Loss of lanolin patch-test positivity.
Thirty-seven patients who had shown a relevant positive patch-test response to lanolin within the previous 5 years were retested. Only 41% demonstrated persistence of the positive patch test to lanolin. Analysis according to age, sex, atopic status, interval between patch testings, strength of the original response and the number of concurrent reactions, were not associated with the persistence of the lanolin response.


Search for pleiotropic QTL on chromosome BTA6 affecting yield traits of milk production.
The primary aim of this study was to investigate whether previous findings of similar quantitative trait loci (QTL) positions for correlated yield traits are due to a pleiotropic QTL. We applied a multitrait variance component based QTL mapping method to a dataset involving five granddaughter families from the German Holstein dairy cattle population. The marker map contained 16 microsatellite markers, distributed across chromosome BTA6. A chromosomewise significance threshold was used, because BTA6 is known to harbor QTL for several milk traits. To evaluate the results from the multivariate, across-family analysis, we also conducted single-family analyses using the least squares method of QTL estimation. The results provided two significant QTL findings at 49 and 64 cM for milk yield in different families and putative QTL at 68 cM for fat yield and at 71 cM for protein yield in another family. The results for fat and protein yield were confirmed by a univariate, across-family variance components analysis. The multivariate analysis of three bivariate trait combinations resulted in a significant pleiotropic QTL finding at 68 cM for fat yield and protein yield, bracketed by markers TGLA37 and FBN13. The estimates of variance contribution due to this QTL were 23% and 25%, respectively.


ESBL-plasmids carrying toxin-antitoxin systems can be "cured" of wild-type Escherichia coli using a heat technique.
Plasmid-encoded extended-spectrum beta-lactamase (ESBL)-enzymes are frequently produced by Escherichia coli. Several ESBL-plasmids contain genes for toxin-antitoxin (TA) systems, which assure the maintenance of plasmids in bacteria and prevent the cells from "post-segregational killing". These systems limit options to "cure" plasmids of ESBL-wild-type strains due to the death of the bacterial cells. A helpful tool to understand the role of ESBL-plasmids in the dissemination of pandemic multi-resistant E. coli are ESBL-plasmid-"cured"-variants (PCVs) and their comparison to ESBL-wild-type strains. The purpose of this study was to construct PCVs of ESBL-wild-type E. coli strains despite the presence of genes for TA systems. Using enhanced temperatures and brain-heart-infusion broth it was possible to construct viable PCVs of wild-type ESBL-E. coli strains. The occurrence of TA system-genes including hok/sok, srnB/C, vagC/D, pemI/K on ESBL-plasmids of replicon types FIA or FIB was demonstrated by bioinformatic analyses. The loss of the plasmid and the genetic identity of PCV and corresponding wild-type strain was confirmed via different methods including plasmid-profile-analysis, pulsed-field gel electrophoresis and bioinformatics using generated whole genome data of the strains. This short report describes the successful construction of viable PCVs of ESBL-wild-type E. coli strains. The results are hence surprising due to the fact that all "cured" ESBL-plasmids contained at least one complete toxin-antitoxin system, whose loss would normally mean the death of bacterial cells.


Isolation and characterization of disaggregatase from Methanosarcina mazei LYC.
At certain stages in its growth cycle, Methanosarcina mazei produces an enzyme (disaggregatase) that causes aggregates to separate into single cells. M. mazei S-6 and LYC both produce this enzymatic activity, although the specificities of activities differ. The disaggregatase of M. mazei S-6 had little effect on strain LYC cells, but the disaggregatase of M. mazei LYC disaggregated both strain LYC and strain S-6 cells. The disaggregatase of M. mazei LYC was purified by column chromatography, and it apparently consisted of two similar subunits with a combined molecular size of about 180,000 Da. Strain S-6 culture supernatants contained 14 U of activity per liter when activity was measured as uronic acids released from purified cell wall material. When the activity was quantified as the release of uronic acids from boiled M. mazei S-6 cells, the highest activity was found at pH 4.7 and at 35 degrees C.


Acceleration of Intrusion Detection in Encrypted Network Traffic Using Heterogeneous Hardware.
More than 75% of Internet traffic is now encrypted, and this percentage is constantly increasing. The majority of communications are secured using common encryption protocols such as SSL/TLS and IPsec to ensure security and protect the privacy of Internet users. However, encryption can be exploited to hide malicious activities, camouflaged into normal network traffic. Traditionally, network traffic inspection is based on techniques like deep packet inspection (DPI). Common applications for DPI include but are not limited to firewalls, intrusion detection and prevention systems, L7 filtering, and packet forwarding. With the widespread adoption of network encryption though, DPI tools that rely on packet payload content are becoming less effective, demanding the development of more sophisticated techniques in order to adapt to current network encryption trends. In this work, we present HeaderHunter, a fast signature-based intrusion detection system even for encrypted network traffic. We generate signatures using only network packet metadata extracted from packet headers. In addition, we examine the processing acceleration of the intrusion detection engine using different heterogeneous hardware architectures.


Versatile broadband electrode assembly for cell electroporation.
In this paper, a versatile electrode assembly for cell electroporation is proposed. For validation of the delivery system, biological cell electroporation experiments using 2.5 ns and 5 ns, 10 MV/m pulsed electric fields have been conducted. Electromagnetic, time domain, and frequency analyses demonstrate the broadband behavior of the delivery system.


[Achieving the target lipid levels in Hungary, 2004].
Recent European and Hungarian guidelines of cardiovascular prevention have clearly defined the target levels in lipid lowering therapy. To analyze the risk status of patients receiving long term lipid lowering therapy and the rate of achievement of target level in a Hungarian multicenter trial. The investigation was performed in January and February of 2004 involving general practitioners and specialists (cardiologists, lipidologists). Applying a questionnaire the authors asked for risk factors and the further implementations in the knowledge of results of each doctors' 10 consecutive patients receiving lipid lowering therapy for at least one year. LDL target levels accepted by the Hungarian Therapic Consensus Conference was achieved in 22% of GP's patients and 27% of specialists' patients, in 24% of patients, in average. According to risk stratification, the 83% of patients receiving lipid lowering therapy were at high risk, and 79% of these did not reach the suggested target level of serum total cholesterol. In 54% of patients not achieving target level the doctors continue the therapy without any modification. Considering therapy modification in the rest of patients, a dose increase was intended in 61%, change of drug in 31% of cases, and rarely the combination therapy. While only a quarter of patients receiving lipid lowering treatment achieved the target levels, along with wide spreading of this kind of therapy further efforts should be made in order to achieve the levels defined in guidelines with dose increase or combination of appropriate drugs.


Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome.
Parkinson's disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson's disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson's disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson's disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson's disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson's disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson's disease drug development.


Evaluation of antiviral activity of Oligonol, an extract of Litchi chinensis, against betanodavirus.
Betanodaviruses, members of the family Nodaviridae, are the causal agents of viral nervous necrosis (VNN) in many species of marine farmed fish. In the aquaculture industry, outbreaks of betanodavirus infection result in devastating damage and heavy economic losses. Although an urgent need exists to develop drugs against betanodavirus infection, there have been few reports about antibetanodavirus drugs. In this study, we examined the inhibitory effect of Oligonol, a purified phenolic extract from lychee fruit, on betanodavirus infection in fish cells. Oligonol significantly inhibited replication of betanodavirus (EC(50) = 0.9-1.8 μg/mL) as shown by the reduction of the virus-induced cytopathogenic effect (CPE) and the protection of cells in the crystal violet staining assay. The inhibition was dose dependent. A time-of-addition assay indicated that Oligonol's action takes place at an early stage of the viral infection. According to an attachment inhibition assay, it is possible that Oligonol partially inhibits attachment of the virion to the cell. Our data show that Oligonol could serve as an antiviral agent against betanodavirus.


Theory of defect-mediated morphogenesis.
Growing experimental evidence indicates that topological defects could serve as organizing centers in the morphogenesis of tissues. Here, we provide a quantitative explanation for this phenomenon, rooted in the buckling theory of deformable active polar liquid crystals. Using a combination of linear stability analysis and computational fluid dynamics, we demonstrate that active layers, such as confined cell monolayers, are unstable to the formation of protrusions in the presence of disclinations. The instability originates from an interplay between the focusing of the elastic forces, mediated by defects, and the renormalization of the system's surface tension by the active flow. The posttransitional regime is also characterized by several complex morphodynamical processes, such as oscillatory deformations, droplet nucleation, and active turbulence. Our findings offer an explanation of recent observations on tissue morphogenesis and shed light on the dynamics of active surfaces in general.


Water Soluble Vitamins and their Role in Diabetes and its Complications.
Diabetes is a metabolic disorder associated with abnormally high levels of glucose in the blood due to inadequate production of insulin or inadequate sensitivity of cells to the action of insulin. Diabetes has become an increasing challenge in the world. The predicted diabetic population according to the World Health Organization is 8.7% between the age group 20-70 years. There are many complications linked to prolonged high blood glucose levels, such as microvascular complications and macrovascular complications. Vitamins play an important role in glucose metabolism and the potential utility of supplementation is relevant for the prevention and/or management of diabetes mellitus and its complications. Literature search was performed using various dataset like PUBMED, EBSCO, ProQuest, Scopus and selected websites like the National Institute of Health and the World Health Organization. Water-soluble vitamins have been thoroughly studied for their activity in diabetes and diabetic complications. Water-soluble vitamins like B1, B3, B6, B7, B9 and B12 have notable effects in diabetes mellitus and its related complications like nephropathy, neuropathy, retinopathy and cardiomyopathy.


Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans.
The present study examines the effect of the route of insulin delivery on glucose turnover in humans. By using a new noninvasive in vivo method, the acute effect of insulin secreted by the pancreas can be compared with that of insulin delivered by a peripheral vein. Three euglycemic-hyperinsulinemic studies were performed in lean healthy men. In the first study (n = 10), constant portal hyperinsulinemia was produced using a programmed intravenous tolbutamide infusion algorithm, and the insulin secretion rate was mathematically derived by deconvolution from peripheral plasma C-peptide levels. In the second study (n = 10), exogenous insulin was infused by peripheral vein at the same rate as that determined in the first study. In the third study (n = 7), the peripheral insulin levels in the first study were matched by infusing exogenous insulin into a peripheral vein at half that rate. Peripheral insulin levels were higher (P < 0.001) with the full-rate peripheral insulin infusion (266.3 +/- 28.1 pmol/l) than with the portal delivery of insulin (171.1 +/- 30.4 pmol/l) or the half-rate peripheral insulin infusion (158.6 +/- 7.4 pmol/l) (portal versus half-rate peripheral insulin infusion, NS). Calculated hepatic insulin levels were higher (P < 0.001) in the portal insulin study (443.1 +/- 52.6 pmol/l) than in the full-rate peripheral insulin study (303.6 +/- 30.9 pmol/l) or in the half-rate peripheral insulin study (204.5 +/- 9.8 pmol/l). Hepatic glucose production (HGP) was suppressed to a greater extent with the full-rate peripheral insulin infusion (69.3 +/- 7.8%, P < 0.001 vs. portal or half-rate peripheral insulin) than portal (50.3 +/- 9.8%) or half-rate peripheral insulin infusion (36.8 +/- 3.8%). In the portal insulin study, however, suppression was greater than in the half-rate peripheral insulin study (P < 0.01), in spite of equal peripheral insulin levels. The assumption that tolbutamide, when used in this fashion, has no independent effect on glucose turnover, glucagon, or gluconeogenic precursor and energy substrates for gluconeogenesis was validated in five C-peptide-negative patients with IDDM. We conclude that in nondiabetic humans, 1) peripheral effects of insulin are important in suppressing HGP, as evidenced by the greater suppression of HGP with equivalent rate peripheral versus portal insulin delivery, and 2) because HGP was suppressed to a greater extent with portal verus peripheral insulin delivery at half the rate when peripheral insulin levels were matched, insulin-induced suppression of HGP is also partly mediated by a direct hepatic effect.


Cancer stem cell differentiation: TGFβ1 and versican may trigger molecules for the organization of tumor spheroids.
Cancer stem cells (CSCs) have the ability to self-renew similar to normal stem cells. This process is linked with metastasis and resistance to chemotherapy and radiotherapy. In the present study, we constructed an in vitro differentiation model for CSCs. CSCs isolated and proliferated for one passage were maintained as monolayers or spheroid-forming cells with serum included media for differentiation process. Differentiation of adhesion molecules and cellular ultrastructural properties were investigated and compared in both monolayer and spheroid cultures. CD133+/CD44+ cancer-initiating cells were isolated from DU-145 human prostate cancer cell line monolayer cultures and propagated as tumor spheroids and compared with the remaining heterogeneous cancer cell bulk population. Microarray-based gene expression analysis was applied to determine genes with differential expression and protein expression levels of candidates were analyzed by immunohistochemistry. Electron microscopy showed detailed analysis of morphology. TGFβ1 was found to be significantly upregulated in monolayer CSCs. High expression levels of VCAN, COL7A1, ITGβ3, MMP16, RPL13A, COL4A2 and TIMP1 and low expression levels of THBS1, MMP1 and MMP14 were detected when CSCs were maintained as serum-grown prostate CSC spheroids. Immunohistochemistry supported increased immunoreactivity of TGFβ1 in monolayer cultures and VCAN in spheroids. CSCs were found to possess multipotential differentiation capabilities through upregulation and/or downregulation of their markers. TGFβ1 is a triggering molecule, it stimulates versican, Col7A1, ITGβ3 and, most importantly, the upregulation of versican was only detected in CSCs. Our data support a model where CSCs must be engaged by one or more signaling cascades to differentiate and initiate tumor formation. This mechanism occurs with intracellular and extracellular signals and it is possible that CSCc themselves may be a source for extracellular signaling. These molecules functioning in tumor progression and differentiation may help develop targeted therapy.


The role and therapeutic significance of the anoikis pathway in renal clear cell carcinoma.
Anoikis is a specialized mode of programmed cell death. Specifically, once cells detach from the original extracellular matrix, an apoptotic program is initiated, preventing colonization of the cells in distant parts of the organ. Therefore, both distant metastasis and colonization of cancer cells rely on the anoikis resistance of cancer cells. Bioinformatics analysis was performed to confirm the relation of anoikis to kidney renal cell carcinoma (KIRC). To construct a prognostic model for patients with KIRC, we investigated several genes of the anoikis pathway most closely related to KIRC and also contrasted the effects of common anticancer drugs on the KIRC pathway. Besides KIRC, we explored the expression of anoikis-related genes in various other cancers. We classified patients with KIRC into three clusters based on the coefficients and mRNA expression levels of anoikis-related genes selected using the GSVA algorithm. We used the GDSC database to predict the response of the anoikis pathway to common anticancer drugs and explored the potential targets of the anoikis pathway in KIRC. We then analyzed the response of common immunotherapies to the anoikis pathway to analyze the correlation between anoikis and immune checkpoint inhibitor therapy. Finally, eleven cancer-related genes were screened and a prognostic model was constructed using LASSO regression.


Hepatosplenic gammadelta T-cell lymphoma.
To investigate the clinicopathologic characteristics, immunophenotype and TCR gene rearrangements of hepatosplenic T-cell lymphoma in eight Chinese patients. Eight Chinese patients with hepatosplenic gammadelta T-cell lymphomas were studied. Hematoxylin-eosin-stained slides and clinical histories were reviewed. We also carried out immunohistochemical staining for CD3, CD4, CD8, CD20, CD43, CD56, CD79a, UCHL-1, and TCR gammadelta. Rearrangements of TCR gamma and delta chain genes were also studied. The spleens were enlarged and the cut surfaces were homogeneous and red-purple in color without identifiable gross lesions or enlarged hilar lymph nodes. Histologically, lymphoma cells infiltrated the cords of Billroth and often packed the sinuses. Liver biopsy showed lymphoma cell infiltrations in the sinusoids, and three cases showed involvements of the portal tracts. Immunohistochemically lymphoma cells were positive for CD3, CD43, and CD56 in all cases. Four of eight cases were positive for CD8, and all cases were negative for CD4 (6/6). Monoclonal rearrangements of TCR gamma gene were demonstrated by PCR analysis in five out of the eight cases. TCR delta gene rearrangements were detected in six out of the eight cases, which demonstrated single bands on PAGE gel, and the amplification products in two cases were confirmed by sequencing. The clinicopathology of hepatosplenic gammadelta T-cell lymphoma in Chinese patients is similar to what was previously reported except that the splenomegaly is not so massive, and CD8 is positive.


Photoinduced Enhanced Raman from Lithium Niobate on Insulator Template.
Photoinduced enhanced Raman spectroscopy from a lithium niobate on insulator (LNOI)-silver nanoparticle template is demonstrated both by irradiating the template with 254 nm ultraviolet (UV) light before adding an analyte and before placing the substrate in the Raman system (substrate irradiation) and by irradiating the sample in the Raman system after adding the molecule (sample irradiation). The photoinduced enhancement enables up to an ∼sevenfold increase of the surface-enhanced Raman scattering signal strength of an analyte following substrate irradiation, whereas an ∼threefold enhancement above the surface-enhanced signal is obtained for sample irradiation. The photoinduced enhancement relaxes over the course of ∼10 h for a substrate irradiation duration of 150 min before returning to initial signal levels. The increase in Raman scattering intensity following UV irradiation is attributed to photoinduced charge transfer from the LNOI template to the analyte. New Raman bands are observed following UV irradiation, the appearance of which is suggestive of a photocatalytic reaction and highlight the potential of LNOI as a photoactive surface-enhanced Raman spectroscopy substrate.


Species determination of Culicoides biting midges via peptide profiling using matrix-assisted laser desorption ionization mass spectrometry.
Culicoides biting midges are vectors of bluetongue and Schmallenberg viruses that inflict large-scale disease epidemics in ruminant livestock in Europe. Methods based on morphological characteristics and sequencing of genetic markers are most commonly employed to differentiate Culicoides to species level. Proteomic methods, however, are also increasingly being used as an alternative method of identification. These techniques have the potential to be rapid and may also offer advantages over DNA-based techniques. The aim of this proof-of-principle study was to develop a simple MALDI-MS based method to differentiate Culicoides from different species by peptide patterns with the additional option of identifying discriminating peptides. Proteins extracted from 7 Culicoides species were digested and resulting peptides purified. Peptide mass fingerprint (PMF) spectra were recorded using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and peak patterns analysed in R using the MALDIquant R package. Additionally, offline liquid chromatography (LC) MALDI-TOF tandem mass spectrometry (MS/MS) was applied to determine the identity of peptide peaks in one exemplary MALDI spectrum obtained using an unfractionated extract. We showed that the majority of Culicoides species yielded reproducible mass spectra with peak patterns that were suitable for classification. The dendrogram obtained by MS showed tentative similarities to a dendrogram generated from cytochrome oxidase I (COX1) sequences. Using offline LC-MALDI-TOF-MS/MS we determined the identity of 28 peptide peaks observed in one MALDI spectrum in a mass range from 1.1 to 3.1 kDa. All identified peptides were identical to other dipteran species and derived from one of five highly abundant proteins due to an absence of available Culicoides data. Shotgun mass mapping by MALDI-TOF-MS has been shown to be compatible with morphological and genetic identification of specimens. Furthermore, the method performs at least as well as an alternative approach based on MS spectra of intact proteins, thus establishing the procedure as a method in its own right, with the additional option of concurrently using the same samples in other MS-based applications for protein identifications. The future availability of genomic information for different Culicoides species may enable a more stringent peptide detection based on Culicoides-specific sequence information.


2-Cyanoethylmercapturic acid (CEMA) in the urine as a possible indicator of exposure to acrylonitrile.
The aim of this study was to evaluate the efficiency of metabolism of acrylonitrile (ACN) to N-acetyl-S-(2-cyanoethyl)-L-cysteine (2-cyanoethylmercapturic acid (CEMA) in man, the kinetics of excretion of this metabolite, and the relation between the uptake of ACN and the excretion of CEMA in urine. Eleven experiments were performed on six male volunteers exposed for eight hours to ACN at concentrations of 5 or 10 mg/m3. The average respiratory retention of ACN was 52% and 21.8% of the retained ACN was excreted as CEMA in urine. Elimination approximated first order kinetics with half life of about eight hours. The best correlation between the uptake of ACN in the lungs and excretion of CEMA in urine was obtained when the concentration of CEMA in the urine fraction, collected between the sixth and eighth hours after the beginning of exposure, was adjusted to a specific gravity of 1.016 (y = 0.33x-13.3; r = 0.83). CEMA excretion, however, cannot be used as an individual index of exposure.


Continuation therapy with amitriptyline in depression.
Thirty-two patients who had responded to amitriptyline (150 mg daily) when suffering from a depressive illness were allocated either to receive placebo or to remain on the same medication for one year. Plasma concentrations of the drug were regularly estimated. There was no correlation between plasma concentration and subsequent residual affective morbidity. In spite of considerable encouragement, three of the patients did not take the prescribed amitriptyline and they all relapsed. Five out of sixteen patients who received placebo relapsed. None of the patients who continued to take amitriptyline relapsed. It is emphasized that the patients studied were selected, inasmuch as they were apparent responders to amitriptyline. It is concluded that this group of patients should continue to be treated with antidepressant medication for eight months after apparent recovery, and care should be taken to ensure the patients' compliance.


Drug resistance and its significance for treatment decisions in non-small-cell lung cancer.
Non-small-cell lung cancer (nsclc) constitutes about 85% of all lung cancers. Approximately 50% of patients diagnosed with nsclc present with advanced disease (stage iii or iv) that is not amenable to curative treatment. The number of patients with stage iiib or iv disease who are alive at 1 year after diagnosis has increased from 10% in the untreated population in the early 1980s to 50% in patients with a good performance status receiving treatment today. However, those statistics remain dismal, and the two dominant reasons are the large number of patients diagnosed with advanced-stage disease and the observed primary or secondary resistance to current therapies. The present article addresses the question of drug resistance in lung cancer, focusing on subjects that are currently topical and under intense scrutiny.


Regulation of vascular smooth muscle tone by adipose-derived contracting factor.
Obesity and arterial hypertension, important risk factors for atherosclerosis and coronary artery disease, are characterized by an increase in vascular tone. While obesity is known to augment vasoconstrictor prostanoid activity in endothelial cells, less is known about factors released from fat tissue surrounding arteries (perivascular adipose). Using lean controls and mice with either monogenic or diet-induced obesity, we set out to determine whether and through which pathways perivascular adipose affects vascular tone. We unexpectedly found that in the aorta of obese mice, perivascular adipose potentiates vascular contractility to serotonin and phenylephrine, indicating activity of a factor generated by perivascular adipose, which we designated "adipose-derived contracting factor" (ADCF). Inhibition of cyclooxygenase (COX) fully prevented ADCF-mediated contractions, whereas COX-1 or COX-2-selective inhibition was only partially effective. By contrast, inhibition of superoxide anions, NO synthase, or endothelin receptors had no effect on ADCF activity. Perivascular adipose as a source of COX-derived ADCF was further confirmed by detecting increased thromboxane A2 formation from perivascular adipose-replete aortae from obese mice. Taken together, this study identifies perivascular adipose as a novel regulator of arterial vasoconstriction through the release of COX-derived ADCF. Excessive ADCF activity in perivascular fat under obese conditions likely contributes to increased vascular tone by antagonizing vasodilation. ADCF may thus propagate obesity-dependent hypertension and the associated increased risk in coronary artery disease, potentially representing a novel therapeutic target.


Efficiency of a strategy for detecting back random responding on the personality assessment inventory.
The efficiency of a new strategy to identify back random responding (BRR) on the Personality Assessment Inventory (L. C. Morey, 1991) was studied using random manipulations of item responses from community (904 adult nonpatients) and clinical (1,079 adult patients) respondents. The strategy involved a comparison of short-form and full-instrument T scores on 2 scales found to be particularly sensitive to BRR in a recent study. This strategy was found to be reasonably sensitive and specific to even relatively low levels of BRR.


Origins of U.S. Hispanics. Implications for diabetes.
The purpose of this article was to characterize the origins of the United States Hispanic population and discuss the implications of these origins in the context of diabetes risk. Particular attention was focused on the genetic origins of the three major U.S. Hispanic groups, i.e., Mexican Americans, Puerto Ricans, and Cubans. The U.S. Census figures provided basic demographic information. Genetic marker data for ancestral populations were taken from a review of the literature and compendia. Genetic marker data for the Puerto Rican and Cuban populations were extracted from the literature. Genetic markers determined on approximately 1000 randomly selected Mexican Americans from Starr County, Texas, were taken as representative of the Mexican-American population. The Hispanic population is the second largest and fastest growing minority in the U.S. Estimates of the Hispanic population in 1988 indicated some 19.4 million residents, of whom 62% were classified as Mexican, 13% as Puerto Rican, and the remaining 25% as Cubans and others. Various lines of evidence can be used to characterize the Hispanic population and its origins. These include ethnohistory, self-assessment of ancestry, surname distributions, speech and cultural characteristics, quantitative traits, and genetic structure. Genetic data were used to estimate the contribution of putative ancestral populations to the contemporary gene pool. For Mexican Americans, 31% of the contemporary gene pool is estimated to be Native American derived, whereas 61 and 8% are Spanish and African derived, respectively. In Puerto Rico, the percentage of contributions of Spanish, Native American, and African admixture to the population are 45, 18, and 37%, respectively. For Cuba, the parallel estimates are 62, 18, and 20%. The high frequency of Native American-derived genes in the contemporary Hispanic population predict a higher frequency of non-insulin-dependent diabetes mellitus (NIDDM) under the assumption that genes are important in NIDDM etiology. Our results are consistent with the finding of the significant role of genes in determining risk.


The effect of time trial cycling position on physiological and aerodynamic variables.
To reduce aerodynamic resistance cyclists lower their torso angle, concurrently reducing Peak Power Output (PPO). However, realistic torso angle changes in the range used by time trial cyclists have not yet been examined. Therefore the aim of this study was to investigate the effect of torso angle on physiological parameters and frontal area in different commonly used time trial positions. Nineteen well-trained male cyclists performed incremental tests on a cycle ergometer at five different torso angles: their preferred torso angle and at 0, 8, 16 and 24°. Oxygen uptake, carbon dioxide expiration, minute ventilation, gross efficiency, PPO, heart rate, cadence and frontal area were recorded. The frontal area provides an estimate of the aerodynamic drag. Overall, results showed that lower torso angles attenuated performance. Maximal values of all variables, attained in the incremental test, decreased with lower torso angles (P < 0.001). The 0° torso angle position significantly affected the metabolic and physiological variables compared to all other investigated positions. At constant submaximal intensities of 60, 70 and 80% PPO, all variables significantly increased with increasing intensity (P < 0.0001) and decreasing torso angle (P < 0.005). This study shows that for trained cyclists there should be a trade-off between the aerodynamic drag and physiological functioning.


Inflammatory effect of cleaved bovine lactoferrin by elastase on staphylococcal mastitis.
Elastase activity and concanavalin A (Con A) low affinity bovine lactoferrin (bLf) molecule were detected in mammary gland secretions (MGSs) from mammary glands (MGs) with clinical staphylococcal mastitis. Changes in clinical symptoms correlated with increases in both elastase activity and the concentration of Con A low-affinity Lf in MGSs from mastitic MGs. Bovine Lf treated with elastase (elastase-Lf) showed various small bLf molecules and the same image on Con A two-dimensional immunoelectrophoresis as low Con A affinity bLf in MGSs. We confirmed the presence of four common bLf peptides for the elastase-bLf and low Con A affinity bLf molecules in mastitic MGSs, and synthesized four peptides. Strong mRNA expression of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) was induced in bovine mammary epithelial cells on stimulation with low Con A affinity bLf, elastase-bLf, and GQRDLLFKDSAL, a synthesis bLf peptide based on nuclear factor kappa B (NFkappaB) activation. These results suggest that bLf was cleaved by elastase, and that this cleavage changed the physical function of Lf. Our results indicate that elastase induced production of low Con A affinity bLf, including the bLf peptide GQRDLLFKDSAL, and had an inflammatory effect on staphylococcal mastitis.


Calcium glucarate inhibits DMBA-induced oral carcinogenesis in the hamster: histomorphometric evaluation.
Calcium glucarate (CGT) is a promising chemopreventive agent. This study evaluated the in vivo efficacy of CGT in preventing 7,12-dimethylbenz(alpha) anthracene (DMBA)-induced oral carcinogenesis in the hamster. Matherials and Methods: Seventy-six Syrian hamsters were used, divided into four groups: group 1, untreated animals; 2, CGT controls; 3, DMBA-treated; 4, DMBA- and CGT-treated. Hamsters were painted three times weekly with 0.5% solution of DMBA and were fed a diet supplemented with CGT (64 mmol/kg, 2%). Animals were sacrificed at week 9 and 12 and pathology and histomorphometric analyses were performed. At week 9, four dysplastic lesions and six carcinomas were identified in group 3 while only three dysplasias and five carcinomas were detected in group 4. At week 12, five animals of group 3 displayed a dysplasia, which was only detected in one animal of group 4. Squamous carcinomas were identified in all animals of both group 3 and 4. However, in group 3 four of the animals displayed multifocal lesions and carcinomas displayed histological features indicative of increased aggressiveness. The results obtained suggest that CGT can exert an inhibitory effect on oral carcinogenesis in tha hamster and that further studies are warranted to evaluate its potential use as a chemopreventive agent in humans.


Clinicopathological features of primary leiomyosarcoma of the gastrointestinal tract following recognition of gastrointestinal stromal tumours.
We aimed to elucidate the clinicopathological and immunohistochemical features of leiomyosarcoma (LMS) of the gastrointestinal (GI) tract. We encountered seven cases of GI-LMS in the colon (n = 4), rectum (n = 1), jejunum (n = 1) and stomach (n = 1). They ranged from 1 to 25 cm (median, 8.5 cm) in size and had high mitotic counts (median 38 per 50 high-power fields). Morphologically, the tumours were composed mainly of spindle cells with eosinophilic cytoplasm and various degrees of nuclear atypia and pleomorphism. Immunohistochemically, the tumours were positive for α-smooth muscle actin (86%), muscle-specific actin (71%), desmin (86%), calponin (71%), h-caldesmon (57%) and smoothelin (71%). All were negative for KIT, CD34, protein kinase C theta and DOG1. Local recurrence and distant metastasis occurred in one and three patients, respectively. We then reviewed 55 cases of GI-LMS from the era following the recognition of gastrointestinal stromal tumours. Among 29 of 55 cases for whom follow-up information was available, the estimated 5-year overall survival rate was 51.6%; tumour size ≥5 cm was correlated significantly with shorter overall survival time (P = 0.0016), while mitotic count (≥50 or ≥100 per 50 high-power fields) proved to be no prognostic factor. GI-LMSs have distinctive clinicopathological and immunohistochemical features and exhibit aggressive biological behaviour.


Noninvasive ventilation in acute respiratory failure--a meta-analysis update.
To present a meta-analytic update on the effects of noninvasive ventilation (NIV) in the management of acute respiratory failure. Meta-analysis of randomized controlled clinical trials in acute respiratory failure comparing NIV with standard medical therapy. Randomized controlled trials of NIV in acute respiratory failure were identified by search of i) MEDLINE (1966-2000), ii) published abstracts from scientific meetings, and iii) bibliographies of relevant articles. Of the 15 randomized controlled trials that were identified (13 published and 2 in abstract form), 8 studies were on exacerbations of chronic obstructive pulmonary disease (COPD) and 7 on diverse disease processes in both COPD and non-COPD groups ("mixed-group"). Because of underlying heterogeneity of treatment effects, only the DerSimonian-Laird random effects estimator was used and reported. The effects of NIV vs. standard therapy on mortality and subsequent invasive mechanical ventilation (MV) was assessed as risk difference, and hospital length of stay as mean weighted difference (days). NIV was associated with reduction in mortality (8%, p = .03), reduced need for MV (19%, p = .001) and shortened hospital length of stay (2.74 days, p = .004). In the COPD cohort, significant reductions in mortality (13%, p = .001), need for MV (18%, p = .02), and hospital length of stay (5.66 days, p = .01) were observed in the group treated with NIV. In contrast, in the mixed-group, there was no demonstrable reduction in mortality (0%, p = .98). However, there was significant reduction in the need for MV (22%, p = .001). Publication bias was not evident on analysis. Treatment effect i) as mortality or need for mechanical ventilation was not modified by enrollment pH, PaCO2, nor age and ii) was not related (as log odds ratio) to underlying risk (control arm log odds). Cumulative meta-analysis did not demonstrate any substantial variation in the point estimates with the addition of the recently published studies. However a contraction in the confidence intervals was observed in the COPD subgroup. Complication rates were not significantly different in the standard medical therapy group and the NIV treated patients. Substantial reductions in mortality and the need for subsequent MV were associated with NIV in acute respiratory failure, especially in the COPD subgroup. Hospital length of stay was variably affected. Heterogeneity of treatment effects was observed.


Murine models of hyperhomocysteinemia and their vascular phenotypes.
Hyperhomocysteinemia is an established risk factor for arterial as well as venous thromboembolism. Individuals with severe hyperhomocysteinemia caused by inherited genetic defects in homocysteine metabolism have an extremely high incidence of vascular thrombosis unless they are treated aggressively with homocysteine-lowering therapy. The clinical value of homocysteine-lowering therapy in individuals with moderate hyperhomocysteinemia, which is very common in populations at risk for vascular disease, is more controversial. Considerable progress in our understanding of the molecular mechanisms underlying the association between hyperhomocysteinemia and vascular thrombotic events has been provided by the development of a variety of murine models. Because levels of homocysteine are regulated by both the methionine and folate cycles, hyperhomocysteinemia can be induced in mice through both genetic and dietary manipulations. Mice deficient in the cystathionine beta-synthase (CBS) gene have been exploited widely in many studies investigating the vascular pathophysiology of hyperhomocysteinemia. In this article, we review the established murine models, including the CBS-deficient mouse as well as several newer murine models available for the study of hyperhomocysteinemia. We also summarize the major vascular phenotypes observed in these murine models.


Shape control of platinum and palladium nanoparticles for catalysis.
Platinum and palladium are important catalysts for a wide variety of industrial processes. With the increasing demands of these materials, the development of high-performance catalysts is an important area of research, and as a result, shape control synthesis has become one of the leading research focuses. This minireview surveys the different approaches in solution-phase synthesis that have been successfully adopted for achieving shaped platinum and palladium nanoparticles that are enclosed with specific crystallographic facets. In addition, catalytic studies of the shaped nanoparticles are highlighted, in which promising results have been reported in terms of enhanced activity and selectivity. The future outlook discusses the aspects in synthesis and catalysis to be considered for the development of highly efficient and effective catalysts.


Prevalence and control of hypertension in the general practice in Italy: updated analysis of a large database.
Systematic assessment of blood pressure (BP) control rates may help to improve the clinical management of hypertension in clinical practice. This approach had limited application in Europe over the last three decades and only recently has been implemented in some countries. The present study is aimed at evaluating hypertension prevalence and control among adult outpatients followed by a large, representative sample of general practitioners (GPs) in Italy. We retrospectively analysed the data derived from the GP Health Search-CSD database in 2013. Hypertension prevalence and control were estimated within the overall population sample and in hypertensive outpatients, respectively, according to age and gender. Hypertension diagnosis was defined according to the International Classification of Diseases 9. Clinic BP levels were measured according to the European guidelines. BP control was defined as systolic/diastolic BP <140/90 mm Hg. Data from 911 753 individuals (52.2% females) were scrutinized. Hypertension was diagnosed in 236 377 (25.9%) patients, being higher in male aged <70 years than age-matched female. Hypertension control was recorded in 60.6% of hypertensive patients, being higher in female than male individuals aged <70 years. Our current analysis demonstrates that about 26% of adult outpatients followed in the GP setting had hypertension and that about 61% had controlled BP levels. Both prevalence and control of hypertension appear to be higher when compared with the data reported from the analysis of the same database in 2005, thus confirming a positive trend in BP control in the GP clinical setting in Italy.


Metabolome and Transcriptome Association Analysis Reveals the Link Between Pigmentation and Nutrition Utilization in the Juveniles of Sea Cucumber Holothuria leucospilota.
The sea cucumber Holothuria leucospilota is an economically and ecologically important tropical species. Following development into juveniles, H. leucospilota undergoes a color change from white to black, involving a pigmentation process for over a period of several months. In this study, a combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and Next-Generation sequencing (NGS) were employed to investigate the changes in metabolomic and transcriptomic profiles during pigmentation in H. leucospilota juveniles. The metabolomic analysis identified a total of 341 metabolites, of which 52 were found to be differentially regulated (P < 0.05 and VIP > 1), with 27 being upregulated in white individuals and 25 in black individuals. Additionally, 632 differentially expressed genes (DEGs) were identified, with 380 genes upregulated in white samples and 252 genes upregulated in black samples. Interestingly, the melanin content and tyrosinase transcript levels did not display significant differences between the two groups. Metabolomic data suggested the involvement of the linoleic acid metabolic pathway in pigmentation. Transcriptomic analysis, coupled with realtime PCR validation, revealed a decrease in the transcript levels of digestive enzymes like α-amylase, maltase-glucoamylase, and trehalase after the juveniles changed to black. Furthermore, the mRNA expressions of major yolk proteins showed a decline, indicating a shift in the accumulation of protein nutrient sources. Overall, our findings suggest that during the pigmentation process in H. leucospilota, no significant changes were observed in the classical melanin pathway, while notable alterations were observed in their nutritional status. This study provides valuable insights into the regulatory mechanisms of pigmentation in marine organisms.


14-3-3 binding sites in the snail protein are essential for snail-mediated transcriptional repression and epithelial-mesenchymal differentiation.
The Snail transcription factor is a repressor and a master regulator of epithelial-mesenchymal transition (EMT) events in normal embryonic development and during tumor metastases. Snail directly regulates genes affecting cell adhesion, motility, and polarity. Invasive tumor cells express high levels of Snail, which is a marker for aggressive disease and poor prognosis. Transcriptional repression and EMT induction by Snail requires binding to its obligate corepressor, the LIM protein Ajuba. It is unclear how this complex is assembled and maintained on Snail target genes. Here we define functional 14-3-3 binding motifs in Snail and Ajuba, which selectively bind 14-3-3 protein isoforms. In Snail, an NH(2)-terminal motif in the repression domain cooperates with a COOH-terminal, high-affinity motif for binding to 14-3-3 proteins. Coordinate mutation of both motifs abolishes 14-3-3 binding and inhibits Snail-mediated gene repression and EMT differentiation. Snail, 14-3-3 proteins, and Ajuba form a ternary complex that is readily detected through chromatin immunoprecipitation at the endogenous E-cadherin promoter. Collectively, these data show that 14-3-3 proteins are new components of the Snail transcriptional repression machinery and mediate its important biological functions.


Ozonation of textile wastewater: physicochemical and phytotoxic aspects.
The purpose of this work was to evaluate the performance of ozonation as a technique to treat textile effluents. This performance evaluation was made using physico-chemical parameters and phytotoxic endpoints (i.e. biomass growth enzyme activities - catalase and peroxidase). After ozonation, the color absorbance (523 nm) was reduced by 80.9% and the pH decreased from 10.9 to approximately 7.5 while COD reduction reached nearly 87%. Phytotoxicity tests carried out in solution with three plant species (i.e. soybean, rice and wheat) allowed us to compare toxicity data of both, raw and ozonated effluents. The biomass (fresh weight) of the 3 plant species clearly decreases as a function of the increase in raw effluent concentration with LOEC values of 100% for rice and wheat, and 50% for soybean. Activities of catalase and peroxidase in the 3 plant species exposed to the raw textile effluent were significantly different from plant controls. The LOEC values for catalase were 6.2% (in wheat and soybean plants), and 25% (in rice plants), while for peroxidase the LOEC values were 6.2% (in rice plants), 25% (in soybean plants), and 50% (in wheat plants). Reduction in the phytotoxicity of textile effluent samples after ozonation is likely due to the elimination of the toxic organic fraction oxidized during this process. Regarding endpoint sensitivity, our results showed that biomass endpoint was less sensitive than biochemical endpoint. In conclusion, ozonation was relatively effective in reducing physico-chemical parameters and phytotoxic effects of textile effluents. Plant enzyme assays used in this study proved to be a sensitive tool in order to determine the toxicity of industrial effluents and may be used to evaluate efficiency of established (or emergent) wastewater treatment technology.


Cardiac imaging: current and emerging applications.
Cardiac magnetic resonance imaging (MRI) and computed tomography (CT) scan have made big inroads as modalities used for evaluation of various pathologies of the heart. Cardiac MRI is typically used for perfusion and viability studies as well as to study various cardiomyopathies, valvular diseases and the pericardium. It has been used in the evaluation of congenital heart diseases over the last two decades. Cardiac CT is used mainly for the evaluation of the coronary arteries, typically in the setting of "to rule out coronary artery disease".


Patient and parent preferences for orthodontic practices.
This study was designed to identify who chooses an orthodontic office and what factors might induce the attraction. Patients and parents from the lists provided by suburban orthodontic offices were contacted. A mail-out survey instrument was used to gather the data. Results revealed that the reputation of the practitioner was most important along with the level of caring attitude the office projected. It was also important that the office is located near home, interestingly, the mother is the most significant decision-maker in the family in choosing an orthodontic office. Moreover, not the cost of treatment but the payment plan was the critical element in the decision process. The higher income families with three or less children were attracted to office characteristics such as excellence of the orthodontist, attention, and convenience. A marketing strategy based on these elements might provide the best return on the investment.


[Decidua in the peritoneal surface mimicking metastatic nodules. Findings during cesarean section].
The occurrence of ectopic decidua has been observed most often in the ovaries, uterus, and cervix. A peritoneal localization is less frequent and usually an asymptomatic incidental finding. Ectopic decidua was investigated in biopsies taken during cesarean sections, elective tubal ligations, appendectomy and in tubal pregnancies. Histologic studies have been carried out of fragments from the epiploon, appendiceal serosa, tubal serosa, retroperitoneal lymph nodes and various abdominal organs. Our purpose is to report a case of peritoneal deciduosis in a 46-year-old woman, asymptomatic, discovered during cesarean section and mimicking metastatic nodules (incidental finding). The histopathological diagnosis was done based on specimen studied with the common technique of paraffin embedding and hematoxilin--eosin staining. We believe that this decidual transformation of the peritoneum arises from a progesterone-induced metaplasia of the coelomic stroma, being often a totally reversible phenomenon.


Medical practice in the Eastern Cape.
The Eastern Cape developed slightly different medical traditions from the Western Cape. The majority Xhosa population had healing practices of their own which they shared only partly with the Khoi, while Boer medical practice had become more remote from modern Western medicine. Missionary medicine was relatively undeveloped in this period but through the Grey Hospital the Governor, Sir George Grey, promoted Western medicine amongst Africans. In this frontier territory, British military doctors encouraged early scientific societies and, in the absence of other medical men, treated civilians both black and white. The advent of the British settlers after 1820 placed a strongly British stamp on the practice of Eastern Cape medicine.


[Transcutaneous electrostimulation and its place in the treatment of chronic pain syndromes].
In 107 patients with chronic pain syndromes, transcutaneous electrostimulation by an apparatus ELIMAN -101 was used in conjunction with drug treatment and physiotherapy. On the basis of a complex of estimation tests, the patients studied were divided into three groups depending on the degree of the analgesic effect. A good analgesic response was obtained in 65.4% of the patients, satisfactory in 28.1%, unsatisfactory in 6.5%. It is considered advisable to include the method of transcutaneous electrostimulation into the regimen of the treatment for chronic pain syndromes.


Personal Protective Equipment Use and Handwashing Among Animal Farmers: A Multi-site Assessment.
The goal of this study was to compare and contrast the use of personal protective equipment (PPE) and the practice of handwashing among participants of four studies assessing poultry and swine farms in the midwestern United States and in Thailand. This largely descriptive exercise was designed to assess and compare the frequency of these protective practices among the study populations. There were a total of 1113 surveys analyzed across the four studies. The respondents included workers in direct contact with animals as well as flock owners and veterinarians tending to farms. Handwashing was the most common practice observed among all participants with 42% "always" and 35% "sometimes" washing their hands after contact with the animals. This practice was least common among Minnesota swine workers. Even Thai poultry farmers, who demonstrated the lowest overall PPE use, reported a higher frequency of handwashing. Mask use during animal farming activities ("always" or "sometimes") was least commonly practiced, ranging from 1% in Thailand to 26% among backyard poultry farmers in Minnesota. Minnesota poultry and swine farmers had similar frequencies of mask (26%) and glove use (51% and 49%). All other comparisons differed significantly across the four sites (p-values <0.05). The use of PPE in animal farming differed by study location and is likely related to prevalent norms in the respective regions. Overall, the use of PPE did not appear to be influenced by the particular animal (poultry or swine) being farmed. These findings may prove useful to regulating bodies and farm owners in formulating policy or planning strategies for improving personal hygiene practices in animal farming and preparing for influenza and other potential zoonotic disease outbreaks.


Impaired sarcoplasmic reticulum Ca(2+) release rate after fatiguing stimulation in rat skeletal muscle.
The purpose of the study was to characterize the sarcoplasmic reticulum (SR) function and contractile properties before and during recovery from fatigue in the rat extensor digitorum longus muscle. Fatiguing contractions (60 Hz, 150 ms/s for 4 min) induced a reduction of the SR Ca(2+) release rate to 66% that persisted for 1 h, followed by a gradual recovery to 87% of prefatigue release rate at 3 h recovery. Tetanic force and rate of force development (+dF/dt) and relaxation (-dF/dt) were depressed by approximately 80% after stimulation. Recovery occurred in two phases: an initial phase, in which during the first 0.5-1 h the metabolic state recovered to resting levels, and a slow phase from 1-3 h characterized by a rather slow recovery of the mechanical properties. The recovery of SR Ca(2+) release rate was closely correlated to +dF/dt during the slow phase of recovery (r(2) = 0.51; P < 0.05). Despite a slowing of the relaxation rate, we did not find any significant alterations in the SR Ca(2+) uptake function. These data demonstrate that the Ca(2+) release mechanism of SR is sensitive to repetitive in vitro muscle contraction. Moreover, the results indicate that +dF/dt to some extent depends on the rate of Ca(2+) release during the slow phase of recovery.


Assessing the transmission potential of mpox in East Asia during 2022-2023: A focus on Taiwan, China, Japan, and South Korea.
This study aims to estimate the transmission potential of mpox in East Asia, focusing on the hardest hit nations: Taiwan, China, Japan, and South Korea. We utilized six phenomenological dynamic growth models to fit the case incidence during the initial 30 epidemic days. The best-fit model was selected to calculate the reproduction number (Rt). Additionally, we used the latest case data and a Bayesian framework to compute the instantaneous effective Rt by applying the Cori et al. During the early phase, China demonstrated the highest estimated Rt of 2.89 (95% CI: 1.44-3.33); followed by South Korea, 2.18 (95% CI: 0.96-3.57); Japan, 1.73 (95% CI: 0.66-3.94); and Taiwan, 1.36 (95% CI: 0.71-3.30). However, by June 30, 2023, estimated Rt dropped below 1.00 in all countries: China at 0.05 (95% credible interval [CrI]: 0.02-0.10), Japan at 0.32 (95% CrI: 0.15-0.59), South Korea at 0.23 (95% CrI: 0.11-0.42), and Taiwan at 0.41 (95% CrI: 0.31-0.53), indicating the potential decline of the outbreak. Our analysis shows effective containment by each country. It is crucial to sustain effective management to ensure the ultimate eradication of the outbreak.


Entry, Intracellular Survival, and Multinucleated-Giant-Cell-Forming Activity of Burkholderia pseudomallei in Human Primary Phagocytic and Nonphagocytic Cells.
The human pathogen Burkholderia pseudomallei and the related species Burkholderia thailandensis are facultative intracellular bacteria characterized by the ability to escape into the cytosol of the host cell and to stimulate the formation of multinucleated giant cells (MNGCs). MNGC formation is induced via an unknown mechanism by bacterial type VI secretion system 5 (T6SS-5), which is an essential virulence factor in both species. Despite the vital role of the intracellular life cycle in the pathogenesis of the bacteria, the range of host cell types permissive for initiation and completion of the intracellular cycle is poorly defined. In the present study, we used several different types of human primary cells to evaluate bacterial entry, intracellular survival, and MNGC formation. We report the capacity of B. pseudomallei to enter, efficiently replicate in, and mediate MNGC formation of vein endothelial and bronchial epithelial cells, indicating that the T6SS-5 is important in the host-pathogen interaction in these cells. Furthermore, we show that B. pseudomallei invades fibroblasts and keratinocytes and survives inside these cells as well as in monocyte-derived macrophages and neutrophils for at least 17 h postinfection; however, MNGC formation is not induced in these cells. In contrast, infection of mixed neutrophils and RAW264.7 macrophages with B. thailandensis stimulated the formation of heterotypic MNGCs in a T6SS-5-dependent manner. In summary, the ability of the bacteria to enter and survive as well as induce MNGC formation in certain host cells may contribute to the pathogenesis observed in B. pseudomallei infection.


Sleep Quality and Cognitive Decline Across the Adult Age Range: Findings from the Maastricht Aging Study (MAAS).
Sleep disturbances have been linked with cognitive decline and a higher risk of dementia. However, there is a lack of studies with sufficient follow-up duration, a detailed neuropsychological assessment and adequate control of main confounders. To investigate the relation between self-reported sleep quality and cognitive decline over 12 years in cognitively healthy individuals from the general population. We used data from the Maastricht Aging Study (MAAS), a Dutch population-based prospective cohort study of 1,823 community-dwelling adults aged 24 to 82 years at baseline. Cognitive performance was measured at baseline, 6 and 12 years on verbal memory, executive functions, and information processing speed. Sleep quality was assessed at baseline using the sleep subscale score of the 90-item Symptom Checklist (SCL-90). Additional modifiable dementia risk factors were summarized in the LIfestyle for BRAin health (LIBRA) risk score. Weighted linear mixed models tested the association between continuous scores and tertiles of subjective sleep quality and change in cognitive performances over time. Models were adjusted for age, gender, educational level, LIBRA, and use of hypnotic (sleep) medication. Worse sleep quality was associated with faster decline in processing speed. At older age (≥65 years), it was also associated with faster decline in verbal memory. Association were independent of other modifiable dementia risk factors and use of hypnotic medication. Directionally similar but non-significant associations were found between worse sleep quality and executive functions. In this population-based study across the adult age range, poor self-reported sleep was associated with accelerated cognitive decline.


Liposome-mediated delivery of tobacco mosaic virus RNA into tobacco protoplasts: A sensitive assay for monitoring liposome-protoplast interactions.
Tobacco mosaic virus (TMV) RNA was encapsulated in large, unilamellar phospholipid vesicles (liposomes), and the encapsulated TMV RNA was shown to be infectious when incubated with tobacco protoplasts under appropriate conditions. Maximal virus production in protoplasts was observed after their incubation with TMV RNA entrapped in phosphatidylserine/cholesterol liposomes. Infection was dependent on the presence of polyalcohols in the incubation mixture. Other parameters, such as the extent of vesicle binding, the cell-induced leakage of vesicle contents, and the degree of liposome toxicity were shown to be important in determining the efficiency of infectivity. Liposome-mediated delivery offers an efficient and reproducible method for introducing RNA into plant protoplasts.


Alterations in state of molecular aggregation of collagen induced in chick embryos by beta-aminopropionitrile (lathyrus factor).
The lathyrogenic agents, beta-aminopropionitrile and semicarbizide, when applied to the chorio-allantoic membrane of the chick embryo produced a dramatic increase in fragility of the embryo. This alteration was not associated with a change in the concentration of collagen, except in aorta, but was accompanied by a sharp increase in the amount of collagen extractible in cold 1 M NaCl from skin, bone, and aorta. Increase in fragility and extractible collagen began within 3 hours after introduction of the agent and rose steadily for at least 72 hours. Essentially no collagen could be extracted from tissues of normal chick embryos. Both fragility and amount of extractible collagen were dosage- and time-dependent. It is concluded that the extractible collagen in lathyrism consists of a large proportion of dissolved fibers previously insoluble and formed prior to administration of the agent. The data also suggest that the "lathyritic" collagen in vivo is not in molecular dispersion but in an aggregate or fibrillar form. It is dispersed by cooling. The extracted collagen could be reconstituted to typical striated fibrils in vitro and the molecule appeared to be normal in the gross, with regard to asymmetry ratio and intramolecular helical structure. The evidence at hand suggests that at least one of the defects induced by lathyrogenic agents is an interference with the normal intermolecular cross-linking within the collagen fibril.


An enantioselective assembly of naphthopyran via NHC-catalyzed [3 + 3] annulation of bromoenal with β-tetralone.
An asymmetric assembly of naphthopyran was realized via the N-heterocyclic carbene (NHC)-catalyzed formal [3 + 3] annulation of bromoenal and β-tetralone. The key advantages of this protocol include ready availability of starting materials, mild reaction conditions, good yields and excellent enantioselectivities.


Purinergic P2Y1 receptors take centre stage in autocrine stimulation of human beta cells.
Insulin secretory vesicles contain high concentrations of adenine nucleotides, which are co-released with insulin during exocytosis. There is strong evidence that ATP and ADP serve as autocrine messengers in pancreatic beta cells, but the functional effects and detailed mechanisms of action are under debate. In this issue of Diabetologia, Khan and colleagues (DOI: 10.1007/s00125-014-3368-8 ) present the results of their study of autocrine purinergic signalling in isolated human beta cells. Using a combination of electrophysiological techniques, Ca(2+) imaging and measurements of insulin secretion, it is demonstrated that voltage-dependent Ca(2+) influx triggers release of ATP/ADP, which activates purinergic receptors of the Gq/11-coupled P2Y1 isoform. Activation of these receptors leads to membrane depolarisation and phospholipase C-mediated mobilisation of Ca(2+) from endoplasmic reticulum stores, which amplifies the exocytosis-triggering Ca(2+) signal. In contrast, there is little evidence for involvement of ionotropic P2X receptors in the autocrine stimulation of human beta cells. This commentary discusses these findings as well as various functional and therapeutic implications of the complex purinergic signalling network in the pancreatic islet.


Fc-engineering significantly improves the recruitment of immune effector cells by anti-ICAM-1 antibody MSH-TP15 for myeloma therapy.
Despite several therapeutic advances, patients with multiple myeloma (MM) require additional treatment options since no curative therapy exists yet. In search of a novel therapeutic antibody, we previously applied phage display with myeloma cell screening and developed TP15, a scFv targeting intercellular adhesion molecule 1 (ICAM-1/CD54). To more precisely evaluate the antibody's modes of action, fully human IgG1 antibody variants were generated bearing wild-type (MSH-TP15) or mutated Fc to either enhance (MSH-TP15 Fc-eng.) or prevent (MSH-TP15 Fc k.o.) Fc gamma receptor binding. Especially MSH-TP15 Fc-eng. induced potent antibody-dependent cell-mediated cytotoxicity (ADCC) against malignant plasma cells by efficiently recruiting NK cells and engaged macrophages for antibody-dependent cellular phagocytosis (ADCP) of tumor cells. Binding studies with truncated ICAM-1 demonstrated MSH-TP15 binding to ICAM-1 domain 1-2. Importantly, MSH-TP15 and MSH-TP15 Fc-eng. both prevented myeloma cell engraftment and significantly prolonged survival of mice in an intraperitoneal xenograft model. In the subcutaneous model MSH-TP15 Fc-eng. was superior to MSH-TP15, whereas MSH-TP15 Fc k.o. was not effective in both models - reflecting the importance of Fc-dependent mechanisms of action also in vivo. The efficient recruitment of immune cells and the potent anti-tumor activity of the Fc-engineered MSH-TP15 antibody hold significant potential for myeloma immunotherapy.


Cerebral hemodynamic response to a therapeutic bed for procedural pain management in preterm infants in the NICU: a randomized controlled trial.
We developed a novel device, Calmer, that mimics key components of skin-to-skin holding to reduce stress in preterm infants. Our feasibility trial showed that Calmer worked 50% better than no treatment and no differently from our standard of care, facilitated tucking (FT), for reducing pain scores during a heel lance in preterm infants in the neonatal intensive care unit. We compared the effects of Calmer on regional cerebral hemodynamic activity during a noxious stimulation to FT. During a clinically required heel lance, we measured frontal cortex tissue oxygenation in a subsample of 29 preterm infants (27-33 weeks gestational age) from our larger randomized controlled trial. Infants were randomized to either FT (n = 16) or Calmer treatment (n = 12). The outcome measure, obtained using near-infrared spectroscopy, was a change in the tissue oxygenation index (TSI) across study phases (Baseline, Heel Lance, Recovery; median duration 517 seconds [421-906 seconds]). No statistically significant differences were found between groups in the median TSI during any of the study phases. In response to the heel lance, 7 infants (27.6%) had a TSI that dipped below the 60% threshold (3 in the Calmer group 25% and 4 in the FT group 25%); none below 50%. Infants on Calmer maintained normal regional cerebral oxygen levels (55%-85%) no differently from infants receiving a human touch intervention during blood collection. Parental skin-to-skin holding is one of the most effective strategies to relieve procedural pain in preterm infants. When parents or FT are not available, Calmer shows potential for filling this gap in care.


'It is still so deep-seated, the fear': psychological stress reactions as consequences of intimate partner violence.
The negative mental health consequences of intimate partner violence have been well documented in recent years. One aim of the present study was to examine psychological distress and mental problems in assaulted women who have left their relationships. Another aim was to explore these women's sense of coherence (SOC). A combination of qualitative in-depth interviews and quantitative measurement instruments was used. Data were collected from 14 assaulted women with a mean age of 38, living in different places in Sweden. Impact of event scale-revised and symptom checklist-90-R show that the violence creates long-term psychological stress reactions and confirm previous research on the subject. Twelve of the 14 women have symptoms of post-traumatic stress disorder (PTSD). The result of the interviews confirmed complex PTSD and disorders of extreme stress not otherwise specified. On the other hand we found a surprisingly high SOC level among several of the respondents, a fact which could explain why these women finally managed to leave mainly by their own efforts. We call for more both qualitative and quantitative studies on this serious public health issue.


No osteotomy rhinoplasty: indications and surgical details.
Lateral osteotomy is a particular step in rhinoplasty that aims to close an open roof deformity after hump reduction, narrow the lateral walls of the nose, and symmetrically align the nasal bony framework in cases with asymmetry. When the only reason for performing lateral osteotomy is to close an open roof, this can be avoided by using auto spreader flaps. In component hump reduction, the entire length of the upper lateral cartilage is preserved, including the portion under the nasal bone bilaterally. The basic principles involve suturing the flaps in the midline with a modified technique and supporting the lateral nasal walls with onlay cartilage grafts. This method was used for 34 patients. The lack of lateral wall support was obvious in one of the patients. With precise indications and a well-designed surgery, can be achieved. Further studies with more patients and a longer follow-up period are needed to determine the accuracy of this philosophy. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Medication adherence: A practical measurement selection guide using case studies.
Medication adherence is a complex problem and can be evaluated using a variety of methods. There is no single or perfect strategy to assess adherence. The "best" measure depends on contextual factors. Our objective is to provide a practical, illustrative guide for selecting the most appropriate measure of medication adherence in common contexts. We present three case studies - from the perspectives of an academic researcher, health care payer, and clinical care provider - to describe common problems and processes for measuring medication adherence, as well as proposing possible solutions. The most appropriate measure will depend on the context (tightly controlled clinical trial setting vs. clinical setting), intended purpose (research vs. clinical), available resources (data, personnel, materials, and funding), time (quick screening vs. comprehensive review), and phase of interest (initiation, implementation, or discontinuation). Framing the problem of medication non-adherence and methods for measuring adherence are discussed using three representative case studies. A simple tool is provided that may help stakeholders interested in medication adherence make decisions regarding the appropriate selection of measures. A medication adherence measure should be selected through the lens of each situation's unique objectives, resources, and needs.


Long-term outcomes in patients surviving acute respiratory distress syndrome.
Recent studies have begun to describe the long-term outcomes of acute respiratory distress syndrome (ARDS) survivors. These patients experience several physical, mental, and psychological morbidities that significantly impair their health-related quality of life (HRQL). Persistent for years after hospital discharge, decrements in functional and neuropsychological outcomes result in lost savings, employment reduction, and a reduction in HRQL among survivors and their caregivers. Future research should focus on the early identification of patients and their family members at risk for long-term sequelae, the mechanisms of injury leading to long-term ARDS consequences, and therapeutic modalities designed to prevent or decrease these morbidities. Clinicians, caregivers, and patients should be made aware of the deleterious long-term effects of the intensive care unit stay because they are currently poorly recognized and potentially modifiable.


Use of the rhomboid flap in pilonidal sinus.
Our experiences with transposed rhomboid flaps in the treatment of pilonidal disease are described. Results show that primary healing occurred in all twenty patients in our series, with a maximum inpatient hospital stay of four days. A single recurrent sinus has occurred during a follow-up time of eighteen months.


Protective effect of gamma-linolenic acid on aspirin-induced gastric hemorrhage in rats.
The effects of feeding with gamma-linolenic acid (GLA) in comparison with linoleic acid on aspirin-induced gastric hemorrhage were studied in the rat. Gastric damage was examined macroscopically and histologically. Intragastric administration of 100 mg aspirin daily for 4 weeks produced hemorrhage in 3 of 8 rats receiving a linoleic-acid-enriched diet, but none in 8 rats receiving GLA-enriched diet. The levels of linoleic acid in plasma and liver phospholipids were significantly increased, whereas those of arachidonic acid (AA) were reduced in plasma and liver phospholipids of aspirin-treated animals fed linoleic acid. Similar, more pronounced changes occurred in those animals with hemorrhage. The reduced ratios of arachidonate/linoleate suggest that fatty acid desaturation in these animals was depressed. Treatment with GLA prevented these changes. Our results demonstrated that GLA could protect the gastric mucosa from aspirin-induced damage by bypassing the depressed delta-6-desaturation and thus providing a precursor for the synthesis of AA and prostaglandins.


Genetic analysis of Indian aromatic and quality rice (Oryza sativa L.) germplasm using panels of fluorescently-labeled microsatellite markers.
Genetic relationships among Indian aromatic and quality rice (Oryza sativa) germplasm were assessed using 30 fluorescently labeled rice microsatellite markers. The 69 rice genotypes used in this study included 52 Basmati and other scented/quality rice varieties from different parts of India and 17 indica and japonica varieties that served as controls. A total of 235 alleles were detected at the 30 simple sequence repeat (SSR) loci, 62 (26.4%) of which were present only in Basmati and other scented/quality rice germplasm accessions. The number of alleles per locus ranged from 3 to 22, with an average of 7.8, polymorphism information content (PIC) values ranged from 0.2 to 0.9, with an average of 0.6, and the size range between the smallest and the largest allele for a given microsatellite locus varied between 3 bp and 68 bp. Of the 30 SSR markers, 20 could distinguish traditional Basmati rice varieties, and a single panel of eight markers could be used to differentiate the premium traditional Basmati, cross-bred Basmati, and non-Basmati rice varieties having different commercial value in the market-place. When estimates of inferred ancestry or similarity coefficients were used to cluster varieties, the high-quality Indian aromatic and quality rice genotypes could be distinguished from both indica and japonica cultivars, and crossbred varieties could be distinguished from traditional Basmati rices. The results indicate that Indian aromatic and quality germplasm is genetically distinct from other groups within O. sativa and is the product of a long independent pattern of evolution. The data also suggest that there is scope for exploiting the genetic diversity of aromatic/quality rice germplasm available in India for national Basmati rice breeding programs.


The epidemic status and risk factors of lung cancer in Xuanwei City, Yunnan Province, China.
Xuanwei City (formerly known as Xuanwei County) locates in the northeastern of Yunnan Province and is rich in coal, iron, copper and other mines, especially the smoky (bituminous) coal. Unfortunately, the lung cancer morbidity and mortality rates in this region are among China's highest, with a clear upward trend from the mid-1970s to mid-2000s. In 2004-2005, the crude death rate of lung cancer was 91.3 per 100,000 in the whole Xuanwei City, while that for Laibin Town in this city was 241.14 per 100,000. The epidemiologic distribution (clustering patterns by population, time, and space) of lung cancer in Xuanwei has some special features, e.g., high incidence in rural areas, high incidence in females, and an early age peak in lung cancer deaths. The main factor that associates with a high rate of lung cancer incidence was found to be indoor air pollution caused by the indoor burning of smoky coal. To a certain extent, genetic defects are also associated with the high incidence of lung cancer in Xuanwei. Taken together, lung cancer in this smoky coal combustion region is a unique model for environmental factor-related human cancer, and the current studies indicate that abandoning the use of smoky coal is the key to diminish lung cancer morbidity and mortality.


Plasmon-induced hyperthermia: hybrid upconversion NaYF4:Yb/Er and gold nanomaterials for oral cancer photothermal therapy.
Nanocomposites consisting of upconversion nanoparticles (UCPs) and plasmonic materials have been widely explored for bio-imaging and cancer photothermal therapy (PTT). However, several challenges, including incomprehensible efficiency of energy transfer processes and optimization of the conditions for plasmon-induced photothermal effects, still exist. In this study, we fabricated NaYF4:Yb3+/Er3+ nanoparticles (NPs) conjugated with gold nanomaterials (Au NMs), such as Au NPs and gold nanorods (Au NRs). NaYF4:Yb3+/Er3+ NPs were used as photoconverters, which could emit green and red light under excitation of a 980 nm laser; Au NPs and Au NRs were also prepared and used as heat producers. The silica shell was further coated around UCPs to improve biocompatibility and as a bridge linking UCPs and the Au NMs. Most importantly, the thickness of the silica shell was tuned precisely to investigate the effective distance of the plasmonic field for heat induction. Energy transfer was confirmed by the declining UCL photoluminescence and emission decay time after connecting to the Au NMs. Moreover, a simulative model was built using the finite element method to assess the differences in heat generation between UCP@SiO2-NPs and UCP@SiO2-NRs. The surfaces of the hybrid nanocomposites were modified with folic acid to improve the specific targeting to cancer cells. The performance of the modified hybrid nanocomposites in PTT for OECM-1 oral cancer cells was evaluated.


Management of hepatic encephalopathy in the hospital.
Hepatic encephalopathy (HE) develops in up to 50% of patients with cirrhosis and is a feature of decompensated cirrhosis. With the goal of reviewing the evidence for treatment and prevention of overt hepatic encephalopathy, pubmed was searched using search terms hepatic encephalopathy AND treatment, limited to human studies from January 1, 2003, through December 1, 2013, and supplemented by key references. The inpatient incidence of HE is approximately 23,000 annually, and management of these patients is common for internists and subspecialists. Treatment of the hospitalized patient with HE has changed in recent years. Treatment entails 2 phases: induction and maintenance of remission. Most cases of significant HE are precipitated by infection, gastrointestinal bleeding, medications, or other culprits. All patients should be evaluated for secondary triggers of HE, and treatment should be initiated with a nonabsorbable disaccharide (ie, lactulose) in most patients. Rifaximin (off label) can be added in patients not responding to lactulose. Neomycin is a less preferred alternative to rifaximin owing to its adverse effect profile. Other therapies, including zinc, L-ornithine-L-aspartate, and branched-chain amino acids, can be considered for patients not responding to disaccharides and nonabsorbable antibiotics. Large portosystemic shunts may be embolized in patients with medically refractory recurrent or severe HE with otherwise well-compensated cirrhosis. Molecular Adsorbent Recirculating System is now available for patients with severe HE who do not respond to medical therapy. It is critically important that patients hospitalized with significant HE continue maintenance therapy at the time of dismissal to prevent further episodes. Patients with a first-time episode of HE can be administered lactulose, and careful instructions should be provided to patients and caregivers about dose titration to achieve 3 bowel movements daily. Patients with recurrent HE episodes despite lactulose use benefit from the addition of rifaximin, which decreases the frequency of recurrent HE episodes and related hospitalizations. Last, patients and their families should be counseled about the risk of motor vehicle accidents, which require mandatory reporting to the Department of Motor Vehicles in some states.


Batch- and continuous-culture transients for two substrate systems.
Batch growth of Escherichia coli in the presence of equal initial concentrations of glucose and a secondary substrate (xylose) is characterized by sequential utilization of the substrates, whereas continuous-culture systems with equal concentrations of the two substrates in the feed are characterized by complete utilization of both substrates at both high and low dilution rates. Such systems at steady state at a low dilution rate, when suddenly shifted to a higher dilution rate, experience a transient drop in population density accompanied by accumulation of the secondary substrate but virtually no accumulation of glucose. Systems at steady state with 200 mg of glucose per liter were found to undergo a transient population decrease and eventual recovery when switched to feed containing 200 mg of a secondary substrate per liter.


[Clinical role of lipid metabolism indices in the plasma and erythrocytes in progressive muscular dystrophies].
Patterns of lipid metabolism were studied in blood plasma and erythrocytes of patients with various forms of hereditary myopathies (Duchenn disease, Bekker-Kiner disease, Erba-Roth disease, Landuzy-Dejerin disease, Sharko-Mary neural amyotrophy). These diseases were characterized by a number of common patterns: deficiency of phospholipids, specific alterations in properties of lipoproteins and in content of cholesterol. In the Duchenn disease specific alterations typical for each step of the disease were shown. These alterations might be of prognostic significance for evaluation of the rate of myodystrophy development.


Staphylococcus aureus hyaluronidase is a CodY-regulated virulence factor.
Staphylococcus aureus is a Gram-positive pathogen that causes a diverse range of bacterial infections. Invasive S. aureus strains secrete an extensive arsenal of hemolysins, immunomodulators, and exoenzymes to cause disease. Our studies have focused on the secreted enzyme hyaluronidase (HysA), which cleaves the hyaluronic acid polymer at the β-1,4 glycosidic bond. In the study described in this report, we have investigated the regulation and contribution of this enzyme to S. aureus pathogenesis. Using the Nebraska Transposon Mutant Library (NTML), we identified eight insertions that modulate extracellular levels of HysA activity. Insertions in the sigB operon, as well as in genes encoding the global regulators SarA and CodY, significantly increased HysA protein levels and activity. By altering the availability of branched-chain amino acids, we further demonstrated CodY-dependent repression of HysA activity. Additionally, through mutation of the CodY binding box upstream of hysA, the repression of HysA production was lost, suggesting that CodY is a direct repressor of hysA expression. To determine whether HysA is a virulence factor, a ΔhysA mutant of a community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 strain was constructed and found to be attenuated in a neutropenic, murine model of pulmonary infection. Mice infected with this mutant strain exhibited a 4-log-unit reduction in bacterial burden in their lungs, as well as reduced lung pathology and increased levels of pulmonary hyaluronic acid, compared to mice infected with the wild-type, parent strain. Taken together, these results indicate that S. aureus hyaluronidase is a CodY-regulated virulence factor.


Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy.
Apoptosis has been implicated as a possible mechanism in the development of heart failure (HF), but the mechanisms involved remain unclear. In patients with severe dilated cardiomyopathy, we evaluated cardiomyocyte apoptosis in relation to the transmural distribution of Bax and Bcl-2 proteins (2 molecules inhibiting or promoting apoptosis, respectively) and left ventricular wall stresses. We studied the presence and distribution of cardiomyocyte apoptosis in 90 tissue samples obtained from 8 patients who were undergoing left ventricular reduction with the Batista (ventricular remodeling) operation. Apoptosis was assessed in tissue samples taken from the entire left ventricular thickness (subdivided in subepicardial, midmyocardial, and subendocardial sections) with the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL) technique and DNA agarose gel electrophoresis. The expression of Bcl-2 and Bax proteins were determined with both Western analysis and immunohistochemistry. TUNEL-positive cells (apoptotic index) were 2.3% +/- 1.4%. Apoptotic cells were predominantly distributed in the subendocardium, where higher levels of Bax protein were detected. The ratio of Bax to Bcl-2 proteins (Bax/Bcl-2) was similar in the midmyocardium or subepicardium, but increased in the subendocardium, where it was directly related to systolic wall stress (y = 0.009x - 0.629; r2 = 0.85, P <.001). The apoptotic index was also directly related to systolic and end-diastolic stresses calculated from hemodynamic and echocardiographic data (r2 = 0.77, P <.001 and r2 = 0.40, P <.01, respectively). In patients with dilated cardiomyopathy, in whom cardiomyocyte apoptosis is an important cause of cell loss, apoptosis is more extensively localized in the subendocardium and strictly related to ventricular wall stresses and the Bax/Bcl-2 ratio.


Lessons from natural and artificial polyploids in higher plants.
Polyploidy in higher plants is a major source of genetic novelty upon which selection may act to drive evolution, as evidenced by the widespread success of polyploid species in the wild. However, research into the effects of polyploidy can be confounded by the entanglement of several processes: genome duplication, hybridisation (allopolyploidy is frequent in plants) and subsequent evolution. The discovery of the chemical agent colchicine, which can be used to produce artificial polyploids on demand, has enabled scientists to unravel these threads and understand the complex genomic changes involved in each. We present here an overview of lessons learnt from studies of natural and artificial polyploids, and from comparisons between the 2, covering basic cellular and metabolic consequences through to alterations in epigenetic gene regulation, together with 2 in-depth case studies in Senecio and Glycine. See also the sister article focusing on animals by Arai and Fujimoto in this themed issue.


Physical drivers facilitating a toxigenic cyanobacterial bloom in a major Great Lakes tributary.
The Maumee River is the primary source for nutrients fueling seasonal Microcystis-dominated blooms in western Lake Erie's open waters though such blooms in the river are infrequent. The river also serves as source water for multiple public water systems and a large food services facility in northwest Ohio, USA. On 20 September 2017, an unprecedented bloom was reported in the Maumee River estuary within the Toledo metropolitan area, which triggered a recreational water advisory. Here we (1) explore physical drivers likely contributing to the bloom's occurrence, and (2) describe the toxin concentration and bacterioplankton taxonomic composition. A historical analysis using ten-years of seasonal river discharge, water level, and local wind data identified two instances when high-retention conditions occurred over ≥10 days in the Maumee River estuary: in 2016 and during the 2017 bloom. Observation by remote sensing imagery supported the advection of cyanobacterial cells into the estuary from the lake during 2017 and the lack of an estuary bloom in 2016 due to a weak cyanobacterial bloom in the lake. A rapid-response survey during the 2017 bloom determined levels of the cyanotoxins, specifically microcystins, in excess of recreational contact limits at sites within the lower 20 km of the river while amplicon sequencing found these sites were dominated by Microcystis. These results highlight the need to broaden our understanding of physical drivers of cyanobacterial blooms within the interface between riverine and lacustrine systems, particularly as such blooms are expected to become more prominent in response to a changing climate.


Optimal cut-off score for diagnosing depression with the Patient Health Questionnaire (PHQ-9): a meta-analysis.
The brief Patient Health Questionnaire (PHQ-9) is commonly used to screen for depression with 10 often recommended as the cut-off score. We summarized the psychometric properties of the PHQ-9 across a range of studies and cut-off scores to select the optimal cut-off for detecting depression. We searched Embase, MEDLINE and PsycINFO from 1999 to August 2010 for studies that reported the diagnostic accuracy of PHQ-9 to diagnose major depressive disorders. We calculated summary sensitivity, specificity, likelihood ratios and diagnostic odds ratios for detecting major depressive disorder at different cut-off scores and in different settings. We used random-effects bivariate meta-analysis at cutoff points between 7 and 15 to produce summary receiver operating characteristic curves. We identified 18 validation studies (n = 7180) conducted in various clinical settings. Eleven studies provided details about the diagnostic properties of the questionnaire at more than one cut-off score (including 10), four studies reported a cut-off score of 10, and three studies reported cut-off scores other than 10. The pooled specificity results ranged from 0.73 (95% confidence interval [CI] 0.63-0.82) for a cut-off score of 7 to 0.96 (95% CI 0.94-0.97) for a cut-off score of 15. There was major variability in sensitivity for cut-off scores between 7 and 15. There were no substantial differences in the pooled sensitivity and specificity for a range of cut-off scores (8-11). The PHQ-9 was found to have acceptable diagnostic properties for detecting major depressive disorder for cut-off scores between 8 and 11. Authors of future validation studies should consistently report the outcomes for different cut-off scores.


Endogenous Klebsiella endophthalmitis as the presentation of both Klebsiella liver abscess and underlying anti-IFN-3 autoimmunity.
This case study is one of the first ever reported examples of infection in a patient with anti-IFN-3 autoimmunity and demonstrates how overwhelming infection can sometimes present with visual symptoms. We report the case of a previously fit middle-aged patient presenting with painless loss of vision and loss of appetite. Examination showed choroidal abscess and a pan-uveitis, leading to admission for vitreous biopsy. Klebsiella pneumoniae was isolated both in the vitreous and in blood cultures. Subsequent investigation discovered a liver abscess which was treated with percutaneous drainage. Despite the administration of intravitreal antibiotics from the time of presentation, intravenous antibiotics and vitrectomy on the same day, the patient proceeded to need enucleation 19 days later, and now has only light perception in the remaining eye. The strong association between K. pneumoniae endophthalmitis and underlying liver abscess leads to a significant mortality rate. Early diagnosis is essential, with prompt aggressive treatment with antibiotics, but sadly the visual prognosis remains poor. In cases of suspected choroidal abscess, initiation of sepsis screen and immediate empirical treatment is vital to improve this prognosis. This patient had no significant past medical history, no known immunocompromise, was not diabetic and had no recent significant foreign travel. However, further immunological analysis demonstrated the presence of anti-IFN-3 antibodies, a hitherto under-reported potential cause of increased susceptibility to infection, and so cases of sepsis in previously healthy individuals should be considered for further immunology assessment.


[Leptin: adipocyte hormone].
The authors reviewed the most recent literature on leptin, a protein produced by adipocytes which exerts its action on hypothalamus, modifying eating behavior and inhibiting the lust for food consumption. This one appeared to be the main, if not the only, physiologic action of leptin. Later leptin has been acknowledged a major role in the homeostasis. The regulation of the synthesis, and the mechanisms by which the protein modulates both food intake and energetic balance have been evaluated, and the hypotheses on the regulatory function exerted by leptin on the homeostasis, by acting on neuroendocrine system, on sexual maturity and fertility, on the sympathetic nervous system, on hemopoiesis and hydroelectrolytic balance have been discussed, some of which being already supported by experimental evidences.


[Measurement of central motor conduction time (CMCT) in healthy Chinese subjects].
Transcutaneous electrical stimulation of the central nervous system was used to measure CMCT between the human cerebral cortex and spinal cord. 64 normal volunteers (46 healthy adult males and 18 females, age of 20-67 years, body height of 156-185 cm) were recruited as experimental subjects. Action potentials of muscles were recorded from upper limb (Thenar) and lower limb (Muscle tibialis anterior) following cortical and spinal stimulation. The cortical and spinal latent periods (Lcor., Lsp.) were measured and CMCT was obtained by subtracting Lsp. from Lcor. for each muscle. The CMCT between the cerebral cortex and the first thoracic (Th1) cord was 6.69 +/- 1.48 ms, while that between the cerebral cortex and the first lumber (L1) cord was 12.90 +/- 1.59 ms. Statistical analysis indicated that CMCT was not related to sex, age, body height and left or right side of the body as well. The motor conduction velocity in spinal cord (MCVsp) between Th1 and L1, [distance (Th1 to L1)/CMCT (Muscle tibialis anterior)-CMCT (Thenar)] was found to be 71.34 +/- 10.89 m/s, which corresponds to the conduction velocity of the large fibers in the pyramidal tract. The results of the present study are valuable in diagnosis and prognosis of motor system diseases in CNS.


Investigation of a Quantum Monte Carlo Protocol To Achieve High Accuracy and High-Throughput Materials Formation Energies.
High-throughput calculations based on density functional theory (DFT) methods have been widely implemented in the scientific community. However, depending on both the properties of interest as well as particular chemical/structural phase space, accuracy even for correct trends remains a key challenge for DFT. In this work, we evaluate the use of quantum Monte Carlo (QMC) to calculate material formation energies in a high-throughput environment. We test the performance of automated QMC calculations on 21 compounds with high quality reference data from the Committee on Data for Science and Technology (CODATA) thermodynamic database. We compare our approach to different DFT methods as well as different pseudopotentials, showing that errors in QMC calculations can be progressively improved especially when correct pseudopotentials are used. We determine a set of accurate pseudopotentials in QMC via a systematic investigation of multiple available pseudopotential libraries. We show that using this simple automated recipe, QMC calculations can outperform DFT calculations over a wide set of materials. Out of 21 compounds tested, chemical accuracy has been obtained in formation energies of 11 structures using our QMC recipe, compared to none using DFT calculations.