[Mental disorders in German soldiers after deployment - impact of personal values and resilience].
Soldiers are at increased risk of developing mental health disorders after military deployment. The impact of personal values on psychological symptomatology based on an empirical working model has not yet been studied in a military environment. 117 German Armed Forces soldiers completed the Portrait-Values-Questionnaire (PVQ), the Patient-Health-Questionnaire (PHQ) and the Resilience-Scale (RS-11) after their deployment to Afghanistan. In the regression analyses the values hedonism, benevolence, tradition, self-direction and universalism had a differential significant impact on depression, anxiety and somatoform symptoms of the PHQ. The RS-11 sum scale values were negatively correlated with symptomatology. Personal values and resilience seem to be associated with psychological symptomatology in soldiers after military deployment. The results can contribute to the further development of both preventive and therapeutic approaches.


Amplified follicular immune complex deposition in mice lacking the Fc receptor gamma-chain does not alter maturation of the B cell response.
The role of Ag-Ab complexes (or immune complexes; ICs) in the regulation of the maturation of the B cell immune response was investigated in mice perturbed in the deposition and retention of such complexes. Loss of surface expression of Fc gammaRI and Fc gammaRIII due to targeted disruption of the common FcR gamma-chain gene results in dramatically increased deposition of ICs on follicular dendritic cells (FDCs) in germinal centers (GCs), attributed to altered clearance of circulating ICs. Despite these changes in the trapping of ICs by FDCs, serum Ab production, V gene hypermutation, isotype class switching and Ab affinity maturation are overtly unaltered. Thus, substantially augmenting B cell cognate Ag density on FDCs does not alter the outcome of the maturation of the B cell response. The significance of this finding in terms of the currently accepted model for the generation of B cell memory is discussed.


Salmonella infections associated with mung bean sprouts: epidemiological and environmental investigations.
We investigated an outbreak of Salmonella Enteritidis (SE) infections linked to raw mung bean sprouts in 2000 with two case-control studies and reviewed six similar outbreaks that occurred in 2000-2002. All outbreaks were due to unusual phage types (PT) of SE and occurred in the United States (PT 33, 1, and 913), Canada (PT 11b and 913), and The Netherlands (PT 4b). PT 33 was in the spent irrigation water and a drain from one sprout grower. None of the growers disinfected seeds at recommended concentrations. Only two growers tested spent irrigation water; neither discarded the implicated seed lots after receiving a report of Salmonella contamination. We found no difference in the growth of SE and Salmonella Newport on mung beans. Mung bean sprout growers should disinfect seeds, test spent irrigation water, and discontinue the use of implicated seed lots when pathogens are found. Laboratories should report confirmed positive Salmonella results from sprout growers to public health authorities.


Simple and rapid determination of triclabendazole and its metabolites in bovine and goat muscle tissue.
Triclabendazole (TCB) is widely used for prevention and treatment of parasitic infections in animals. Improper use can result in drug residues in animal tissues and cause health problems to humans through consumption. A simple and reliable analytical method for the determination of TCB and its metabolites in bovine and goat muscle using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. Analytes were extracted using acetonitrile and purified using enhanced matrix removal cartridge. Chromatographic separation was carried out on a BEH Shield RP18 column. The analytes were detected in positive-mode electrospray ionization mass spectrometry using multiple reaction monitoring. Average recoveries of 96.1%-105.6% with coefficients of variation of 1.9%-8.4% were obtained at fortification levels of 0.5, 2.5, 25, and 50 μg/kg for TCB and 5.0, 25, 250, and 500 μg/kg for its metabolites (triclabendazole sulfoxide, triclabendazole sulfone, and keto-TCB). A good linear regression was obtained with the mixed standard solutions in the range of 0.05-20 μg/L for TCB and 0.5-200 μg/L for its metabolites. The limit of quantification and limit of detection ranged from 0.05 to 0.75 μg/kg and from 0.1 to 1.5 μg/kg, respectively. Moreover, this method was successfully applied to 33 real samples.


Phenogenotypic Characterization of Escherichia coli O157:H7 Strains Isolated from Cattle at Slaughter.
Shiga toxin-producing Escherichia coli (STEC) O157:H7 was isolated from 30 (4%) of 744 cattle hide swab samples collected at Estonian slaughterhouses within a 3-year monitoring program of zoonotic pathogens. The isolates were characterized by determining the presence of STEC main virulence factors, the antimicrobial resistance profiles, and the genetic relatedness by pulsed-field gel electrophoresis (PFGE). Thirteen strains carried the stx2 gene alone and 17 both the stx1 and stx2 genes. The most frequently detected stx subtype was stx2c, occurring alone (n = 12) or in combination with subtype stx1a (n = 13). All isolates harbored the intimin-coding eae gene and produced enterohemolysin. Twelve isolates (40%) showed resistance to at least one of the 14 antimicrobials and the isolates were predominantly resistant to streptomycin, sulfamethoxazole, and ampicillin. No extended-spectrum beta-lactamase-producing isolates were detected. PFGE characterization of the isolates showed an overall similarity higher than 75%, and four clusters based on 100% similarity were revealed.


Method of Food Preparation Influences Blood Glucose Response to a High-Carbohydrate Meal: A Randomised Cross-over Trial.
The aim of this study was to establish the blood glucose response to different cooking methods of pasta. Participants consumed three identical meals in a random order that were freshly cooked (hot), cooled and reheated. Blood glucose concentrations were assessed before, and every 15 min after ingestion of each meal for 120 min. There was a significant interaction between temperature and time (F ( 8.46 - 372.34 ) = 2.75, p = 0.005), with the reheated (90 min) condition returning to baseline faster than both cold (120 min) and hot conditions. Blood glucose area under the curve (AUC) was significantly lower in the reheated (703 ± 56 mmol·L-1·min-1) than the hot condition (735 ± 77 mmol·L-1·min-1, t ( 92 ) = -3.36, pbonferroni = 0.003), with no significant difference with the cold condition (722 ± 62 mmol·L-1·min-1). To our knowledge, the current study is the first to show that reheating pasta causes changes in post-prandial glucose response, with a quicker return to fasting levels in both the reheated and cooled conditions than the hot condition. The mechanisms behind the changes in post-prandial blood glucose seen in this study are most likely related to changes in starch structure and how these changes influence glycaemic response.


HIF-1α in Myeloid Cells Promotes Adipose Tissue Remodeling Toward Insulin Resistance.
Adipose tissue hypoxia is an important feature of pathological adipose tissue expansion. Hypoxia-inducible factor-1α (HIF-1α) in adipocytes reportedly induces oxidative stress and fibrosis, rather than neoangiogenesis via vascular endothelial growth factor (VEGF)-A. We previously reported that macrophages in crown-like structures (CLSs) are both hypoxic and inflammatory. In the current study, we examined how macrophage HIF-1α is involved in high-fat diet (HFD)-induced inflammation, neovascularization, hypoxia, and insulin resistance using mice with myeloid cell-specific HIF-1α deletion that were fed an HFD. Myeloid cell-specific HIF-1α gene deletion protected against HFD-induced inflammation, CLS formation, poor vasculature development in the adipose tissue, and systemic insulin resistance. Despite a reduced expression of Vegfa in epididymal white adipose tissue (eWAT), the preadipocytes and endothelial cells of HIF-1α-deficient mice expressed higher levels of angiogenic factors, including Vegfa, Angpt1, Fgf1, and Fgf10 in accordance with preferable eWAT remodeling. Our in vitro study revealed that lipopolysaccharide-treated bone marrow-derived macrophages directly inhibited the expression of angiogenic factors in 3T3-L1 preadipocytes. Thus, macrophage HIF-1α is involved not only in the formation of CLSs, further enhancing the inflammatory responses, but also in the inhibition of neoangiogenesis in preadipocytes. We concluded that these two pathways contribute to the obesity-related physiology of pathological adipose tissue expansion, thus causing systemic insulin resistance.


Gaussian process robust regression for noisy heart rate data.
Heart rate data collected during nonlaboratory conditions present several data-modeling challenges. First, the noise in such data is often poorly described by a simple Gaussian; it has outliers and errors come in bursts. Second, in large-scale studies the ECG waveform is usually not recorded in full, so one has to deal with missing information. In this paper, we propose a robust postprocessing model for such applications. Our model to infer the latent heart rate time series consists of two main components: unsupervised clustering followed by Bayesian regression. The clustering component uses auxiliary data to learn the structure of outliers and noise bursts. The subsequent Gaussian process regression model uses the cluster assignments as prior information and incorporates expert knowledge about the physiology of the heart. We apply the method to a wide range of heart rate data and obtain convincing predictions along with uncertainty estimates. In a quantitative comparison with existing postprocessing methodology, our model achieves a significant increase in performance.


News about VDAC1 in Hypoxia.
The voltage-dependent anion channel (VDAC) is the main interface between the cytosol and mitochondria of cells. It plays a crucial role in both mitochondrial metabolism and cell death. The main basic function of this channel is to mediate and gate the flux of small ions, metabolites, and adenosine triphosphate. Changes in its structure, and thus conformation, are expected to affect its activity and modulate the ability of cancer cells to expand. In this review, we describe a novel mechanism by which mitochondria of cells in hypoxia, a low level of oxygen, protects from apoptosis. In hypoxia, some mitochondria become enlarged due to hyperfusion. These mitochondria possess a truncated form of VDAC1 (VDAC1-ΔC), which is linked to the higher metabolic capacity and the greater resistance to cell death of hypoxic cells. However, not all of the VDAC1 protein is truncated, but the amount of the full-length form is diminished compared to the amount in normoxic cells. First, we describe how such a decrease effects cell proliferation, respiration, glycolysis, and other processes. Second, we report on a novel mitochondrial-endolysosomal crosstalk that leads to VDAC1 truncation. By pharmacological targeting of VDAC1-ΔC, the production of energy could be turned off and the sensitivity to cell death restored. This could counteract the favorable microenvironment that gives cancer cells a growth advantage and thereby disrupts the balance between life and death, which is controlled by VDAC1.


Tuning the Electronic and Dynamical Properties of a Molecule by Atom Trapping Chemistry.
The ability to trap adatoms with an organic molecule on a surface has been used to obtain a range of molecular functionalities controlled by the choice of the molecular trapping site and local deprotonation. The tetraphenylporphyrin molecule used in this study contains three types of trapping sites: two carbon rings (phenyl and pyrrole) and the center of a macrocycle. Catching a gold adatom on the carbon rings leads to an electronic doping of the molecule, whereas trapping the adatom at the macrocycle center with single deprotonation leads to a molecular rotor and a second deprotonation leads to a molecular jumper. We call "atom trapping chemistry" the control of the structure, electronic, and dynamical properties of a molecule achieved by trapping metallic atoms with a molecule on a surface. In addition to the examples previously described, we show that more complex structures can be envisaged.


A qPCR-Based Tool to Diagnose the Presence of Harmful Cyanobacteria and Cyanotoxins in Drinking Water Sources.
Harmful cyanobacteria have been an important concern for drinking water quality for quite some time, as they may produce cyanotoxins and odorants. Microcystis and Cylindrospermopsis are two common harmful cyanobacterial genera detected in freshwater lakes and reservoirs, with microcystins (MCs) and cylindrospermopsin (CYN) as their important metabolites, respectively. In this study, two sets of duplex qPCR systems were developed, one for quantifying potentially-toxigenic Microcystis and Microcystis, and the other one for cylindrospermopsin-producing cyanobacteria and Cylindrospermopsis. The duplex qPCR systems were developed and validated in the laboratory by using 338 samples collected from 29 reservoirs in Taiwan and her offshore islands. Results show that cell numbers of Microcystis and Cylindorspermopsis enumerated with microscopy, and MCs and CYN concentrations measured with the enzyme-linked immuno-sorbent assay method, correlated well with their corresponding gene copies determined with the qPCR systems (range of coefficients of determination R² = 0.392-0.740). The developed qPCR approach may serve as a useful tool for the water industry to diagnose the presence of harmful cyanobacteria and the potential presence of cyanotoxins in source waters.


Cellularity of adipose tissue in meat animals.
Present information indicates that for meat animals adipocyte number is achieved most rapidly in the perirenal depot and least rapidly in the interfascicular of intramuscular depot. Adipocyte volume appears to be largest in the perirenal depot and smallest in the interfascicular and intermuscular depots. The best estimates available suggest that adipocyte hyperplasia is completed by 14 months of age in bovine animals and 5 months of age in porcine animals. However, because of certain technique limitations and the presence of many small adipocytes in very obese animals, these estimates must be considered very tentative. Studies in ovine and porcine animals indicate that early under-nutrition is not effective in reducing the number of subcutaneous and perirenal adipocytes later in life. However, the number of interfascicular adipocytes may be reduced. Several studies have demonstrated that the interfascicular adipocytes are very late developing and that adipocyte number is very important to the total quantity of intramuscular lipid.


Roadmap on neurophotonics.
Mechanistic understanding of how the brain gives rise to complex behavioral and cognitive functions is one of science's grand challenges. The technical challenges that we face as we attempt to gain a systems-level understanding of the brain are manifold. The brain's structural complexity requires us to push the limit of imaging resolution and depth, while being able to cover large areas, resulting in enormous data acquisition and processing needs. Furthermore, it is necessary to detect functional activities and 'map' them onto the structural features. The functional activity occurs at multiple levels, using electrical and chemical signals. Certain electrical signals are only decipherable with sub-millisecond timescale resolution, while other modes of signals occur in minutes to hours. For these reasons, there is a wide consensus that new tools are necessary to undertake this daunting task. Optical techniques, due to their versatile and scalable nature, have great potentials to answer these challenges. Optical microscopy can now image beyond the diffraction limit, record multiple types of brain activity, and trace structural features across large areas of tissue. Genetically encoded molecular tools opened doors to controlling and detecting neural activity using light in specific cell types within the intact brain. Novel sample preparation methods that reduce light scattering have been developed, allowing whole brain imaging in rodent models. Adaptive optical methods have the potential to resolve images from deep brain regions. In this roadmap article, we showcase a few major advances in this area, survey the current challenges, and identify potential future needs that may be used as a guideline for the next steps to be taken.


Potato: a comparative study of the effect of cultivars and cultivation conditions and genetic modification on the physico-chemical properties of potato tubers in conjunction with multivariate analysis towards authenticity.
Potato (Solanum tuberosum L.) is a highly nutritious, mild flavored, easy to blend food that has many possibilities for "building in" desired nutrients. Varietal and environmental differences are known to exist in the shape, size, and nutritional content of potatoes. Different populations opt for varying sensory properties in relation to their diets. Potatoes are a low energy food in comparison to cereals and legumes. The aim of this review was to present an update of the currently conducted studies both on the characterization of several potato varieties (physical, chemical, and sensory analysis) and by means of genetic modification. Towards this target, five comprehensive tables were compiled where all recent data (physicochemical properties) and GM varieties were presented in conjunction with multivariate analysis (chemometrics). The latter was shown to be effectively used towards authenticity purposes (identification of geographical origin, variety, GM).


Prevalence and Healthcare Burden of Fungal Infections in the United States, 2018.
Fungal infections are responsible for >1.5 million deaths globally per year, primarily in those with compromised immune function. This is concerning as the number of immunocompromised patients, especially in those without human immunodeficiency virus (HIV), has risen in the past decade. The purpose of this analysis was to provide the current prevalence and impact of fungal disease in the United States. We analyzed hospital discharge data from the most recent (2018) Healthcare Cost and Utilization Project National Inpatient Sample, and outpatient visit data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. Costs are presented in 2018 United States (US) dollars. In the 35.5 million inpatient visits documented in 2018 in the US, approximately 666 235 fungal infections were diagnosed, with an estimated attributable cost of $6.7 billion. Aspergillus, Pneumocystis, and Candida infections accounted for 76.3% of fungal infections diagnosed, and 81.1% of associated costs. Most fungal disease occurred in patients with elevated risk of infection. The visit costs, lengths of stay, and risks of mortality in this population were more than twice that of those without fungal diagnoses. A further 6.6 million fungal infections were diagnosed during outpatient visits. Fungal disease is a serious clinical concern with substantial healthcare costs and significant increases in morbidity and mortality, particularly among predisposed patients. Increased surveillance, standardized treatment guidelines, and improvement in diagnostics and therapeutics are needed to support the rising numbers of at-risk patients.


Spectroscopic properties of benzene at the air-ice interface: a combined experimental-computational approach.
A combined experimental and computational approach was used to study the spectroscopic properties of benzene at the ice-air interface at 253 and 77 K in comparison with its spectroscopic behavior in aqueous solutions. Benzene-contaminated ice samples were prepared either by shock-freezing of benzene aqueous solutions or by benzene vapor-deposition on pure ice grains and examined using UV diffuse reflectance and emission spectroscopies. Neither the absorption nor excitation nor emission spectra provided unambiguous evidence of benzene associates on the ice surface even at a higher surface coverage. Only a small increase in the fluorescence intensity in the region above 290 nm found experimentally might be associated with formation of benzene excimers perturbed by the interaction with the ice surface as shown by ADC(2) excited-state calculations. The benzene associates were found by MD simulations and ground-state DFT calculations, although not in the arrangement that corresponds to the excimer structures. Our experimental results clearly demonstrated that the energy of the S0 → S1 electronic transition of benzene is not markedly affected by the phase change or the microenvironment at the ice-air interface and its absorption is limited to the wavelengths below 268 nm. Neither benzene interactions with the water molecules of ice nor the formation of dimers and microcrystals at the air-ice interface thus causes any substantial bathochromic shift in its absorption spectrum. Such a critical evaluation of the photophysical properties of organic contaminants of snow and ice is essential for predictions and modeling of chemical processes occurring in polar regions.


Colloidal Gels with Extracellular Matrix Particles and Growth Factors for Bone Regeneration in Critical Size Rat Calvarial Defects.
Colloidal gels encapsulating natural materials and exhibiting paste-like properties for placement are promising for filling complex geometries in craniofacial bone regeneration applications. Colloidal materials have demonstrated modest clinical outcomes as bone substitutes in orthopedic applications, but limited success in craniofacial applications. As such, development of a novel colloidal gel will fill a void in commercially available products for use in craniofacial reconstruction. One likely application for this technology is cranial reconstruction. Currently, traumatic brain injury (TBI) is often treated with a hemi-craniectomy, a procedure in which half the cranium is removed to allow the injured brain to swell and herniate beyond the enclosed cranial vault. The use of colloidal gels would allow for the design of a pliable material capable of expansion during brain swelling and facilitate cranial bone regeneration alleviating the need for a second surgery to replace the previously removed hemi-cranium. In the current study, colloidal nanoparticles of hydroxyapatite (HAp), demineralized bone matrix (DBM), and decellularized cartilage (DCC) were combined with hyaluronic acid (HA) to form colloidal gels with desirable rheological properties ([Formula: see text] ≥ 100 Pa). BMP-2 and VEGF growth factors were included to assess extracellular matrix (ECM) contribution of DBM and DCC. The HA-HAp (BMP-2) and HA-HAp-DCC group had 89 and 82% higher bone regeneration compared to the sham group, respectively (p < 0.01). Material retention issues observed may be alleviated by implementing chemical crosslinking. Overall, DCC may be a promising material for bone regeneration in general, and colloidal gels may hold significant potential in craniofacial applications.


Fever hospitals in counties Armagh and Down: 1817-39.
This paper outlines the provision for fever patients, (other than those suffering from cholera during the epidemic of 1832-34), in counties Armagh and Down in the two decades prior to the introduction of the Poor Law to Ireland. Possible causes of fever and the numbers of patients treated are discussed. The establishment and location of fever hospitals and the state of the premises are considered and an assessment of the contribution of these institutions to the development of medical provision in the early nineteenth century is also provided.


Migration from Mexico to the United States and subsequent risk for depressive and anxiety disorders: a cross-national study.
Migration is suspected to increase risk for depressive and anxiety disorders. To test the hypothesized increase in risk for depressive and anxiety disorders after arrival in the United States among Mexican migrants. We combined data from surveys conducted separately in Mexico and the United States that used the same diagnostic interview. Discrete time survival models were specified to estimate the relative odds of first onset of depressive disorders (major depressive episode and dysthymia) and anxiety disorders (generalized anxiety disorder, social phobia, panic disorder, and posttraumatic stress disorder) among migrants after their arrival in the United States compared with nonmigrant Mexicans who have a migrant in their immediate family. Population surveys in the United States and Mexico. Two thousand five hundred nineteen nonmigrant family members of migrants in Mexico and 554 Mexican migrants in the United States. First onset of any depressive or anxiety disorder. After arrival in the United States, migrants had a significantly higher risk for first onset of any depressive or anxiety disorder than did nonmigrant family members of migrants in Mexico (odds ratio, 1.42; 95% confidence interval, 1.04-1.94). Associations between migration and disorder varied across birth cohorts. Elevated risk among migrants relative to nonmigrants was restricted to the 2 younger cohorts (those aged 18-25 or 26-35 years at interview). In the most recent birth cohort, the association between migration and first onset of any depressive or anxiety disorder was particularly strong (odds ratio, 3.89; 95% confidence interval, 2.74-5.53). This is, to our knowledge, the first study to compare risk for first onset of psychiatric disorder between representative samples of migrants in the United States and nonmigrants in Mexico. The findings are consistent with the hypothesized adverse effect of migration from Mexico to the United States on the mental health of migrants, but only among migrants in recent birth cohorts.


Higher Surgical Morbidity for Ulcerative Colitis Patients in the Era of Biologics.
To investigate differences in surgical approach and postoperative outcomes for patients with ulcerative colitis (UC) before and after the introduction of biologic therapy. Biologic use has dramatically increased since Food and Drug Administration approval of infliximab. Studies conflict as to the effect of these agents on surgical outcomes with some demonstrating worse surgical outcomes whereas others have found no difference. We used an administrative, all-payer, all-age group database located in New York State. Patients were included if they had a diagnosis of UC and underwent surgery for their disease from 1995 to 2013. Outcomes were compared for the index admission, at 90-day, and 1-year follow up. A total of 7070 patients were included for analysis; 54% patients underwent surgery between 1995 and 2005 and the remaining 46% patients underwent surgery between 2005 and 2013. There was a significant increase in the proportion of patients who underwent at least 3 procedures after 2005(14% vs 9%, P < 0.01). On adjusted analysis, patients undergoing surgery after 2005 had higher likelihood of major events (odd s ratio, OR = 1.42; 95% confidence interval, CI = 1.13-1.78), procedural complications (OR = 1.42; 95% CI = 1.20-1.68), and nonroutine discharge (OR = 3.17; 95% CI = 2.79-3.60) during the index admission. Similar trends for worse adjusted outcomes in patients initially undergoing surgery after 2005 were seen at 90-day and 1-year follow up. Since the introduction of biologic agents in 2005, surgery for patients with UC is more likely to require multiple procedures. Despite robust adjustments, patients having surgery recently have worse postoperative morbidity during the index hospitalization, at 90-day and 1-year follow up. More work is necessary to improve outcomes in these higher risk patients that undergo surgery.


Lapatinib-Related Rash and Breast Cancer Outcome in the ALTTO Phase III Randomized Trial.
Previously we have shown that early development of rash is associated with a higher chance of achieving pathological complete response to neoadjuvant lapatinib. In the current analysis, we investigate its impact on survival in the ALTTO phase III adjuvant trial. In ALTTO, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomly assigned to adjuvant trastuzumab, lapatinib, their sequence, or their combination for a total duration of one year. We evaluated whether the development of early lapatinib-related rash (ie, within 6 weeks) is associated with disease-free (DFS) and overall survival (OS). Landmark analysis at eight weeks and time-dependent analysis were tested in a multivariable model stratifying on trial's stratification factors. All statistical tests were two-sided. Out of 6098 lapatinib-treated patients, 3973(65.2%) were included in the landmark analysis, of whom 1389 (35.0%) had developed early rash. After median follow-up of 4.5 years, the development of early rash was associated with a trend of improved DFS (multivariable: hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.73 to 1.03,P= .10) and statistically significantly improved OS (multivariable: HR = 0.63, 95% CI = 0.48 to 0.82,P< .001) compared with subjects without early rash. Compared with patients randomly assigned to trastuzumab (n = 2051), patients who were randomly assigned to trastuzumab/lapatinib combination and developed early rash (n = 692) had superior DFS (multivariable: HR = 0.72, 95% CI = 0.55 to 0.92,P= .01) and OS (multivariable: HR = 0.59, 95% CI = 0.39 to 0.90,P= .01). Time-dependent analysis suggests that the occurrence of rash is predictive of lapatinib benefit, both when given in combination or sequential to trastuzumab. Our results indicate that early development of rash identifies patients who derive superior benefit from lapatinib-based therapy.


A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy.
To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD). Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg-1·d-1, tadalafil 0.6 mg·kg-1·d-1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome. Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state. Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age. NCT01865084. This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy.


Archaeal lipids in oral delivery of therapeutic peptides.
Archaea contain membrane lipids that differ from those found in the other domains of life (Eukarya and Bacteria). These lipids consist of isoprenoid chains attached via ether bonds to the glycerol carbons at the sn-2,3 positions. Two types of ether lipids are known, polar diether lipids and bipolar tetraether lipids. The inherent chemical stability and unique membrane-spanning characteristics of tetraether lipids render them interesting for oral drug delivery purposes. Archaeal lipids form liposomes spontaneously (archaeosomes) and may be incorporated in conventional liposomes (mixed vesicles). Both types of liposomes are promising to protect their drug cargo, such as therapeutic peptides, against the acidic environment of the stomach and proteolytic degradation in the intestine. They appear to withstand lipolytic enzymes and bile salts and may thus deliver orally administered therapeutic peptides to distant sections of the intestine or to the colon, where they may be absorbed, eventually by the help of absorption enhancers. Archaeal lipids and their semisynthetic derivatives may thus serve as biological source for the next generation oral drug delivery systems. The aim of this review is to present a systematic overview over existing literature on archaea carrying diether and tetraether lipids, lipid diversity, means of lipid extraction and purification, preparation and in vitro stability studies of archaeal lipid-based liposomal drug carriers and in vivo proof-of concepts studies.


An adenosine triphosphate-dependent calcium uptake pump in human neutrophil lysosomes.
Regulation of the cytosolic free calcium concentration is important to neutrophil function. In these studies, an ATP-dependent calcium uptake pump has been identified in human neutrophil lysosomes. This energy-dependent Ca++ uptake pump has a high affinity for Ca++ (Michaelis constant [Km] Ca++ = 107 nM) and a maximum velocity (Vmax) of 5.3 pmol/mg of protein per min. ATP was the only nucleotide that supported Ca++ uptake by lysosomes. The Km for ATP was 177 microM. ATP-dependent Ca++ uptake by neutrophil lysosomes was temperature- and pH-sensitive with optimal Ca++ pump activity at 37 degrees C and pH 7.0-7.5. Mg++ was also essential for ATP-dependent Ca++ uptake by lysosomes. Azide and antimycin A had no effect on the energy-dependent uptake of Ca++ by neutrophil lysosomes. The chemotactic peptide formyl-methionyl-leucyl-phenylalanine inhibited ATP-dependent Ca++ accumulation by isolated lysosomes. Butoxycarbonyl-phenylalanine-leucine-phenylalanine-leucine-phenylalanine , a competitive antagonist of the chemotactic peptide, blocked this inhibitory effect. These studies demonstrate the presence of an ATP-dependent Ca++ uptake pump in human neutrophil lysosomes that functions at physiologic intracellular concentrations of Ca++, ATP, and H+ and may be important to regulating neutrophil function by modulating cytosolic Ca++.


Efficiency and Duration of Orthodontic/Orthognathic Surgery Treatment.
To investigate the combined orthodontic-orthognathic treatment times at an academic hospital in the UK and to consider the level of occlusal change in delivering this treatment by the way of comparing peer assessment rating (PAR) scores pre- and post-treatment. It was a retrospective longitudinal study of orthognathic patients between 2010 and 2013 who had completed orthognathic treatment. Analysis of records of 50 patients was carried out. Age, gender malocclusion, and skeletal pattern, extraction/nonextraction of teeth, duration of active orthodontic treatment, number of appointments, transfer of patients between orthodontists mid-treatment, and PAR scores pre and post-treatment were recorded for each patient. The skeletal pattern was III in 70% of and II in 28% of patients. Mean duration of active orthodontic treatment was 27.9 months. Age, gender, malocclusion, and skeletal pattern did not seem to affect treatment times. Extraction of teeth and transfer of operators increased treatment times. The mean PAR reduction was 89% with the PAR efficiency factor (reduction in PAR scores divided by duration of treatment in months) of 1.61. Younger patients, those with class III malocclusions and patients starting with higher PAR scores, achieved greater PAR reductions. Gender, number of appointments, extractions, transfer of operators, and total duration of treatment were not shown to affect the PAR % reduction. Combined orthodontic-orthognathic treatment has been effective in treating patients with severe skeletal discrepancies. Transfer of operators and extractions protracted treatment times. Younger patients and those with class III malocclusions achieved higher PAR % reduction.


An EXAFS spectroscopic, large-angle X-ray scattering, and crystallographic study of hexahydrated, dimethyl sulfoxide and pyridine 1-oxide hexasolvated mercury(II) ions.
The structure of the solvated mercury(II) ion in water and dimethyl sulfoxide has been studied by means of large-angle X-ray scattering (LAXS) and extended X-ray absorption fine structure (EXAFS) techniques. The distribution of the Hg-O distances is unusually wide and asymmetric in both solvents. In aqueous solution, hexahydrated [Hg(OH(2))(6)](2+) ions in a distorted octahedral configuration, with the centroid of the Hg-O distance at 2.38(1) A, are surrounded by a diffuse second hydration sphere with HgO(II) distances of 4.20(2) A. In dimethyl sulfoxide, the six Hg-O and HgS distances of the hexasolvated [Hg{OS(CH(3))(2)}(6)](2+) complex are centered around 2.38(1) and 3.45(2) A, respectively. The crystal structure of hexakis(pyridine 1-oxide)mercury(II) perchlorate has been redetermined. The space group R(-)3 implies six equal Hg-O distances of 2.3416(7) A for the [Hg(ONC(5)H(5))(6)](2+) complex at 100 K. However, EXAFS studies of this compound, and of the solids hexaaquamercury(II) perchlorate and hexakis(dimethyl sulfoxide)mercury(II) trifluoromethanesulfonate, also with six equidistant Hg-O bonds according to crystallographic results, reveal in all cases strongly asymmetric Hg-O distance distributions. Vibronic coupling of valence states in a so-called pseudo-Jahn-Teller effect probably induces the distorted configurations.


First biological measurements of deep-sea corals from the Red Sea.
It is usually assumed that metabolic constraints restrict deep-sea corals to cold-water habitats, with 'deep-sea' and 'cold-water' corals often used as synonymous. Here we report on the first measurements of biological characters of deep-sea corals from the central Red Sea, where they occur at temperatures exceeding 20°C in highly oligotrophic and oxygen-limited waters. Low respiration rates, low calcification rates, and minimized tissue cover indicate that a reduced metabolism is one of the key adaptations to prevailing environmental conditions. We investigated four sites and encountered six species of which at least two appear to be undescribed. One species is previously reported from the Red Sea but occurs in deep cold waters outside the Red Sea raising interesting questions about presumed environmental constraints for other deep-sea corals. Our findings suggest that the present understanding of deep-sea coral persistence and resilience needs to be revisited.


Two-dimensional scattering of a plane wave from a periodic array of dielectric cylinders with arbitrary shape.
A two-dimensional scattering of a plane wave from a periodic array of dielectric cylinders with arbitrary shape using the multigrid-moment method is examined. The scattered field is expressed in terms of the integral form by an infinite summation of the surface integral over the cross section of the reference cylinder. The integral form is converted into the matrix equation by using the moment method. The integration in the elements of the matrix equation is evaluated by the lattice-sums technique to obtain a precise solution. The multigrid method is applied to the matrix equation to improve the CPU time. The CPU time and the residual norm are examined numerically for a given number of iterations and cycle indices. Then the effects of shape and material of the periodic structure on the power reflection coefficient of the fundamental Floquet mode are shown. In addition, the results indicate the effect of changing the relative permittivity of the dielectric coated body and the reflection coefficient.


[Non-destructive neutron activation analysis of dental porcelain powders (author's transl)].
Determination of 15 elements in the dental porcelain powders (Vita VMK 68) marketed in Japan was done by means of non-destructive neutron activation analysis. The potassium and sodium contents showed less variations from powder to powder, and the uranium contents varied from a few ppm to 1090 ppm in a wide range. The high contents of uranium (345--1090 ppm) were detected in the powders of Enamel, Dentin, Effect, Color and Gum which were used for the superficial parts of a porcelain crown, while the low contents of uranium (1.6--2.7 ppm) were detected in those of Opaque and Translucent which were used for the core part and the top of the crown. Cerium and samarium were also detected in each powder in the amounts similar to those of uranium. The main radionuclides present in the porcelain powders were 238U, 235U, 234U, 234mPa, 234Th, 231Th and 40K. The activities of these nuclides were calculated and discussed.


The regulation of Enzyme IIA(Glc) expression controls adenylate cyclase activity in Escherichia coli.
During the last few years, several genes, such as pap, bgl and flhDC, have been shown to be coregulated by the histone-like nucleoid-structuring (H-NS) protein and the cyclic AMP-catabolite activator protein (cAMP/CAP) complex, suggesting an interaction between both systems in the control of some cellular functions. In this study, the possible effect of H-NS on the cAMP level was investigated. In a CAP-deficient strain, the presence of an hns mutation results in a strong reduction in the amount of cAMP, due to a decrease in adenylate cyclase activity. This is caused by the reduced expression of crr, which encodes the Enzyme IIA(Glc) of the phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS), from its specific P2 promoter. This leads to a twofold reduction in the global amount of Enzyme IIA(Glc), the adenylate cyclase activator, responsible for the decrease in adenylate cyclase activity observed in the hns crp strain.


Predictive performance of universal termination of resuscitation rules in an Asian community: are they accurate enough?
Prehospital termination of resuscitation (TOR) rules have not been widely validated outside of Western countries. This study evaluated the performance of TOR rules in an Asian metropolitan with a mixed-tier emergency medical service (EMS). We analysed the Utstein registry of adult, non-traumatic out-of-hospital cardiac arrests (OHCAs) in Taipei to test the performance of TOR rules for advanced life support (ALS) or basic life support (BLS) providers. ALS and BLS-TOR rules were tested in OHCAs among three subgroups: (1) resuscitated by ALS, (2) by BLS and (3) by mixed ALS and BLS. Outcome definition was in-hospital death. Sensitivity, specificity, positive predictive value (PPV), negative predictive value and decreased transport rate (DTR) among various provider combinations were calculated. Of the 3489 OHCAs included, 240 were resuscitated by ALS, 1727 by BLS and 1522 by ALS and BLS. Overall survival to hospital discharge was 197 patients (5.6%). Specificity and PPV of ALS-TOR and BLS-TOR for identifying death ranged from 70.7% to 81.8% and 95.1% to 98.1%, respectively. Applying the TOR rules would have a DTR of 34.2-63.9%. BLS rules had better predictive accuracy and DTR than ALS rules among all subgroups. Application of the ALS and BLS TOR rules would have decreased OHCA transported to the hospital, and BLS rules are reasonable as the universal criteria in a mixed-tier EMS. However, 1.9-4.9% of those who survived would be misclassified as non-survivors, raising concern of compromising patient safety for the implementation of the rules.


An evaluation of patient safety culture in a secondary care setting in Kuwait.
To improve patient safety outcomes, it is considered essential to create a positive culture of patient safety. This study carried out an initial evaluation of the patient safety culture in a secondary care setting in Kuwait. This cross-sectional questionnaire study was conducted in a general hospital medical department in Kuwait, using the Hospital Survey on Patient Safety Culture (HSPSC). Multiple linear regression analyses were used to identify patient safety culture predictors. Both an ANOVA and a Kruskal Wallis test were carried out to assess the differences between participants' total scores and the scores they achieved in each dimension, categorized by nationality. A total of 1008 completed questionnaires were received, yielding a response rate of 75.2%. Three dimensions of patient safety culture were found to be priority areas for improvement: non-punitive responses to errors, staffing, and communication openness. Teamwork within units and organizational learning with continuous improvement were identified as areas of strength. Respondents from Kuwait and the Gulf State countries had a less positive perception of the hospital's patient safety culture than did Asian respondents. A regression analysis showed that the respondents' countries of origin, professions, age, and patient safety course/lecture attendance were significantly correlated with their perceptions of the hospital's patient safety culture. This study demonstrates that patient safety is perceived differently by medical staff members from different countries of origin, professional groups, and age groups. These variables must be acknowledged and addressed when planning or evaluating patient safety initiatives.


Alterations in the Levels of Circulating and Endothelial Progenitor Cells Levels in Young Adults with Type 1 Diabetes: A 2-Year Follow-Up from the Observational METRO Study.
Type 1 diabetes is associated with high risk of cardiovascular disease (CVD). Reduced levels of circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) have been indicated as a risk factor for adverse cardiovascular outcomes and death in people at high cardiovascular risk. The aim of the present study was to evaluate the change in CPCs and EPCs levels in a population of young type 1 diabetic patients treated with intensive insulin regimen over a period of 2 years. A total of 204 type 1 diabetic patients, of whom 84 treated with insulin pump (CSII) and 120 with multiple daily insulin injections (MDI), completed a 2-year follow-up. Clinical measurements, including the indices of glycemic control and glucose variability, were collected at baseline and after 2 years. Both CPC and EPC cell count were assessed by flow cytometry. Mean age of participants was 24.5 years and mean diabetes duration was 13.6 years. After 2 years, we found a significant reduction of HbA1c (-0.3% versus baseline, P <0.001), associated with decrease in mean amplitude of glucose excursion (MAGE) (-0.5 mmol/L versus baseline, P<0.001), continuous overall net glycemic action (CONGA) (-0.2 mmol/L versus baseline, P=0.006), and blood glucose standard deviation (BGSD) (-0.2 mmol/L versus baseline, P<0.001). The number of all EPCs phenotypes, but not CPC cell count, significantly raised up in the entire population, with higher increase in CSII group. MAGE resulted as an independent predictor for increased levels of both CD34+ (P = 0.020) and CD34+KDR+ (P = 0.004) cell count in the whole population. Over a 2-year follow-up, young type 1 diabetic patients showed an increase in circulating EPCs levels, which was higher in patients with CSII. Glucose variability resulted as an independent predictor of the raised levels of EPCs in this selected population.


Introduction To quantify the effect of Christmas vs. New Year's resolutions season on snacking preferences by measuring intake of four different snacks. Methods Prospective ad libitum intervention snacking study with four combinations of sweet/savory and fatty/non-fatty snacks: cookies, candy, TUC crackers, and rye crackers. A snacking buffet, continuously refilled by a secret Santa, was provided during the Christmas season and New Year's Resolutions season by the secret Santas of the office. Participants were diabetes researchers and were not informed about the study before the end of data collection. The main outcome was daily intake (g) of the four snacks. Results In general, the intake of candy was high compared to the other snacks. The average intake of cookies was significantly higher during the Christmas season compared to New Year's resolution season (8 g/day/participant, p = 0.03), but decreased when approaching Christmas and increased again as time passed by after Christmas (although not significantly). The strongest correlation between the intake of snacks was found between the two sweet snacks, i.e., candy and cookies. Conclusion Researchers have a high preference for sweet foods, especially candy. Irrespective of the type of snack, the preference for cookies was high during the Christmas season but seemed to decrease with decreasing proximity to Christmas, hence, canceling Christmas will unlikely improve diet quality. In fact, we encourage further research to consider whether having Christmas all year could be a potential prevention strategy in the combat of the obesity pandemic. Funding none. Trial registration none.


Axial spondyloarthritis: new advances in diagnosis and management.
Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing spondylitis required advanced changes on plain radiographs of the sacroiliac joints. Classification criteria released in 2009, however, identified a subset of patients, under the age of 45, with back pain for more than three months in the absence of radiographic sacroiliitis who were classified as axSpA based on a positive magnetic resonance imaging or HLAB27 positivity and specific clinical features. This subgroup was labeled non-radiographic (nr)-axSpA. These patients, compared with those identified by the older New York criteria, contained a larger percentage of women and demonstrated less structural damage. However, their clinical manifestations and response to biologics were similar to radiographic axSpA. The discovery of the interleukin (IL) IL-23/IL-17 pathway revealed key molecules involved in the pathophysiology of axSpA. This discovery propelled the generation of antibodies directed toward IL-17A, which are highly effective and demonstrate treatment responses in axSpA that are similar to those observed with anti-TNF agents. The finding that agents that block IL-23 were not effective in axSpA came as a surprise and the potential underlying mechanisms underlying this lack of response are discussed. New agents with dual inhibition of the IL-17A and F isoforms and some oral small molecule agents that target the Jak-STAT pathway, have also shown efficacy in axSpA.


Air Pollution Associated With Incident Stroke, Poststroke Cardiovascular Events, and Death: A Trajectory Analysis of a Prospective Cohort.
Ambient air pollution has been widely linked with morbidity and mortality of stroke. However, its effects on dynamic progression trajectory of stroke remain unknown.We investigated the effects of ambient air pollution on progression trajectory from healthy status to incident stroke, poststroke cardiovascular diseases, and subsequent death. We retrieved 318,752 participants from the UK Biobank. The annual concentrations of air pollution [particulate matter (PM2.5, PMcoarse, PM10 and PM2.5 absorbance), nitrogen dioxide (NO2), and nitrogen oxides (NOx)] were estimated through land use regressions. A multistate regression model was used to investigate the effects of air pollution on each stage of the progression of stroke. During 3,765,630 person-years of follow-up, we identified 5,967 incident stroke patients, 2,985 poststroke cardiovascular patients, and 1,020 deaths afterward. Each 5 μg/m3 increase in PM2.5, NO2, and NOx was associated with the transition from healthy status to incident stroke [hazard ratios (HRs) (95% confidence intervals (CI)) = 1.24 (1.10, 1.40); 1.02 (1.00, 1.03); 1.01 (1.00, 1.02)] and transitions from healthy status to death directly [1.30 (1.21, 1.40); 1.03 (1.02, 1.04); and 1.02 (1.01, 1.02)]. We also observed positive associations for poststroke CVDs, especially for NO2 [1.04 (95% CI: 1.02, 1.06)], but these effects gradually declined for mortality outcome. This study provides the first evidence that ambient air pollution is one important factor associated with the progression of stroke, and the effects differed across different clinical stages. A better understanding of the differential effects of air pollutants on different stroke transition stages could provide valuable insight toward targets for health management and clinical prevention.


Evolution of South Atlantic density and chemical stratification across the last deglaciation.
Explanations of the glacial-interglacial variations in atmospheric pCO2 invoke a significant role for the deep ocean in the storage of CO2. Deep-ocean density stratification has been proposed as a mechanism to promote the storage of CO2 in the deep ocean during glacial times. A wealth of proxy data supports the presence of a "chemical divide" between intermediate and deep water in the glacial Atlantic Ocean, which indirectly points to an increase in deep-ocean density stratification. However, direct observational evidence of changes in the primary controls of ocean density stratification, i.e., temperature and salinity, remain scarce. Here, we use Mg/Ca-derived seawater temperature and salinity estimates determined from temperature-corrected δ(18)O measurements on the benthic foraminifer Uvigerina spp. from deep and intermediate water-depth marine sediment cores to reconstruct the changes in density of sub-Antarctic South Atlantic water masses over the last deglaciation (i.e., 22-2 ka before present). We find that a major breakdown in the physical density stratification significantly lags the breakdown of the deep-intermediate chemical divide, as indicated by the chemical tracers of benthic foraminifer δ(13)C and foraminifer/coral (14)C. Our results indicate that chemical destratification likely resulted in the first rise in atmospheric pCO2, whereas the density destratification of the deep South Atlantic lags the second rise in atmospheric pCO2 during the late deglacial period. Our findings emphasize that the physical and chemical destratification of the ocean are not as tightly coupled as generally assumed.


Highlighting nonlinear patterns in population genetics datasets.
Detecting structure in population genetics and case-control studies is important, as it exposes phenomena such as ecoclines, admixture and stratification. Principal Component Analysis (PCA) is a linear dimension-reduction technique commonly used for this purpose, but it struggles to reveal complex, nonlinear data patterns. In this paper we introduce non-centred Minimum Curvilinear Embedding (ncMCE), a nonlinear method to overcome this problem. Our analyses show that ncMCE can separate individuals into ethnic groups in cases in which PCA fails to reveal any clear structure. This increased discrimination power arises from ncMCE's ability to better capture the phylogenetic signal in the samples, whereas PCA better reflects their geographic relation. We also demonstrate how ncMCE can discover interesting patterns, even when the data has been poorly pre-processed. The juxtaposition of PCA and ncMCE visualisations provides a new standard of analysis with utility for discovering and validating significant linear/nonlinear complementary patterns in genetic data.


Bone marrow-derived mesenchymal stem cells abate CCl4-induced lung damage via their modulatory effects on inflammation, oxidative stress and apoptosis.
The aim of this study was to assess and compare the therapeutic effects of allogenic and xenogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) on a rat model for treating experimental lung inflammation, oxidative stress, and apoptosis. Male Wistar rats were randomly divided into four groups. Group 1 received an intraperitoneal injection of olive oil vehicle (2 mL/kg body weight) for 8 weeks. Group 2 received an intraperitoneal injection of carbon tetrachloride (CCl4) (0.5 mL/kg body weight, twice/week) dissolved in olive oil for 8 weeks. Groups 3 and 4 received the CCl4 similar to group 2, followed by the intravenous injection of rat and mouse BM-MSCs (1 × 106 cells/rat twice/week into a lateral tail vein), respectively, for 4 weeks. Subsequently, the rats were sacrificed, and lung tissues were excised for molecular, histological, and ultrastructural investigations. Fibrosis, interstitial bleeding, dilatation and congestion of blood vessels, intra-alveolar edema, damaged alveoli, scattered mononuclear leucocytic infiltrates, and an increased number of apoptotic cells and apoptotic remnants were observed in the lungs of rats exposed to CCl4; the treatment with rat and mouse BM-MSCs attenuated these changes. The effects of CCl4 on the increase in collagen fibers in the lungs and the expression levels of cyclooxygenase-2, tumor necrosis factor-α, and apoptotic protein p53 were considerably reduced following treatment with the BM-MSCs. The higher levels of lipid peroxidation, the lower-level glutathione content, and the activities of superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase in CCl4-injected rats were significantly improved by treatments with rat and mouse BM-MSCs. These findings indicate that mouse and rat BM-MSCs, which were more potent, can protect against CCl4-induced lung damage and fibrosis by reducing inflammation, apoptosis, and oxidative stress and boosting the antioxidant defense system.


Stress, health, noise exposures, and injuries among electronic waste recycling workers in Ghana.
Electronic waste (e-waste) recycling workers in low and middle-income countries have the potential for occupational injuries due to the nature of their work at informal e-waste sites. However, limited research exists on stress, noise, occupational injuries, and health risks associated with this work environment. This study evaluated injury experience, noise exposures, and stress risk factors among e-waste workers at the large recycling site in the Agbogbloshie market, Accra, Ghana. Participants completed a survey addressing their work, health status, stress, exposures to several occupational hazards (including noise), use of personal protective equipment at work, and injury experience. A subset of participants also completed personal noise dosimetry measurements. Poisson regression was used to evaluate the association between the number of injuries experienced by participants and various factors evaluated in the survey. Forty-six male e-waste workers completed the survey, and 26 completed a noise dosimetry measurement. Participants experienced an average of 9.9 ± 9.6 injuries per person in the previous 6 months (range: 1-40). The majority of injuries were lacerations (65.2%), and the most common injury location was the hand (45.7%). Use of personal protective equipment was rare. The mean time-weighted average noise level was 78.8 ± 5.9 dBA. Higher perceived stress, greater age, poorer health status, not using gloves, and involvement in dismantling activities were associated with an increased number of injuries. After controlling for each of these risk factors, perceived stress level and perceived noise exposure were associated with a significantly greater number of injuries. Our study identified a large number of injuries among informal e-waste recyclers, and we found that higher levels of perceived stress and perceived noise were associated with an increased number of occupational injuries, even after controlling for other injury risk factors.


Vial wall effect on freeze-drying speed.
The vial wall thermal conductivity and thickness effect on freeze-drying speed is simulated. A 2D axisymmetric numerical simulation of Mannitol freeze-drying is employed using the boundary element method. The originality of the presented approach lies in the simulation of heat transfer in the vial walls as an additional computational domain in contrast to the typical methodology without a vial wall. The numerical model was validated using our measurements and the measurements from the literature. Increasing the glass vial thickness from 1 mm to 2 mm has been found as the major factor in primary drying time, increasing the gravimetrical Kv up to 20 % for all the simulated chamber pressures. The effect of thermal conductivity was simulated using a polymer and aluminium vial replacing the standard glass vial of the same thickness. The polymer vial's decreased Kv value is 5.6 % at a low chamber pressure of 50 mTorr, and 12.2 % at 400 mTorr, which is in excellent agreement with the experiment. Using higher conductivity materials, for example, aluminium, only 3.7 % and 2.3 % Kv increase were computed for low and high chamber pressures respectively.


Interspecies Genomic Variation and Transcriptional Activeness of Secondary Metabolism-Related Genes in Aspergillus Section Fumigati.
Filamentous fungi produce various bioactive compounds that are biosynthesized by sets of proteins encoded in biosynthesis gene clusters (BGCs). For an unknown reason, many BGCs are transcriptionally silent in laboratory conditions, which has hampered the discovery of novel fungal compounds. The transcriptional reactiveness of fungal secondary metabolism is not fully understood. To gain the comprehensive view, we conducted comparative genomic and transcriptomic analyses of nine closely-related species of Aspergillus section Fumigati (A. fumigatus, A. fumigatiaffinis, A. novofumigatus, A. thermomutatus, A. viridinutans, A. pseudoviridinutans, A. lentulus, A. udagawae, and Neosartorya fischeri). For expanding our knowledge, we newly sequenced genomes of A. viridinutans and A. pseudoviridinutans, and reassembled and reannotated the previously released genomes of A. lentulus and A. udagawae. Between 34 and 84 secondary metabolite (SM) backbone genes were identified in the genomes of these nine respective species, with 8.7-51.2% being unique to the species. A total of 247 SM backbone gene types were identified in the nine fungi. Ten BGCs are shared by all nine species. Transcriptomic analysis using A. fumigatus, A. lentulus, A. udagawae, A. viridinutans, and N. fischeri was conducted to compare expression levels of all SM backbone genes in four different culture conditions; 32-83% of SM backbone genes in these species were not expressed in the tested conditions, which reconfirmed that large part of fungal SM genes are hard to be expressed. The species-unique SM genes of the five species were expressed with lower frequency (18.8% in total) than the SM genes that are conserved in all five species (56%). These results suggest that the expression tendency of BGCs is correlated with their interspecies distribution pattern. Our findings increase understanding of the evolutionary processes associated with the regulation of fungal secondary metabolism.


Bone Disease in the Common Marmoset: Radiographic and Histological Findings.
The common marmoset (Callithrix jacchus) is a New World primate that is used in biomedical research due to its small size and relative ease of handling compared with larger primates. Although bone disease in common marmosets is well recognized, there are very few detailed descriptions in the literature that cover the range of lesions seen in these animals. For all animals used to model human disease, it is important to be aware of background lesions that may affect the interpretation of study findings. This retrospective study details bone diseases encountered in marmoset breeding colonies at 2 different institutions. Affected marmosets at Johns Hopkins University had lesions compatible with diagnoses of rickets, fibrous osteodystrophy and osteopenia. Affected marmosets at the Wisconsin National Primate Research Center exhibited severe lesions of osteoclastic bone resorption and remodeling that had an unusual distribution and were not easily categorized into a known disease entity. The purpose of this report is to document these naturally occurring skeletal lesions of common marmosets and suggest an approach to evaluating skeletal disease in prospective studies of these animals that will allow the most accurate diagnoses.


Agrobacterium tumefaciens transformation and cotransformation frequencies of Arabidopsis thaliana root explants and tobacco protoplasts.
In view of the recent finding that different T-DNAs tend to ligate and integrate as repeats at single chromosomal positions, the frequency of transformation and cotransformation was determined during cocultivation of Arabidopsis thaliana root explants and Nicotiana tabacum protoplasts with two Agrobacterium strains. The transformation frequency of unselected A. thaliana shoots was lower than 1% whereas that of cocultivated tobacco protoplasts was approximately 18%. The cotransformation frequencies, defined as the frequencies with which cells transformed with a first T-DNA contained a second unselected T-DNA, were approximately 40% reproducible, irrespective of the selection, the transformation frequency, and the plant system used. Extrapolation of these results suggests that at least two independently transferred T-DNAs were present in 64% of the transformed plant cells. Molecular analysis of cocultivated N. tabacum shoots regenerated on nonselective medium showed that only a few transformants had a silenced (2/46) or truncated (1/46) T-DNA. Therefore, most integrated T-DNAs expressed their selectable or screenable markers in primary transgenic plants. Remarkably, 10 to 30% of the selected A. thaliana shoots or progenies lost the T-DNA marker they were selected on. As these regenerants contained the unselected T-DNA with a high frequency (17%), these selected plants might result from the expression of unstable, transiently expressed T-DNAs. In conclusion, a significant part of the T-DNAs is lost from the transformed cells.


[Open auto-keratoplasty and reflected-light microscopy of the endothelium].
Reflecting microscopy of the endothelium is recommended for assessment of the corneal status before open autokeratoplasty and volumic keratoplasty. The density of 1000 per mm2 has been estimated as the transplantation minimum of endothelial cells. The results of autokeratoplasty have been better if the Healon viscous-elastic bioprotector has been employed. The findings of the dynamic follow-up of the endothelial cell density after surgery are presented.


Leishmania (Viannia) panamensis-specific IgE and IgA antibodies in relation to expression of human tegumentary leishmaniasis.
Leishmania (Viannia) panamensis-specific IgE and IgA antibodies were quantified in patients with parasitologically confirmed American tegumentary leishmaniasis using a radioallergosorbent test (RAST) and an enzyme-linked immunosorbent assay (ELISA), respectively. The RAST values, presented as the mean +/- SEM percentage of total isotope added, were significantly elevated in patients having disease evolution greater than 12 months (3.14 +/- 0.91), as compared with those with an evolution time of 12 or fewer months (1.66 +/- 0.15) (P = 0.017). A separate group of patients, those with eosinophils in the biopsy specimen of their lesion, also had elevated mean RAST values (2.55 +/- 0.58) when compared with patients who did not demonstrate these cells in their biopsy specimens (1.32 +/- 0.24) (P = 0.038). Leishmania-specific IgA levels, presented as the mean +/- SEM optical density, were significantly higher for patients with mucocutaneous disease (0.40 +/- 0.03) than for patients with cutaneous disease (0.28 +/- 0.023) (P = 0.0063). Inhibition testing with homologous and heterologous antigens confirmed the specificity of these assays, and were used to assess cross-reactivity among L. (Viannia) subspecies and other kineto-plastic hemoparasites. Results demonstrate that patients with more severe forms of American tegumentary leishmaniasis, defined either as increased duration of disease or invasion of the mucosa, have elevated levels of Leishmania-specific IgE and IgA antibodies, respectively.


Major hyperestrogenism in a feminizing adrenocortical adenoma despite a moderate overexpression of the aromatase enzyme.
A 30-year-old male was referred for the rapid development of gynecomastia, and dramatic hyperestrogenemia was assessed: plasma estrone, estradiol but also cortisol were not suppressed by high-dose dexamethasone, while gonadotropin pulsatility was completely abolished. A 60-mm right adrenal tumor was evidenced on computed tomography-scan, and the patient underwent adrenalectomy. The tumor was found to express a moderate increase in aromatase activity compared with adjacent non-neoplastic adrenal tissue. Quantitative RT-PCR also showed a weak and non-significant increase in total aromatase mRNA in the tumor compared with normal adrenal tissue. Aromatase transcripts were mainly promoter PII-derived, but different patterns of aromatase minor transcripts were found: promoter I.3- and I.6-derived transcripts were identified in the tumor, while only promoter I.4-derived transcripts were found in normal adrenal. This case report demonstrates that a sharp aromatase overexpression is not a prerequisite for clinical and biochemical hyperestrogenism, and further characterizes the aromatase promoter utilization in this feminizing adrenocortical tumor and in the normal adrenal cortex.


Voice quality and tone identification in White Hmong.
This study investigates the importance of source spectrum slopes in the perception of phonation by White Hmong listeners. In White Hmong, nonmodal phonation (breathy or creaky voice) accompanies certain lexical tones, but its importance in tonal contrasts is unclear. In this study, native listeners participated in two perceptual tasks, in which they were asked to identify the word they heard. In the first task, participants heard natural stimuli with manipulated F0 and duration (phonation unchanged). Results indicate that phonation is important in identifying the breathy tone, but not the creaky tone. Thus, breathiness can be viewed as contrastive in White Hmong. Next, to understand which parts of the source spectrum listeners use to perceive contrastive breathy phonation, source spectrum slopes were manipulated in the second task to create stimuli ranging from modal to breathy sounding, with F0 held constant. Results indicate that changes in H1-H2 (difference in amplitude between the first and second harmonics) and H2-H4 (difference in amplitude between the second and fourth harmonics) are independently important for distinguishing breathy from modal phonation, consistent with the view that the percept of breathiness is influenced by a steep drop in harmonic energy in the lower frequencies.


Platelet-to-Lymphocyte Ratio Multiplied by the Cytokeratin-19 Fragment Level as a Predictor of Pathological Response to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.
The standard treatment for resectable advanced esophageal squamous cell carcinoma in Japan is surgery followed by neoadjuvant chemotherapy, and it is important to predict the effect of neoadjuvant chemotherapy before treatment. Therefore, this study aims to extract conventional blood examination data, such as tumor markers and/or inflammatory/nutritional index levels, that can predict the pathological response of patients with esophageal squamous cell carcinoma to neoadjuvant chemotherapy. We retrospectively analyzed the medical records of 66 patients with thoracic esophageal squamous cell carcinoma who received neoadjuvant chemotherapy, followed by curative esophagectomy at Tottori University Hospital between June 2009 and December 2019. We demonstrated that the product of the platelet-to-lymphocyte ratio (PLR) multiplied by the cytokeratin-19 fragment (CYFRA) level, which was termed "PLR-CYFRA," is the most accurate indicator that predicts the pathological response to neoadjuvant chemotherapy, with the highest area under the curve [0.795 (95% confidence interval: 0.665-0.925), P < 0.001] in receiver operating characteristic analyses. Therefore, we divided patients into the PLR-CYFRALow (< 237.6, n = 21) and PLR-CYFRAHigh (≥ 237.6, n = 45) groups and found that the percentage of PLR-CYFRALow was significantly higher in patients with a better pathological response (P < 0.001). Furthermore, patients with good pathological response had significantly better prognoses in terms of disease-specific survival (P = 0.014), recurrence-free survival (P = 0.014), and overall survival (P = 0.032). In the multivariate analysis, PLR-CYFRA was an independent predictor of the pathological response of patients with esophageal squamous cell carcinoma to neoadjuvant chemotherapy (P = 0.002). Pretreatment PLR-CYFRA might be a useful and simple tool that predicts the pathological effect of neoadjuvant chemotherapy in esophageal squamous cell carcinoma.


Macroporous silk fibroin cryogels.
Silk fibroin cryogels with remarkable properties were obtained from frozen fibroin solutions (4.2-12.6%) at subzero temperatures between -5 and -22 °C. This was achieved by the addition of ethylene glycol diglycidyl ether (EGDE) into the cryogelation system. EGDE triggers the conformational transition of fibroin from random coil to β-sheet structure and hence fibroin gelation. One of the unique features of fibroin cryogels is their elasticity that allows them to resist complete compression without any crack development, during which water inside the cryogel is removed. The compressed cryogel immediately swells during unloading to recover its original shape. The scaffolds obtained by freeze-drying of the cryogels consist of regular, interconnected pores of diameters ranging from 50 to 10 μm that could be regulated by the synthesis parameters. The mechanical compressive strength and the modulus of the scaffolds increase with decreasing pore diameter, that is, with decreasing gelation temperature or, with increasing fibroin or EGDE concentrations in the feed. The scaffolds produced at 12.6% fibroin exhibit a very high compressive modulus (50 MPa) making them good candidates as bone scaffold materials.


Clinical assessment of endothelial function in convalescent COVID-19 patients: a meta-analysis with meta-regressions.
Endothelial dysfunction has been proposed to play a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its post-acute sequelae. Flow-mediated dilation (FMD) is recognized as an accurate clinical method to assess endothelial function. Thus, we performed a meta-analysis of the studies evaluating FMD in convalescent COVID-19 patients and controls with no history of COVID-19. A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the random effects method, differences between cases and controls were expressed as mean difference (MD) with 95% confidence intervals (95% CI). The protocol was registered on PROSPERO with reference number CRD42021289684. Twelve studies were included in the final analysis. A total of 644 convalescent COVID-19 patients showed significantly lower FMD values as compared to 662 controls (MD: -2.31%; 95% CI: -3.19, -1.44; p < 0.0001). Similar results were obtained in the sensitivity analysis of the studies that involved participants in either group with no cardiovascular risk factors or history of coronary artery disease (MD: -1.73%; 95% CI: -3.04, -0.41; p = 0.010). Interestingly, when considering studies separately based on enrolment within or after 3 months of symptom onset, results were further confirmed in both short- (MD: -2.20%; 95% CI: -3.35, -1.05; p < 0.0001) and long-term follow-up (MD: -2.53%; 95% CI: -4.19, -0.86; p = 0.003). Meta-regression models showed that an increasing prevalence of post-acute sequelae of COVID-19 was linked to a higher difference in FMD between cases and controls (Z-score: -2.09; p = 0.037). Impaired endothelial function can be documented in convalescent COVID-19 patients, especially when residual clinical manifestations persist. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.Key messagesThe mechanisms underlying the post-acute sequelae of coronavirus disease 2019 (COVID-19) have not been fully elucidated.Impaired endothelial function can be documented in convalescent COVID-19 patients for up to 1 year after infection, especially when residual clinical manifestations persist.Targeting endothelial dysfunction may represent an attractive therapeutic option in the post-acute phase of COVID-19.


Excavation of a buried treasure--DNA, mRNA, miRNA and protein analysis in formalin fixed, paraffin embedded tissues.
Fresh or frozen tissue samples will always be the best tissue source for the analysis of nucleic acids and proteins from tissues. However, their long-term storage is expensive and laborious. Much interest has therefore been focused on the question whether the almost infinite resources of formalin fixed and paraffin embedded tissue samples in the archives of pathology and histology departments can be used for research on biomarkers and molecular mechanisms of disease. In recent years the methods and protocols for the extraction of DNA, mRNA, miRNA and proteins from formalin-fixed and paraffin-embedded tissue samples have improved enormously. Especially, the possibilities of analysing DNA and miRNA in FFPE have reached a level that allows their application as a first line approach in the search for biomarkers. In contrast, many questions remain in terms of quantification of mRNA and protein expression levels in formalin-fixed and paraffin-embedded tissue samples. This review gives an overview on current potentials and limitations of the quantification of DNA, miRNA, mRNA and the proteome in FFPE tissue samples. The chemical events during formalin fixation and paraffin embedding and alternatives to formalin fixation are described. In addition, methods and general problems of DNA, miRNA, mRNA and protein extraction and the current knowledge on the feasibility and accuracy of quantitative gene expression analysis in FFPE tissues is summarized.


Dietary and Pharmacological Interventions That Inhibit Mammalian Target of Rapamycin Activity Alter the Brain Expression Levels of Neurogenic and Glial Markers in an Age-and Treatment-Dependent Manner.
Intermittent fasting (IF) and its mimetic, rapamycin extend lifespan and healthspan through mechanisms that are not fully understood. We investigated different short-term durations of IF and rapamycin on cellular and molecular changes in the brains of young (6-10 months) and old (26-31 months) zebrafish. Interestingly, our results showed that IF significantly lowered glucose levels while increasing DCAMKL1 in both young and old animals. This proliferative effect of IF was supported by the upregulation of foxm1 transcript in old animals. Rapamycin did not change glucose levels in young and old animals but had differential effects depending on age. In young zebrafish, proliferating cell nuclear antigen and the LC3-II/LC3-I ratio was decreased, whereas glial fibrillary acidic protein and gephyrin were decreased in old animals. The changes in proliferative markers and a marker of autophagic flux suggest an age-dependent interplay between autophagy and cell proliferation. Additionally, changes in glia and inhibitory tone suggest a suppressive effect on neuroinflammation but may push the brain toward a more excitable state. Mammalian target of rapamycin (mTOR) activity in the brain following the IF and rapamycin treatment was differentially regulated by age. Interestingly, rapamycin inhibited mTOR more potently in young animals than IF. Principal component analysis supported our conclusion that the regulatory effects of IF and rapamycin were age-specific, since we observed different patterns in the expression levels and clustering of young and old animals. Taken together, our results suggest that even a short-term duration of IF and rapamycin have significant effects in the brain at young and old ages, and that these are age and treatment dependent.


Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality.
Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence and mortality from many cancers. The metabolic abnormalities associated with type 2 diabetes develop many years before the onset of diabetes and, therefore, may be contributing to cancer risk before individuals are aware that they are at risk. Multiple factors potentially contribute to the progression of cancer in obesity and type 2 diabetes, including hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, adipokines and cytokines, and the gut microbiome. These metabolic changes may contribute directly or indirectly to cancer progression. Intentional weight loss may protect against cancer development, and therapies for diabetes may prove to be effective adjuvant agents in reducing cancer progression. In this review we discuss the current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes.


Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles.
Drug resistance remains a major barrier to the successful treatment of cancer. The mechanisms by which therapeutic resistance arises are multifactorial. Recent evidence has shown that extracellular vesicles (EVs) play a role in mediating drug resistance. EVs are small vesicles carrying a variety of macromolecular cargo released by cells into the extracellular space and can be taken up into recipient cells, resulting in transfer of cellular material. EVs can mediate drug resistance by several mechanisms. They can serve as a pathway for sequestration of cytotoxic drugs, reducing the effective concentration at target sites. They can act as decoys carrying membrane proteins and capturing monoclonal antibodies intended to target receptors at the cell surface. EVs from resistant tumor cells can deliver mRNA, miRNA, long noncoding RNA, and protein inducing resistance in sensitive cells. This provides a new model for how resistance that arises can then spread through a heterogeneous tumor. EVs also mediate cross-talk between cancer cells and stromal cells in the tumor microenvironment, leading to tumor progression and acquisition of therapeutic resistance. In this review, we will describe what is known about how EVs can induce drug resistance, and discuss the ways in which EVs could be used as therapeutic targets or diagnostic markers for managing cancer treatment. While further characterization of the vesiculome and the mechanisms of EV function are still required, EVs offer an exciting opportunity in the fight against cancer.


Understanding Public Attitudes to Hate: Developing and Testing a U.K. Version of the Hate Crime Beliefs Scale.
Against the backdrop of an increase in reported hate crimes, we present the development of a U.K.-focussed instrument designed to evaluate the nature of public beliefs about hate crime, legislation, offenders and victims. In Study 1, 438 participants completed an Anglicized version of the Hate Crime Beliefs Scale (HCBS). Factor analyses revealed three subfactors: Denial (high scores represent a denial of hate crime severity and need for legislation), Compassion (high score reflect compassion toward victims and affected communities) and Sentencing (higher scores reflect more punitive attitudes). In Study 2 (N = 134) we show that scores on Denial are positively associated with those on Right-Wing Authoritarianism (RWA) and Social Dominance Orientation (SDO), ideologies known to be associated with prejudice. Compassion was negatively associated with these ideologies. Mediation analyses showed that Big Five personality traits Openness to Experience and Conscientiousness predicted Denial and Compassion via RWA, whereas Agreeableness and Openness predicted scores via SDO, consistent with a dual-process motivation model of hate crime beliefs. Results are discussed in terms of the nature of hate crime beliefs and the importance of understanding public attitudes which may support undesirable social norms and influence jury decision making in trials of hate related offenses.


[CEA, CA 19.9 and CA 195 in patients with colorectal carcinoma. ROC analysis].
The aim of this study was to assess the utility of determining serum levels of the CEA, CA 19.9 and CA 195 tumor markers in 906 patients with colorectal carcinoma for a 5-year follow-up period. In addition to calculating sensitivity and specificity for the common normal limits, the results were analyzed with RO curves. Sensitivity values for 90% and 95% specificity were also obtained. The results of the areas under the curve (CEA: 0.887; CA 19.9: 0.802; CA 195: 0.971) and sensitivities and specificities at different normality limits showed better behavior for CEA with respect to CA 19.9 and CA 195, the last two presenting similar results. CEA continues to be the best tumor marker to monitor patients with colorectal carcinoma.


Two chorismate mutase genes from the root-knot nematode Meloidogyne incognita.
SUMMARY Parasitism genes encoding secretory proteins expressed in the oesophageal glands of phytoparasitic nematodes play critical roles in nematode invasion of host plants, establishment of feeding sites and suppression of host defences. Two chorismate mutase (CM) genes potentially having a role in one or more of these processes were identified from a Meloidogyne incognita oesophageal gland-cell subtractive cDNA library. These M. incognita enzymes (designated as MI-CM-1 and MI-CM-2) with amino-terminal signal peptides, were significantly similar to chorismate mutases in M. javanica and bacteria. The complementation of an Escherichia coli CM-deficient mutant by the expression of Mi-cm-1 or Mi-cm-2 confirmed their CM activity. In-situ mRNA hybridization showed that the transcripts of Mi-cm-1 and Mi-cm-2 accumulated specifically in the two subventral oesophageal gland cells of M. incognita. RT-PCR analysis confirmed that their transcript abundances were high in the early parasitic juvenile stages, and low (Mi-cm-1) or undetectable (Mi-cm-2) in later parasitic stages of the nematode. Southern blot analysis revealed that these CM genes were members of a small multigene family in Meloidogyne species. The widespread presence of CMs in the specialized sedentary endoparasitic nematode species suggests that this multifunctional enzyme may be a key factor in modulating plant parasitism.


Towards a Long-Read Sequencing Approach for the Molecular Diagnosis of RPGRORF15 Genetic Variants.
Sequencing of the low-complexity ORF15 exon of RPGR, a gene correlated with retinitis pigmentosa and cone dystrophy, is difficult to achieve with NGS and Sanger sequencing. False results could lead to the inaccurate annotation of genetic variants in dbSNP and ClinVar databases, tools on which HGMD and Ensembl rely, finally resulting in incorrect genetic variants interpretation. This paper aims to propose PacBio sequencing as a feasible method to correctly detect genetic variants in low-complexity regions, such as the ORF15 exon of RPGR, and interpret their pathogenicity by structural studies. Biological samples from 75 patients affected by retinitis pigmentosa or cone dystrophy were analyzed with NGS and repeated with PacBio. The results showed that NGS has a low coverage of the ORF15 region, while PacBio was able to sequence the region of interest and detect eight genetic variants, of which four are likely pathogenic. Furthermore, molecular modeling and dynamics of the RPGR Glu-Gly repeats binding to TTLL5 allowed for the structural evaluation of the variants, providing a way to predict their pathogenicity. Therefore, we propose PacBio sequencing as a standard procedure in diagnostic research for sequencing low-complexity regions such as RPGRORF15, aiding in the correct annotation of genetic variants in online databases.


Polymorphisms of MTHFR and MTR genes are not related to susceptibility to childhood ALL in North India.
Acute lymphoblastic leukemia (ALL) is the most worldwide common type of childhood cancer. Methylenetetrahydrofolate reductase (MTHFR) and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) participate in folate pathways and are known as critical factors for DNA integrity as well as DNA hypomethylation. The aim of this work is to investigate frequency of MTHFR (677C→T and 1298A→C) and MTR (2756A→G) polymorphisms and their interaction with respect to possible effect on risk of childhood ALL among North Indian population. A case control study from has been conducted on bone marrow and peripheral blood samples from 125 ALL patients and 100 sex-age matched healthy controls using PCR-RFLP method. No statistically significant differences were observed for different genotypes between patients and controls (p>0.05). Significant difference for the risk of ALL in individuals having genotype of MTHFR 677TT (OR=0.61, 95% CI=0.21-1.77) and MTHFR 1298CC (OR=0.56, 95% CI=0.18-1.68) was not observed. The correlation of SNP of MTR gene and risk of ALL was not observed, too. The differences in distribution of possible combined genotypes of MTHFR (677C→T, 1298A→C) and MTR (2756A→G) between ALL patients and controls were statistically insignificant.


Development of Na+-dependent hexose transport in a cultured line of porcine kidney cells.
LLC-PK1 cells in culture do not concentrate alpha-methylglucoside (alpha-meG) during their early growth phase but develop the capacity to concentrate this hexose as the growth rate decreases in confluent cultures. The concentrating ability is dependent on the Na+ electrochemical gradient and is inhibited by phlorizin with KI,0.5 approximately 0.2 microM. The development of the concentrative capacity can be accelerated by the Friend cell inducer hexamethylene bisacetamide (HMBA) and by the phosphodiesterase inhibitors dibutyryl cAMP, theophylline, and 1-methyl-3-isobutylxanthine (MIX). In cultures treated with any of these differentiation-accelerating chemicals, the development of alpha-meG concentrating capacity is severely inhibited by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) but not by inactive (in tumor promotion) analogs of TPA. In all cases, an early event in the development of alpha-meG accumulating capacity is an elevated intracellular cAMP concentration; however the results suggest that this increase in cAMP may be necessary but not sufficient to induce the differentiated hexose-accumulating capacity.


Characterization of human afferent lymph dendritic cells from seroma fluids.
Dendritic cells (DCs) migrate from peripheral tissues to secondary lymphoid organs (SLOs) through the afferent lymph. Owing to limitations in investigating human lymph, DCs flowing in afferent lymph have not been properly characterized in humans until now. In this study, DCs present in seroma, an accrual of human afferent lymph occurring after lymph node surgical dissection, were isolated and analyzed in detail. Two main DC subsets were identified in seroma that corresponded to the migratory DC subsets present in lymph nodes, that is, CD14(+) and CD1a(+). The latter also included CD1a(bright) Langerhans cells. The two DC subsets appeared to share the same monocytic precursor and to be developmentally related; both of them spontaneously released high levels of TGF-β and displayed similar T cell-activating and -polarizing properties. In contrast, they differed in the expression of surface molecules, including TLRs; in their phagocytic activity; and in the expression of proteins involved in Ag processing and presentation. It is worth noting that although both subsets were detected in seroma in the postsurgical inflammatory phase, only CD1a(+) DCs migrated via afferent lymph under steady-state conditions. In conclusion, the high numbers of DCs contained in seroma fluids allowed a proper characterization of human DCs migrating via afferent lymph, revealing a continuous stream of DCs from peripheral regions toward SLOs under normal conditions. Moreover, we showed that, in inflammatory conditions, distinct subsets of DCs can migrate to SLOs via afferent lymph.


Nasal staphylococci microbiota and resistome in healthy adults in La Rioja, northern Spain: High frequency of toxigenic S. aureus and MSSA-CC398 subclade.
This study determined the nasal staphylococci diversity and characterized their resistome, with a focus on the mobilome of methicillin-susceptible Staphylococcus aureus (MSSA)-CC398 subclade from healthy adults in La Rioja (northern Spain). Nasal staphylococci recovered from 57 healthy individuals (HI) were identified (MALDI-TOF-MS) and their antimicrobial resistance, virulence determinants and genetic lineages were studied. The relatedness of MSSA-CC398 isolates was assessed by core-genome single-nucleotide-polymorphisms (SNPs). One-hundred-forty-three non-repetitive staphylococci were obtained from most HI (98.2%), of which S. epidermidis (87.7%) and S. aureus (36.8%) were the predominant species. About 15% of the 27 S. aureus and 30.1% of the 116 coagulase-negative staphylococci (CoNS) isolates presented a multidrug resistance (MDR) phenotype. All S. aureus isolates were MSSA but 30.2% of CoNS isolates were mecA-positive and carried SCCmec types III, IV, and V. The highest non-beta-lactam resistance (frequency/genes) in S. aureus and CoNS were: erythromycin-clindamycin-inducible (25.9%/ermT, ermC) and mupirocin (30.1%/mupA), respectively. About 85% of S. aureus isolates carried relevant virulence genes. Eight clonal complexes (CCs) of MSSA were identified, of which CC398 was the predominant (33.3%). About 78% of the CC398 isolates harboured rep13-bound ermT gene, however, one carried a rep10-bound ermC gene. Only the ermT-positive MSSA-CC398 isolates were closely related (<50 SNPs) and carried the φSa3. Diverse MDR-S. epidermidis isolates were identified which included the lineages ST59 and ST210. The high rate of toxigenic S. aureus and of MSSA-CC398 subclade highlight the ability of HI to carry and transmit virulent isolates. Moreover, the high frequency of MDR-CoNS, often linked with SCCmec, needs to be monitored for their potential human health implications.


[Effect of the beta-carboline derivative FG 7142 on inhibition in hippocampal sections].
The action of anxiogenetic derivative of beta-carboline FG7142 on evoked activity of neurons in hippocampal sections was investigated using extra- and intracellular recordings. The activity in CAI area was registered upon stimulation of Schaffer's collaterals (SC). Excitatory effect of FG7142 (5 microM) on population spike (PS) was blocked by simultaneous diazepam (5 microM) or RO15-1788 (5 microM) application. This suggests that FG7142 action is mediated by benzodiazepine receptors. To evaluate the action of FG7142 on hippocampal inhibitory processes paired-pulse stimulation of SC was used. It was shown that FG7142 (5 microM) increased 4-5 times the amplitude of the second PS, the amplitude of the first one being much less augmented (10-20%). Such an effect may probably be associated with specific action of GABA inhibition. The following application of diazepam (5 microM) partially reversed disinhibitory effect of FG7142. The main intracellular change observed was the appearance of the local depolarization following the single action potential (AP). With the application continued, this depolarization gave rise to the second AP. The data suggest that suppression of hippocampal inhibitory circuits may contribute to the development of the anxiety feeling.


Mass trapping Popillia quadriguttata using Popillia japonica (Coleoptera: Scarabaeidae) pheromone and floral lures in northeastern China.
Popillia quadriguttata (F.) has caused extensive damage to ≍20 families and 25 species of plants in Asia, especially in China and Korea. Adult feeding causes serious damage to soybean leaves, and larvae develop on the roots of soybean, turf, and horticultural crops. As Japanese beetle (Popillia japonica Newman) lures have been used for trapping P. quadriguttata in a previous study, mass trapping this pest with various densities of the Japanese beetle pheromone, Japonilure, and floral lure, alone and in combination, were carried out during 2012-2013 in a northeastern China soybean field. Mass trapping in 2012 with Japonilure gave the best results with 72 and 75% adult and larval reduction, respectively. In 2013, mass trapping (30 traps per hectare) with Japonilure, floral lure, or the combination resulted in a 93, 70, and 74% reduction of adults trapped, and a 90, 77, and 93% reduction of overwintering larvae, respectively. In addition, field tests showed that almost twice as many beetles approached the lure combination compared with the floral lure alone, and the pheromone residual was ≍80% of the initial dosage after 30 d. Because reduction of overwintering larvae is the most critical parameter indicating treatment efficacy, the results here indicate that the lure or lure combinations can be recommended for use by Chinese soybean farmers.


Understanding peace through the world news.
Peace is a principal dimension of well-being and is the way out of inequity and violence. Thus, its measurement has drawn the attention of researchers, policymakers, and peacekeepers. During the last years, novel digital data streams have drastically changed the research in this field. The current study exploits information extracted from a new digital database called Global Data on Events, Location, and Tone (GDELT) to capture peace through the Global Peace Index (GPI). Applying predictive machine learning models, we demonstrate that news media attention from GDELT can be used as a proxy for measuring GPI at a monthly level. Additionally, we use explainable AI techniques to obtain the most important variables that drive the predictions. This analysis highlights each country's profile and provides explanations for the predictions, and particularly for the errors and the events that drive these errors. We believe that digital data exploited by researchers, policymakers, and peacekeepers, with data science tools as powerful as machine learning, could contribute to maximizing the societal benefits and minimizing the risks to peace. The online version contains supplementary material available at 10.1140/epjds/s13688-022-00315-z.