highly chemo-sensitive tumor. Radical resection may be possible after combination chemotherapy in the childhood period, but since the disease is extremely rare in adults, an optimal treatment approach is still unknown.


Effects of bisphenol A and its analogs on reproductive health: A mini review.
Known endocrine disruptor bisphenol A (BPA) has been shown to be a reproductive toxicant in animal models. Its structural analogs: bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), and tetrabromobisphenol A (TBBPA) are increasingly being used in consumer products. However, these analogs may exert similar adverse effects on the reproductive system, and their toxicological data are still limited. This mini-review examined studies on both BPA and BPA analog exposure and reproductive toxicity. It outlines the current state of knowledge on human exposure, toxicokinetics, endocrine activities, and reproductive toxicities of BPA and its analogs. BPA analogs showed similar endocrine potencies when compared to BPA, and emerging data suggest they may pose threats as reproductive hazards in animal models. While evidence based on epidemiological studies is still weak, we have utilized current studies to highlight knowledge gaps and research needs for future risk assessments.


Preparation Method of Crack-free PVDF Microfiltration Membrane with Enhanced Antifouling Characteristics.
This study proposes a method to prepare a crack-free poly(vinylidene fluoride) (PVDF) microfiltration (MF) membrane with enhanced antifouling property. In the study, blending 4% poly(vinylidene fluoride)-graft-poly(sulfopropyl methacrylate) (PVDF-g-PSPMA) and 1.5% potassium perchlorate (KClO4) led to crack prevention during membrane preparation via nonsolvent induced phase separation (NIPS) when compared with blending with 4% PVDF-g-PSPMA only (without KClO4). The resulting crack-free membrane (A3) had both smooth surface structure and hydrophilicity in comparison with pristine PVDF membrane (A1). In addition, blending with PVDF-g-PSPMA and KClO4 also allowed the A3 membrane to exhibit uniform pore size distribution (PSD) and smooth surface structure, compared with PVDF membrane commercially available from company "M" in Germany. The aforementioned properties led to antifouling characteristics in the crack-free membrane (A3). According to flux performances, flux recovery and cumulative permeate volume (between 120 and 240 min) of crack-free membrane (A3) were 11.41 and 17.41% superior to those of commercial membrane, respectively.


[Radiology of gastrointestinal stromal tumors (GIST) and a case of Carney syndrome].
Gastrointestinal stromal tumors (GIST) represent an extremely rare group of tumors, which are mostly of smooth muscle origin like leiomyomas, leiomyosarcomas and leiomyoblastomas. With the introduction of immunohistochemical analysis an epithelioid and an autonomic nerve variant can be distinguished. The purpose of this review is to demonstrate the image morphological appearance of these rare tumors together with the pathology based upon a retrospective analysis of five of our own cases since 1997. There are no pathognomonic imaging findings for characterizing a gastrointestinal stromal tumor; however, it should be included in the differential diagnosis if one or multiple large, round or oval, well-delineated gastrointestinal tumors occur in combination with central necrosis. Carney's syndrome is characterized by the syndromal association of a gastrointestinal stromal tumor (originally: gastric leiomyosarcoma) with an extra-adrenal paraganglioma and a pulmonary chondroma. In this rare syndrome, the radiological approach is important to diagnose or rule out the--simultaneous or consecutive--appearance of at least two of the three tumor entities (GIST, extra-adrenal paraganglioma, pulmonary chondroma).


Robot-assisted mitral valve repair: a single institution review.
Mitral valve repair (MVR) is the definitive therapy for mitral myxomatous degeneration. Median sternotomy has been the traditional approach to repair until the advent of the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA). Minimally invasive surgical approaches for mitral repair have been slow to gain acceptance in cardiac surgery. We review the MVR results from our single-institution academic robotic program. From August 2004 through April 2008, patients who underwent a robotic-assisted (RA) MVR were identified. RA technique included a 4-cm right minithoracotomy, femoral cardiopulmonary bypass with transthoracic aortic occlusion, and RA-MVR. Repair types were combinations of quadrangular/triangular leaflet resection, sliding plasty, chordal transfer/replacement, and edge-to-edge approximation, with band annuloplasty in all cases. Postrepair echocardiography and morbidity follow-ups were completed in all patients. Our primary outcome was adequacy of repair, and secondary outcome was major complications. There were 43 patients (29 male and 14 female) who underwent RA-MVR for severe (4+) mitral regurgitation during the 4-year review. Average operative time was 272.26 minutes. Only one patient had mild postoperative mitral regurgitation, whereas 20 had trace and 22 had no regurgitation after repair. Mean ventilator time was 32.1 hours, and length of stay was 5.7 days. One third of the patients (33%) received postoperative-packed red blood cell transfusions (average: 2.4 units per patient). Twenty-eight percent of patients developed atrial fibrillation after repair. Most of the patients (95.3%) were discharged home. There were no 30-day mortalities. Based on our small single-institution experience, RA-MVR provides an effective treatment for severe mitral valve regurgitation. Although procedure durability is slowly being established, preliminary results are promising. Careful programmatic advances with an integrated team approach can facilitate acceptable postoperative outcomes and excellent MVR.


Exploration of Visible-Light Photocatalysis in Heterocycle Synthesis and Functionalization: Reaction Design and Beyond.
Visible-light photocatalysis has recently received increasing attention from chemists because of its wide application in organic synthesis and its significance for sustainable chemistry. This catalytic strategy enables the generation of various reactive species, frequently without stoichiometric activation reagents under mild reaction conditions. Manipulation of these reactive intermediates can result in numerous synthetically useful bond formations in a controllable manner. In this Account, we describe our recent advances in the rational design and strategic application of photocatalysis in the synthesis of various synthetically and biologically important heterocycles. Our main research efforts toward this goal can be classified into four categories: formal cycloaddition and cyclization reactions, radical-mediated olefin functionalization/cyclization cascades, photocatalytic generation and cyclization of N-centered radicals, and photocatalytic functionalization of heterocycles by visible-light-induced dual catalysis. Inspired by the wide application of tertiary amines as reductive additives in photoredox catalysis, we exploited a series of readily accessible or rationally designed tertiary amines with reactive sites in a range of photocatalytic formal cycloaddition and cyclization reactions, providing efficient access to diverse nitrogen heterocycles. Employing various photogenerated radical species, we further developed a series of radical-mediated olefin functionalization/cyclization cascade reactions to successfully assemble various five- and six-membered heterocycles. We have also achieved for the first time the direct catalytic conversion of recalcitrant N-H bonds into neutral N-centered radicals through a visible-light-photocatalytic oxidative deprotonation electron transfer. Using this generic strategy, we have devised several types of radical cyclizations of unsaturated hydrazones, leading to the construction of diversely functionalized pyrazoline and pyridazine derivatives in good yields and selectivity. Moreover, we have demonstrated that this photocatalysis can serve as a mild and highly selective tool for direct functionalization of heterocycles because of its powerful capability to controllably generate diverse reactive intermediates under mild reaction conditions. Guided by the fundamental principles of photocatalysis and the redox properties of the photocatalysts, we successfully developed an array of dual-catalyst systems by combining the photocatalysts with palladium, nickel, or amine, enabling efficient and selective coupling reactions. An intriguing phototandem catalytic system using a single photocatalyst was also identified for the development of cascade reactions. Notably, some of the newly developed methodologies have also been successfully utilized for late-stage modification of biologically active natural compounds and complex molecules and as key steps for formal synthesis of natural products. This Account presents a panoramic view and the logic of our recent contributions to the design, development, and application of photocatalytic systems and reactions that provide not only methods for the efficient synthesis of heterocycles but also useful insights into the exploration of new photochemical reactions.


Benefit-risk review of different drug classes used in chronic heart failure.
Heart failure (HF) is an important public health problem with an increasing prevalence across the globe. The mortality rates from this complex clinical problem have stabilized in the recent years with the use of pharmacotherapeutics which demonstrated survival benefits in patients with HF with reduced ejection fraction (HFrEF). We reviewed the seven classes of medications which constitute the guideline-directed medical therapy (GDMT) in chronic HF patients. We discussed clinical trials which support or contradict their use, potential adverse events, and available real-world data on utilization and safety. Loop diuretics form a major component of baseline therapy in HF patients to maintain euvolemia. As diastolic HF is more volume sensitive then systolic HF, diuretic use should be judiciously monitored to prevent states of volume depletion and associated complications. Neurohormonal modulation with pharmacotherapies are efficacious in reducing morbidity and mortality in the chronic HFrEF population. However, registry data showed that treatment intolerance and adverse events result in lower prescription rates of GDMT. Sacubitril/valsartan represents a major therapeutic advance in the treatment of HFrEF patients and can be safely used in addition to other GDMTs. Therapies to improve outcomes in diastolic HF patients are needed.


Antiallodynic effect of pregabalin in rat models of sympathetically maintained and sympathetic independent neuropathic pain.
Pregabalin binds to the voltage-dependent calcium channel alpha2delta subunit and modulates the release of neurotransmitters, resulting in analgesic effects on neuropathic pain. Neuropathic pain has both sympathetically maintained pain (SMP) and sympathetic independent pain (SIP) components. We studied the antiallodynic effects of pregabalin on tactile allodynia (TA) and cold allodynia (CA) in SMP-and SIP-dominant neuropathic pain models. Allodynia was induced by ligation of the L5 and L6 spinal nerves (SMP model) or by transection of the tibial and sural nerves (SIP model) in rats. For intrathecal drug administration, a PE-10 catheter was implanted through the atlantooccipital membrane to the lumbar enlargement. Pregabalin was administered either intraperitoneally (IP) or intrathecally (IT) and dosed up incrementally until an antiallodynic effect without sedation or motor impairment was apparent. TA was assessed using von Frey filaments, and CA was assessed using acetone drops. IP-administered pregabalin dose-dependently attenuated TA in both models and CA in the SMP model, but not CA in the SIP model. IT-administered pregabalin dose-dependently attenuated both TA and CA in both models. However, the dose response curve of IT-administered pregabalin in SMP was shifted to left from that of SIP and the ED50 of IT-administered pregabalin for CA in SMP was about 900 times less than that in SIP. These findings suggest that pregabalin exerts its antiallodynic effect mainly by acting at the spinal cord, and that IT-administered pregabalin has more potent antiallodynic effects in SMP. The alpha2delta subunit might be less involved in the CA in SIP.


Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions.
Procedures are described for the isolation of lipoproteins from human serum by precipitation with polyanions and divalent cations. A mixture of low and very low density lipoproteins can be prepared without ultracentrifugation by precipitation with heparin and either MnCl(2) alone or MgCl(2) plus sucrose. In both cases the precipitation is reversible, selective, and complete. The highly concentrated isolated lipoproteins are free of other plasma proteins as judged by immunological and electrophoretic methods. The low density and very low density lipoproteins can then be separated from each other by ultracentrifugation. The advantage of the method is that large amounts of lipoproteins can be prepared with only a single preparative ultracentrifugation. Polyanions other than heparin may also be used; when the precipitation of the low and very low density lipoproteins is achieved with dextran sulfate and MnCl(2), or sodium phosphotungstate and MgCl(2), the high density lipoproteins can subsequently be precipitated by increasing the concentrations of the reagents. These lipoproteins, containing small amounts of protein contaminants, are further purified by ultracentrifugation at d 1.22. With a single preparative ultracentrifugation, immunologically pure high density lipoproteins can be isolated from large volumes of serum.


An introduction to the Emergency Department Adult Clinical Escalation protocol: ED-ACE.
This study demonstrates how a participatory action research approach was used to address the challenge of the early and effective detection of the deteriorating patient in the ED setting. The approach enabled a systematic approach to patient monitoring and escalation of care to be developed to address the wide-ranging spectrum of undifferentiated presentations and the phases of ED care from triage to patient admission. This paper presents a longitudinal patient monitoring system, which aims to provide monitoring and escalation of care, where necessary, of adult patients from triage to admission to hospital in a manner that is feasible in the unique ED environment. An action research approach was taken to designing a longitudinal patient monitoring system appropriate for the ED. While the first draft protocol for post-triage monitoring and escalation was designed by a core research group, six clinical sites were included in iterative cycles of planning, action, reviewing and further planning. Reasons for refining the system at each site were collated and the protocol was adjusted accordingly before commencing the process at the next site. The ED Adult Clinical Escalation longitudinal patient monitoring system (ED-ACE) evolved through iterative cycles of design and testing to include: (1) a monitoring chart for adult patients; (2) a standardised approach to the monitoring and reassessment of patients after triage until they are assessed by a clinician; (3) the ISBAR (I=Identify, S=Situation, B=Background, A=Assessment, R=Recommendation) tool for interprofessional communication relating to clinical escalation; (4) a template for prescribing a patient-specific monitoring plan to be used by treating clinicians to guide patient monitoring from the time the patient is assessed until when they leave the ED and (5) a protocol for clinical escalation prompted by single physiological triggers and clinical concern. This tool offers a link in the 'Chain of Prevention' between the Manchester Triage System and ward-based early warning scores taking account of the importance of standardisation, while being sufficiently adaptable for the unique working environment and patient population in the ED.


[Monitoring of patients with breast cancer after multimodal treatment].
Breast cancer is a frequent neoplasm in Latin America. Its control implies surveillance for about 10 years after diagnosis. The possibilities of metastatic disease depend on stage at diagnosis and the treatment administered to the patient. It is important that all medical centers implement their own follow-up that fits its needs. Surveillance must include physical therapy, attention to psychosocial aspects as well as treatment for toxicity, secondary effects, recurrence and second primaries. The American Society of Clinical Oncology (ASCO) includes monthly self-examination, annual mammography, office visits every three months for the first three years, and then biannual visits for the next two years and then annually. Randomized studies and the Cochrane database have proved that intensive follow-up is of no value compared with periodic appointments and annual mammography. Existing evidence suggests that postoperative surveillance of breast cancer patients is extremely expensive, time consuming and of no benefit in terms of survival. Most of recurrences present out of context from follow up visits. Thus, efficacy of routine doctor visits is questionable and a prospective study is needed to outline the adequate strategy.


Fruit and vegetable intake and breast cancer prognosis: a meta-analysis of prospective cohort studies.
The effect of fruit and vegetable intake on breast cancer prognosis is controversial. Thus, a meta-analysis was carried out to explore their associations. A comprehensive search was conducted in PubMed, Web of Science, OVID, ProQuest and Chinese databases from inception to April 2016. The summary hazard ratios (HR) and 95 % CI were estimated using a random effects model if substantial heterogeneity existed and using a fixed effects model if not. Subgroup analyses and sensitivity analyses were also performed. In total, twelve studies comprising 41 185 participants were included in the meta-analysis. Comparing the highest with the lowest, the summary HR for all-cause mortality were 1·01 (95 % CI 0·72, 1·42) for fruits and vegetables combined, 0·96 (95 % CI 0·83, 1·12) for total vegetable intake, 0·99 (95 % CI 0·89, 1·11) for cruciferous vegetable intake and 0·88 (95 % CI 0·74, 1·05) for fruit intake; those for breast cancer-specific mortality were 1·05 (95 % CI 0·77, 1·43) for total vegetable intake and 0·94 (95 % CI 0·69, 1·26) for fruit intake; and those for breast cancer recurrence were 0·89 (95 % CI 0·53, 1·50) for total vegetable intake and 0·98 (95 % CI 0·76, 1·26) for cruciferous vegetable intake. This meta-analysis found no significant associations between fruit and vegetable intake and breast cancer prognosis.


High-throughput screening for daunorubicin-mediated drug resistance identifies mometasone furoate as a novel ABCB1-reversal agent.
The overexpression of P-glycoprotein, encoded by the ATP Binding Cassette B1 (ABCB1) gene, contributes to multidrug resistance (MDR) and is considered one of the major obstacles to successful cancer chemotherapy. The authors previously developed a T-lineage acute lymphoblastic leukemia (T-ALL) cell line that overexpresses ABCB1 and exhibits MDR to daunorubicin (DNR), prednisolone, and vincristine. Using this cell line and the fluorescent probe JC-1, they developed a flow cytometry-based, high-throughput screening (HTS) assay that quantifies ABCB1 efflux. They screened a library of 880 off-patent drugs for their ability to inhibit ABCB1 efflux and then measured the ability of 11 lead compounds to reverse in vitro DNR-mediated drug resistance and the toxic doses for each agent. Seven of the 11 drugs were able to reverse drug resistance at a concentration significantly below its toxic dose. Of the remaining 7, only 1 compound, mometasone furoate, has not been previously described as an ABCB1 antagonist to DNR-mediated drug resistance. On the basis of its high ABC modulator activity and relatively large in vitro therapeutic window, this drug warrants further investigation. In addition, the approach used in this study is useful for identifying off-patent drugs that may be repurposed for novel clinical indications.


Evaluation of a Nondepleted Plasma Multiprotein-Based Model for Discriminating Psychiatric Disorders Using Multiple Reaction Monitoring-Mass Spectrometry: Proof-of-Concept Study.
Psychiatric evaluation relies on subjective symptoms and behavioral observation, which sometimes leads to misdiagnosis. Despite previous efforts to utilize plasma proteins as objective markers, the depletion method is time-consuming. Therefore, this study aimed to enhance previous quantification methods and construct objective discriminative models for major psychiatric disorders using nondepleted plasma. Multiple reaction monitoring-mass spectrometry (MRM-MS) assays for quantifying 453 peptides in nondepleted plasma from 132 individuals [35 major depressive disorder (MDD), 47 bipolar disorder (BD), 23 schizophrenia (SCZ) patients, and 27 healthy controls (HC)] were developed. Pairwise discriminative models for MDD, BD, and SCZ, and a discriminative model between patients and HC were constructed by machine learning approaches. In addition, the proteins from nondepleted plasma-based discriminative models were compared with previously developed depleted plasma-based discriminative models. Discriminative models for MDD versus BD, BD versus SCZ, MDD versus SCZ, and patients versus HC were constructed with 11 to 13 proteins and showed reasonable performances (AUROC = 0.890-0.955). Most of the shared proteins between nondepleted and depleted plasma models had consistent directions of expression levels and were associated with neural signaling, inflammatory, and lipid metabolism pathways. These results suggest that multiprotein markers from nondepleted plasma have a potential role in psychiatric evaluation.


Metastatic bone disease: future directions.
Bone cancer is common and difficult to treat. Current bone-targeted therapies include radiation and bisphosphonates. Both treatments can provide pain relief, but neither has been shown to prolong survival. Because bisphosphonates are osteoclast-targeted therapies, they do not exhibit significant tumor-killing properties in humans. Often, patients with asymptomatic skeletal metastases are treated with observation. New treatments are needed for patients known to have bone metastases and those who are at high risk for having bone metastases develop. Enzyme prodrug gene therapy treatment strategies currently are being explored for their potential benefit in designing novel therapies for bone cancer.


Integrating the Divided Nasal Cannula Into Routine Polysomnography to Assess Nasal Cycle: Feasibility and Effect on Outcomes.
Patients suspected to have sleep-disordered breathing underwent an overnight polysomnography using a divided nasal cannula to gain additional information about the nasal cycle during sleep. This was a prospective, observational cohort study replacing the undivided nasal cannula with a divided nasal cannula during routine polysomnography (n = 28). Integration of the divided nasal cannula pressure transducer system into routine polysomnography was easy and affordable. Most patients (89%) demonstrated nasal cycle changes during the test. Nasal cycle changes tended to occur during body position changes (62%) and transitions from non-rapid eye movement sleep to rapid eye movement sleep (41%). The mean nasal cycle duration was 2.5 ± 2.1 hours. Other sleep study metrics did not reveal statistically significant findings in relation to the nasal cycle. Replacing an undivided nasal cannula with a divided nasal cannula is easy to implement, adding another physiologic measure to polysomnography. Although the divided nasal cannula did not significantly affect traditional polysomnographic metrics such as the apnea-hypopnea index or periodic limb movement index based on this small pilot study, we were able to replicate past nasal cycle findings that may be of interest to sleep clinicians and researchers. Given the ease with which the divided nasal cannula can be integrated, we encourage other sleep researchers to investigate the utility of using a divided nasal cannula during polysomnography.


New insights into the echinocandins and other fungal non-ribosomal peptides and peptaibiotics.
Non-ribosomal peptide synthetases (NRPSs) are a primary modality for fungal peptidic natural product assembly and are responsible for some of the best known, most useful, and most destructive fungal metabolites. Through genome sequencing and computer-assisted recognition of modular motifs of catalytic domains, one can now confidently identify most NRPS biosynthetic genes of a fungal strain. The biosynthetic gene clusters responsible for two of the most important classes of NRP fungal derived drugs, cyclosporine and the echinocandins, have been recently characterized by genomic sequencing and annotation. Complete biosynthetic gene clusters for the pneumocandins and echinocandins have been mapped at the genetic level and functionally characterized to some extent. Genomic sequencing of representative strains of most of the variants in the echinocandin family, including the wild-type of the three fungal strains employed for industrial-scale production of caspofungin, micafungin and anidulofungin, has enabled characterization of the basic architecture of the echinocandin NRPS pathways. A comparative analysis of how pathway genes cause variations in lipoinitiation, biosynthesis of the non-proteinogenic amino acids, amino acid substitutions, and hydroxylations and sulfonations of the core peptide and contribute to the molecular diversity of the family is presented. We also review new information on the natural functions of NRPs, the differences between fungal and bacterial NRPSs, and functional characterization of selected NRPS gene clusters. Continuing discovery of the new fungal nonribosomal peptides has contributed new structural diversity and potential insights into their biological functions among other natural peptides and peptaibiotics. We therefore provide an update on new peptides, depsipeptides and peptaibols discovered in the Fungi since 2009.


Evaluation of antioxidant status in children with acute bacterial meningitis and encephalitis.
Antioxidant status was investigated in children with acute bacterial meningitis and encephalitis to investigate the possible role of free radicals in children with meningitis and encephalitis. Our study included 16 children with acute bacterial meningitis, 13 with encephalitis, and 17 control subjects. Serum ceruloplasmin, uric acid, albumin, bilirubin superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) levels were studied in all subjects within 6 h of admission. There was a statistically significant difference between the groups for all parameters except for serum uric acid. All antioxidant activities except for albumin level were increased in the study groups. Albumin level was higher in the control group than those of meningitis and encephalitis groups. When the values of meningitis and encephalitis were compared, there was a statistically significant difference between the groups for serum SOD, GPx, ceruloplasmin, and albumin. In conclusion, our study showed that serum SOD, GPx, catalase, and ceruloplasmin were higher in children with acute bacterial meningitis and serum SOD, GPx, catalase, ceruloplasmin, and total bilirubin levels were increased in children with encephalitis. These findings suggest that antioxidant status was almost similar in both acute bacterial meningitis and encephalitis conditions in childhood.


The Emerging Role of Stem Cells in Regenerative Dentistry.
Progress of modern dentistry is accelerating at a spectacular speed in the scientific, technological and clinical areas. Practical examples are the advancement in the digital field, which has guaranteed an average level of prosthetic practices for all patients, as well as other scientific developments, including research on stem cell biology. Given their plasticity, defined as the ability to differentiate into specific cell lineages with a capacity of almost unlimited self-renewal and release of trophic/immunomodulatory factors, stem cells have gained significant scientific and commercial interest in the last 15 years. Stem cells that can be isolated from various tissues of the oral cavity have emerged as attractive sources for bone and dental regeneration, mainly due to their ease of accessibility. This review will present the current understanding of emerging conceptual and technological issues of the use of stem cells to treat bone and dental loss defects. In particular, we will focus on the clinical application of stem cells, either directly isolated from oral sources or in vitro reprogrammed from somatic cells (induced pluripotent stem cells). Research aimed at further unraveling stem cell plasticity will allow to identify optimal stem cell sources and characteristics, to develop novel regenerative tools in dentistry.


N-lobe versus C-lobe complexation of bismuth by human transferrin.
Interactions of recombinant N-lobe of human serum transferrin (hTF/2N) with Bi3+, a metal ion widely used in medicine, have been investigated by both UV and NMR spectroscopy. The bicarbonate-independent stability constant for Bi3+ binding (K*) to hTF/2N was determined to be log K* 18.9+/-0.2 in 5 mM bicarbonate/10 mM Hepes buffer at 310 K, pH7.4. The presence of Fe3+ in the C-lobe of intact hTF perturbed Bi3+ binding to the N-lobe, whereas binding of Bi3+ to the C-lobe was unaffected by the presence of Fe3+ in the N-lobe. Reactions of Bi3+ (as bismuth nitrilotriacetate or ranitidine bismuth citrate) with hTF/2N in solutions containing 10 mM bicarbonate induced specific changes to high-field 1H-NMR peaks. The 1H co-ordination shifts induced by Bi3+ were similar to those induced by Fe3+ and Ga3+, suggesting that Bi3+ binding causes similar structural changes to those induced by hTF/2N. 13C-NMR data showed that carbonate binds to hTF/2N concomitantly with Bi3+.


[Molecular bases of cellular senescence: Hayflick phenomenon 50 years later].
Normal human somatic cells have strictly limited proliferative capacity and reach a state of senescence when it becomes exhausted. It is believed that senescence is a response to extensive and irreparable DNA injury, localized in telomeric and/or non-telomeric regions of the genome. Main cause of this damage is oxidative stress, increasing due to deteriorated function of mitochondria. Senescent cells accumulate in tissues during aging, which is causatively linked with the development of various pathologies in elderly individuals, including cancer. This paper, prepared exactly 50 years after Leonard Hayflick's discovery of the relationship between cellular senescence and organismal aging is aimed at presenting the current knowledge about molecular determinants of senescence, with particular emphasis paid to the role of oxidative stress, effectors of senescence at the level of cell cycle, markers of this phenomenon, and the effect of senescent cells on the development of certain age-related diseases.


8-Hydroxydaidzein Downregulates JAK/STAT, MMP, Oxidative Phosphorylation, and PI3K/AKT Pathways in K562 Cells.
A metabolite isolated from fermented soybean, 8-hydroxydaidzein (8-OHD, 7,8,4'-trihydroxyisoflavone, NSC-678112), is widely used in ethnopharmacological research due to its anti-proliferative and anti-inflammatory effects. We reported previously that 8-OHD provoked reactive oxygen species (ROS) overproduction, and induced autophagy, apoptosis, breakpoint cluster region-Abelson murine leukemia viral oncogene (BCR-ABL) degradation, and differentiation in K562 human chronic myeloid leukemia (CML) cells. However, how 8-OHD regulates metabolism, the extracellular matrix during invasion and metastasis, and survival signaling pathways in CML remains largely unexplored. High-throughput technologies have been widely used to discover the therapeutic targets and pathways of drugs. Bioinformatics analysis of 8-OHD-downregulated differentially expressed genes (DEGs) revealed that Janus kinase/signal transducer and activator of transcription (JAK/STAT), matrix metalloproteinases (MMPs), c-Myc, phosphoinositide 3-kinase (PI3K)/AKT, and oxidative phosphorylation (OXPHOS) metabolic pathways were significantly altered by 8-OHD treatment. Western blot analyses validated that 8-OHD significantly downregulated cytosolic JAK2 and the expression and phosphorylation of STAT3 dose- and time-dependently in K562 cells. Zymography and transwell assays also confirmed that K562-secreted MMP9 and invasion activities were dose-dependently inhibited by 8-OHD after 24 h of treatment. RT-qPCR analyses verified that 8-OHD repressed metastasis and OXPHOS-related genes. In combination with DisGeNET, it was found that 8-OHD's downregulation of PI3K/AKT is crucial for controlling CML development. A STRING protein-protein interaction analysis further revealed that AKT and MYC are hub proteins for cancer progression. Western blotting revealed that AKT phosphorylation and nuclear MYC expression were significantly inhibited by 8-OHD. Collectively, this systematic investigation revealed that 8-OHD exerts anti-CML effects by downregulating JAK/STAT, PI3K/AKT, MMP, and OXPHOS pathways, and MYC expression. These results could shed new light on the development of 8-OHD for CML therapy.