Kinetic characterization of sporulation in Streptomyces albidoflavus SMF301 during submerged culture.
We report the first quantitative analysis of the relationship between environmental changes and sporulation of a streptomycete, Streptomyces albidoflavus SMF301, in submerged culture. A chemically defined medium was constructed for sporulation, over 10(9) spores ml-1 being formed in the submerged batch culture. Kinetic parameters calculated from batch and chemostat cultures showed that specific submerged spore formation rate (qspo) was inversely related to the specific mycelial growth rate (mu). The optimum growth rate for submerged spore formation was 0.05 h-1, when the maximum value of qspo was 1.0 x 10(6) spores g-1 h-1. The turnover rate of biomass at maximum growth yield was 0.029 h-1, when 5.6 x 10(6) spores were formed from 1 g mycelium. The present quantitative analysis of submerged spore formation using a controlled system opens the way for biochemical and molecular biological studies related to the morphological differentiation of Streptomyces spp.


Anterior cingulate N-acetylaspartate/creatine ratios during clonidine treatment in a maltreated child with posttraumatic stress disorder.
Posttraumatic stress disorder in maltreated children is associated with dysregulation of biological stress systems, adverse brain development, and neuronal loss in the anterior cingulate region of the medial prefrontal cortex. A maltreated boy with posttraumatic stress disorder was followed prospectively using single voxel proton magnetic resonance spectroscopy measures of anterior cingulate N-acetylaspartate/creatine ratios, a marker of neural integrity. N-acetylaspartate/creatine ratios increased, and sleep measures improved upon symptom remission.


Four new Amynthas and Metaphire earthworm species from nine provinces in southern China.
Four new species belonging to genera Amyntha and Metaphire were discovered from an extensive area in southern China, covering the provinces Sichuan, Yunnan, Guizhou, Guangdong, Guangxi, Fujian, Hunan, Jiangxi and Anhui. The species are named Amynthas dispersus Sun Qiu, sp. nov., Amynthas shanghangensis Sun Qiu, sp. nov., Amynthas dentiformis Sun Jiang, sp. nov. and Metaphire sanmingensis Sun Jiang, sp. nov. The first two new species have four pairs of intersegmental spermathecal pores in 5/6-8/9. A. dispersus has elliptical and glandular male pore porophores raised on a low pad-like area surrounded by two to three shallow skin folds, the genital papillae are variable in the spermathecal pore and male pore regions, and prostate glands are vestigial or rudimentary. Amynthas shanghangensis has male porophores surrounded by three papillae, each prostate gland accompanied by an accessory gland, and the distal ½-⅓ of the spermathecal diverticulum dilated into a rod-shaped seminal chamber. Amynthas dentiformis has two pairs of spermathecal pores in 7/8-8/9, male pores always surrounded by two papillae, and small sacs on the dorsal and ventral margins of the intestinal caecae; the prostate gland occasionally has stalked accessory glands. M. sanmingensis is in the Metaphire houlleti-group, and has secondary male pores opening to copulatory pouches, rod-shaped spermathecal seminal chamber, as well as variable genital papillae in spermathecal and male pores regions. The GenBank accession numbers of DNA barcode data are attached under the description of each species.


Stereoselective, dual-mode ruthenium-catalyzed ring expansion of alkynylcyclopropanols.
A novel, dual-pathway ring expansion of alkynylcyclopropanols is described. On treatment with a ruthenium catalyst, these compounds undergo highly selective enlargement to either (Z)-alkylidene cyclobutanones or beta-substituted cyclopentenones. The unique ability to access the least selective double bond isomers of alkylidene cyclobutanones and the dramatic shift of reactivity observed further illustrate the particular intricacies of ruthenium catalysis when compared to other alkynophilic transition metals.


Repositioning-dependent fate of duplicate genes.
Gene duplication is the main source of evolutionary novelties. However, the problem with duplicates is that the purifying selection overlooks deleterious mutations in the redundant sequence, which therefore, instead of gaining a new function, often degrades into a functionless pseudogene. This risk of functional loss instead of gain is much higher for small populations of higher organisms with a slow and complex development. We propose that it is the epigenetic tissue/stage-complementary silencing of duplicates that makes them exposable to the purifying selection, thus saving them from pseudogenization and opening the way towards new function(s). Our genome-wide analyses of gene duplicates in several eukaryotic species combined with the phylogenetic comparison of vertebrate alpha- and beta-globin gene clusters strongly support this epigenetic complementation (EC) model. The distinctive condition for a new duplicate to survive by the EC mechanism seems to be its repositioning to an ectopic site, which is accompanied by changes in the rate and direction of mutagenesis. The most distinguished in this respect is the human genome. In this review, we extend and discuss the data on the EC- and repositioning-dependent fate of gene duplicates with the special emphasis on the problem of detecting brief postduplication period of adaptive evolution driven by positive selection. Accordingly, we propose a new CpG-focused measure of selection that is insensitive to translocation-caused biases in mutagenesis.


[Influence of Enterobacter toxin on the cellular immunity].
Study of dynamics of formation of spontaneous and mitogen (phytohemagglutinin - PHA, concanavalin A - ConA)-activated blast lymphocytes showed increase of number of transforming T-lymphocytes under the influence of Enterobacter cloacae thermolabile enterotoxin. Itwas noted that PHA mainly stimulated mitosis of T-cell population, ConA - of natural killers, whereas enterotoxin stimulated mitotic activity of both cell types.


Effects of Multiple Factors on Treatment Outcome in the Three-Dimensional Maxillary Arch Morphometry of Children With Unilateral Cleft Lip and Palate.
Studies have claimed that the maxillary arch dimension of unilateral cleft lip and palate (UCLP) patient is significantly smaller than normal patient. Multiple factors (both congenital and post natal treatment factors) are believed to have an impact on the treatment outcome (maxillary arch retardation) of UCLP patient. The aim of this study was to evaluate the effects of multiple factors on the treatment outcome by assessing the maxillary arch dimension of UCLP Children. Eighty-five Malaysian UCLP children were taken who received cheiloplasty and palatoplasty. Laser scanned 3D digital models of UCLP subjects were prepared before any orthodontic treatment and bone grafting at 7.69 ± 2.46 (mean± SD) years of age. Intercanine width (ICW), intermolar width (IMW), and arch depth (AD) measurements of maxillary arch were measured with Mimics software. Multiple linear regression analyses were used to evaluate the association between multiple factors (gender, UCLP type, UCLP side, family history of cleft, family history of class III malocclusion, techniques of cheiloplasty, and techniques of palatoplasty) and maxillary arch dimensions (ICW, IMW, and AD). P value was set at 5%. Significant association was found between 2 techniques of cheiloplasty and ICW (P = 0.001) and also between 2 techniques of palatoplasty and ICW (P = 0.046) of maxilla. No significant association observed in IMW and AD in relation to all other factors. Modified Millard techniques of Cheiloplasty and Bardach technique of palatoplasty had unfavorable effect on the treatment outcome by assessing the maxillary arch dimension (ICW) using laser scanned 3D digital models in Malaysian UCLP children.


Non-Antidepressant Long-term Treatment in Post-Traumatic Stress Disorder (PTSD).
Post-traumatic stress disorder (PTSD) is a frequent and disabling condition that occurs after exposure to a traumatic event, and Selective Serotonin Reuptake Inhibitors (SSRIs) are considered the first-line treatment approach for this disorder. However, a large proportion of patients remain symptomatic and other pharmacological agents have been investigated, based on the understanding of the underlying biological dysfunctions of PTSD. We conducted a review of the literature on the pharmacological options for PTSD other than the antidepressants, using MedLine and Web of Science databases, with search terms including the pharmacologic class of each agent plus PTSD, or pharmacotherapy, or fear conditioning. The literature review covered articles published until august 2012, including reviews and original articles. Agents like antipsychotics, anticonvulsants, benzodiazepines, anti-adrenergic agents, have been studied in randomized clinical trials (RCTs), with general positive results for antipsychotics, especially as adjunct therapy, and for prazosin for sleep-related disturbances. However, one important target for novel medications is the modulation of the fear conditioning process, through the alteration of retrieval/reconsolidation or enhancement of fear extinction. This is traditionally targeted in prolonged exposure therapy, but pre-clinical findings from studies investigating agents like propanolol, clonidine, N-Methyl-D-aspartic Acid Receptor (NMDAR) compounds, 3,4-methylenedioxy-N-methylamphetamine (MDMA) and cannabinoids, indicate promising results in affecting the fear conditioning process and thus improving PTSD core symptoms. Antipsychotics can be considered a reasonable alternative option to PTSD, with the largest body of evidence for risperidone, even though larger RCTs are warranted. Prazosin is also a promising agent, especially for sleep-related disturbances, while anticonvulsants and benzodiazepines lack empirical support. However, the most promising area for pharmacotherapy in PTSD is the modulation of the fear conditioning process, through agents used in adjunct to exposure therapy.


Using X-ray Crystallography, Biophysics, and Functional Assays to Determine the Mechanisms Governing T-cell Receptor Recognition of Cancer Antigens.
Human CD8+ cytotoxic T lymphocytes (CTLs) are known to play an important role in tumor control. In order to carry out this function, the cell surface-expressed T-cell receptor (TCR) must functionally recognize human leukocyte antigen (HLA)-restricted tumor-derived peptides (pHLA). However, we and others have shown that most TCRs bind sub-optimally to tumor antigens. Uncovering the molecular mechanisms that define this poor recognition could aid in the development of new targeted therapies that circumnavigate these shortcomings. Indeed, present therapies that lack this molecular understanding have not been universally effective. Here, we describe methods that we commonly employ in the laboratory to determine how the nature of the interaction between TCRs and pHLA governs T-cell functionality. These methods include the generation of soluble TCRs and pHLA and the use of these reagents for X-ray crystallography, biophysical analysis, and antigen-specific T-cell staining with pHLA multimers. Using these approaches and guided by structural analysis, it is possible to modify the interaction between TCRs and pHLA and to then test how these modifications impact T-cell antigen recognition. These findings have already helped to clarify the mechanism of T-cell recognition of a number of cancer antigens and could direct the development of altered peptides and modified TCRs for new cancer therapies.


Licochalcone A inhibits IgE-mediated allergic reaction through PLC/ERK/STAT3 pathway.
Licochalcone (LicA) is a flavonoid commonly derived from the licorice plant that is reported to have a variety of pharmacological activities. However, few studies have focused on its anti-allergic properties. IgE-mediated passive and systemic anaphylaxis mice models were used to assess the in vivo anti-allergic effect of LicA and its underlying mechanism, while degranulation, cytokines, and chemokines released from laboratory of allergic disease (LAD2) cells were used to assess its in vitro anti-allergic effect. We used western blot analysis to explore the downstream signaling pathway of its anti-allergic effect. We found that in the mouse model, LicA attenuated IgE-mediated paw inflammation, recovered the allergy-induced drop in body temperature, and reduced the concentrations of tumor necrosis factor-alpha and monocyte chemo-attractant protein-1 in mouse serum in a dose-dependent manner. LicA inhibited the allergic reaction via inhibition of IgE-mediated LAD2 cell activation through the PLC/ERK/STAT3 pathway.


School functioning and chronic pain: a review of methods and measures.
School functioning is among the most important life domains impacted by chronic pain. This review provides a summary of the measures currently used by researchers to assess school functioning in children with chronic pain. We conducted a systematic review of the literature on school absenteeism and school functioning in children and adolescents with pain. Searches were restricted to a time frame including January 1985 to December 2010. Fifty-three articles are reviewed: all include some form of assessment of school absenteeism or school functioning as part of the study outcome measures. Of the 53 articles, 26 assessed school absenteeism and 27 assessed an aspect of school functioning; 14 of these 27 articles assessed both. Understanding the comprehensive impact of pain on school functioning will require improvements in our current assessment methods.


Plant antimutagenic agents, 1. General bioassay and isolation procedures.
An antimutagenic assay in Salmonella typhimurium has been utilized for a study of the inhibition of the mutagenic activity of 2-aminoanthracene in the presence of the Ames S-9 metabolic activation preparation by crude organic solvent extracts of plant materials. More than 2000 extracts representing 39 families have been tested to date. Confirmed inhibitory activity has been found in 80 samples. More than 60% were nontoxic. Methods for isolation and characterization of pure compounds are presented. Of particular interest is the utilization of large scale preparative hplc for rapid purification of inhibitory chromatographic fractions that were still highly impure.


Application of the methylene blue staining method to the study of experimentally PNNG-induced intestinal metaplasia of the canine stomach.
To elucidate the developmental process of the intestinal metaplasia of the stomach, PNNG was orally administered to dogs and the sequential endoscopic examination was performed by using the methylene blue staining method. In the early period of the drug administration dogs showed the findings of erosive gastritis at the antral portion. In the 42nd experimental week, a clearly stained lesion was observed at the gastric angle. The histological findings of the biopsy specimens from the stained lesion showed the elongation of the foveolar epithelium and goblet cell-like mucous cells. Apparently stained lesion was observed at the antral portion in the 128th week. The close-up endoscopic appearance was very similar to that of stained intestinal metaplasia seen in the human stomach. The endoscopic methylene blue staining method as performed in the experimental dogs could provide useful results in the observation of minute lesions especially intestinal metaplasia in human stomach. This experiment, and further studies, may help to elucidate the pathogenesis of the gastric carcinoma in humans.


The Schnitzler syndrome.
The Schnitzler syndrome is a rare and underdiagnosed entity which is considered today as being a paradigm of an acquired/late onset auto-inflammatory disease. It associates a chronic urticarial skin rash, corresponding from the clinico-pathological viewpoint to a neutrophilic urticarial dermatosis, a monoclonal IgM component and at least 2 of the following signs: fever, joint and/or bone pain, enlarged lymph nodes, spleen and/or liver, increased ESR, increased neutrophil count, abnormal bone imaging findings. It is a chronic disease with only one known case of spontaneous remission. Except of the severe alteration of quality of life related mainly to the rash, fever and pain, complications include severe inflammatory anemia and AA amyloidosis. About 20% of patients will develop a lymphoproliferative disorder, mainly Waldenström disease and lymphoma, a percentage close to other patients with IgM MGUS. It was exceedingly difficult to treat patients with this syndrome until the IL-1 receptor antagonist anakinra became available. Anakinra allows a complete control of all signs within hours after the first injection, but patients need continuous treatment with daily injections.In many aspects, the Schnitzler syndrome resembles the genetically determined auto-inflammatory syndromes involving activating mutations of the NLRP3 inflammasome. This latter point and its consequences will be addressed.


The Efficacy of Some Commercially Available Insect Repellents for Aedes aegypti (Diptera: Culicidae) and Aedes albopictus (Diptera: Culicidae).
Reducing the number of host-vector interactions is an effective way to reduce the spread of vector-borne diseases. Repellents are widely used to protect humans from a variety of protozoans, viruses, and nematodes. DEET (N,N-Diethyl-meta-toluamide), a safe and effective repellent, was developed during World War II. Fear of possible side effects of DEET has created a large market for "natural" DEET-free repellents with a variety of active ingredients. We present a comparative study on the efficacy of eight commercially available products, two fragrances, and a vitamin B patch. The products were tested using a human hand as attractant in a Y-tube olfactometer setup with Aedes aegypti (Linnaeus) and Aedes albopictus (Skuse), both major human disease vectors. We found that Ae. albopictus were generally less attracted to the test subject's hand compared with Ae, aegypti. Repellents with DEET as active ingredient had a prominent repellency effect over longer times and on both species. Repellents containing p-menthane-3,8-diol produced comparable results but for shorter time periods. Some of the DEET-free products containing citronella or geraniol did not have any significant repellency effect. Interestingly, the perfume we tested had a modest repellency effect early after application, and the vitamin B patch had no effect on either species. This study shows that the different active ingredients in commercially available mosquito repellent products are not equivalent in terms of duration and strength of repellency. Our results suggest that products containing DEET or p-menthane-3,8-diol have long-lasting repellent effects and therefore provide good protection from mosquito-borne diseases.


Communicative participation outcomes in individuals with Parkinson's disease receiving standard care speech-language therapy services in community settings.
The Communicative Participation Item Bank (CPIB) is a patient-reported outcome measure (PROM) designed to measure the extent of interference, or difficulty, experienced by adults with communication disorders participating in their day-to-day communication activities. To date, there is limited evidence regarding sensitivity of the CPIB for capturing change with intervention in people with Parkinson's disease (PwPD). The purpose of this study was to examine the following measurement properties of the CPIB in PwPD who received community-based, standard care, speech-language therapy focusing on motor speech concerns: Change over time between treatment and observation groups, comparison to patient-defined ideal and satisfactory targets, comparison of static short form to computerised adaptive testing (CAT), comparison of self to proxy-rated scores, and comparison to other common PROMs. Forty-six PwPD (20 treatment/26 observation) completed data collection upon enrolment (pre-treatment) and 6 months later. In addition to the CPIB, PROMs included the Voice Handicap Index 10-item short form (VHI-10), PROMIS Global Health-Related Quality of Life, Levels of Speech Usage, self-rated speech severity, and Patient Health Questionnaire-9 (PHQ-9). Participants also engaged in qualitative interviews. Forty-four family members completed proxy CPIB ratings. There were no significant differences between treatment and observation groups on the CPIB pre-treatment, but there were significant differences post-treatment. The differences appeared to be largely due to significant gains in the treatment group. No participants reached their ideal CPIB target, and few reached their satisfactory target. Static CPIB short form and CAT scores were not significantly different, with an average of five CAT items administered per participant. Overall group similarities between patient and proxy scores may have obscured wide variability across individual patient-proxy pairs. Associations between CPIB and VHI-10, health-related quality of life, self-reported speech severity, and depression ranged from weak to moderate. The CPIB appears to be sensitive to capturing change with intervention, and similar results are obtained with the static short form and CAT formats. One clinical caution is that even with gains observed in the treatment group, no participants obtained their ideal communicative participation goals, and few obtained a satisfactory level of communicative participation. Thus, while current interventions are beneficial, they may not meet the full range of clients' communication needs. While responding to the CPIB through a proxy rater may be feasible, caution is warranted due to concerns about maintaining the autonomy of PwPD. What is already known on this subject The communication disorders associated with Parkinson's disease (PD) can have a negative impact on quality of life and life participation as measured by patient (or person)-reported outcome measures (PROMs). The Communicative Participation Item Bank (CPIB) is one PROM available to use with adults with communication disorders. However, little is known about whether the CPIB captures changes in communicative participation as a result of standard care treatment for people with Parkinson's disease (PwPD). Use of computerised adaptive testing (CAT), proxy report and comparison to targeted participation outcomes have not been explored. What this study adds to existing knowledge As a result of this study, we know that the CPIB captured differences between treatment and observation groups after community-based, standard care speech therapy intervention focusing on motor speech production in PwPD. Static short form and CAT scores did not differ significantly, so the CAT option provides better efficiency requiring, on average, five items to administer compared to the 10-item short form. Proxy and PwPD scores did not differ as a group, but wide variability was noted. What are the potential or actual clinical implications of this work? The CPIB may be a clinically sensitive instrument for capturing changes in communicative participation after treatment. No participants met their ideal CPIB target, and few reached their satisfactory target, suggesting that while current interventions contribute to gains in communicative participation, there are still unmet needs that may call for support and interventions addressing the more complex array of factors affecting communicative participation outcomes for PwPD.


Mesenchymal Stem Cell Derived Biocompatible Membrane Vesicles Demonstrate Immunomodulatory Activity Inhibiting Activation and proliferation of Human Mononuclear Cells.
Immune-mediated diseases are characterized by abnormal activity of the immune system. The cytochalasin B-induced membrane vesicles (CIMVs) are innovative therapeutic instruments. However, the immunomodulating activity of human mesenchymal stem cell (MSC)-derived CIMVs (CIMVs-MSCs) remains unknown. Therefore, we sought to investigate the immunological properties of CIMVs-MSCs and evaluate their effect on human peripheral blood mononuclear cells (PBMCs). We found that CIMVs-MSCs are primarily uptaken by monocytes and B-cells. Additionally, we demonstrated that CIMVs-MSCs inhibit phytohemagglutinin (PHA)-induced proliferation of PBMCs, with more pronounced effect on T-lymphocytes expansion as compared to that of B-cells. In addition, activation of T-helpers (CD4+CD25+), B-cells (CD19+CD25+), and T-cytotoxic lymphocytes (CD8+CD25+) was also significantly suppressed by CIMVs-MSCs. Additionally, CIMVs-MSCs decreased secretion of epidermal growth factor (EGF) and pro-inflammatory Fractalkine in a population of PBMCs, while the releases of FGF-2, G-CSF, anti-inflammatory GM-CSF, MCP-3, anti-inflammatory MDC, anti-inflammatory IL-12p70, pro-inflammatory IL-1b, and MCP-1 were increased. We analyzed the effect of CIMVs-MSCs on an isolated population of CD4+ and CD8+ T-lymphocytes and demonstrated their different immune response and cytokine secretion. Finally, we observed that no xenogeneic nor allogeneic transplantation of CIMVs induced an immune response in mice. Our data suggest that CIMVs-MSCs have immunosuppressive properties, are potential agents for immunomodulating treatment, and are worthy of further investigation.


Texture analysis as imaging biomarker of tumoral response to neoadjuvant chemoradiotherapy in rectal cancer patients studied with 3-T magnetic resonance.
The aim of this study was to determine whether texture features of rectal cancer on T2-weighted (T2w) magnetic resonance images can predict tumoral response in patients treated with neoadjuvant chemoradiotherapy (CRT). We prospectively enrolled 15 consecutive patients (6 women, 63.2 ± 13.4 years) with rectal cancer, who underwent pretreatment and midtreatment 3-T magnetic resonance imaging. Treatment protocol consisted of neoadjuvant CRT with oxaliplatin and 5-fluorouracile. Texture analysis using a filtration-histogram technique was performed using a commercial research software algorithm (TexRAD Ltd, Somerset, England, United Kingdom) on unenhanced axial T2w images by manually delineating a region of interest around the tumor outline for the largest cross-sectional area. The technique selectively filters and extracts textures at different anatomic scales followed by quantification of the histogram using kurtosis, entropy, skewness, and mean value of positive pixels. After CRT, all patients underwent complete surgical resection and the surgical specimen served as the gold standard. Six patients showed pathological complete response (pCR), and 4 patients, partial response (PR). Five patients were classified as nonresponders (NRs). Pretreatment medium texture-scale quantified as kurtosis was significantly lower in the pCR subgroup in comparison with the PR + NR subgroup (P = 0.01). Midtreatment kurtosis without filtration was significantly higher in pCR in comparison with PR + NR (P = 0.045). The change in kurtosis between midtreatment and pretreatment images was significantly lower in the PR + NR subgroup compared with the pCR subgroup (P = 0.038). Pretreatment area under the receiver operating characteristic curves, to discriminate between pCR and PR + NR, was significantly higher for kurtosis (0.907, P < 0.001) compared with all other parameters. The optimal cutoff value for pretreatment kurtosis was 0.19 or less. Using this value, the sensitivity and specificity for pCR prediction were 100% and 77.8%, respectively. Texture parameters derived from T2w images of rectal cancer have the potential to act as imaging biomarkers of tumoral response to neoadjuvant CRT.


Microfluidic-Based Continuous Fabrication of Ultrathin Hydrogel Films with Controllable Thickness.
Ultrathin hydrogel films composed of cross-linked polymer networks swollen by water, with soft and moisturized features similar to biological tissue, play a vital role in flexible biosensors and wearable electronics. However, achieving efficient and continuous fabrication of such films remains a challenge. Here, we present a microfluidic-based strategy for the continuous fabrication of free-standing ultrathin hydrogel films by using laminar flow, which can be precisely controlled in the micrometer scale. Compared with conventional methods, the microfluidic-based method shows advantages in producing hydrogel films with a high homogeneity as well as maintaining the structural integrity, without the need of supporting substrates and sophisticated equipment. This strategy allows the precise control over the thickness of the hydrogel films ranging from 15 ± 0.2 to 39 ± 0.5 μm, by adjusting the height of the microfluidic channels, with predictable opportunities for scaling up. Therefore, our strategy provides a facile route to produce advanced thin polymer films in a universal, steerable, and scalable manner and will promote the applications of thin polymer films in biosensors and wearable electronics.


ST-segment elevation resolution in lead aVR: a strong predictor of adverse outcomes in patients with non-ST-segment elevation acute coronary syndrome.
The impact of ST-segment elevation resolution in lead aVR on outcomes in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) is unclear. Electrocardigrams (ECGs) were recorded on admission and 6 h later in 367 patients with NSTE-ACS. ST-segment deviation >or=0.5 mm was considered significant: 92 patients had ST-segment elevation in lead aVR on admission ECG (ST upward arrowaVR), and 275 did not. Among patients with ST upward arrowaVR, 50 had ST resolution, defined as a reduction >50% in the degree of ST-segment elevation in lead aVR from admission to 6 h later, and 42 did not. ST upward arrowaVR without ST resolution was associated with older age, greater ST-segment depression in other leads on admission and 6 h later, higher rates of positive troponin T, left main and/or 3-vessel coronary disease, and adverse events such as death, (re)infarction, or urgent revascularization within 30 days after admission. Multivariate analysis showed that ST upward arrowaVR without ST resolution was the strongest independent predictor of death or (re)infarction within 30 days after admission (hazard ratio 5.62, p=0.018). ST upward arrowaVR without ST resolution is a strong predictor of 30-day adverse outcomes and correlates with the extent and severity of coronary artery disease in patients with NSTE-ACS.


Pathophysiological significance and therapeutic applications of snake venom protease inhibitors.
Protease inhibitors are important constituents of snake venom and play important roles in the pathophysiology of snakebite. Recently, research on snake venom protease inhibitors has provided valuable information to decipher the molecular details of various biological processes and offer insight for the development of some therapeutically important molecules from snake venom. The process of blood coagulation and fibrinolysis, in addition to affecting platelet function, are well known as the major targets of several snake venom protease inhibitors. This review summarizes the structure-functional aspects of snake venom protease inhibitors that have been described to date. Because diverse biological functions have been demonstrated by protease inhibitors, a comparative overview of their pharmacological and pathophysiological properties is also highlighted. In addition, since most snake venom protease inhibitors are non-toxic on their own, this review evaluates the different roles of individual protease inhibitors that could lead to the identification of drug candidates and diagnostic molecules.


Estimating a panel MSK dataset for comparative analyses of national absorptive capacity systems, economic growth, and development in low and middle income countries.
Within the national innovation system literature, the low- and middle-income countries (LMICs) eligible for the World Bank's International Development Association (IDA) support, are rarely part of empirical discourses on growth, development, and innovation. One major issue hindering empirical analyses in LMICs is the lack of complete data availability. This work offers a new full panel dataset with no missing values for IDA-eligible LMICs. I use a standard, widely respected multiple imputation method (specifically, Predictive Mean Matching) developed by Rubin in the 1980s, which conforms to the structure of multivariate continuous panel data at the country level. The incomplete input data consisting of many variables come from publicly available established sources. These variables, in turn, capture six crucial country-level capacities: technological capacity, financial capacity, human capital capacity, infrastructural capacity, public policy capacity, and social capacity. Such capacities are part and parcel of the National Absorptive Capacity Systems (NACS). The dataset (MSK dataset) thus produced contains data on 47 variables for 82 LMICs between 2005 and 2019. The dataset has passed a quality and reliability check and can therefore be used for comparative analyses of national absorptive capacities and development, transition, and convergence among LMICs.


Elucidating the Mechanism of Fe Incorporation in In Situ Synthesized Co-Fe Oxygen-Evolving Nanocatalysts.
Ni- and Co-based catalysts with added Fe demonstrate promising activity in the oxygen evolution reaction (OER) during alkaline water electrolysis, with the presence of Fe in a certain quantity being crucial for their enhanced performance. The mode of incorporation, local placement, and structure of Fe ions in the host catalyst, as well as their direct/indirect contribution to enhancing the OER activity, remain under active investigation. Herein, the mechanism of Fe incorporation into a Co-based host was investigated using an in situ synthesized Co-Fe catalyst in an alkaline electrolyte containing Co2+ and Fe3+. Fe was found to be uniformly incorporated, which occurs solely after the anodic deposition of the Co host structure and results in exceptional OER activity with an overpotential of 319 mV at 10 mA cm-2 and a Tafel slope of 28.3 mV dec-1. Studies on the lattice structure, chemical oxidation states, and mass changes indicated that Fe is incorporated into the Co host structure by replacing the Co3+ sites with Fe3+ from the electrolyte. Operando Raman measurements revealed that the presence of doped Fe in the Co host structure reduces the transition potential of the in situ Co-Fe catalyst to the OER-active phase CoO2. The findings of our facile synthesis of highly active and stable Co-Fe particle catalysts provide a comprehensive understanding of the role of Fe in Co-based electrocatalysts, covering aspects that include the incorporation mode, local structure, placement, and mechanistic role in enhancing the OER activity.


Wegener's granulomatosis: case report and review of the literature.
The clinical manifestations of Wegener's granulomatosis (WG) may be varied and easily overlooked. Awareness of distinguishing signs and symptoms allows early recognition and appropriate management. The body of literature dealing with the various facets of this disorder has grown in the past few years. Development of new diagnostic markers and successful therapies has rekindled interest in this disease. To assure early diagnosis and optimal prognosis the physician must maintain a high index of suspicion for WG. Although introduction of immunosuppressive therapy has dramatically improved the course of this disorder, treatment-related morbidity is often profound.


Specialized nutrition support in the hospitalized obese patient.
The rising prevalence of obesity in the United States has resulted in concerns regarding the implementation of safe and effective specialized nutrition support in hospitalized obese patients. This review discusses complications associated with the provision of specialized nutrition support for obese patients and emphasizes the scientific basis for and against the provision of hypocaloric, high-protein parenteral and enteral nutrition support. Because there is a paucity of data concerning enteral nutrition support, some practical aspects of implementing hypocaloric high-protein enteral nutrition are also given.


[Research on marrow mesenchymal stem cell proliferation by coculturing with Schwann cell].
To evaluate the effect of Schwann cell (SC) on the proliferation of marrow mesenchymal stem cells (MSCs) and provide evidence for application of SC in construction of the tissue engineered vessels. SC and MSCs were harvested from SD rats (weight 40 g). SC were verified immunohistochemically by the S-100 staining, and MSCs were verified by CD 44, CD 105, CD 34 and CD 45. The 3rd passages of both the cells were cocultured in the Transwell system and were amounted by the 3H-TDR integration technique at 1, 3, 5 and 7 days, respectively. The results were expressed by the CPM(counts per minute, CPM) values. However, MSCs on both the layers were served as the controls. The Western blot was performed to assess the expression of the vascular endothelial growth factor (VEGF), its receptor Flk-1, and the associated receptor neuropilin 1 (NRP-1) in SC, the trial cells, and the controls. SC had a spindle shape in the flasks, and more than 90% of SC had a positive reaction for the S-100 staining. MSCs expressed CD44 and CD105, and had a negative signal in CD 34 and CD 45. The CPM values of MSCs in the trial groups were 2,411.00+/-270.84, 3,016.17+/-241.57, 6,570.83+/-2,848.27 and 6,375.8+/-1,431.28 at 1, 3, 5 and 7 days, respectively. They were significantly higher in their values than the control group (2,142.17+/- 531.63, 2,603.33+/-389.64, 2,707.50+/-328.55, 2,389.00+/-908.01), especially at 5 days (P<0.05). The Western blot indicated that VEGF was expressed obviously in both the SC group and the cocultured MSCs group and was less visible in the control cells. The expressions of Flk-1 and NRP-1 in the cocultured MSCs were much stronger than in the controls. SC can significantly promote the proliferation of MSCs when they are cocultured. The peak time of the proliferation effect appeared at 5 days. This effect may be triggered by the up-regulation of VEGF in MSCs, which also leads to the upregulation of Flk-1 and NRP-1.


Genetic Characterisation of Colistin Resistant Klebsiella pneumoniae Clinical Isolates From North India.
Increasing use of colistin has led to the world-wide emergence of mobile colistin resistant gene (mcr). The present study aimed to identify and characterise mcr and other drug-resistant genes in colistin resistant Klebsiella pneumoniae clinical isolates. Twenty-two colistin resistant K. pneumoniae were analysed for mcr and other drug-resistant genes, efflux pumps, and virulence genes, and for their biofilm forming ability. Pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST) were performed for all mcr-1 positive isolates. S1-PFGE and Southern hybridisation were performed for localisation of mcr-1 and blaNDM. Nineteen colistin resistant K. pneumoniae harboured mcr-1 and 3 had mgrB disruption. All isolates harboured blaOXA-48-type and ESBL genes; eight strains (five with mcr-1 and three with mgrB disruption) co-harboured blaNDM. Efflux pumps genes AcrAB and mdtK were detected in all 22 and tol-C in 21 isolates. Virulence-related genes entB and irp-1 were detected in all 22, mrkD in 20, and fimH-1 in 18 isolates; 11 isolates were strong biofilm producers. PFGE clustered mcr-1 positive isolates into eight groups based on ≥90% similarity; MLST revealed diverse sequence types, predominant being ST-15 (n = 4) and ST-16 (n = 4). Both mcr-1 and blaNDM were localised on plasmid and chromosome; mcr-1 was present on IncFII type and blaNDM on IncFIB and IncA/C type plasmids. Colistin resistance in K. pneumoniae was predominantly mediated by mcr-1. Co-existence of colistin, carbapenem, and other drug-resistant genes along with efflux pumps indicates towards enormous genomic plasticity in K. pneumoniae with ability to emerge as super-spreader of drug-resistance.


[Incidence of rubella in 2010-2012 in Kinshasa, Democratic Republic of Congo: data from the measles case-based surveillance system].
No surveillance system or survey data on the congenital rubella syndrome are available in the Democratic Republic of Congo. This article describes the incidence of primary rubella infection between 2010 and 2012 based on the measles case-based surveillance system in Kinshasa. Suspected cases of measles notified in Kinshasa between 2010 and 2012 were retrospectively analyzed. From January 2010 to December 2012, 1,892 suspected cases of measles were reported, and 1013 serum samples were collected according to the surveillance standard and analyzed in the laboratory. There were more cases of confirmed rubella than measles among the investigated cases. The proportion of confirmed cases of rubella has increased significantly over the last 3 years. The proportion of affected individuals of childbearing age was 15.4%, with a female predominance in this age-group. The Democratic Republic of Congo should consider revising the definition of cases used in the measles surveillance system in order to take into account the incidence of measle, establish sentinel sites for surveillance of CRS and use measles eradication activities and other mass activities to introduce rubella vaccination.


Porphyrin-Based Symmetric Redox-Flow Batteries towards Cold-Climate Energy Storage.
Electrochemical energy storage with redox-flow batteries (RFBs) under subzero temperature is of great significance for the use of renewable energy in cold regions. However, RFBs are generally used above 10 °C. Herein we present non-aqueous organic RFBs based on 5,10,15,20-tetraphenylporphyrin (H2 TPP) as a bipolar redox-active material (anode: [H2 TPP]2- /H2 TPP, cathode: H2 TPP/[H2 TPP]2+ ) and a Y-zeolite-poly(vinylidene fluoride) (Y-PVDF) ion-selective membrane with high ionic conductivity as a separator. The constructed RFBs exhibit a high volumetric capacity of 8.72 Ah L-1 with a high voltage of 2.83 V and excellent cycling stability (capacity retention exceeding 99.98 % per cycle) in the temperature range between 20 and -40 °C. Our study highlights principles for the design of RFBs that operate at low temperatures, thus offering a promising approach to electrochemical energy storage under cold-climate conditions.


Antihypertensive effect of a dopamine beta hydroxylase inhibitor, bupicomide: a comparison with hydralazine.
The cardiovascular effects of a new antihypertensive drug, bupicomide, were compared with those of hydralazine in 6 patients with mild to moderate hypertension. The mean supine arterial pressure of patients was reduced 15.2 mm Hg by bupicomide (900 to 2,000 mg/day) and 15.7 mm Hg by hydralazine (300 to 600 mg/day). Heart rate increased an average of 11.3 bpm during bupicomide and 14.5 bpm by hydralazine. Neither drug was associated with a postural decrease in mean arterial pressure. The heart rate response during maximum tolerated treadmill exercise was not diminished by either drug. Cardiac index was increased during administration of both drugs. Bupicomide and hydralazine reduced forearm vascular resistance, while renal blood flow and renal vascular resistance were not significantly modified. Evidence of equivalent augmentation of sympathetic nervous activity during administration of both drugs consisted of equal and significant increases in heart rate and urinary norepinephrine excretion, and decreases in duration of the pre-ejection period. The absolute values of these parameters were correlated with mean arterial pressure, which may indicate that the increase in sympathetic nervous activity was mediated by baroreceptor reflexes. Although bupicomide inhibits dopamine beta-hydroxylase, our results suggest that it is acting as a direct vasodilator.


GENETIC CONSTRAINTS AND THE PHYLOGENY OF INSECT-PLANT ASSOCIATIONS: RESPONSES OF OPHRAELLA COMMUNA (COLEOPTERA: CHRYSOMELIDAE) TO HOST PLANTS OF ITS CONGENERS.
We ask whether patterns of genetic variation in a phytophagous insect's responses to potential host plants shed light on the phylogenetic history of host association. Ophraella communa feeds chiefly, and in eastern North America exclusively, on Ambrosia (Asteraceae: Ambrosiinae). Using mostly half-sib breeding designs, we screened for genetic variation in feeding responses to and larval survival on its own host and on seven other plants that are hosts (or, on one case, closely related to the host) of other species of Ophraella. We found evidence for genetic variation in feeding responses to five of the seven test plants, other than the natural host. We found no evidence of genetic variation in feeding responses to two plant species, nor in capacity for larval survival on six. These results imply constraints on the availability of genetic variation; however, little evidence for constraints in the form of negative genetic correlations was found. These results are interpreted in the context of a provisional phylogeny of, and a history of host shifts within, the genus. Ophraella communa does not present evidence of genetic variation in its ability to feed and/or survive on Solidago, even though it is probably descended from a lineage that fed on Solidago or related plants, possibly as recently as 1.9 million years ago. Genetic variation in performance on this plant may have been lost. Based on evidence for genetic variation and on mean performance, by far the greatest potentiality for adaptation to a congener's host was evinced in responses to Iva frutescens, which not only is related and chemically similar to Ambrosia, but also is the host of a closely related species of Ophraella that may have been derived from an Ambrosia-associated ancestor. Genetic variation in O. communa's capacity to feed and/or survive on its congeners' hosts is less evident for plants that do not represent historically realized host shifts (with one exception) than for those that may (but see Note Added in Proof). The results offer some support for the hypothesis that the evolution of host shifts has been guided in part by constrained genetic variation.


Oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX-4) combination chemotherapy as a salvage treatment in advanced gastric cancer.
This study was designed to determine the efficacy and safety of FOLFOX-4 chemotherapy as a salvage treatment for patients with advanced gastric cancer (AGC). The AGC patients with an ECOG performance status of 0~1 and progressive disease after prior treatments were registered onto this phase II trial. The patients received oxaliplatin (85 mg/m² on day 1), leucovorin (200 mg/m² on days 1 and 2) and 5-fluorouracil (400 mg/m² as a bolus and 600 mg/m² as a 22-hour infusion on days 1 and 2) every 2 weeks. For the 42 treated patients, a total of 228 chemotherapy cycles (median: 5, range: 1~12) were administered. Twenty-nine patients (69%) received FOLFOX-4 chemotherapy as a third-(50%) or fourth-line (19%) treatment. On the intent-to-treat analysis, 9 patients (21%) achieved a partial response, which was maintained for 4.6 months. The median progression-free survival and overall survival were 3.0 months and 6.2 months, respectively. The frequently encountered toxicities were neutropenia and gastrointestinal side effects, including anorexia. Although there was one possible treatment-related death, the toxicity profiles were generally predictable and manageable. Salvage chemotherapy with FOLFOX-4 is an effective and tolerable regimen for those heavily pretreated AGC patients who have a good performance status.


Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention--a randomized, double-blind, multicentre, placebo-controlled study.
The efficacy and tolerability of a CO(2)-extract of feverfew (MIG-99, 6.25 mg t.i.d.) for migraine prevention were investigated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients (N = 170 intention-to-treat; MIG-99, N = 89; placebo, N = 81) suffering from migraine according to International Headache Society criteria were treated for 16 weeks after a 4-week baseline period. The primary endpoint was the average number of migraine attacks per 28 days during the treatment months 2 and 3 compared with baseline. Safety parameters included adverse events, laboratory parameters, vital signs and physical examination. The migraine frequency decreased from 4.76 by 1.9 attacks per month in the MIG-99 group and by 1.3 attacks in the placebo group (P = 0.0456). Logistic regression of responder rates showed an odds ratio of 3.4 in favour of MIG-99 (P = 0.0049). Adverse events possibly related to study medication were 9/107 (8.4%) with MIG-99 and 11/108 (10.2%) with placebo (P = 0.654). MIG-99 is effective and shows a favourable benefit-risk ratio.


The Effect of User Psychology on the Content of Social Media Posts: Originality and Transitions Matter.
Multiple studies suggest that frequencies of affective words in social media text are associated with the user's personality and mental health. In this study, we re-examine these associations by looking at the transition patterns of affect. We analyzed the content originality and affect polarity of 4,086 posts from 70 adult Facebook users contributed over 2 months. We studied posting behavior, including silent periods when the user does not post any content. Our results show that more extroverted participants tend to post positive content continuously and that more agreeable participants tend to avoid posting negative content. We also observe that participants with stronger depression symptoms posted more non-original content. We recommend that transitions of affect pattern derived from social media text and content originality should be considered in further studies on mental health, personality, and social media.


Tools for Assessment of Country Preparedness for Public Health Emergencies: A Critical Review.
Recent international communicable disease crises have highlighted the need for countries to assure their preparedness to respond effectively to public health emergencies. The objective of this study was to critically review existing tools to support a country's assessment of its health emergency preparedness. We developed a framework to analyze the expected effectiveness and utility of these tools. Through mixed search strategies, we identified 12 tools with relevance to public health emergencies. There was considerable consensus concerning the critical preparedness system elements to be assessed, although their relative emphasis and means of assessment and measurement varied considerably. Several tools identified appeared to have reporting requirements as their primary aim, rather than primary utility for system self-assessment of the countries and states using the tool. Few tools attempted to give an account of their underlying evidence base. Only some tools were available in a user-friendly electronic modality or included quantitative measures to support the monitoring of system preparedness over time. We conclude there is still a need for improvement in tools available for assessment of country preparedness for public health emergencies, and for applied research to increase identification of system measures that are valid indicators of system response capability.


Convolutional Embedding of Attributed Molecular Graphs for Physical Property Prediction.
The task of learning an expressive molecular representation is central to developing quantitative structure-activity and property relationships. Traditional approaches rely on group additivity rules, empirical measurements or parameters, or generation of thousands of descriptors. In this paper, we employ a convolutional neural network for this embedding task by treating molecules as undirected graphs with attributed nodes and edges. Simple atom and bond attributes are used to construct atom-specific feature vectors that take into account the local chemical environment using different neighborhood radii. By working directly with the full molecular graph, there is a greater opportunity for models to identify important features relevant to a prediction task. Unlike other graph-based approaches, our atom featurization preserves molecule-level spatial information that significantly enhances model performance. Our models learn to identify important features of atom clusters for the prediction of aqueous solubility, octanol solubility, melting point, and toxicity. Extensions and limitations of this strategy are discussed.


[Update on muscle relaxation : What comes after succinylcholine, rocuronium and sugammadex?]
Due to the great advantages, it is not possible to imagine current practice in anesthesia without the adminstration of muscle relaxants. For a long time the administration of succinylcholine for rapid sequence induction (RSI) was considered to be the state of the art for patients at risk for aspiration. The favorable characteristics are, however, accompanied by many, sometimes severe side effects. Due to the development of non-depolarizing muscle relaxants, in particular rocuronium in combination with sugammadex, there is the possibility to achieve a profile of action similar to succinylcholine with low side effects. After the introduction of sugammadex onto the market, further substances were conceived, which enable a complete encapsulation of muscle relaxants. Calabadion is a very promising new substance for the antagonization of muscle relaxants, which can antagonize the action of steroid as well as benzylisoquinoline types. In the USA new muscle relaxants are currently being tested, which have a rapid onset and the effect can be reversed by L‑cysteine. One of the most promising substances is gantacurium, which is currently being tested in the USA in phase III trials. It remains to be seen whether these muscle relaxants, which are not yet on the market and drugs for reversal of neuromuscular blockade have the potential to become a real alternative to the combination of rocuronium and sugammadex.


A Review of GnRH Antagonists as Treatment for Abnormal Uterine Bleeding-Leiomyoma (AUB-L) and Their Influence on the Readiness of Service Members.
Not too long ago, Lupron Depot® (leuprolide acetate), an injectable gonadotropin-releasing hormone (GnRH) agonist, was the only Food and Drug Administration (FDA) approved GnRH analog used to clinically treat abnormal uterine bleeding associated with uterine leiomyoma (AUB-L) when second-line medical management was warranted; however, the FDA has now approved elagolix and relugolix, GnRH antagonists, to be treatment options as well. This is a review of GnRH antagonists for the management of uterine fibroids reviewing their treatment efficacy, side effect profile, and current use in military medicine. This is a review of studies from multiple electronic databases (Pubmed, ACOG, FDA, U.S. Military Guidelines) published between 1990 and 2021. Keywords used for the search include GnRH antagonist, elagolix, relugolix, uterine leiomyoma, and abnormal uterine bleeding. Our inclusion criteria for articles reviewed were: systematic reviews with the listed keywords, multicenter randomized trials, and meta-analyses. The DODI on Medical Standards for Medical Service, Air Force Aerospace Medicine Waiver Guide, Navy Guidance Aeromedical Reference and Waiver Guide, and the Army Regulation 40-501 Standards of Medical Fitness were used to review the military standards and current restrictions placed on service members. Thirty-three articles were reviewed and summarized. Uterine leiomyoma can impact service members' eligibility and fitness for duty. The oral administration of elagolix and relugolix adds convenience to this drug class through its oral administration while lengthening the duration of treatment up to 24 months. All military medical facilities should advocate for the well-being of their service members by stocking all options available. Health care providers should collaborate with patients in making the best therapy choice that is suited for their lifestyle and military occupation.


Burnout syndrome: a preliminary study of a population of nurses in italian prisons.
Burnout is a set of psychological manifestations ("emotional exhaustion", "depersonalization" and reduced "personal accomplishment") that principally affects healthcare professionals. Analysis of the level of burnout among twelve nurses who work in two Italian prisons. The Maslach Burnout Inventory was administered. In order to explore possible correlations between the three dimensions of the Maslach Burnout Inventory and such variables as age, years of service in general and years of service in prisons, multiple regression based on the ordinary least squares method (OLS model) was performed. The response rate was 100%, of whom 66.6% female and 33.4% male. The average age is 38.1 years. Over half of the sample had worked from 0 to 10 years in prisons (58.4%), and only one respondent had done so between 21 and 30 years (8.3%). The data indicate that the highest levels of burnout concerned the dimension of "depersonalization" (66.7%) and "personal accomplishment" (41.6%). Emotional exhaustion of nurses in carrying out their work diminished with the increase of the independent variable of "personal accomplishment" (p-value 0.0361); it increased with the increase of the age variable (p-value 0.0117). Personal accomplishment decreased with the increase of the independent variables of emotional exhaustion (p-value 0.0361) and years of service in prisons (p-value 0.0238). For depersonalization, no statistically significant coefficients were observed. Model 1 of multiple regression showed a significant statistical association between the emotional exhaustion (dependent variable) and personal achievement (p-value 0.0361), and increase in age (p-value 0.0117). Model 2 showed significant statistical association between personal achievement (dependent variable) and emotional exhaustion (p=value 0.0361) and years of service nursing in prisons (p-value 0.0238). Model 3 showed no statistical association between depersonalization (dependent variable) and the other variables. While twelve nurses formed this small sample, the study nonetheless indicated how the variables examined can influence the levels of burnout. Given that thorough inquiries into the levels of burnout among nurses who work in Italian prisons, specifically in the Marche Region, have yet to be conducted, this pilot study can serve as a point of reference for future research to improve evidence-based medicine.


The effect of neuropeptide Y on mucociliary activity in the rabbit maxillary sinus.
The effect of neuropeptide Y (NPY) on mucociliary activity in the rabbit maxillary sinus was investigated in vivo by injecting NPY at increasing dosages into the maxillary artery, response being recorded photoelectrically. At dosages of 0.1-5.0 micrograms/kg, NPY reduced mucociliary activity dose-dependently, the maximum decrease being 14.6 +/- 1.8%, at a dosage of 5.0 micrograms/kg. The NPY-induced reduction of the mucociliary activity manifested brief latency, the peak effect occurring within 3 min followed by a slow return to the baseline value 4-9 min after injection. The response of mucociliary activity to NPY remained unaffected by pretreatment with the alpha-adrenergic antagonists yohimbine (alpha 2) at 100.0 micrograms/kg and phentolamine (alpha 1 + alpha 2) at 0.2-1.0 mg/kg, indicating that the effect of NPY is not mediated via alpha-receptors. Pretreatment with the calcium antagonist nifedipine at 100.0 micrograms/kg inhibited the effect of NPY, suggesting that the NPY-induced decrease may be calcium dependent.


Primary retroperitoneal tumors.
Seventy-five cases of primary retroperitoneal tumors observed at the Istituto Nazionale Tumori of Milan during the period 1932 to 1973, 56 of which had a histopathologic classification (51 malignant and 5 benign), are reported. By examination of the diagnostic and therapeutic criteria employed and the survival data (9 of the 51 malignant cases were alive at 3 years, and 3 of these were alive at 5 years), the authors point out the difficulty of an early diagnosis and, therefore, of a radical surgery, the need for a programmed therapy, and the importance of the angiographic examination in the diagnostic strategy.


Novel papillomaviruses in free-ranging Iberian bats: no virus-host co-evolution, no strict host specificity, and hints for recombination.
Papillomaviruses (PVs) are widespread pathogens. However, the extent of PV infections in bats remains largely unknown. This work represents the first comprehensive study of PVs in Iberian bats. We identified four novel PVs in the mucosa of free-ranging Eptesicus serotinus (EserPV1, EserPV2, and EserPV3) and Rhinolophus ferrumequinum (RferPV1) individuals and analyzed their phylogenetic relationships within the viral family. We further assessed their prevalence in different populations of E. serotinus and its close relative E. isabellinus. Although it is frequent to read that PVs co-evolve with their host, that PVs are highly species-specific, and that PVs do not usually recombine, our results suggest otherwise. First, strict virus-host co-evolution is rejected by the existence of five, distantly related bat PV lineages and by the lack of congruence between bats and bat PVs phylogenies. Second, the ability of EserPV2 and EserPV3 to infect two different bat species (E. serotinus and E. isabellinus) argues against strict host specificity. Finally, the description of a second noncoding region in the RferPV1 genome reinforces the view of an increased susceptibility to recombination in the E2-L2 genomic region. These findings prompt the question of whether the prevailing paradigms regarding PVs evolution should be reconsidered.


[Differentiation of stem cells regulated by biophysical cues].
Stem cells have been regarded with promising application potential in tissue engineering and regenerative medicine due to their self-renewal and multidirectional differentiation abilities. However, their fate is relied on their local microenvironment, or niche. Recent studied have demonstrated that biophysical factors, defined as physical microenvironment in which stem cells located play a vital role in regulating stem cell committed differentiation. In vitro, synthetic physical microenvironments can be used to precisely control a variety of biophysical properties. On this basis, the effect of biophysical properties such as matrix stiffness, matrix topography and mechanical force on the committed differentiation of stem cells was further investigated. This paper summarizes the approach of mechanical models of artificial physical microenvironment and reviews the effects of different biophysical characteristics on stem cell differentiation, in order to provide reference for future research and development in related fields.


Circulating Soluble IL-6 Receptor Concentration and Visceral Adipocyte Size Are Related to Insulin Resistance in Taiwanese Adults with Morbid Obesity.
Morbid obesity is related to chronic inflammation and many metabolic complications. Interleukin (IL)-6 plays a pivotal pathophysiological role in obesity, and IL-6 trans-signaling through the soluble IL-6 receptor (sIL-6R) has a major proinflammatory effect. The aim of this study was to investigate the association between sIL-6R, adipocyte size, and insulin resistance in morbidly obese individuals. We measured concentrations of sIL-6R, high-sensitivity C-reactive protein, and lipid parameters and estimated homeostasis model assessment of insulin resistance (HOMA-IR) before the patients underwent bariatric surgery. Mesenteric adipose tissue was collected during surgery, and adipocyte size and concentrations of membrane-bound IL-6 receptor (mIL-6R) were evaluated. In total, 35 adults (20 men and 15 women) were recruited. The subjects with high HOMA-IR (≥2.4) had higher fasting glucose/insulin, triglycerides, sIL-6R, and adipocyte size and lower high-density lipoprotein cholesterol and mIL-6R than those with low HOMA-IR (<2.4). Adipocyte size positively correlated with sIL-6R (r = 0.559, P = 0.001) and HOMA-IR (r = 0.773, P ≤ 0.001) independent of age, gender, body mass index (BMI), waist, and use of diabetic drugs. In addition, every 1 ng/mL increase in sIL-6R concentration corresponded to a 10.2% decrease in the likelihood of maintaining lower insulin resistance. Furthermore, an sIL-6R level of 77.45 ng/mL was a reasonable cutoff level to propose lower insulin resistance in morbidly obese subjects. Circulating sIL-6R is more closely associated with insulin resistance status than waist-to-hip ratio or BMI in morbidly obese Taiwanese adults. sIL-6R may be a useful biomarker to assess insulin resistance among morbidly obese subjects.


Hematopoietic stem cell function requires 12/15-lipoxygenase-dependent fatty acid metabolism.
Fatty acid metabolism governs multiple intracellular signaling pathways in many cell types, but its role in hematopoietic stem cells (HSCs) is largely unknown. Herein, we establish a critical role for 12/15-lipoxygenase (12/15-LOX)-mediated unsaturated fatty acid metabolism in HSC function. HSCs from 12/15-LOX-deficient mice are severely compromised in their capacity to reconstitute the hematopoietic compartment in competitive and serial reconstitution assays. Furthermore, we demonstrate that 12/15-LOX is required for the maintenance of long-term HSC quiescence and number. The defect in HSCs is cell-autonomous and associated with a selective reduction in 12/15-LOX-mediated generation of bioactive lipid mediators and reactive oxygen species and with a decrease in canonical Wnt signaling as measured by nuclear beta-catenin staining. These results have implications for development, aging, and transformation of the hematopoietic compartment.


Antidepressant effects of magnolol in a mouse model of depression induced by chronic corticosterone injection.
Evidence showed that the stress hormone corticosterone (CORT) injection resulted in dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis implicated in major depressive disorder. Magnolol, main constituent identified in the barks of Magnolia officinalis, exerted antidepressant effects in a rat model of depression induced by chronic unpredictable mild stress in previous studies. However, its antidepressant-like effects and mechanisms have never been studied in depression model induced by CORT administration in rodents. This study aimed to investigate the antidepressant-like effects and possible mechanisms of magnolol in CORT-treated mice by utilizing a combination of behavioral and biochemical analysis. The depressive model was developed by subcutaneous injection of CORT for 21 days at a dose of 20 mg/kg. CORT administration formed depressive-like behaviors in mice, as indicated by increased immobility time in the forced swim test (FST) and tail suspension test (TST), as well as decreased sucrose intake in sucrose preference test (SPT). Moreover, we also found that CORT levels in serum were significantly increased, along with the decrease of brain-derived neurotrophic factor (BDNF) mRNA, BDNF protein, 5-hydroxytryptamine (5-HT) and norepinephrine (NE) levels in the hippocampus. Treatment with magnolol alleviated depressive-like behaviors, reduced the levels of CORT, and improved the levels of BDNF protein, 5-HT, and NE compared with those in CORT-treated mice. These findings indicated that magnolol possessed antidepressant effects in mice exposed to CORT, which might be partially related to modulate HPA axis, up-regulate BDNF expression and increase neurotransmitters levels in the hippocampus.


[The human circadian system: physiology, pathophysiology and interactions with sleep and stress reactivity].
The dramatic fluctuations in the energy demands of living organisms by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for a biological temporal organization necessary for maintenance of homeostasis and adaptation to environmental changes across phylogeny. The intrinsic circadian system (CS) represents a highly conserved and complex internal biological "clock", adjusted to the 24-hour rotation of the earth about itself. This system creates and maintains cellular and organismal rhythmicity and enables a nyctohemeral coordination of multi-level physiologic processes, ranging from gene expression to behaviour. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker of the circadian system of the organism, while a ubiquitous peripheral oscillating network of cellular molecular clocks participates in a complex circadian hierarchy. A critical loss of this harmoniously timed circadian order at different organizational levels is defined as "chronodisruption", a condition that may alter the fundamental properties of basic homeostatic systems at molecular, cellular and organismal levels, and lead to a breakdown of biobehavioral adaptive mechanisms, resulting in maladaptive stress regulation and increased sensitivity and vulnerability to stress. Chronodisruption has been linked to neuroendocrine, immune, cardiometabolic and autonomic dysregulation, with blunted diurnal rhythms, specific sleep pattern pathologies and cognitive deficits, as well as with altered circadian gene expression. This condition may, thus, play a central role in the development of mental and somatic disease. Nevertheless, circadian and sleep disturbances are often clinically considered as "secondary" manifestations in most disorders, neglecting the potentially important pathophysiological role of CS. Understanding the pathophysiologic mechanisms of circadian dysregulation and their role in stress-related, systemic disease could provide new insights into disease mechanisms and could help advance chronobiological treatment possibilities and preventive strategies in populations at risk.


Functions, Roles, and Biological Processes of Ferroptosis-Related Genes in Renal Cancer: A Pan-Renal Cancer Analysis.
Ferroptosis is a cell death process discovered in recent years, highly related to cancer, acute kidney injury, and other diseases. In this study, a pan-renal cancer analysis of ferroptosis-associated genes in renal cancer was performed to construct a multigene joint signature for predicting prognosis in renal cancer patients. First, gene expression profiles were downloaded from the TCGA and GTEx databases to search for genes significantly associated with renal cancer prognosis through differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and survival analysis. Thereafter, the gene-set enrichment analysis (GSEA) was used to identify the biological processes in which ferroptosis-associated genes might be involved. Weighted gene co-expression network analysis resulted in 4,434 differentially expressed genes (DEGs) and 42 co-expression modules, among which ferroptosis-related genes were distributed in 11 gene modules. The survival analysis screening resulted in three DEGs associated with renal cancer prognosis, namely SLC7A11, HMOX1, and MT1G. Specifically, SLC7A11 and HMOX1 were upregulated in renal cancer tissues, while MT1G was downregulated. Receiver operating characteristic (ROC) curves, combined with Kaplan-Meier and Cox regression analysis, revealed that high expression of SLC7A11 was a prognostic risk factor for four different renal cancers, that low expression of HMOX1 was a poor prognostic marker for patients, and that increased expression of MT1G increased the prognostic risk for three additional classes of renal cancer patients, except for renal papillary cell carcinoma. The GSEA results showed that the ferroptosis-related genes from these screens were mainly associated with signaling pathways related to tumor progression and tumor immunity. This study provides potential biological markers for prognosis prediction in renal cancer patients with different subtypes, and these results imply that ferroptosis is highly associated with renal carcinogenesis progression.


[Infections and bone marrow autograft carried out for leukemias in children. Apropos of 47 cases].
This study included 44 children undergoing autologous marrow transplantation for leukemia between August 1979 and June 1987. Three of them received a second transplant. In the phase of neutropenia, 38 children presented with fever. Nineteen septicemia occurred (13 Gram positive cocci, 6 Gram negative bacteria), and 2 interstitial pneumonitis were observed. All children with documented infection or a fever of unknown origin recovered after treatment, except 3, who died from infection. The latest antimicrobial therapy used was a combination of an aminoglycoside and a third generation cephalosporin. When necessary, vancomycin or amphotericin B were added. After engraftment (granulocyte count greater than 0.5 X 10(9)/l) 14 septicemia (which recovered) and 10 herpes zoster infections were observed. Only one patient died of infection (herpes zoster with encephalitis).


Morphology of the rat cochlear primary afferents during prenatal development: a Cajal's reduced silver and rapid Golgi study.
In this study, we analyse the process of spatial organisation of the cochlear root related to the morphological and topographical changes in the CN during the prenatal development of Wistar rats, placing special emphasis on aspects of the latero-medial distribution of the cochlear afferents. A total of 35 embryos from 8 Wistar rats was employed, corresponding to embryonic days 14, 16, 18 and 20. Twenty of these embryos were studied by the Cajal's reduced silver stain and 15 by the rapid Golgi method (osmium dichromate method). The otocyst, the vestibulo-cochlear ganglion and vestibulo-cochlear nerve were first observed at embryonic Day 14 (E14). At E16, a sharp separation between the cochlear and vestibular roots was distinguished. The final position of the primary afferents and their main branches (anterior and posterior) in the CN was observed at E18 and E20, when the total number of cochlear turns had been formed. The cochlear afferents coming from the apical coil, the last to be incorporated into the cochlear root, project their posterior branches at the bifurcation towards more medial portions of the PVCN and their anterior branches towards the more lateral regions of the AVCN.


High-performance adsorption and separation of anionic dyes in water using a chemically stable graphene-like metal-organic framework.
A highly stable graphene-like metal-organic framework (BUC-17) was prepared and used as an adsorbent to carry out the adsorption of anionic dyes from simulated wastewater, which exhibited excellent adsorption performance, particularly towards Congo red (CR) up to 4923.7 mg g-1 at room temperature. It was used to fix a SPE column to conduct rapid separation of anionic dyes from an organic dye matrix. A related mechanism was also proposed.


Hyperglycaemia and infarct size in animal models of middle cerebral artery occlusion: systematic review and meta-analysis.
Poststroke hyperglycaemia (PSH) is common, has an unclear pathophysiology, and is associated with poor outcomes. Animal studies report conflicting findings. We systematically reviewed the effects of hyperglycaemia on infarct volume in middle cerebral artery occlusion (MCAO) models, generating weighted mean differences between groups using random effects models summarised as effect size (normalised to control group infarct volume as 100%) and 95% confidence interval. Of 72 relevant papers, 23 reported infarct volume. Studies involved 664 animals and 35 distinct comparisons. Hyperglycaemia was induced by either streptozotocin (STZ, 17 comparisons, n=303) or dextrose (18 comparisons, n=356). Hyperglycaemic animals had infarcts that were 94% larger, but STZ was associated with significantly greater increase in infarct volumes than dextrose infusion (140% larger versus 48% larger). In seven studies, insulin did not significantly reduce infarct size and results were heterogeneous. Although hyperglycaemia exacerbates infarct volume in MCAO models, studies are heterogeneous, and do not address the common clinical problem of PSH because they have used either the STZ model of type I diabetes or extremely high glucose loads. Insulin had a nonsignificant and significantly heterogeneous effect. Further studies with relevant models may inform clinical trial design.


Cone-Beam Computed Tomography-Based Three-Dimensional McNamara Cephalometric Analysis.
This article introduces a method that extends the McNamara cephalometric analysis to produce 3-dimensional (3D) measurement values from cone-beam computed tomography images. In the extended method, the cephalometric landmarks are represented by 3D points; the bilateral cephalometric landmarks are identified on both sides of the skull; the cephalometric lines, with the exception of the facial axis, are represented by 3D lines; the cephalometric planes, with the exception of the facial plane, are represented by planes; the effective mandibular length, the effective midfacial length, and the lower anterior facial height are measured as 3D point-to-point distances; the nasion perpendicular to point A, the pogonion to nasion perpendicular, the upper incisor to point A vertical, and the lower incisor to point A-pogonion line are measured each as components of a vector; the facial axis angle is measured as a line-to-plane angle; and the mandibular plane angle is measured as a plane-to-plane angle. As a result, the method provides real effective lengths of the maxilla and mandible on both sides of the skull; real height of the lower anterior face; directed distances from the point A to the nasion perpendicular, from the pogonion to the nasion perpendicular, from the left and right upper incisor to the point A vertical, and from the left and right lower incisor to the point A-pogonion line for both the lateral and posteroanterior views of the skull; and real angles of the facial axis and the mandibular plane. Additionality, the method enables the identification of craniofacial asymmetries.


Assessment of faecal occult blood loss by qualitative and quantitative methods.
Various methods exist for the assessment of faecal occult blood loss in a patient with suspected gastrointestinal blood loss. The present study examined the effectiveness and financial implications of a qualitative guaiac-based method (Haemoccult) of faecal occult blood detection and a quantitative measure of haeme-derived porphyrins (Hemoquant) in 184 patients who underwent assessment of faecal blood loss by both methods over a three year period during assessment of iron deficiency anaemia. At least one Haemoccult test was positive in 72.2% of patients while Hemoquant was suggestive of significant blood loss (> 2mg haemoglobin/g faeces) in 29.9%. Patients underwent a total of 324 further endoscopic or radiological investigations of which 76.5% demonstrated no abnormality. A diagnosis was reached in 60 patients (32.6%). A significant potential source of gastrointestinal bleeding was found in 48 patients (26.1%). Hemoquant achieved a sensitivity of 62.5% and a specificity of 81.6% while with Haemoccult it was 85.4% and 32.4%, respectively. Hemoquant was normal in 18 patients with significant gastrointestinal conditions including peptic ulcers and colonic polyps. While Haemoccult only missed 7 lesions, two of these were colonic cancers. The quantitative nature of the Hemoquant test gave little clue as to diagnosis. Neither of the tests examined was ideal but Hemoquant had an overall better performance and further investigation of patients with evidence of blood loss from this test should be mandatory.


Adrenocortical and adipose responses to high-altitude-induced, long-term hypoxia in the ovine fetus.
By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA) axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m), long-term hypoxia (LTH) in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN), anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress.


Recognizing and responding to adolescent depression.
We have seen that depression is increasingly recognized as a problem which affects adolescents as well as adults. Race by itself is not a factor which increases vulnerability to depression, but the multitude of sociodemographic, biological, and personal factors contributing to the development of depression are not fully understood. Research is needed to better understand how these factors interact in order to better develop prevention strategies and treatment modalities. With regard to treatment, adolescents are truly underserved. There is an awkward fit between the traditional mental health system and the developmental needs of adolescents. Unlike the majority of depressed adults who receive some treatment from general practitioners and medical clinics, adolescents do not tend to visit their pediatricians when they are depressed. One proposed solution is the adolescent comprehensive health care clinic providing a holistic approach to assessment, early intervention, and collaborative treatment between primary provider and mental health worker. Data from our adolescent program suggest that this approach has been successful in dealing with the problem of depression, especially in its early stages. Again, more research is needed to support these preliminary findings, but we believe that the adolescent comprehensive health care approach can be an effective, efficient way of addressing the health needs, mental and physical, of our teens at risk. Federal money for research must be made available, liberalization of health insurance must occur, and state-sponsored services must be developed so that these programs can be made more effective and can be brought to more of the adolescents who need them.


Subcategorization of intermediate suspicion thyroid nodules based on suspicious ultrasonographic findings.
This study compared the malignancy risk of intermediate suspicion thyroid nodules according to the presence of suspicious ultrasonographic (US) findings. From January 2014 to December 2014, 299 consecutive intermediate suspicion thyroid nodules in 281 patients (mean age, 50.6±12.5 years) with final diagnoses were included in this study. Two radiologists retrospectively reviewed the US findings and subcategorized the intermediate suspicion category into nodules without suspicious findings and nodules with suspicious findings, including punctate echogenic foci, nonparallel orientation, or irregular margins. The malignancy rates were compared between the two subcategory groups. Of the 299 intermediate suspicion thyroid nodules, 230 (76.9%) were subcategorized as nodules without suspicious findings and 69 (23.1%) as nodules with suspicious findings. The total malignancy rate was 33.4% (100/299) and the malignancy rate of nodules with suspicious findings was significantly higher than that of nodules without suspicious findings (47.8% vs. 29.1%, P=0.004). In nodules with suspicious findings, the most common suspicious finding was punctate echogenic foci (48/82, 58.5%) followed by nonparallel orientation (22/82, 26.8%) and irregular margins (12/82, 14.6%). Thirteen nodules had two suspicious findings simultaneously. A linearly increasing trend in the malignancy rate was observed according to the number of suspicious US findings (P for trend=0.001). Intermediate suspicion thyroid nodules with suspicious findings showed a higher malignancy rate than those without suspicious findings. Further management guidelines for nodules with suspicious findings should differ from guidelines for nodules without suspicious findings, even in the same US category.


Exploratory Data Analysis of the Groundwater Contaminants at the Former Panna Maria Uranium Recovery Facility.
The former Panna Maria mill was a uranium recovery facility that operated from 1979 to December 1992. Sulfuric acid leach was used to process several tons of ore daily. Therefore, the groundwater was sampled at the site to monitor the concentration of background chemical pollutants. The purpose of this study was to perform exploratory data analysis to evaluate whether the arsenic, nickel, selenium, sulfate, and uranium concentrations were in accord with state-regulated groundwater drinking standards at the site. To accomplish this, a substitution method was used to replace concentration values that were below measurable ranges of well monitoring units. Additionally, random forest regression was employed to account for missing not-at-random values in the dataset. Groundwater samples collected in wells before the facility began operations were used to determine an upper bound on background pollutants consistent with US Environmental Protection Agency Standards. The upper tolerance limit comprising 90% of the groundwater sample at a confidence coefficient of 95% was used to establish alternate concentration limits for each chemical based on well data from the National Uranium Resource Hydrogeochemical and Stream Sediment Reconnaissance program. Results obtained in this analysis establish a baseline on the chemical concentrations in the background groundwater at the former Panna Maria mill.


The membrane-associated enzyme phosphatidylserine synthase is regulated at the level of mRNA abundance.
To precisely define the functional sequence of the CHO1 gene from Saccharomyces cerevisiae, encoding the regulated membrane-associated enzyme phosphatidylserine synthase (PSS), we subcloned the original 4.5-kilobase (kb) CHO1 clone. In this report a 2.8-kb subclone was shown to complement the ethanolamine-choline auxotrophy and to repair the defect in the synthesis of phosphatidylserine, both of which are characteristic of cho1 mutants. When this subclone was used as a hybridization probe of Northern and slot blots of RNA from wild-type cells, the abundance of a 1.2-kb RNA changed in response to alterations in the levels of the soluble phospholipid precursors inositol and choline. The addition of inositol led to a 40% repression of the 1.2-kb RNA level, while the addition of choline and inositol led to an 85% repression. Choline alone had little repressive effect. The level of 1.2-kb RNA closely paralleled the level of PSS activity found in the same cells as determined by enzyme assays. Disruption of the CHO1 gene resulted in the simultaneous disappearance of 1.2-kb RNA and PSS activity. Cells bearing the ino2 or ino4 regulatory mutations, which exhibit constitutively repressed levels of a number of phospholipid biosynthetic enzymes, had constitutively repressed levels of 1.2-kb RNA and PSS activity. Another regulatory mutation, opi1, which causes the constitutive derepression of PSS and other phospholipid biosynthetic enzymes, caused the constitutive derepression of the 1.2-kb RNA. When cho1 mutant cells were transformed with the 2.8-kb subclone on a single-copy plasmid, the 1.2-kb RNA and PSS activity levels were regulated in a wild-type fashion. The presence of the 2.8-kb subclone on a multicopy plasmid, however, led to the constitutive overproduction of 1.2-kb RNA and PSS in cho1 cells.


In Vitro and In Vivo Antimalarial Activity of LZ1, a Peptide Derived from Snake Cathelicidin.
Antimalarial drug resistance is an enormous global threat. Recently, antimicrobial peptides (AMPs) are emerging as a new source of antimalarials. In this study, an AMP LZ1 derived from snake cathelicidin was identified with antimalarial activity. In the in vitro antiplasmodial assay, LZ1 showed strong suppression of blood stage Plasmodium falciparum (P. falciparum) with an IC50 value of 3.045 μM. In the in vivo antiplasmodial assay, LZ1 exerted a significant antimalarial activity against Plasmodium berghei (P. berghei) in a dose- and a time- dependent manner. In addition, LZ1 exhibited anti-inflammatory effects and attenuated liver-function impairment during P. berghei infection. Furthermore, by employing inhibitors against glycolysis and oxidative phosphorylation in erythrocytes, LZ1 specifically inhibited adenosine triphosphate (ATP) production in parasite-infected erythrocyte by selectively inhibiting the pyruvate kinase activity. In conclusion, the present study demonstrates that LZ1 is a potential candidate for novel antimalarials development.


Colorectal Cancer Screening in Average Risk Patients.
Colorectal cancer (CRC) contributes a major burden of cancer mortality in the United States. There are multiple effective screening approaches that can reduce CRC mortality. These approaches are supported by different levels of evidence, and each has its own advantages and disadvantages. Implementing a systematic approach to screening that addresses the multiple steps involved in the screening process is essential to improving population-level CRC screening. Offering patients stool-based screening is important for increasing screening uptake. However, programs that offer stool testing must support the population health infrastructure needed to promote adherence to repeat testing and follow-up of abnormal tests.


Homogenization of periodic 1-3 piezocomposite using wave propagation: Toward an experimental method.
1-3 piezocomposites are first choice materials for integration in ultrasonic transducers due to their high electromechanical performance, particularly, in their thickness mode. The determination of a complete set of effective electroelastic parameters through a homogenization scheme is of primary importance for their consideration as homogeneous. This allows for the simplification of the transducer design using numerical methods. The method proposed is based on acoustic wave propagation through an infinite piezocomposite, which is considered to be homogeneous material. Christoffel tensor components for the 2 mm symmetry were expressed to deduce slowness curves in several planes. Simultaneously, slowness curves of a numerical phantom were obtained using a finite element method (FEM). Dispersive curves were initially calculated in the corresponding heterogeneous structure. The subsequent identification of the effective parameters was based on a fitting process between the two sets of slowness curves. Then, homogenized coefficients were compared with reference results from a numerical method based on a fast Fourier transform for heterogeneous periodic piezoelectric materials in the quasi-static regime. A relative error of less than 2% for a very large majority of effective coefficients was obtained. As the aim of this paper is to implement an experimental procedure based on the proposed homogenization scheme to determine the effective parameters of the material in operating conditions, it is shown that simplifications to the procedure can be performed and a careful selection of only seven slowness directions is sufficient to obtain the complete database for a piezocomposite containing square-shaped fibers. Finally, further considerations to adapt the present work to a 1-3 piezocomposite with a fixed thickness are also presented.


Evaluation of an automated connective tissue disease screening assay in Korean patients with systemic rheumatic diseases.
This study aimed to evaluate the diagnostic utilities of the automated connective tissues disease screening assay, CTD screen, in patients with systemic rheumatic diseases. A total of 1093 serum samples were assayed using CTD screen and indirect immunofluorescent (IIF) methods. Among them, 162 were diagnosed with systemic rheumatic disease, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCT). The remaining 931 with non-systemic rheumatic disease were assigned to the control group. The median ratios of CTD screen tests were significantly higher in the systemic rheumatic disease group than in the control group. The positive likelihood ratios of the CTD screen were higher than those of IIF in patients with total rheumatic diseases (4.1 vs. 1.6), including SLE (24.3 vs. 10.7). The areas under the receiver operating characteristic curves (ROC-AUCs) of the CTD screen for discriminating total rheumatic diseases, RA, SLE, and MCT from controls were 0.68, 0.56, 0.92 and 0.80, respectively. The ROC-AUCs of the combinations with IIF were significantly higher in patients with total rheumatic diseases (0.72) and MCT (0.85) than in those of the CTD screen alone. Multivariate analysis indicated that both the CTD screen and IIF were independent variables for predicting systemic rheumatic disease. CTD screen alone and in combination with IIF were a valuable diagnostic tool for predicting systemic rheumatic diseases, particularly for SLE.


Coalescence and Linkage Disequilibrium in Facultatively Sexual Diploids.
Under neutrality, linkage disequilibrium results from physically linked sites having nonindependent coalescent histories. In obligately sexual organisms, meiotic recombination is the dominant force separating linked variants from one another, and thus in determining the decay of linkage disequilibrium with physical distance. In facultatively sexual diploid organisms that principally reproduce clonally, mechanisms of mitotic exchange are expected to become relatively more important in shaping linkage disequilibrium. Here we outline mathematical and computational models of a facultative-sex coalescent process that includes meiotic and mitotic recombination, via both crossovers and gene conversion, to determine how linkage disequilibrium is affected with facultative sex. We demonstrate that the degree to which linkage disequilibrium is broken down by meiotic recombination simply scales with the probability of sex if it is sufficiently high (much greater than [Formula: see text] for population size N). However, with very rare sex (occurring with frequency on the order of [Formula: see text]), mitotic gene conversion plays a particularly important and complicated role because it both breaks down associations between sites and removes within-individual diversity. Strong population structure under rare sex leads to lower average linkage disequilibrium values than in panmictic populations, due to the influence of low-frequency polymorphisms created by allelic sequence divergence acting in individual subpopulations. These analyses provide information on how to interpret observed linkage disequilibrium patterns in facultative sexuals and to determine what genomic forces are likely to shape them.


Dissolution assessment of allopurinol immediate release tablets by near infrared spectroscopy.
The purpose of this study was to develop a NIR spectroscopic method for assessment of drug dissolution from allopurinol immediate release tablets. Thirty three different batches of allopurinol immediate release tablets containing constant amount of the active ingredient, but varying in excipients content and physical properties were introduced in a PLS calibration model. Correlating allopurinol dissolution reference values measured by the routinely used UV/Vis method, with the data extracted from the NIR spectra, values of correlation coefficient, bias, slope, residual prediction determination and root mean square error of prediction (0.9632, 0.328%, 1.001, 3.58, 3.75%) were evaluated. The obtained values implied that the NIR diffuse reflectance spectroscopy could serve as a faster and simpler alternative to the conventional dissolution procedure, even for the tablets with a very fast dissolution rate (>85% in 15minutes). Apart from the possibility of prediction of the allopurinol dissolution rate, the other multivariate technique, PCA, provided additional data on the non-chemical characteristics of the product, which could not be obtained from the reference dissolution values. Analysis on an independent set of samples confirmed that a difference between the UV/Vis reference method and the proposed NIR method was not significant. According to the presented results, the proposed NIR method may be suitable for practical application in routine analysis and for continuously monitoring the product's chemical and physical properties responsible for expected quality.


The effect of chronic stress on prenatal development of the central nervous system.
The survival of developing embryos depends on the control and maintenance of homeostasis. Stress caused by chronic immobilization during pregnancy in rats may alter the normal development of the nervous system and increase susceptibility to psychiatric disorders. We investigated the effects of chronic stress on cell proliferation in the forebrains of embryos at 12 days of gestation, and in the hippocampus, dentate gyrus and cortex in embryos at 17 and 21 days of gestation. We examined serial sections of the embryonic brains of control and stressed rats at days 12, 17 and 21 of gestation. Brain sections were immunolabeled with anti-PCNA and stereological analysis was performed on 540 images. The results showed no statistical differences on days 12 and 17 of gestation in the proliferation area of the structures studied, whereas on day 21 of gestation, proliferation decreased in the cortex and dentate gyrus of embryos of the stressed group. These changes were related to decreased prolactin and increased corticosterone concentrations in the plasma.


Therapeutic Potential of Adjuvant Stereotactic Body Radiotherapy for Gallbladder Cancer.
Surgical treatment remains the only curative treatment for gallbladder cancer. However, even after liver resection, locoregional failure seems to be a significant problem. While there is no Level I evidence, multiple studies have shown benefit for adjuvant radiation in high-risk patients. After extensive liver resection, tolerance to conventional chemoradiation may be limited by potential liver toxicity. Stereotactic body radiotherapy has been used safely and effectively in hepatobiliary malignancies. We present a case report, highlighting the potential therapeutic role of adjuvant stereotactic body radiotherapy (SBRT) for gallbladder cancer.