Identification, analysis, and interpretation of a human serum metabolomics causal network in an observational study.
Untargeted metabolomics, measurement of large numbers of metabolites irrespective of their chemical or biologic characteristics, has proven useful for identifying novel biomarkers of health and disease. Of particular importance is the analysis of networks of metabolites, as opposed to the level of an individual metabolite. The aim of this study is to achieve causal inference among serum metabolites in an observational setting. A metabolomics causal network is identified using the genome granularity directed acyclic graph (GDAG) algorithm where information across the genome in a deeper level of granularity is extracted to create strong instrumental variables and identify causal relationships among metabolites in an upper level of granularity. Information from 1,034,945 genetic variants distributed across the genome was used to identify a metabolomics causal network among 122 serum metabolites. We introduce individual properties within the network, such as strength of a metabolite. Based on these properties, hypothesized targets for intervention and prediction are identified. Four nodes corresponding to the metabolites leucine, arichidonoyl-glycerophosphocholine, N-acyelyalanine, and glutarylcarnitine had high impact on the entire network by virtue of having multiple arrows pointing out, which propagated long distances. Five modules, largely corresponding to functional metabolite categories (e.g. amino acids), were identified over the network and module boundaries were determined using directionality and causal effect sizes. Two families, each consists of a triangular motif identified in the network had essential roles in the network by virtue of influencing a large number of other nodes. We discuss causal effect measurement while confounders and mediators are identified graphically.


Diabetes Care in Republic of Macedonia: Challenges and Opportunities.
The Republic of Macedonia (RoM) has experienced a rapid rise in the prevalence of type 2 diabetes (T2D) over the past 2 decades, a period characterized by significant social, political, and economic change. RoM now has one of the highest rates of diabetes in Europe. To explore the modifiable conditions that may underlie and exacerbate the T2D epidemic; describe the state of diabetes care; and consider improved mechanisms for prevention and treatment, including research priorities, in RoM. Methods included data mining from reliable sources and collaboration of authors to consider and describe applications of research from outside RoM and to identify evidence-based strategies to reduce the burden of T2D in RoM. In 2014, the national prevalence of diabetes was 11.44% of the population (20-79 years) of RoM. Per capita caloric intake has increased significantly over the past 2 decades, with the majority of these calories coming from sugar, pork, chicken, beef, and sunflower oil. Excess calories, in the form of nutrient-deficient foods, animal products, and added oils promote insulin resistance and T2D. Tobacco use and lack of physical activity also contribute to the diabetes epidemic. Insulin, especially insulin analogues, are widely available and used to manage diabetes, often over other interventions that are more appropriate for patients with T2D, and more frequently than in other more developed countries, resulting in higher and unsustainable related costs. A new National eHealth System allows for better identification and monitoring of citizens with diabetes. However, the rapidly growing expense of insulin in the past has been unsustainable. The potential exists for a stronger role for lifestyle interventions in prevention and treatment of T2D. Significant changes in dietary patterns parallel the rise in diabetes prevalence and are likely a leading cause of diabetes and its complications. Research in RoM is needed to determine the impact and acceptability of dietary interventions for prevention and treatment of T2D, as a first step toward reduction of diabetes prevalence and its complications and controlling spiraling health care costs.


Does Type of Residential Housing Matter for Depressive Symptoms in the Aftermath of a Disaster? Insights From the Great East Japan Earthquake and Tsunami.
The 2011 Great East Japan Earthquake and Tsunami resulted in widespread property destruction and over 250,000 displaced residents. We sought to examine whether the type of housing arrangement available to the affected victims was associated with a differential incidence of depressive symptoms. In this prospective cohort study, which comprised participants aged ≥65 years from Iwanuma as a part of the Japan Gerontological Evaluation Study, we had information about the residents' mental health both before the disaster in 2010 and 2.5 years afterward. The Geriatric Depression Scale was used. Type of accommodation after the disaster was divided into 5 categories: no move, prefabricated housing (temporary housing), existing private accommodations (temporary apartment), newly established housing, and other. Poisson regression analysis was adopted, with and without multiple imputation. Among the 2,242 participants, 16.2% reported depressive symptoms at follow-up. The adjusted rate ratio for depressive symptoms among persons moving into prefabricated housing, compared with those who did not, was 2.07 (95% confidence interval: 1.45, 2.94). Moving into existing private accommodations or other types of accommodations was not associated with depression. The relationship between living environment and long-term mental health should be considered for disaster recovery planning.


The role of N-acetylglucosaminyltransferase III and V in the post-transcriptional modifications of E-cadherin.
It has long been recognized that E-cadherin dysfunction is a major cause of epithelial cell invasion. However, very little is known about the post-transcriptional modifications of E-cadherin and its role in E-cadherin mediated tumor progression. N-acetylglucosaminyltransferase III (GnT-III) catalyzes the formation of a bisecting GlcNAc structure in N-glycans, and has been pointed as a metastasis suppressor. N-acetylglucosaminyltransferase V (GnT-V) catalyzes the addition of beta1,6 GlcNAc branching of N-glycans, and has been associated to increase metastasis. The regulatory mechanism between E-cadherin expression and the remodeling of its oligosaccharides structures by GnT-III and GnT-V were explored in this study. We have demonstrated that wild-type E-cadherin regulates MGAT3 gene transcription resulting in increased GnT-III expression. We also showed that GnT-III and GnT-V competitively modified E-cadherin N-glycans. The GnT-III knockdown cells revealed a membrane de-localization of E-cadherin leading to its cytoplasmic accumulation. Further, the GnT-III knockdown cells also caused modifications of E-cadherin N-glycans catalyzed by GnT-III and GnT-V. Altogether our results have clarified the existence of a bidirectional crosstalk between E-cadherin and GnT-III/GnT-V that was, for the first time, reproduced in an in vivo model. This study opens new insights into the post-transcriptional modifications of E-cadherin in its biological function, in a tumor context.


Screening for microRNA-based diagnostic markers in hepatic alveolar echinococcosis.
This study aims to screen differentially expressed host miRNAs that could be used as diagnostic markers for liver alveolar echinococcosis (LAE).Differentially expressed miRNAs were first screened by miRNA microarray in liver tissues from2 LAE patients and normal liver tissues from 3 LAE patients, followed by qRT-PCR validation in 15 LAE tissues and 15 normal tissues. Target genes of differentially expressed miRNAs were predicted using Targetscan, PITA and microRNAorg database, and the overlapped predicted target genes were analyzed by GO and KEGG.The hsa-miR-1237-3p, hsa-miR-33b-3p, and hsa-miR-483-3p were up-regulated whereas the hsa-miR-4306 was down-regulated in LAE tissues compared with normal controls (P < .05). The expression change of miR-483-3p was further confirmed in both liver tissues and plasma. Several predicted targets of miR-1237-3p, miR-4306, and miR-483-3p were related to DNA-dependent transcriptional regulation, developmental regulation of multicellular organisms, and biological functions such as cellular immune responses (T cell proliferation). The overlapped predicted target genes of the 4 differentially expressed miRNAs were enriched in mRNA surveillance, cancer signaling pathway, intestinal immune network, and other signal pathways.Our results indicate that miR-483-3p is a potential marker for the diagnosis of LAE, and targets of this miRNA could be the focus of further studies.


Low-Grade Endometrial Stromal Sarcoma Extending to The Right Atrium.
Endometrial Stromal Sarcoma (ESS) are very uncommon malignant tumors that make around 0.2% of the entire uterine related malignancies. They represent the endometrial stromal cells in the proliferative stage. The annual incidence of ESS is 1-2 per million women. We present an unusual case of ESS, which originates from the uterine artery through the Inferior Vena Cava (IVC) and extends to the right atrium. A 48 years old woman presented with menorrhagia and right flank pain for seven months. Physical examination was normal except for a palpable suprapubic mass. Computed tomography (CT) showed the right gonadal vein and IVC tumoral thrombus extending into the right atrium. An echocardiogram and Transesophygeal echocardiogram revealed a large non-mobile echogenic density in the right atrium. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was done. Extensive myometrial and vascular invasion was noted along with the extensive lymphovascular invasion of the uterus. Eventually, distal IVC resections were done, and there was no chance to remove the tumor because it was too attached and invaded the IVC filter. Owing to the unresectability of the tumor, the patient was assigned for palliative chemotherapy. Keywords: Endometrial Stromal Sarcoma, Right Atrium, Inferior Vena Cava, Spindle Cell Sarcoma.


Increased Lytic Efficiency of Bovine Macrophages Trained with Killed Mycobacteria.
Innate immunity is evolutionarily conserved in multicellular organisms and was considered to lack memory until very recently. One of its more characteristic mechanisms is phagocytosis, the ability of cells to engulf, process and eventually destroy any injuring agent. We report the results of an ex vivo experiment in bovine macrophages in which improved clearance of Mycobacterium bovis (M. bovis) was induced by pre-exposure to a heat killed M. bovis preparation. The effects were independent of humoral and cellular adaptive immune responses and lasted up to six months. Specifically, our results demonstrate the existence of a training effect in the lytic phase of phagocytosis that can be activated by killed mycobacteria, thus suggesting a new mechanism of vaccine protection. These findings are compatible with the recently proposed concept of trained immunity, which was developed to explain the observation that innate immune responses provide unspecific protection against pathogens including other than those that originally triggered the immune response.


Sustained Activity of Stimuli-Responsive Curcumin and Acemannan Based Hydrogel Patches in Wound Healing.
Natural plant extract, namely acemannan (Ac) and curcumin (Cur), coencapsulated pluronic micelles, showing thermoresponsive properties, were designed for efficient and safe in vivo wound healing applications. Ac and Cur, widely used antimicrobials, find limited applications because of their low stability, short biological half-life, poor solubility, and low bioavailability. Herein, we report the extraction of Ac from aloe vera and coencapsulation of it with Cur in pluronic micelles to take advantage of the combined effects of both components. Both Ac and Cur preserved their bioactive functionality upon encapsulation. Single photon emission computed tomography imaging confirmed that NPAcC2 hydrogel masked the whole wound by forming a layer. Cur and Ac synergistically resulted in rapid wound closure on the seventh day, and full-grown hair was observed on the 10th day. Individually they both take more than 20 days for wound closure. The increase in the concentration of curcumin increases the healing properties of the material. For days 1, 6, and 10 of the wound dressing experiment, the percentages of wound closure of the mice were the highest for NPAcC2 (i.e., 100%) compared to the untreated control (25%) while maintaining the integrity of the skin. These natural product-based hydrogels have limited side effects vs those caused by commercial drugs in wound healing.


Hydrogen Electrooxidation in Ionic Liquids Catalyzed by the NTf2 Radical.
Hydrogen electrooxidation via a "hydrogen abstraction" mechanism in an aprotic ionic liquid 1-butyl-1-methylpyrrolidinium bis-(trifluoromethylsulfonyl) [Bmpy][NTf2] under anaerobic conditions was investigated using cyclic voltammetry and density functional theory (DFT). It is found that a platinum bound NTf2 radical (NTf2•) formed by the oxidation of NTf2- at anodic potential can catalyze the oxidation of hydrogen and enhance its reaction rate. Both experimental and theoretical studies (DFT) have supported a mechanism involving a NTf2• radical intermediate that catalyzes the hydrogen redox processes.


Wrestling with native chemical ligation.
An improved method for the semisynthesis of a potassium channel involving native chemical ligation allows the introduction of short sequences containing non-canonical amino acids at any position within the polypeptide chain. The work enhances the technology available for a range of fundamental investigations of membrane proteins and for applications of membrane channels and pores in biotechnology.


The nutrition transition in South Korea.
An accelerating shift from infectious to noncommunicable diseases and concurrent shifts in diet, activity, and body composition are universal trends but are especially apparent in middle- and lower-income countries. A unique nutrition transition has occurred in South Korea, a country that modernized earlier than most Asian countries did. The purpose of this analysis was to describe the South Korean nutrition transition, focusing on specific features that other countries might follow to retain the healthful elements of their traditional diets. We used secondary data on economics, dietary intake, anthropometry, and causes of death, including a series of comparable nationally representative dietary surveys (the National Nutrition Survey). The structure of South Korea's economy, along with the country's dietary and disease patterns, began an accelerated shift in the 1970s. Major dietary changes included a large increase in the consumption of animal food products and a fall in total cereal intake. Uniquely, the amount and rate of increase in fat intake have remained low in South Korea. South Korea also has a relatively low prevalence of obesity compared with other Asian countries with similar or much lower incomes. The nutrition transition in South Korea is unique. National efforts to retain elements of the traditional diet are thought to have shaped this transition in South Korea in the midst of rapid economic growth and the introduction of Western culture.


Functional Exploitation of Carob, Oat Flour, and Whey Permeate as Substrates for a Novel Kefir-Like Fermented Beverage: An Optimized Formulation.
This study investigated the fortification of a carob-based kefir-like beverage (KLB) with whey permeate (WP) and oat flour (OF). The response surface method was used to show the effect of WP and OF concentrations on lactic acid bacteria and yeast cell densities, pH, total titratable acidity (TTA), total phenolics content (TCP), DPPH radical scavenging activity, and overall acceptability (OA) in KLB. The statistical design provided thirteen formulations where OF concentration varied from 3% to 5% and WP from 10% to 15%. The enrichment of carob pods decoction with WP and OF had a positive effect on biomass production. Overall fermentation was shown to increase TPC of KLB. Furthermore, OF supplementation led to the higher levels of TPC and antiradical activity. WP negatively affected OA at linear and quadratic levels, whereas no effect of OF was observed at the linear level. The optimum point was found by using WP at 11.51% and OF at 4.77%. Optimized KLB resulted in an enrichment of bioavailable phenolics derivatives and highly digestible proteins.


Prognostic Importance of Inflammatory Indexes in Patients Treated by Pazopanib for Soft Tissue Sarcoma.
The goal of this study was to evaluate the predictive and prognostic importance of the lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (DNLR), and systemic immune inflammation index (SSI) in STS cases treated with pazopanib. Thirty STS patients treated with pazopanib were included in this study. SSI, DNLR, LMR, and NLR values were calculated at baseline and in the first month. Median values of these predictors in these patients (SSI (944), DNLR (1.8), LMR (2.7), and NLR (3.0)) were taken as cutoff values. The associations between the survival time (both overall survival (OS) and progression-free survival (PFS)) and cutoff values were evaluated using Kaplan Meier curves and Cox regression models. Patients with low SSI, NLR, and DNLR values at pretreatment and after the initial response had longer OS (for OS - p = 0.024, p = 0.015, and p = 0.041, respectively). Longer OS was also found in patients who showed increasing LMR and decreasing NLR after one month of therapy (for ΔLMR, p = 0.016; for ΔNLR, p = 0.016). Pa-tients with low SSI and NLR values at pretreatment and after the initial response had longer PFS (for PFS, p = 0.014, p = 0.04, p ˂ 0.001, respectively). In terms of initial responses to treatment, SSI, NLR, DNLR, and increased LMR were detected as independent risk factors in univariate analysis, but initial response was found to be the only independent risk factor for PFS in multivariate analysis. Low values of SSI, NLR, and DNLR at pretreatment and at initial response may predict long-term survival rates. After one month of treatment with pazopanib, decreased NLR and increased LMR are predictive of favorable outcomes in these cases.


[Drug therapy of chronic congestive heart failure: the why and how].
As the prevalence of congestive heart failure is steadily increasing correct treatment becomes more and more important. In pathophysiology, clinical signs once believed to express the effort of the body to "compensate" for the failure (hypervolaemia, tachycardia, sympathetic stimulation) have been recognized as sort of a physiological error: to a primary signal which still remains not fully understood, the body responds in a similar way as to dehydration. As late as the mid-sixties, "function curves" represented a framework for our conceptual thinking and digitalis the essential treatment. Since then, we had to realize that the function of the failing ventricle is not determined just by filling and contractility-the way it is in the healthy ventricle is-but also by aortic impedance. Vasodilators have become the cornerstone of therapy. At present, diuretics are the most important drugs for congestive heart failure treatment. Thiazides, given together with loop diuretics, ameliorate extracellular fluid volume in all treated patients, but their effect is accompanied by potassium losses due to increased aldosterone levels. Angiotensin converting enzyme (ACE) inhibitors are unique in not only decreasing ventricular afterload and improving haemodynamics but, also, in decreasing circulating norepinephrine levels, protecting kidneys from inappropriate efferent arteriolo-constriction and suppression of aldosterone secretion. In other words, ACE inhibitors change the essential physiological set-up: they turn a high-perfusion-pressure body into a low-perfusion-pressure one. Furthermore, they convincingly improve life expectancy. Combination of diuretics and ACE inhibitors is the best we can do for our patients today. Although useful in some patients, the definite value of digitalis, and particularly its effect on longevity, remains an unresolved question.


Quantitative proteomics on the cerebrospinal fluid of hydrocephalus in neonatal bacterial meningitis.
Hydrocephalus in bacterial meningitis (BM) is a devastating infectious neurological disease and the proteins and pathways involved in its pathophysiology are not fully understood. Label-free quantitative (LFQ) proteomics analyses was used to identify differentially expressed proteins (DEPs) in cerebrospinal fluid (CSF) samples from infants with hydrocephalus and bacterial meningitis (HBM group, N = 8), infants with bacterial meningitis (BM group, N = 9); and healthy infants (N group, N = 11). Bioinformatics analysis was subsequently performed to investigate Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enriched signaling pathways of these DEPs. Six proteins (AZU1, COX4I1, EDF1, KRT31, MMP12, and PRG2) were selected for further validation via enzyme-linked immunosorbent assay (ELISA). Compared with BM group and N group, HBM group had a higher whole CSF protein level (5.6 ± 2.7 vs. 1.7 ± 1.0 vs. 1.2 ± 0.5 g/l) and lower whole CSF glucose level (0.8 ± 0.6 vs. 1.8 ± 0.7 vs. 3.3 ± 0.8 mmol/l) (both P < 0.05). Over 300 DEPs were differentially expressed in HBM group compared with BM group and BM compared with N group, of which 78% were common to both. Cluster analysis indicated that the levels of 226 proteins were increased in BM group compared with N group and were decreased in HBM group compared with BM group. Bioinformatics analysis indicated the involvement of the cell adhesion, immune response and extracellular exosome signaling were significantly enriched in HBM compared with BM group and BM compared with N group. 267 DEPs were identified between HBM group with N group, KEGG analysis indicated that DEPs mainly involved in filament cytoskeleton and immune response. The ELISA results further verified that the expression levels of AZU1 were significantly different from among three groups (both P < 0.05). This is the first reported characterization of quantitative proteomics from the CSF of infants with HBM. Our study also demonstrated that AZU1 could be a potential biomarker for the diagnosis of hydrocephalus in bacterial meningitis.


[Angiotensin II receptors in a rat model of hypobaric hypoxic pulmonary hypertension].
Hypoxic pulmonary hypertension is characterized by profound remodeling of the walls of small pulmonary arteries: endothelial swelling and proliferation of media and adventitia to a degree that may narrow the lumen. The molecular mechanism responsible for these changes is unknown. Recent studies have demonstrated the existence of a vascular and cardiac renin-angiotensin system. This system can induce hypertrophy and proliferation of aortic smooth muscle cells and cardiac muscle cells in animal models of systemic hypertension. In the present experiments, Northern blot analysis and a receptor binding assay specific to angiotensin II (Ang II) receptors was used to study the pulmonary renin angiotensin system in a rat model of hypobaric hypoxic pulmonary hypertension. mRNA transcripts for the Ang II receptor AT(1A) were constitutively expressed, and specific binding of Ang II to the receptors occurred in lung tissue of control rats that breathed ambient air. After 3 days of hypobaric hypoxia (380 Torr), the AT(1A) mRNA level and the index of Ang II receptors had increased, but right ventricular hypertrophy was not still evident. Ang II receptors were significantly increased after 14 days of hypoxia, when histological evidence of pulmonary hypertension was observed. In addition, the Ang II level in pulmonary tissue was higher after 14 days of hypoxia than in normal controls. These findings suggest that the renin-angiotensin system in pulmonary tissue was activated in these rats, and that it contributes to the morphological changes observed in hypoxic pulmonary hypertension.


Highly diastereoselective addition of silyldihalomethyllithiums to chiral alkyl esters.
Treatment of benzoate, formate, or trifluoroacetate esters with silyldibromomethyllithiums provides alkyl silyl mixed acetals via the 1,3-rearrangement of a silyl group from carbon to oxygen. A high level of asymmetric induction onto the acetal carbon is observed when chiral alkyl esters are employed. The stereochemical assignment of the silyl acetal 13j was accomplished on the basis of X-ray crystallographic analysis. A one-pot synthesis of a three-component coupling product R(1)C(OR(2))(OSiMe(2)-t-Bu)CX(2)E' (X = Cl, Br) by sequential additions of an ester (R(1)CO(2)R(2)) and the second electrophile was achieved.


Molecular differences between cerebral blood volume and vessel size in glioblastoma multiforme.
The purpose of this study was to investigate the molecular background of cerebral blood volume (CBV) and vessel size (VS) of capillaries in glioblastoma multiforme (GBM). Both parameters are derived from extended perfusion MR imaging.A prospective case study including 21 patients (median age 66 years, 10 females) was performed. Before operation, CBV and VS of contrast enhancing tumor were assessed. Tissue was sampled from the assessed areas under neuronavigation control. After RNA extraction, transcriptional data was analyzed by Weighted Gene Co-Expression Network Analysis (WGCNA) and split into modules based on its network affiliations. Gene Set Enrichment Analysis (GSEA) identified biological functions or pathways of the genetic modules. These were applied on 484 GBM samples of the TCGA database.Ten modules were highly correlated to CBV and VS. One module was exclusively associated to VS and highly correlated to hypoxia, another one exclusively to CBV showing strong enrichments in the Epithelial Growth Factor (EGF) pathway and Epithelial-to-Mesenchymal-Transition (EMT). Moreover, patients with increased CBV and VS predominantly showed a mesenchymal gene-expression, a finding that could be corroborated by TCGA data.In conclusion, CBV and VS mirror different genetic pathways and reflect certain molecular subclasses of GBM.


The Emergence of the Tobacco 21 Movement From Needham, Massachusetts, to Throughout the United States (2003-2019).
In February 2003, Needham, Massachusetts, became the first town in the nation to raise the minimum legal sales age for tobacco and nicotine products to 21 years (Tobacco 21). This legislation marked a dramatic departure from existing state and federal laws, which generally set the minimum sales age at 18 years. The Needham law significantly preceded and ultimately heralded the emergence of a nationwide movement to raise such sales age. As of May 2019, 14 states and more than 450 cities and counties have passed legislation raising the minimum legal sales age for tobacco and nicotine products to 21 years, covering more than 30% of the United States' population. The National Academy of Medicine projects that this policy will lower tobacco use rates, particularly among adolescents, and save a substantial number of lives. This narration of the process that led to Needham's passing of Tobacco 21 legislation and to the growth and spread of the Tobacco 21 movement highlights the significant role of public health advocacy and policy in the control of tobacco, the leading preventable cause of disease and death in the United States. (Am J Public Health. 2019;109:1540-1547. doi: 10.2105/AJPH. 2019.305209).


Controversies in the treatment of high-risk prostate cancer--what is the optimal combination of hormonal therapy and radiotherapy: a review of literature.
In high-risk prostate carcinoma, there is controversy whether these patients should be treated with escalated-dose (> or =74 Gy) or conventional-dose radiotherapy (<74 Gy) combined with hormonal therapy. Furthermore, the issue of the optimal duration and timing of hormonal therapy are not well crystallized. A search for evidence from randomized- and large non-randomized studies in order to address these issues, was therefore initiated. For this purpose, MedLine, EMbase, and PubMed and the data base of the Dutch randomized dose-escalation trial, were consulted. From this search it was concluded that the benefit of hormonal therapy in combination with conventional-dose radiotherapy (<74 Gy) in high-risk prostate cancer is evident (Level 2 evidence); Levels 2 and 3 evidence were provided by several studies supporting the use of escalated-dose radiotherapy in high-risk prostate cancer. For the combination of hormonal therapy with escalated-dose radiotherapy in these patients, there is Level 2 evidence for moderately escalated dose (74 Gy) and high escalated dose (> or =78 Gy). The optimal duration and timing of hormonal therapy are not well defined. More randomized-controlled trials and meta-analyses are therefore needed to clearly determine the independent role of dose-escalation in high-risk patients treated with hormonal therapy and the optimal duration and timing of hormonal therapy.


Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence.
Environments associated with prior drug use provoke craving and drug taking, and set the stage for lapse/relapse. Although the neurobehavioral bases of environment-induced drug taking have been investigated with animal models, the influence of drug-environments on brain function and behavior in clinical populations of substance users is largely unexplored. Adult smokers (n=40) photographed locations personally associated with smoking (personal smoking environments; PSEs) or personal nonsmoking environment (PNEs). Following 24-h abstinence, participants underwent fMRI scanning while viewing PSEs, PNEs, standard smoking and nonsmoking environments, as well as proximal smoking (eg, lit cigarette) and nonsmoking (eg, pencil) cues. Finally, in two separate sessions following 6-h abstinence they viewed either PSEs or PNEs while cue-induced self-reported craving and smoking behavior were assessed. Viewing PSEs increased blood oxygen level-dependent signal in right posterior hippocampus (pHPC; F(2,685)=3.74, p<0.024) and bilateral insula (left: F(2,685)=6.87, p=0.0011; right: F(2,685)=5.34, p=0.005). In the laboratory, viewing PSEs, compared with PNEs, was associated with higher craving levels (F(2,180)=18.32, p<0.0001) and greater ad lib smoking (F(1,36)=5.01, p=0.032). The effect of PSEs (minus PNEs) on brain activation in right insula was positively correlated with the effect of PSEs (minus PNEs) on number of puffs taken from a cigarette (r=0.6, p=0.001). Our data, for the first time in humans, elucidates the neural mechanisms that mediate the effects of real-world drug-associated environments on drug taking behavior under conditions of drug abstinence. These findings establish targets for the development and evaluation of treatments seeking to reduce environment provoked relapse.


A Syndrome of Variable Allergy, Short Stature, and Fatty Liver.
SLC22A18 (solute carrier family 22 member 18) is an imprinted gene, but its role in growth and development is not clear. In the present study, we recorded the clinical information of six male patients of six unrelated families. Real-time quantitative PCR, Sanger sequencing, and DNA methylation sequencing were performed in these patients. The results suggested that the patients with the clinical characteristics of allergic allergy, short stature, and fatty liver had a lower expression of SLC22A18. One novel variant (chr11: 2899732 delA) with clinical significance was found in the core promoter region of the patients. Overall, this study found a syndrome associated with SLC22A18.


Study of a Novel Gemini Viscoelastic Surfactant with High Performance in Clean Fracturing Fluid Application.
Gemini surfactant, as a functionally flexible polymer-like material in the aqueous solution, has attracted increased attention in reservoir stimulation of hydraulic fracturing in recent decades. A new Gemini cationic viscoelastic surfactant named JS-N-JS, which has a secondary amine spacer group and two ultra-long hydrophobic tails, was synthesized from erucamidopropyl dimethylamine, diethanolamine, and thionyl chloride as a thickener for hydraulic fracturing fluid. Compared with some Gemini cationic surfactant with methylene spacer, JS-N-JS showed a lower critical micellar concentration (CMC) and higher surface activity due to the hydrogen bond formed between the secondary amine and water molecule intends to reduce electrostatic repulsion, which is more beneficial to be the fracturing fluid thickener. Moreover, the performance of JS-N-JS solution can be further improved by salts of potassium chloride (KCl) or sodium salicylate (NaSal), while organic salt behaved better according to the measurements. The SEM observation confirmed that JS-N-JS/NaSal system owned a tighter network microstructure, and JS-N-JS/NaSal system exhibited a distinct superior viscoelasticity system at a sweep frequency of 0.1⁻10 Hz. As a fracturing fluid, the solution with a formula of 30 mmol JS-N-JS and 100 mmol NaSal was evaluated according to the petroleum industrial standard and presented excellent viscoelastic properties, the viscosity of which can maintain above 70 mPa·s for 110 min under a shear rate of 170 s-1 at 120 °C. Meanwhile, the drag reducing rate of the formula could reach above 70% with the increase of shear rate. Finally, the viscous fracturing fluid can be broken into the water-like fluid in 1.2 h after being fully exposed to hydrocarbons and the water-like fluid presented a low damage to the tight sand reservoirs according to the core flooding experiments, in which the permeability recovery rate can reach 85.05%. These results fully demonstrate that the JS-N-JS solution fully meets the requirement of the industrial application of hydraulic fracturing.


Spectral-envelope-group-delay models for transients.
Transient signals such as plosives in speech or Castanets in audio do not have a specific modulation or periodic structure in time domain. However, in the spectral domain they exhibit a prominent modulation structure, which is a direct consequence of their narrow time localization. Based on this observation, a spectral-domain AM-FM model for transients is proposed. The spectral AM-FM model is built starting from real spectral zero-crossings. The AM and FM correspond to the spectral envelope (SE) and group delay (GD), respectively. Taking into account the modulation structure and spectral continuity, a local polynomial regression technique is proposed to estimate the GD function from the real spectral zeros. The SE is estimated based on the phase function computed from the estimated GD. Since the GD estimation is parametric, the degree of smoothness can be controlled directly. Simulation results based on synthetic transient signals generated using a beta density function are presented to analyze the noise-robustness of the SEGD model. Three specific applications are considered: (1) SEGD based modeling of Castanet sounds; (2) appropriateness of the model for transient compression; and (3) determining glottal closure instants in speech using a short-time SEGD model of the linear prediction residue.


Synergetic Effect of Water, Temperature, and Pressure on Methane Adsorption in Shale Gas Reservoirs.
Adsorption is one of the most important forms of storage of gas in shale reservoirs. Shale gas adsorption in the actual reservoir is not only affected by individual factors such as water content, temperature, and pressure but also by the synergetic effect of these factors. In this study, we conducted laboratory experiments on methane adsorption in dry and wet shale at different pressures and temperatures. The synergetic effect of water content, temperature, and pressure on shale gas adsorption is explored. The results show that increasing temperature weakens the interaction between methane and shale and reduces adsorption capacity due to the exothermic nature of adsorption. Water reduces methane adsorption capacity by occupying adsorption sites and blocking pores in the shale system. Although temperature and water reduce methane adsorption individually, the effect of these two factors weakens each other. Temperature has a more significant effect on methane adsorption in shales with low water content, while water has a more remarkable impact on methane adsorption at a low temperature. Furthermore, the increase in pressure reduces the negative influence of water and temperature on methane adsorption. By quantitatively analyzing the relationship between methane adsorption in dry and wet shales, a predictive adsorption model for wet shale considering the influence of in situ conditions is proposed and validated. Validation shows that the proposed model has high accuracy and broad applicability to shales with different properties.


Anxiety and depression in patients with hand eczema: A population-based study among 853 middle-aged subjects.
Hand eczema (HE) is a common dermatological disorder with considerable effect on the health-related quality of life (HRQoL). The data on mental comorbidities of HE is sparse and mostly studied among selected patient groups. We aimed to investigate symptoms of depression and anxiety in patients with HE in general population. Study subjects (n = 6695) belonging to the Northern Finland Birth Cohort 1966 Study (NFBC1966) responded to an extensive health questionnaire including questions about HE. Depression and anxiety symptoms were evaluated according to the Hopkins Symptom Checklist-25 (HSCL-25). Having ever suffered from HE was reported by 853 (12.8%) study subjects. Symptoms scores of depression were significantly higher among (n = 172, 20.3%) HE subjects compared with (n = 884, 15.4%) subjects without HE (Odds ratio [OR] 1.40, 95% confidence interval [CI]: 1.17-1.68, P < 0.001). Correspondingly, symptoms scores of anxiety were also more common among (n = 90, 10.6%) HE subjects than among (n = 448, 7.8%) subjects without HE (OR 1.40, 95% CI: 1.10-1.78, P = 0.007). In an adjusted model, the associations remained statistically significant (OR 1.30, 95% CI: 1.08-1.57, P = 0.007 and OR 1.34, 95% CI: 1.04-1.72, P = 0.021, respectively). Symptoms associated with mental health should be taken into account when managing patients with HE.


CHD7 regulates cardiovascular development through ATP-dependent and -independent activities.
CHD7 encodes an ATP-dependent chromatin remodeling factor. Mutation of this gene causes multiple developmental disorders, including CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome, in which conotruncal anomalies are the most prevalent form of heart defects. How CHD7 regulates conotruncal development remains unclear. In this study, we establish that deletion of Chd7 in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development, thereby clarifying a long-standing controversy in the literature. Using transcriptomic analyses, we show that CHD7 fine-tunes the expression of a gene network that is critical for cardiac NCC development. To gain further molecular insights into gene regulation by CHD7, we performed a protein-protein interaction screen by incubating recombinant CHD7 on a protein array. We find that CHD7 directly interacts with several developmental disorder-mutated proteins including WDR5, a core component of H3K4 methyltransferase complexes. This direct interaction suggested that CHD7 may recruit histone-modifying enzymes to target loci independently of its remodeling functions. We therefore generated a mouse model that harbors an ATPase-deficient allele and demonstrates that mutant CHD7 retains the ability to recruit H3K4 methyltransferase activity to its targets. Thus, our data uncover that CHD7 regulates cardiovascular development through ATP-dependent and -independent activities, shedding light on the etiology of CHD7-related congenital disorders. Importantly, our data also imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations; these patients might therefore require personalized therapeutic interventions.


HER2 Amplification in Advanced NSCLC Patients After Progression on EGFR-TKI and Clinical Response to EGFR-TKI Plus Pyrotinib Combination Therapy.
HER2 (or ERBB2) amplification is an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). The benefits of HER2-targeted therapy have been limited. Herein, we investigated the molecular and clinical patterns of HER2 amplification in non-small cell lung cancer (NSCLC) patients during progression on EGFR-TKIs and the potential of combining EGFR-TKI and pyrotinib to overcome resistance. In this study, 1,637 NSCLC cases from Geneseeq after progression of EGFR-TKIs were screened and analyzed by next generation sequencing (NGS), in which 48 patients with HER2 amplification were eligible and enrolled. A total of 403 patients from Sun Yat-sen University Cancer Center (SYSUCC) were screened and five patients with concomitant EGFR mutations and HER2 amplification were retrospectively collected to assess the effect of afatinib or combination of EGFR-TKI and pyrotinib. In the 48 patients from the Geneseeq cohort, 27 (56.2%) patients suffered from resistance of 1st/2nd generation EGFR-TKI, and 21 (43.8%) patients from 3rd generation. As for the five patients forming the SYSUCC cohort, three patients were treated with afatinib, one achieved partial response (PR) with progression-free survival (PFS) of 6 months and two quickly developed disease progression. Two patients were treated with EGFR-TKIs plus pyrotinib, one receiving gefitinib plus pyrotinib achieved PR with PFS of 8 months and benefited from osimertinib plus pyrotinib for 3 months till data-off; one receiving osimertinib plus pyrotinib achieved SD for 4 months till data-off. The most common co-occurring alteration was TP53 (91.7%) in the mutation profile of the 48 patients from the Geneseeq cohort, and four patients had TP53 co-mutations of the five patients from the SYSUCC cohort. In this study, we detected 7% HER2 amplification present in EGFR-TKIs resistance. Patients with concomitant EGFR mutation and HER2 amplification may derive clinical benefit from therapies that target both EGFR and HER2.


Effect of a fermented infant formula containing viable bifidobacteria on the fecal flora composition and pH of healthy full-term infants.
We assessed the growth, tolerance, and acceptability as well as fecal flora composition and stool pH of 20 healthy full-term infants fed with a fermented whey-adapted infant formula containing viable bifidobacteria (10(6)/g of powder) during the first 2 months of life. This fermented infant formula, first biologically acidified by Streptococcus thermophilus and Lactobacillus helveticus, was compared to a whey-adapted, nonacidified, low-phosphate infant formula in a double-blind, randomized controlled study. The results were compared to a control group (n = 14) of fully breast-fed infants. The fermented whey-adapted formula containing viable bifidobacteria induced a prevalence of colonization with bifidobacteria at 1 month of age similar to that of breast-fed infants (12/20 versus 8/14) but significantly higher than in the group fed the standard infant formula (4/20). The mean bacterial count of bifidobacteria was similar in all colonized infants; however, fecal pH was significantly lower in the breast-fed infants than in the nonacidified bottle-fed infants. This kind of infant formula was well tolerated and promoted a normal growth during the first 2 months.


Experiences of Older Adults Preparing for Their First Triathlon: "A Qualitative Study of the Participation in an Endurance Training Intervention."
Purpose: The overall aim of the present study was to explore the experiences of older adult exercisers participating in an individualized training program lasting 3 months preparing for completing a triathlon competition. Methods: Fourteen older Norwegian adults (median age (interquartile range, IQR) for males (N=10) and females (N=4) were 70.0 (65.0-75.5) and 57.5 (56.3-62.5) years, respectively) participated in 3-month individualized training program comprising three weekly sessions of running, cycling, and swimming. Both field- and laboratory-based testing were conducted. The participants attended two sports nutrition and competitive psychology seminars focusing on triathlon competition. The participants were interviewed in depth in three different focus groups. Thematic analysis was utilized to analyze the findings. Results: Participants improved their performance in all field-based tests. After completion of the thematic data analysis the main finding and overarching theme of well-being and being fit emerged. Additionally, three main themes were identified: 1) motivation; 2) progress and coping; and 3) breaking barriers. Conclusion: Psychological well-being and satisfaction of being fit seem to be vital to participate in a triathlon competition. Promoting specific age-appropriate participation in sports activities can be an effective strategy for promoting a healthy lifestyle among the elderly.


Transformation of the mitochondrial genome.
Although mitochondrial transformation is highly desirable in mammals and plants, it is only possible in two unicellular organisms, the budding yeast Saccharomyces cerevisiae and the unicellular green alga Chlamydomonas reinhardtii. Here, we give an overview of the attempts made to transform mitochondria of mammals and plants and the possible reasons for their failure. This review briefly describes the mitochondrial transformation principles in yeast and describes in more detail the transformation and its applications in Chlamydomonas.


Electrospun silk material systems for wound healing.
The functional properties of six distinct electrospun silk material groups were evaluated to assess conformational and biocompatible characteristics related to wound dressings. In a hydrated state, all six silk matrices exhibited absorption, water vapor transmission, oxygen permeation and enzymatic biodegradation suitable for full-thickness wound sites. Employing constrained drying techniques, silk concentration was a determinate factor influencing material structural properties related to the storage and distribution of such wound dressing systems. Subsequently, three electrospun silk models demonstrated ideal biomaterial properties with potential utility for wound dressings.


Saddle pulmonary tumor embolus secondary to renal cell carcinoma.
Most pulmonary tumor emboli are microscopic and occlude small arteries and arterioles with subsequent insidious clinical presentation. These emboli usually need conservative treatment. Emboli that spread to large proximal pulmonary arteries, although rare, can be life-threatening. This article focuses on the importance of prompt recognition, diagnosis, and appropriate management of pulmonary tumor emboli.


Regulation of Myogenesis by a Na/K-ATPase α1 Caveolin-Binding Motif.
The N-terminal caveolin-binding motif (CBM) in Na/K-ATPase (NKA) α1 subunit is essential for cell signaling and somitogenesis in animals. To further investigate the molecular mechanism, we have generated CBM mutant human-induced pluripotent stem cells (iPSCs) through CRISPR/Cas9 genome editing and examined their ability to differentiate into skeletal muscle (Skm) cells. Compared with the parental wild-type human iPSCs, the CBM mutant cells lost their ability of Skm differentiation, which was evidenced by the absence of spontaneous cell contraction, marker gene expression, and subcellular myofiber banding structures in the final differentiated induced Skm cells. Another NKA functional mutant, A420P, which lacks NKA/Src signaling function, did not produce a similar defect. Indeed, A420P mutant iPSCs retained intact pluripotency and ability of Skm differentiation. Mechanistically, the myogenic transcription factor MYOD was greatly suppressed by the CBM mutation. Overexpression of a mouse Myod cDNA through lentiviral delivery restored the CBM mutant cells' ability to differentiate into Skm. Upstream of MYOD, Wnt signaling was demonstrated from the TOPFlash assay to have a similar inhibition. This effect on Wnt activity was further confirmed functionally by defective induction of the presomitic mesoderm marker genes BRACHYURY (T) and MESOGENIN1 (MSGN1) by Wnt3a ligand or the GSK3 inhibitor/Wnt pathway activator CHIR. Further investigation through immunofluorescence imaging and cell fractionation revealed a shifted membrane localization of β-catenin in CBM mutant iPSCs, revealing a novel molecular component of NKA-Wnt regulation. This study sheds light on a genetic regulation of myogenesis through the CBM of NKA and control of Wnt/β-catenin signaling.


Therapeutic Targeting of MMP-12 for the Treatment of Chronic Obstructive Pulmonary Disease.
Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically engineered mice reported that during pulmonary inflammation, basophil-derived interleukin-4 can act on lung-infiltrating monocytes causing aberrant expression of the matrix metalloproteinase-12 (MMP-12). MMP-12 activity in turn causes the destruction of alveolar walls leading to emphysema, making it potentially a valid target for pharmacological intervention. Using nuclear magnetic resonance (NMR)- and structure-based optimizations, the current study reports on the optimized novel, potent, and selective MMP-12 inhibitors with single-digit nanomolar affinity in vitro and in vivo efficacy. Using a murine model of elastase-induced emphysema we demonstrated that the most potent agents exhibited a significant decrease in emphysema-like pathology compared to vehicle-treated mice, thus suggesting that the reported agents may potentially be translated into novel therapeutics for the treatment of COPD.


[Mosquitoes as vectors of arboviruses: an endless story].
The recent emergence or re-emergence of vector-borne diseases (VBD) and, more specifically, VBD associated with arboviruses such as dengue, chikungunya, Zika or yellow fever are not new events. The globalization of trade and travels as well as the unplanned urbanization of many tropical and subtropical cities have created the conditions suitable for the establishment of vector mosquitoes offering opportunities for arbovirus introduction. This review describes the major arboviruses important for human health and their epidemic vectors, and the conditions leading to their emergence.


Hemodialysis treatment time: a fresh perspective.
Historical, clinical, economic, and technological developments have driven a shift in clinical practice from predominantly 6-hour-long hemodialysis treatments to much shorter treatment times that are prevalent today. Patients, physicians, and providers had considered shortening dialysis treatments as a means to decrease the overall burden imposed by this necessary life-saving therapy. However, shorter dialysis is not a panacea and may engender trade-offs in terms of patient morbidity and mortality. We examine the literature with the benefit of hindsight and in light of recent studies that have improved understanding of the complex relationship between dialysis dose and outcome. We touch upon the role of dialysis frequency relative to treatment time. We conclude with the suggestion that a new treatment paradigm should consider a minimum adequate dialysis treatment time of 4 hours for the majority of patients, with anything shorter becoming the exception rather than the rule.


Fifty Years of Development of the Skull Vibration-Induced Nystagmus Test.
This review enumerates most of the studies on the Skull Vibration-Induced Nystagmus Test (SVINT) in the past 50 years from different research groups around the world. It is an attempt to demonstrate the evolution of this test and its increased interest around the globe. It explores clinical studies and animal studies, both permitting a better understanding of the importance of SVINT and its pathophysiology.


Clinical importance of parent ratings of everyday cognitive abilities in children with learning and attention problems.
This study addressed two issues: first, whether parental reports contribute information over and above a standardized psychometric assessment, and second, whether parental reports of everyday cognitive functioning might be useful in distinguishing between children with reading disabilities (RD), attention-deficit/hyperactivity disorder (ADHD), and combined ADHD + RD. Parent-reported information on 159 children with learning or attention problems was obtained using a questionnaire called the Parent Ratings of Everyday Cognitive and Academic Abilities (PRECAA). Psychometric information used for comparison included the Woodcock-Johnson Psychoeducational Battery-Revised, the Bruininks-Oseretsky Test of Motor Proficiency-Short Form, the Vocabulary and Block Design subtests of the Wechsler Intelligence Scale for Children, 3rd edition, and the Developmental Test of Visual-Motor Integration. The PRECAA was found to be sensitive to group differences between children with RD and children with ADHD and combined ADHD + RD. Its inclusion resulted in a significant increase in the number of children correctly classified compared to the use of psychometric measures alone. The PRECAA correctly classified more children (66%) than did the standard psychometric measures (50%). In fact, a very high percentage of children with ADHD (81%) were correctly classified using the PRECAA. These findings suggest that the PRECAA may be a useful aid to clinicians in the identification of children with learning and attention problems.


Evaluation of Ultrasound Elastography Combined With Chi-Square Automatic Interactive Detector in Reducing Unnecessary Fine-Needle Aspiration on TIRADS 4 Thyroid Nodules.
Conventional ultrasound diagnosis of thyroid nodules (TNs) had a high false-positive rate, resulting in many unnecessary fine-needle aspirations (FNAs). This study aimed to establish a simple algorithm to reduce unnecessary FNA on TIRADS 4 TNs using different quantitative parameters of ultrasonic elasticity and chi-square automatic interactive detector (CHAID) method. From January 2020 to May 2021, 432 TNs were included in the study, which were confirmed by FNA or surgical pathology. Each TN was examined using conventional ultrasound, sound touch elastography, and Shell measurement function. The quantitative parameters E and E shell were recorded, and the E shell/E values were calculated for each TN. The diagnostic performance of the quantitative parameters was evaluated using the receiver operating characteristic curves. The CHAID was used to classify and analyze the quantitative parameters, and the prediction model was established. A total of 226 TNs were malignant and 206 were benign. E shell and E shell/E ratio were included in the classification algorithm, which showed a depth of two ramifications (E shell/E ≤ 0.988 or 0.988-1.043 or >1.043; if E shell/E ≤ 0.988, then E shell ≤ 64.0 or 64.0-74.0 or >74.0; if E shell/E = 0.988-1.043, then E shell ≤ 66.0 or > 66.0; if E shell/E >1.043, then E shell ≤ 69.0 or >69.0). The unnecessary FNAs could have been avoided in 57.3% of the cases using this algorithm. The prediction model using quantitative parameters had high diagnostic performance; it could quickly distinguish benign lesions and avoid subjective influence to some extent.


A new highly potent parathyroid hormone antagonist: [D-Trp12,Tyr34]bPTH-(7-34)NH2.
Based upon N-terminal parathyroid hormone (PTH) analog structure-activity relationship studies, position 12 was found to possess a wide structural latitude and was chosen as a site for single amino acid substitutions. Replacement of the naturally-occurring Gly with D-Trp at position 12 in the PTH antagonists [Tyr34]bPTH-(7-34)NH2 and [Nle8,18,Tyr34]bPTH-(7-34)NH2 increased in vitro receptor affinity. The D-Trp12 containing analogs were 12-fold more potent than their unsubstituted counterparts as inhibitors of PTH binding to renal and bone PTH receptors and 13-27-fold more potent as inhibitors of PTH-stimulated renal and bone adenylate cyclase activity. Based upon Scatchard analyses of saturation binding experiments and Schild analyses of adenylate cyclase experiments, [D-Trp12,Tyr34]bPTH-(7-34)NH2 was shown to interact with PTH receptors in a competitive manner. These studies demonstrate, therefore, that D-Trp12 substitution in PTH antagonists improves inhibitory properties in vitro and is compatible with a helical conformation at this position as a new direction for the design of PTH antagonists.


Ginsenoside-Rb2 inhibits dexamethasone-induced apoptosis through promotion of GPR120 induction in bone marrow-derived mesenchymal stem cells.
Apoptosis of bone marrow-derived mesenchymal stem cells (BMMSCs) is an essential pathogenic factor of osteoporosis. Ginsenoside-Rb2 (Rb2), a 20(S)-protopanaxadiol glycoside extracted from ginseng, is a potent treatment for bone loss, which raises interest regarding the bone metabolism area. In the present study, we found that dose-response Rb2 inhibited high dosage of dexamethasone (Dex)-induced apoptosis in primary murine BMMSCs. Interestingly, Rb2 promoted GPR120 induction, which is the unsaturated long-chain fatty acid receptor. We further confirmed that GPR120-specific ShRNA reversed the inhibition of Rb2 on Dex-induced apoptosis by activating caspase-3 and reducing cell viability. In addition, Rb2 notably increased phosphorylated ERK1/2 levels and Ras kinase activity dependently through the GPR120. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked the Rb2-induced antiapoptotic effect in response to Dex-induced apoptosis. Together, dose-response Rb2 protected BMMSCs against Dex-induced apoptosis dependently by inducing GPR120 promoted Ras-ERK1/2 signaling pathway. Therefore, in the prevalence of the abuse of Dex in the clinic, our findings suggest for the first time that Rb2 is not only a key to understand the link between Chinese medicine and the pathology of osteoporosis but also an underlying target for the treatment of bone complications in the foreseeable future.


A fluorescence-labeling method for sequencing small RNA on polyacrylamide gel.
A practical fluorescence-labeling method for sequencing small RNAs by the traditional 'direct read out' on polyacrylamide gel electrophoresis was established. The 3' terminus of RNA was oxidized into dialdehyde by sodium periodate and then labeled with fluorescein-5-thiosemicarbazide through the condensation reaction between carbazide and aldehyde. The fluorescence-labeled RNA was partially degraded enzymatically and fractionated by polyacrylamide gel electrophoresis. The fluorescent bands were visualised by ultraviolet photography. A partial sequence of yeast 5S rRNA was determined. The result indicates that this method can be used in sequencing small RNAs rapidly, conveniently and safely.


Predictive diagnosis of myotonic dystrophy with flanking microsatellite markers.
Linkage was shown between the myotonic dystrophy locus (DM) and a highly polymorphic AC repeat marker within the kallikrein (KLK1) locus (Z = 3.00, theta = 0.0). Linkage between KLK1 and the highly polymorphic AC repeat marker within the apolipoprotein C2 (APOC2) locus, which had been established in normal families, was confirmed in myotonic dystrophy families (Z = 4.37, theta = 0.11). These highly polymorphic AC repeat markers flank DM on chromosome 19. The gene order is cen-APOC2 (0.03) DM (0.08) KLK1-qter with recombination frequencies shown in parentheses. Genotypes for the AC repeat markers can be determined simultaneously by multiplex PCR and separation of the two base pair differences between adjacent alleles on sequencing gels. In informative families, this approach provides rapid diagnosis and is more accurate than methods using markers restricted to the proximal side of the myotonic dystrophy gene.


Nuclear localization of p65 reverses therapy-induced senescence.
Senescence is the arrest of cell proliferation and is a tumor suppressor phenomenon. In a previous study, we have shown that therapy-induced senescence of glioblastoma multiforme (GBM) cells can prevent relapse of GBM tumors. Here, we demonstrate that ciprofloxacin-induced senescence in glioma-derived cell lines and primary glioma cultures is defined by SA-β-gal positivity, a senescence-associated secretory phenotype (SASP), a giant cell (GC) phenotype, increased levels of reactive oxygen species (ROS), γ-H2AX and a senescence-associated gene expression signature, and has three stages of senescence -initiation, pseudo-senescence and permanent senescence. Ciprofloxacin withdrawal during initiation and pseudo-senescence reinitiated proliferation in vitro and tumor formation in vivo Importantly, prolonged treatment with ciprofloxacin induced permanent senescence that failed to reverse following ciprofloxacin withdrawal. RNA-seq revealed downregulation of the p65 (RELA) transcription network, as well as incremental expression of SMAD pathway genes from initiation to permanent senescence. Ciprofloxacin withdrawal during initiation and pseudo-senescence, but not permanent senescence, increased the nuclear localization of p65 and escape from ciprofloxacin-induced senescence. By contrast, permanently senescent cells showed loss of nuclear p65 and increased apoptosis. Pharmacological inhibition or genetic knockdown of p65 upheld senescence in vitro and inhibited tumor formation in vivo Our study demonstrates that levels of nuclear p65 define the window of reversibility of therapy-induced senescence and that permanent senescence can be induced in GBM cells when the use of senotherapeutics is coupled with p65 inhibitors.


Association between red blood cell transfusion and long-term mortality in patients with cancer of the esophagus after esophagectomy.
The impact of red blood cell transfusion on long-term mortality has not been well characterized in patients with cancer of the esophagus after esophagectomy. Our retrospective observational study investigated 611 patients with cancer of the esophagus after esophagectomy from January 2005 to December 2012. Perioperative red blood cell transfusion was defined as red blood cell transfusion during intraoperative and postoperative period. One hundred ninety-six (32.1%) patients received red blood cell transfusion. During follow-up period, 153 (36.9%) patients without red blood cell transfusion and 120 (61.2%) patients with red blood cell transfusion died. Multivariable analysis identified that there was an incremental association between the amount of red blood cell transfusion and long-term mortality (hazard ratio 1.06, 95% confidence interval 1.04-1.08, P < 0.001). The association between red blood cell transfusion and worse long-term mortality was also demonstrated in propensity-matched patients (hazard ratio 1.62, 95% confidence interval 1.15-2.28, P = 0.006). Therefore, there might be an independent association between perioperative red blood cell transfusion and worse long-term mortality in patients with cancer of the esophagus after esophagectomy. Furthermore, there was an incremental increase in long-term mortality in patients who was transfused with red blood cell during perioperative period.


Effect of age on rabbit aortic responses to relaxant endothelium-dependent and endothelium-independent agents.
The aim of this study was to evaluate the effects of aging on endothelium-dependent and endothelium-independent relaxation of rabbit thoracic aorta from New Zealand white rabbits aged 4-6 and 7-12 months. The contractile response to noradrenaline (NA) decreased with increasing age, but NA [EC50] did not vary significantly. Acetylcholine (Ach)-induced relaxation of aortic rings precontracted with NA [EC50] did not change significantly with increasing age. The relaxation induced by ATP of aortic rings, precontracted with NA [EC50], was significantly greater in young than in adult rabbits. This difference between young and adult animals became more evident in aortic rings deprived of endothelium: in adult animals, the ATP-induced relaxation of aortic rings with endothelium was significantly greater than in the rings without endothelium. The endothelium-independent relaxation by sodium nitrite (NaNO2) at lower concentrations was significantly greater in young than in adult rabbit aortic rings precontracted with NA [EC50]. Concluding, the age-induced changes in vascular response in male New Zealand white rabbits are related to an impaired mechanism at smooth muscle level.


Marchiafava: Bignami Disease Treated with Parenteral Thiamine.
Marchiafava - Bignami disease is rare sequelae of chronic alcohol use. We present a case with transient ischemic attack like presentation and its management with parenteral thiamine. A 53 year old male with history of country liquor use since 32 years was brought to hospital with acute onset of delirium & mild weakness involving motor functions of left side of the body, non-reactive planters and exaggerated tendon reflexes on left side. The MRI showed bilateral hyper intense signal on T2W and FLAIR images & Hypo intense lesion on T1W images involving body, genu and splenium of corpus callosum. The features are suggestive of Marchiafava - Bignami Disease. There have been few guidelines for management of MBD and literature supports use of parenteral thiamine 500mg leading to remission of symptoms and symptomatic improvement. It is advisable to use parenteral thiamine in all cases as it overlaps management of other co-morbidities of chronic alcoholism.


Sexual Racism, Psychological Symptoms, and Mindfulness Among Ethnically/Racially Diverse Young Men Who Have Sex with Men: a Moderation Analysis.
This study examined the potential moderating role of trait mindfulness on the association between perceived sexual racism and psychological symptoms among a community-based sample of ethnic/racial minority young men who have sex with men (MSM) residing in greater Los Angeles. From a cross-sectional sample of 448 participants, aged 16-24 years, survey data were analyzed to examine rates of perceived sexual racism, mindfulness, psychological symptoms, and moderation by mindfulness through various analyses, including analysis of variance and logistic regression. Results indicated that Latino young MSM reported the lowest scores of sexual racism, and sexual racism was associated with higher odds of psychological symptoms, suicidal ideation with a plan in the past year, and self-injury in the past 3 months. The protective potential of mindfulness was suggested by its main effects on psychological symptoms; however, it only buffered the effects of sexual racism on suicidal ideation with a plan and self-injury, with marginal buffering effects on depression. Findings underscore the potential utility of assessing sexual racism among young MSM of color, as well as the potential benefit of mindfulness approaches to buffer the effects of sexual racism on symptoms of depression. Interpretation of these findings is briefly discussed.


The case for a common ancestor: kinesin and myosin motor proteins and G proteins.
Recent studies have shown surprising structural and functional similarities between the motor domains of kinesin and myosin. Common features have also been described for motor proteins and G proteins. Despite these similarities, the evolutionary relationships between these proteins, even among the motor proteins, has not been obvious, since the topological connectivities of the core overlapping structural elements in these transducing proteins are not identical to one another. Using secondary structure topology, comparison of functional domains and active site chemistry as criteria for relatedness, we propose a set of rules for determining potential evolutionary relationships between proteins showing little or no sequence identity. These rules were used to explore the evolutionary relationship between kinesin and myosin, as well as between motor proteins and other phosphate-loop (P-loop) containing nucleotide-binding proteins. We demonstrate that kinesin and myosin show significant chemical conservations within and outside of the active site, and present an evolutionary scheme that produce their respective topologies from a hypothetical ancestral protein. We also show that, when compared with various other P-loop-containing proteins, the cytoskeletal motors are most similar to G proteins with respect to topology and active site chemistry. We conclude that kinesin and myosin, and possibly G proteins, are probably directly related via divergent evolution from a common core nucleotide-binding motif, and describe the likely topology of this ancestor. These proteins use similar chemical and physical mechanisms to both sense the state of the nucleotide bound in the active site, and then transmit these changes to protein partners. The different topologies can be accounted for by unique genetic insertions that add to the edge of a progenitor protein structure and do not disrupt the hydrophobic core.


Sex bias in the naming of stimulus persons.
Researchers often use sex-typed names (e.g., John vs. Joan) to identify stimulus persons' sex, assuming that such names communicate sex only. In fact, however, such names also create impressions that have little or nothing to do with sex. Study 1 analyzed the age connotations, intellectual-competence connotations, and attractiveness of sex-typed names used in 230 published studies on sexism and fear of success. On each of these variables, the literature was pervasively confounded in a manner favoring male stimulus persons. Study 2 found that the name biases reported in Study 1 were positively correlated with outcome measures in a sample of sexism studies, but only when names were presented with limited other information. Possible causes of the bias are discussed, and recommendations for naming stimulus persons are presented, including a list of male names and female names matched on several key variables.


[Impact of rational use of antibiotics in a third level clinic in Colombia].
The increasing resistance of bacteria to antibiotics threatens the survival of patients and health costs. To determine the impact of an antimicrobial stewardship program in bacterial resistance and antibiotic consumption. Quasi experimental study in a third level clinic in the city of Medellin, that evaluate in two time periods (pre-intervention between October 2012 and September 2013 and post intervention between October 2013 and September 2014) the impact of an antimicrobial stewardship program in terms of antibiotic consumption and bacterial ecology. Adherence to institutional guidelines for management of infections in the post-intervention period was 82%. Antibiotic consumption of meropenem, ceftriaxone, vancomycin and colistin decreased, and imipenem, daptomycin and linezolid was increased. A significant decrease in antibiotic resistance in Pseudomonas aeruginosa was observed, including carbapenems. An increase of extended spectrum beta lactamase production (ESBL) in Enterobacteriaceae (especially E. coli) and piperacillin/tazobactam resistance was observed. The construction and implementation of a strategy in hospitals with guidelines for managing infectious diseases, restrictions in antibiotic use, a permanent monitoring system for the formulation of antibiotics, achieved a positive impact on reducing antibiotic use and bacterial resistance.


Impact of vitamin D on infectious disease.
Observational studies have linked vitamin D status and infectious disease. This association is supported by the presence of the vitamin D receptor and CYP27B1 in immune cells. This review aims to consolidate data from clinical trials that used vitamin D for the treatment or prevention of infectious disease. The authors searched the term "(vitamin D OR ergocalciferol OR cholecalciferol OR vitamin D2 OR vitamin D3 OR calcitriol) AND (infection OR tuberculosis OR sepsis OR pneumonia)" with limits preset to manuscripts published in English and with human subjects. They identified controlled trials that measured infectious outcomes (eg, incidence and severity of disease, time to disease resolution or recurrence, measures of clinical improvement, mortality). Studies that used analog, topical or micronutrient formulations of vitamin D, assessed only vitamin D status or lacked a comparison group were excluded. The references from eligible manuscripts and from 2 recent reviews were scanned for additional manuscripts. One thousand two hundred eighty-four manuscripts were identified with our search terms, with 60 papers still eligible after review of the title and abstract. Full review of these papers, their references and 2 related reviews yielded 38 manuscripts. Although some prospective studies show positive results regarding vitamin D on infectious disease, several robust studies are negative. Factors such as high variability between studies, the difference in individual responsiveness to vitamin D and study designs that do not primarily investigate infectious outcomes may mask the effects of vitamin D on infections.


Prediction of the pharmacokinetics of pemetrexed with a low test dose: A proof-of-concept study.
Pemetrexed is a cytotoxic drug used for the treatment of lung cancer and mesothelioma. The use of a low test dosing of cytotoxic drugs may aid in dose individualization without causing harm. The aim of this proof-of-concept study was to assess if the pharmacokinetics (PKs) of a test dose could predict the PKs of a therapeutic pemetrexed dose. Ten patients received both a low test dose (100 μg) and a therapeutic dose of pemetrexed after which plasma concentrations pemetrexed were measured. PK analysis was performed by means of nonlinear mixed-effects modelling. The predictive performances of test dose clearance and renal function towards a therapeutic dose were assessed. The PKs of a pemetrexed test dose were best described by a one-compartment model with linear elimination. A high variability in the administered dose was observed for the test dose, but not for the therapeutic dose. A statistically significant correlation between test dose clearance and therapeutic dose clearance was observed (Spearman's rho: 0.758, P = 0.02). The predictive performance of test dose clearance was worse than renal function: mean predictive error (+95% confidence interval [CI]) 53.9% (50.1-57.6%) vs 19.4% (12.4-26.4%) and normalized root-mean square error (+95% CI) 57.8% (30.5-85.1%) vs 25.7% (20.3-31.0%). We show that test dosing of pemetrexed is feasible, but there seems no added value for a low test dosing in the dose individualization of pemetrexed.


Natural and human-driven selection of a single non-coding body size variant in ancient and modern canids.
Domestic dogs (Canis lupus familiaris) are the most variable-sized mammalian species on Earth, displaying a 40-fold size difference between breeds.1 Although dogs of variable size are found in the archeological record,2-4 the most dramatic shifts in body size are the result of selection over the last two centuries, as dog breeders selected and propagated phenotypic extremes within closed breeding populations.5 Analyses of over 200 domestic breeds have identified approximately 20 body size genes regulating insulin processing, fatty acid metabolism, TGFβ signaling, and skeletal formation.6-10 Of these, insulin-like growth factor 1 (IGF1) predominates, controlling approximately 15% of body size variation between breeds.8 The identification of a functional mutation associated with IGF1 has thus far proven elusive.6,10,11 Here, to identify and elucidate the role of an ancestral IGF1 allele in the propagation of modern canids, we analyzed 1,431 genome sequences from 13 species, including both ancient and modern canids, thus allowing us to define the evolutionary history of both ancestral and derived alleles at this locus. We identified a single variant in an antisense long non-coding RNA (IGF1-AS) that interacts with the IGF1 gene, creating a duplex. While the derived mutation predominates in both modern gray wolves and large domestic breeds, the ancestral allele, which predisposes to small size, was common in small-sized breeds and smaller wild canids. Our analyses demonstrate that this major regulator of canid body size nearly vanished in Pleistocene wolves, before its recent resurgence resulting from human-imposed selection for small-sized breed dogs.


Isolation and characterization of T4 bacteriophage gp17 terminase, a large subunit multimer with enhanced ATPase activity.
Phage T4 terminase is a two-subunit enzyme that binds to the prohead portal protein and cuts and packages a headful of concatameric DNA. To characterize the T4 terminase large subunit, gp17 (70 kDa), gene 17 was cloned and expressed as a chitin-binding fusion protein. Following cleavage and release of gp17 from chitin, two additional column steps completed purification. The purification yielded (i) homogeneous soluble gp17 highly active in in vitro DNA packaging ( approximately 10% efficiency, >10(8) phage/ml of extract); (ii) gp17 lacking endonuclease and contaminating protease activities; and (iii) a DNA-independent ATPase activity stimulated >100-fold by the terminase small subunit, gp16 (18 kDa), and modestly by portal gp20 and single-stranded binding protein gp32 multimers. Analyses revealed a preparation of highly active and slightly active gp17 forms, and the latter could be removed by immunoprecipitation using antiserum raised against a denatured form of the gp17 protein, leaving a terminase with the increased specific activity (approximately 400 ATPs/gp17 monomer/min) required for DNA packaging. Analysis of gp17 complexes separated from gp16 on glycerol gradients showed that a prolonged enhanced ATPase activity persisted after exposure to gp16, suggesting that constant interaction of the two proteins may not be required during packaging.


Oral health status of preschool children attending Head Start in Maryland, 2000.
The objective of this study was to determine the oral health status of preschool children attending Head Start Centers in Maryland. Clinical caries examinations were conducted on 482 children between ages 3-5 from 37 Maryland Head Start Centers in 2000. Additionally, 560 questionnaires were completed by their caretakers regarding their child's access to care, potential caries risk factors and history of toothaches. The overall prevalence of untreated decay was 52%, with a higher prevalence found in rural than urban centers (64% vs 48%). For all children, the mean decayed, filled surfaces (dfs) was 3.64, while the mean decayed surfaces (ds) was 2.90. For those who had caries experience, the dfs was 6.67 and the ds was 5.32. The percentage of children with caries increased by age from 43% for three-year-olds to 62% for four-year-olds. Of those children with caries experience, 17% had complained of a toothache and 9% reportedly cried because of a toothache. Of significance in this study were the findings that: caries is highly prevalent in this underserved preschool population; pain due to dental caries is not uncommon; and there is little utilization of dental care despite federally mandated and Head Start and Medicaid requirements.


[Psychological support for road accident participants: the program implementation outcome].
Road accident belongs to one of the categories of traumatic events, and can cause posttraumatic stress disorder (PTSD). The most common psychological consequences of road traffic accidents are the emotional disorders, cognitive deficits (disorders concentration of attention and memory function), impaired social relationships, troubles with performing work duties and physical symp-toms of stress. The article discusses the program of psychological support given to the participants of road accidents, conducted in Wroclaw, its theoretical assumptions and the mode of its implementation. Basic theoretical assumptions of the program are inter alia based on the theories of H. Selye and R. Lazarus. The authors of this article also refer to the so-called therapeutic process of education designed by Everly and Rosenfeld, who recommend that the process of developing self-responsibility be used for therapeutic purposes. This requires clarifying the exact nature of the problem, and then looking for possible remedies. The program is open to all road accident participants (victims, perpetrators, witnesses) and their families. Classes are designed to combine theory (lectures) and practice (exercises). Anxiety and cognitive processes, as well as relaxation training, interpersonal training (eg, assertiveness) and kinesiology are the major areas of activities. Psychological support provided for road accident participants is of intervention--and preventive nature; intervention, as it relates to the consequences ofa specific stressogenic event, namely a road accident; preventive, as it serves the overriding purpose--the improvement of road safety. This article presents the main findings of the program, the results of the survey evaluation, and proposals to develop psychological operations aimed at the road accidents participants.


BALLView: a tool for research and education in molecular modeling.
We present BALLView, a molecular viewer and modeling tool. It combines state-of-the-art visualization capabilities with powerful modeling functionality including implementations of force field methods and continuum electrostatics models. BALLView is a versatile and extensible tool for research in structural bioinformatics and molecular modeling. Furthermore, the convenient and intuitive graphical user interface offers novice users direct access to the full functionality, rendering it ideal for teaching. Through an interface to the object-oriented scripting language Python it is easily extensible.


Non-random distribution of intraepithelial lymphoid cells in follicle-associated epithelium of Peyer's patches in mice.
The spatial distribution of intraepithelial lymphoid cells in follicle-associated and villus epithelium within Peyer's patches was studied quantitatively in Balb/C and CFW/L1 mice. The results were essentially the same for both strains. The distribution of the number of lymphoid cells per segmental length (equal to an average width of an epithelial cell) of dome epithelium was found to be non-random, since it deviated significantly from the theoretical Poisson distribution. Some segments of the dome epithelium, therefore, are lymphocyte-rich and some are lymphocyte-depleted, i.e. they contain either more, or less lymphoid cells than expected from the random distribution. This was in contrast to the distribution in the epithelial layer of the villi, in which the distribution of the number of lymphoid cells per segment followed the Poisson distribution. It was also demonstrated that segments rich in lymphocytes in the dome epithelium occurred in series or clusters. Lymphoid cell clustering was not observed in the villus epithelium. Possible mechanisms responsible for the non-random spatial distribution of lymphoid cells within the dome epithelium of the mouse Peyer's patches are discussed.


Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia.
Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10-9) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10-8), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.


Biological sample-compatible Au nanoparticle-containing fluorescent molecularly imprinted polymer microspheres by combining RAFT polymerization and Au-thiol chemistry.
The development of biological sample-compatible fluorescent molecularly imprinted polymers (MIPs) with more functions and/or improved performance is of great importance for various bioanalytical and biomedical applications, but remains challenging. Herein, we report on a versatile strategy for preparing well-defined hydrophilic gold (Au) nanoparticle (AuNP)-containing fluorescent MIP microspheres capable of directly optosensing folic acid (FA) in undiluted urine samples and study of the effect of the incorporated AuNPs on their optosensing sensitivity. Such advanced functional fluorescent MIP particles were readily prepared by combining RAFT polymerization (including RAFT precipitation polymerization and surface-initiated RAFT polymerization) and Au-thiol chemistry [including successive attachment of AuNPs and a thiol-terminated poly(2-hydroxyethyl methacrylate) onto MIP particles after aminolysis of their surface dithioester into thiol groups]. They showed "turn-on" fluorescence and high optosensing selectivity and sensitivity toward FA in the undiluted urine sample (detection limit = 0.088 μM). They also exhibited outstanding photostability and reusability and could directly quantify FA in another undiluted urine sample with good recoveries (96.3-101.6%) and high accuracy (RSD = 0.6-3.1%), even in the presence of several interferents. Unfortunately, the incorporated AuNPs did not improve the optosensing sensitivity of AuNP-containing fluorescent MIPs. Nevertheless, introducing AuNPs onto the surfaces of fluorescent MIPs not only provides an effective new way for grafting with hydrophilic polymer brushes, but it also can endow them with certain new functions [e.g., surface-enhanced Raman scattering (SERS)], thus making them highly promising as both efficient optosensors and potential SERS sensors for rapid FA detection in applications such as clinical diagnostics and food analyses.


Testicular sex cord stromal tumour with granulosa cell differentiation: detection of steroid hormone receptors as a possible basis for tumour development and therapeutic management.
A testicular sex cord stromal tumour with granulosa cell differentiation, typical of granulosa cell tumours of the adult type, was investigated immunohistologically on snap frozen and paraffin wax embedded material. The predominance of vimentin and the additional expression of cytokeratin subtypes 8 and 18, as well as the negative staining for epithelial membrane antigen, accorded with results previously reported, for ovarian granulosa cell tumours; the lack of expression of desmoplakin, however, was a distinctive feature. Together with negative staining for leucocyte common antigen, the antigen pattern facilitates the differential diagnosis between granulosa cell tumour and undifferentiated carcinoma or gonadal lymphoma, although its suitability for differentiating within the group of gonadal stromal tumours seems to be limited. The small growth fraction, shown by the monoclonal antibody Ki-67, is typical of the clinical behaviour of granulosa cell tumours. The expression of oestrogen and progesterone receptors, also recently found in testicular Leydig cell tumours, may provoke new approaches to the management of testicular granulosa cell tumours, as well as a new hypothesis on the development of these tumours.


Medial efferent inhibition produces the largest equivalent attenuations at moderate to high sound levels in cat auditory-nerve fibers.
Previous work has shown that medial efferents can inhibit responses of auditory-nerve fibers to high-level sounds and that fibers with low spontaneous rates (SRs) are inhibited most. However, quantitative interpretation of these data is made difficult by effects of adaptation. To minimize systematic differences in adaptation, efferent inhibition was measured with a randomized presentation of both sound level and efferent stimulation. In anesthetized cats, efferents were stimulated with 200/s shocks and auditory-nerve-fiber responses were recorded for tone bursts (0-100 dB SPL, 5-dB steps) at their characteristic frequencies. Below 50 dB SPL, efferent inhibition (measured as equivalent attenuation) was similar for all fibers with similar CFs in the same cat. At 45-75 dB SPL, low-SR and medium-SR fibers often showed much larger inhibition, and substantial inhibition even at 100 dB SPL. Expressed as a fractional decrease in rate, at 90-100 dB SPL the inhibition was 0%, 6%, and 13% for high-, medium-, and low-SR fibers (differences statistically significant). Finding the largest equivalent attenuations at 45-75 dB SPL does not fit with the hypothesis that medial-efferent inhibition is due solely to a reduction of basilar-membrane motion. The large attenuations, some over 50 dB, indicate that medial efferent inhibition is more potent than previously reported.


[Argas reflexus (Fabricius, 1794) as a cause of acarosis in people].
The studies were carried out between 1997-1999 within the administrative district of Toruń. Forty sports pigeon breeders together with their pigeonswere understudy annually. The collected material allowed noticing the following issues: in 1997 and 1998 the Argas reflexus (Fabricius, 1794) was present in dovecotes (individuals) and t he breeds' owners were pricked. In 1998 numerous specimens of the A. reflexus were obtained from the material from the sanitary-epidemiological station. The specimens were collected from the bodies of the people, family members and from their flat located on the highest third floor of the old house. In the mite-infected dovecotes and in the old houserooms, the following steps were suggested: mechanical cleansing, whitewashing, disinfecting, and triple disinsecting, with fourteen-day-long intervals. The people with the symptoms of acariosis were subjected to treatment with calcium, anti-allergic, and anti-fever mixtures, and, in some cases, cortisone ointments were applied. In spite of a considerable growth in the symptoms, the used methods turned out to be successful in all the studied cases.


Formation mechanisms and yields of small imidazoles from reactions of glyoxal with NH4(+) in water at neutral pH.
Imidazoles have numerous applications in pharmacology, chemistry, optics and electronics, making the development of their environmentally-friendly synthetic procedures worthwhile. In this work, the formation of imidazole, imidazole-2-carboxaldehyde, and 2,2-bis-1H-imidazole was investigated in the self-reaction of glyoxal and its cross-reactions with each of these compounds in aqueous solutions of inorganic ammonium salts at pH =7. Such conditions are relevant both as cheap and environmentally-friendly synthetic procedures and for the chemistry of natural environments where NH4(+) is abundant, such as in atmospheric aerosols. These reactions were investigated both by (1)H-NMR and UV-Vis absorption spectroscopy at room temperature with the objective to determine the formation pathways of the three imidazoles and the parameters affecting their yields, to identify the optimal conditions for their synthesis. The results show that only the simplest imidazole is produced by the self-reaction of glyoxal and that imidazole-2-carboxaldehyde and 2,2-bis-1H-imidazole are produced by cross-reactions of glyoxal with imidazole and imidazole-2-carboxaldehyde, respectively. The yields of imidazole-2-carboxaldehyde and 2,2-bis-1H-imidazole formed by the cross-reactions were close to unity, but the yield of imidazole formed by the self-reaction of glyoxal, YIm, was small and varied inversely with the initial glyoxal concentration, [G]0: YIm > 10% only for [G]0 < 0.1 M. The latter result was attributed to the kinetic competition between the imidazole-forming condensation pathway and the acetal/oligomer formation pathway of the glyoxal self-reaction and constitutes a bottleneck for the formation of higher imidazoles. Other parameters such as pH and the NH4(+) concentration did not affect the yields. Thus, by maintaining small glyoxal concentrations, high imidazole yields can be achieved in environmentally-friendly aqueous ammonium solutions at neutral pH. Under the same conditions, higher yields are expected expected from substituted carbonyl compounds, regardless of their concentration, as they produce less acetals.


Entero-vesical fistulae in surgical practice.
Any disease or traumatic event that involving the integrity of the urinary tract or of the bowel, may led to an entero-vesical fistula formation. The clinical onset of this pathology, is described on the basis of usual clinical pictures and of some unusual cases mimicking a bladder cancer. Moreover, the guide lines for a gold standard in the diagnosis and treatment of such pathology are described.


[Clinical and morphological features of breast cancer in men].
Breast cancer in men is 100 times less common than in women. The main risk factors include: the mutation of genes BRCA 1 and 2, Klinefelter's syndrome, alcohol, liver disease, obesity. Clinical examinations, mammography and ultrasound are informative and highly sensitive for early detection of these tumors, but are rarely implemented due to lack of awareness of general practitioners. Local treatment includes the Patey-Dyson mastectomy and radiation therapy. Adjuvant systemic therapy is determined by pTNM and typically involves tamoxifen.


Production of human monoclonal antibody in mouse ascites.
Human B-cell hybridomas were grown in nude mouse ascites. The growth of cells in ascites requires prior subcutaneous (SC) adaptation, but the amount of antibody harvested is 100-fold that produced in in vitro culture. The relative merits of in vitro versus in vivo production of human monoclonal antibodies are discussed.


Impact of Flushing Response on the Relationship between Alcohol Consumption and Gamma-glutamyl Transpeptidase: the KOBE study.
Individuals with an inactive acetaldehyde dehydrogenase 2 have an. elevated level of serum acetaldehyde after drinking alcohol, and this may cause an alcohol flushing response with symptoms such as facial flushing, tachycardia, headache, and nausea. Recent studies have suggested that the flushing response influences the association between alcohol consumption and various health-related outcomes. In the present study, we investigated the impact of the flushing response on the relationship between alcohol consumption and serum y -GTP levels in Japanese drinkers. We conducted a cross-sectional study of 521 Japanese drinkers (260 men and 261 'vomen) to examine the impact of the alcohol flushing response on the relationship between alcohol consumption and serum y -GTP levels. The subjects were divided into three groups according to the amount .of daily alcohol consumption. (low, <20 g; moderate, 20-39 g;. and high, >40 g). Multiple adjustments were performed with linear regression models to examine the association between daily alcohol consumption and serum y-GTP levels, adjusting for potential con- founders including the flushing response. We found that the proportion of flushers was significantly lower in the high alcohol consumption group than in the low consumption group. The results of a multivariable analysis showed that,serum y -GTP levels were significantly higher in the moderate and high consumption groups than in the low consumption group after. adjusting for all potential confounders other than the flushing response. In addition, the association between serum y -GTP levels and alcohol consumption was unchanged after adjusting for the presence of the flushing response. In conclusion, serum y -GTP levels increased with increasing alcohol-consumption regardless of the flushing response. Screening for heavy drinkers using serum y-GTP levels was very important to prevent alcohol-related diseases or health problems in health examination.


Localization of small heat shock proteins to the higher plant endomembrane system.
Three related gene families of low-molecular-weight (LMW) heat shock proteins (HSPs) have been characterized in plants. We describe a fourth LMW HSP family, represented by PsHSP22.7 from Pisum sativum and GmHSP22.0 from Glycine max, and demonstrate that this family of proteins is endomembrane localized. PsHSP22.7 and GmHSP22.0 are 76.7% identical at the amino acid level. Both proteins have amino-terminal signal peptides and carboxyl-terminal sequences characteristic of endoplasmic reticulum (ER) retention signals. The two proteins closely resemble class I cytoplasmic LMW HSPs, suggesting that they evolved from the cytoplasmic proteins through the addition of the signal peptide and ER retention motif. The endomembrane localization of these proteins was confirmed by cell fractionation. The polypeptide product of PsHSP22.7 mRNA was processed to a smaller-M(r) form by canine pancreatic microsomes; in vivo, GmHSP22.0 polysomal mRNA was found to be predominantly membrane bound. In vitro-processed PsHSP22.7 corresponded in mass and pI to one of two proteins detected in ER fractions from heat-stressed plants by using anti-PsHSP22.7 antibodies. Like other LMW HSPs, PsHSP22.7 was observed in higher-molecular-weight structures with apparent masses of between 80 and 240 kDa. The results reported here indicate that members of this new class of LMW HSPs are most likely resident ER proteins and may be similar in function to related LMW HSPs in the cytoplasm. Along with the HSP90 and HSP70 classes of HSPs, this is the third category of HSPs localized to the ER.