The use of behavioral test batteries, II: effect of test interval.
Test batteries are commonly used to assess the behavioral phenotype of genetically modified and inbred strains of mice. However, few systematic studies have been employed to address several key issues concerning the use of a test battery. The current study was designed to address whether inter-test interval affects behavioral performance. Male mice of 3 different inbred strains and one F1 hybrid strain were randomly assigned to either a test battery with 1 week inter-test intervals, or a rapid test battery with 1-2 day inter-test intervals. The test battery included a neurological exam, open-field activity, light-dark exploration, rotarod test, prepulse inhibition, and startle habituation. The experiment was repeated with female animals of 2 different strains. As expected, there were strain differences on each of the behavioral assays; however, there was no major difference in performance between mice of the standard test battery and the rapid test battery. Similar results were found with females. These results indicate that the interval between most tests could be as little as 1-2 days, with little significant effect on overall performance. Thus, it is possible with the current test battery to reduce the inter-test interval to facilitate the rate of studying and identifying behavioral phenotypes in mice.


Rethinking flourishing: Critical insights and qualitative perspectives from the U.S. Midwest.
In recent years, human flourishing and its relationship to mental health have attracted significant attention in a wide range of fields. As an interdisciplinary, mixed-methods team with strong roots in critical medical anthropology and critical public health, we are intrigued by the possibility that a focus on flourishing may reinvigorate health research, policy, and clinical care in transformative ways. Yet current proposals to this effect, we contend, must be met with caution. In particular, we call attention to the troubling disconnect between current research on flourishing, on one hand, and the voluminous body of scholarship demonstrating the detrimental impact of structural inequities on health, on the other. We illuminate this blind spot in two ways. We begin with a critical assessment of leading conceptions to flourishing in positive psychology, which are compared to current approaches in the critical social sciences of health. In the second half of the paper, we support our argument by presenting original findings from a mixed-methods study with a diverse sample of interviewees in the Midwestern U.S. city of Cleveland, Ohio (n=167). Our interviewees' rich narrative accounts, which we analyze both quantitatively and qualitatively, highlight important ways in which everyday understandings of flourishing diverge from prevailing scholarly accounts. Given these gaps and blind spots, now is an opportune time for robust interdisciplinary discussion about the implicit values and presumptions underpinning leading approaches to flourishing and their wide-ranging implications for research, policy, and clinical care in mental health fields and beyond.


SNPs of hemocyanin C-terminal fragment in shrimp Litopenaeus vannamei.
In this study, we identified a variable region in the C-terminus of hemocyanin from the shrimp Litopenaeus vannamei (2288-2503bp, HcSC) by sequence alignments. A total of 13 SNPs were identified by PCR-SSCP and HcSC clone sequencing. The SSCP patterns of HcSC could be modulated in Vibro parahaemolyticus-treated shrimps. A novel SSCP band with four SNP sites was identified in V. parahaemolyticus-resistant shrimps. More importantly, three of these four SNPs introduced variations in amino acid sequence and possibly secondary structure of the HcSC polypeptide and resulted in a higher agglutinative activity against seven pathogenic bacteria. These results suggest that the C-terminus of shrimp L. vannamei hemocyanin possesses SNPs, which may be related to shrimp resistance to different pathogens.


Determination of mirtazapine in spiked human plasma and tablets by first derivative spectrofluorimetric method.
A sensitive first derivative spectrofluorimetric method ((1)D-spectrofluorimetry) was developed for the determination of mirtazapine. Calibration graph for mirtazapine determination was established using the first derivative amplitudes of the mirtazapine emission spectrum (λ ex = 314 nm) in 0.1 M sulphuric acid measured at 375-435 nm from peak to peak, as the analytical signals. Moreover, the ratio of (1)D-spectrophotometric peak amplitudes at these wavelengths was calculated and used for the detection of the presence of interferences. Linearity range was found to be between 1 and 40 ng ml(-1) with correlation coefficient (r) = 0.9999. The limit of quantitation (LOQ) was 1.0 ng ml(-1) and the limit of detection (LOD) was 0.2 ng ml(-1). The proposed method was validated according to ICH; and it has been applied for the drug determination in human plasma without prior extraction and in tablets. The proposed method's accuracy, reproducibility, selectivity and simplicity suggest its application in quality control analysis of the drug.


The Global Burden of Disease Study Estimates of Brazil's Cervical Cancer Burden.
Cervical cancer represents an important preventable cause of morbidity and mortality in developing countries such as Brazil. Investigating temporal evolution of a disease burden in the different realities of the country is essential for improving public policies. To describe the national and subnational burden of cervical cancer, based on the estimates of the 2017 Global Burden of Disease study. Descriptive study of premature mortality (years of life lost [YLL]) and burden of disease (disability-adjusted life years [DALYs]) associated with cervical cancer among Brazilian women aged 25-64 years, between 2000 and 2017. During the study period, age-standardized incidence decreased from 23.53 (22.79-24.26) to 18.39 (17.63-19.17) per 100,000 women, while mortality rates decreased from 11.3 (11.05-11.56) to 7.74 (7.49-8.02) per 100,000 women. These rates were about two to three times greater than equivalent rates in a developed country, such as England: 11.98 (11.45-12.55) to 10.37 (9.85-10.9), and 3.75 (3.68-3.84) to 2.82 (2.75-2.9) per 100,000 women, respectively. Poorer regions of Brazil had greater rates of the disease; for instance, Amapá State in the Northern Region had rates twice as high as the national rates during the same period. Cervical cancer was the leading cause of premature cancer-related mortality (YLL = 100.69, 91.48-110.61 per 100,000 women) among young women (25-29 years) in Brazil and eight federation units of all country regions except the Southeast in 2017. There was a decrease in the burden of cervical cancer in Brazil from 339.59 (330.82-348.83) DALYs per 100,000 women in 2000 to 238.99 (230.45-247.99) DALYs per 100,000 women in 2017. Although there has been a reduction in the burden of cervical cancer in Brazil, the rates remain high, mainly among young women. The persistence of inequalities between regions of Brazil suggests the importance of socioeconomic determinants in the burden for this cancer.


5-MeO-DALT: the freebase of N,N-diallyl-5-meth-oxy-tryptamine.
The title compound {systematic name: N-[2-(5-meth-oxy-1H-indol-3-yl)eth-yl]-N-(prop-2-en-1-yl)prop-2-en-1-amine), C17H22N2O, has a single tryptamine mol-ecule in the asymmetric unit. The mol-ecules are linked by strong N-H⋯N hydrogen bonds into zigzag chains with graph-set notation C(7) along the [010] direction.


The cardioprotective potentials and the involved mechanisms of phenolic acids in drug-induced cardiotoxicity.
Cardiotoxicity is one of the major safety concerns in the use of drug and is the most common reason for drug removal from the market. At present, several drugs that have been recognized as the clinically effective drug have been reported to be associated with a high risk of cardiotoxicity during clinical use. The most representative ones are doxorubicin, arsenic trioxide, isoproterenol, cyclophosphamide, etc. The adverse effects seriously affect the human health and limit the clinical application of the drugs mentioned above. Over the past years, many strategies have been carried out to prevent the occurrence of drug-induced cardiotoxicity, including early detection of cardiotoxicity by biomarkers, limitation of doses, changing of drug-delivery way, combining with cardioprotective agent. Among them, combining with cardioprotective agent has gained increased interest and has been considered as a promising approach for continued treatment. Therefore, looking for effective cardioprotective agent to avoid the occurrence of drug-induced cardiotoxicity has become a great challenge for many researchers. Interestingly, some phenolic acids compounds from natural plants have been demonstrated to establish a significant protective effect in drug-induced cardiotoxicity. In this work, we reviewed the cardioprotective potentials and the involved mechanisms of phenolic acids in drug-induced cardiotoxicity. To provide a reference for the further application of phenolic acids in the prevention of drug-induced cardiotoxicity.


An Analysis of Political Contributions from Neurosurgeons in the United States.
As the uncertainty surrounding the future of U.S. health care policy intensifies, political advocacy and campaign contributions have become increasingly relevant. This study describes the trends of political contributions of U.S. neurosurgeons from the years 2003-2019. Individual contribution data from 2003-2019 were obtained from the Federal Election Commission website. Contributions were filtered for occupation lines matching either "neurosurg," "neurologic surgeon," or "neurological surgeon." Each contribution is designated to a recipient committee associated with a political candidate or group. The party designations of these committees were used to catalogue donations as "Republican," "Democratic," or "Independent." From 2003-2019 a total of 9242 political donations were made by self-identified neurosurgeons amounting to $8,469,121. Most of these contribution dollars were directed to Independent committees (47.9%). Of all Independent contribution dollars from 2005-2019, 95.9% were directed to the American Association of Neurological Surgeons Political Action Committee. The total number of unique contributions increased from 442 contributions in 2003 to 650 in 2019. Democrats experienced the most substantial increase in support, from 4.8% of all contribution dollars in 2003 to 26.3% in 2019. Republican support was noted to be more widespread across the United States compared with Democratic support. Political contributions from U.S. neurosurgeons have increased steadily over time. Donations were largely Independent but became increasingly partisan in recent years. Overall, this displays an increase in political involvement among the neurosurgeon community. Future studies are warranted into how this involvement translates to representative health policy.


Hippo circuitry and the redox modulation of hippo components in cancer cell fate decisions.
Meticulous and precise control of organ size is undoubtedly one of the most pivotal processes in mammalian development and regeneration along with cell differentiation, morphogenesis and programmed cell death. These processes are strictly regulated by complex and highly coordinated mechanisms to maintain a steady growth state. There are a number of extrinsic and intrinsic factors that dictate the total number and/or size of cells by influencing growth, proliferation, differentiation and cell death. Multiple pathways, such as those involved in promoting organ size and others that restrict disproportionate tissue growth act simultaneously to maintain cellular and tissue homeostasis. Aberrations at any level in these organ size-regulating processes can lead to various pathological states with cancers being the most formidable one (Yin and Zhang, 2011). Extensive research in the realm of growth control has led to the identification of the Hippo-signaling pathway as a critical network in modulating tissue growth via its effect on multiple signaling pathways and through intricate crosstalk with proteins that regulate cell polarity, adhesion and cell-cell interactions (Zhao et al., 2011b). The Hippo pathway controls cell number and organ size by transducing signals from the plasma membrane to the nucleus to regulate the expression of genes involved in cell fate determination (Shi et al., 2015). In this review, we summarize the recent discoveries concerning Hippo pathway, its diversiform regulation in mammals as well as its implications in cancers, and highlight the possible role of oxidative stress in Hippo pathway regulation.


Rethinking sources of representative controls for the conduct of case-control studies in minority populations.
Recruitment of controls remains a challenge in case-control studies and particularly in studies involving minority populations. We compared characteristics of controls recruited through random digit dialing (RDD) to those of community controls enrolled through churches, health events and other outreach sources among women of African ancestry (AA) participating in the Women's Circle of Health Study, a case-control study of breast cancer. Odds ratios and 95% confidence intervals were also computed using unconditional logistic regression to evaluate the impact of including the community controls for selected variables relevant to breast cancer and for which there were significant differences in distribution between the two control groups. Compared to community controls (n=347), RDD controls (n=207) had more years of education and higher income, lower body mass index, were more likely to have private insurance, and less likely to be single. While the percentage of nulliparous women in the two groups was similar, community controls tended to have more children, have their first child at a younger age, and were less likely to breastfeed their children. Dietary intake was similar in the two groups. Compared to census data, the combination of RDD and community controls seems to be more representative of the general population than RDD controls alone. Furthermore, the inclusion of the community group had little impact on the magnitude of risk estimates for most variables, while enhancing statistical power. Community-based recruitment was found to be an efficient and feasible method to recruit AA controls.


Precise cloning and tandem integration of large polyketide biosynthetic gene cluster using Streptomyces artificial chromosome system.
Direct cloning combined with heterologous expression of a secondary metabolite biosynthetic gene cluster has become a useful strategy for production improvement and pathway modification of potentially valuable natural products present at minute quantities in original isolates of actinomycetes. However, precise cloning and efficient overexpression of an entire biosynthetic gene cluster remains challenging due to the ineffectiveness of current genetic systems in manipulating large-sized gene clusters for heterologous as well as homologous expression. A versatile Escherichia coli-Streptomyces shuttle bacterial artificial chromosomal (BAC) conjugation vector, pSBAC, was used along with a cluster tandem integration approach to carry out homologous and heterologous overexpression of a large 80-kb polyketide biosynthetic pathway gene cluster of tautomycetin (TMC), which is a protein phosphatase PP1/PP2A inhibitor and T cell-specific immunosuppressant. Unique XbaI restriction sites were precisely inserted at both border regions of the TMC biosynthetic gene cluster within the chromosome of TMC-producing Streptomyces sp. CK4412, followed by site-specific recombination of pSBAC into the flanking region of the TMC gene cluster. The entire TMC gene cluster was then rescued as a single giant recombinant pSBAC by XbaI digestion of the chromosomal DNA as well as subsequent self-ligation. Next, the recombinant pSBAC construct containing the entire TMC cluster in E. coli was directly conjugated into model Streptomyces strains, resulting in rapid and enhanced TMC production. Moreover, introduction of the TMC cluster-containing pSBAC into wild-type Streptomyces sp. CK4412 as well as a recombinant S. coelicolor strain resulted in a chromosomal tandem repeat of the entire TMC cluster with 14-fold and 5.4-fold enhanced TMC productivities, respectively. The 80-kb TMC biosynthetic gene cluster was isolated in a single integration vector, pSBAC. Introduction of TMC biosynthetic gene cluster in TMC non-producing strains has resulted in similar amount of TMC production yield. Moreover, over-expression of TMC biosynthetic gene cluster in original producing strain and recombinant S. coelicolor dramatically increased TMC production. Thus, this strategy can be employed to develop a custom overexpression scheme of entire metabolite pathway clusters present in actinomycetes.


Structural basis of T cell recognition of peptides bound to MHC molecules.
Helper T lymphocytes play a critical role in immune system activation following recognition of MHC class II-bound peptide ligands (pMHCII). These CD4 T cells stimulate B cell antibody production and cytolytic T cell generation. Until recently, the structural basis of coordinate T cell receptor (TCR) and CD4 co-receptor interaction with a given pMHCII was unknown. Here we review current structural data on specific pMHCII recognition by T cells and compare TCR and co-receptor docking to pMHCI versus pMHCII ligands. The implications of these findings for thymic selection, helper versus cytolytic T cell recognition and alloreactivity are discussed.


Prostamides (prostaglandin-ethanolamides) and their pharmacology.
The prostamides are part of a large and continually expanding series of pharmacologically unique neutral lipids. They are COX-2 derived oxidation products of the endocannabinoid/endovanniloid anandamide. Prostamide pharmacology is unique and, as in the case of the endocannabinoids anandamide and 2-arachidonylglycerol, bears little resemblance to that of the corresponding free acids. By virtue of its close relationship to the anti-glaucoma drug bimatoprost, prostamide F(2alpha) has received the greatest research attention. Prostamide F(2alpha) and bimatoprost effects appear independent of prostanoid FP receptor activation, according to a litany of agonist studies. Studies involving freshly isolated and separate feline iridial smooth muscle cells revealed that bimatoprost and FP receptor agonists stimulated different cells, without exception. This suggests the existence of receptors that preferentially recognize prostamide F(2alpha). The recent discovery of prostamide antagonists has provided further support for prostamide receptors as discrete entities. The prototypical prostamide antagonists, AGN 204396 and 7, blocked the effects of prostamide F(2alpha) and bimatoprost but not those of PGF(2alpha) and FP receptor agonists in the feline iris. Second generation more potent prostamide antagonists, such as AGN 211334, should allow the role of prostamides in health and disease to be elucidated. From the therapeutics standpoint, the prostamide F(2alpha) analogue bimatoprost is the most efficacious ocular hypotensive agent currently available for the treatment of glaucoma.


Isolation of beta-lactamase from a penicillin-susceptible strain of Staphylococcus aureus.
It is generally accepted that strains of Staphylococcus aureus which are susceptible to penicillin G do not produce beta-lactamase. However, we have found that such a strain susceptible to 0.06 mug of penicillin per ml and 0.56 mug of methicillin per ml produces beta-lactamase(s) which hydrolyzes penicillin G, methicillin, 6-aminopenicillanic acid, and probably cephaloridine. The enzyme which is found only during very early log phase of the growth cycle is not inducible either by penicillin or methicillin and is cell bound and liberated only by disruption of the cell. The rate of enzymatic hydrolysis of methicillin was 60% that of benzylpenicillin. This finding suggests that the elaboration per se of beta-lactamase does not necessarily afford resistance to penicillin in this gram-positive-producing cell.


Chronic toxicity of oil sands tailings pond sediments to early life stages of fathead minnow (Pimephales promelas).
In this study fathead minnow (Pimephales promelas) embryo-larval stages were exposed to two oil sands tailings pond sediments which had previously been shown to decrease the survival of embryo-larval larval stages of walleye (Sander vitreus) and northern pike (Esox lucius). Fathead minnow are standard test species and we wanted to compare their sensitivity to the other two species. Fathead minnow larvae were exposed for 20 days (5 days in the egg stage and 15 days in the larval stage) with daily renewal of sediments and waters. Sediments contained polycyclic aromatic hydrocarbons (PAHs) and alkylated PAHs (APAHs). Results from an earlier study showed that Sediment 1 contained 173 μg/g total PAHs + APAHs (97 % alkylated), and sediment 2 contained 401 μg/g total PAHs + APAHs (95 % alkylated). Fathead minnow larvae exposed to oil sands tailings pond sediments had decreased survival, decreased weight, and increased deformities. Fathead minnow survival was unaffected at the embryo stage and at hatch. Most deaths occurred at the larval stages 1-8 days after hatching, showing the importance of exposing the fish for at least a week after hatch. Toxicity was seen at 0.2 g/L of sediment, which was equivalent to the addition of 35 and 80 μg total PAHs + APAHs to 1 L of overlying water for sediment 1 and 2, respectively. When compared to embryo-larval northern pike and walleye results from previous studies, all three species of fish responded more strongly to sediment 2 compared to sediment 1. For effects on lethality, fathead minnow were equally sensitive to pike, but walleye were 5-28 times more sensitive to the lethal effects of the sediments compared to both fathead minnow and pike. The study (and comparisons to our previous studies) shows the difference in sensitivity between a model laboratory species (fathead minnow) and some species of wild fish that are highly relevant to the oil sands area of Alberta.


Recurrent general type-2 fuzzy neural networks for nonlinear dynamic systems identification.
This paper introduces a recurrent general type-2 Takagi-Sugeno-Kang fuzzy neural network (RGT2-TSKFNN) for the identification of nonlinear systems. In the proposed structure, the general type-2 fuzzy set (GT2FS) and a recurrent fuzzy neural network (RFNN) are combined to obviate the data uncertainties. The fuzzy firing strengths in the developed structure are returned to the network input as internal variables. In the proposed structure, GT2FS is utilized to characterize the antecedent parts while the consequent parts are performed using TSK type. The issues of constructing a RGT2-TSKFNN involve type reduction, structure learning as well as parameter learning. An efficient strategy is developed by utilizing alpha-cuts to decompose a GT2FS into several interval type-2 fuzzy sets (IT2FSs). In order to solve the computation time of the type-reduction issue, a direct defuzzification method is used instead of iterative nature of Karnik-Mendel (KM) algorithm. Type-2 fuzzy clustering and Lyapunov criteria are utilized for online structure learning as well as the antecedent and consequent parameters, respectively for reducing the number of rules and guaranteeing the stability of the proposed RGT2-TSKFNN. The reported comparative analysis of the simulation results is utilized to estimate the performance of the proposed RGT2-TSKFNN with respect to other popular type-2 FNNs (T2FNNs) methodologies.


Candidate microRNA biomarkers in human epithelial ovarian cancer: systematic review profiling studies and experimental validation.
Despite advances in detection and therapy, epithelial ovarian cancer (EOC) still represents the most lethal gynecologic malignancy in women worldwide. The high mortality of EOC is mainly due to late-stage diagnosis for more than 70% of patients. There is an urgent need to search for specific and sensitive biomarkers for early diagnosis of EOC. Recently, the cumulative data indicated an essential role for microRNA (miRNA), a class of small non-coding RNAs targeting multiple mRNAs and triggering translation repression and/or RNA degradation, in ovarian caner carcinogenesis and progression. Here, we reviewed the published miRNA expression profiling studies that compared the miRNA expression profiles between EOC tissues or cell lines and normal ovarian tissues or benign ovarian tumor or human primary cultured ovarian surface epithelial cells. A miRNA ranking system that takes the number of comparisons in agreement and direction of differential expression into the consideration was devised and used. Finally, five promising differentially miRNAs (miR-200a, miR-100, miR-141, miR-200b, and miR-200c) were reported with the consistent direction in four or more studies. MiR-200a, miR-200b, miR-200c, and miR-141, all of them belong to miR-200 family, were reported with consistently up-regulated in at least 4 studies, whereas miR-100 was reported with down-regulated in 4 studies. Furthermore, we validated these miRNAs in a clinical setting using qRT-PCR and their dysregulations in EOC tissues confirmed the findings. Conclusively, the five most consistently expressed miRNAs might provide some clues of the potential biomarkers in EOC. Further mechanistic and precise validation studies are needed for their clinical significances and roles in the progression of EOC.


Exploring the utility of fibreoptic endoscopic evaluation of swallowing in young children- A comparison with videofluoroscopy.
In adults, fibreoptic endoscopic evaluation of swallowing (FEES) has established its place in the assessment of dysphagia and aspiration vis-à-vis the current gold standard, videofluoroscopic swallow study (VFSS), almost at parity. However, in children with quite a different set of factors in play, its role is not certain. The primary objective was to measure the accuracy of FEES in young children with dysphagia, compared to VFSS. The secondary objective was to correlate other endoscopic findings with aspiration in videofluoroscopy. Prospective, observational. Sixty-five children, aged 0.4-36 months with suspected oropharyngeal dysphagia and aspiration underwent FEES and VFSS. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy and diagnostic agreement of FEES were calculated using VFSS as the gold standard. To test the statistical significance of the difference in two measurements, Mc Nemar's Chi-square test was used and to test the agreement between FEES and VFSS, Kappa value was calculated. To test the statistical significance of the association of endoscopic findings with VFSS findings, Chi-square test was used. FEES performed in young children was found to be less sensitive (50%) but more specific of aspiration (82%) with an accuracy of 77% in comparison with VFSS. The reverse was true of penetration (81%, 44% and 59% respectively). The agreement between FEES and VFSS in young children, on all parameters were low (k = 0.061-0.302). Endoscopic findings such as glottic secretions (P = 0.02), weak or diminished laryngeal adductor reflex (LAR) (P = 0.001) and penetration (P = 0.01) were significantly associated with aspiration in VFSS. Excessive secretions in the hypopharynx had a stronger correlation with oesophageal dysmotility (P = 0.02) than pharyngeal dysphagia (P = 0.05). FEES in young children appears to have a low agreement with VFSS unlike in adults. Aspiration observed in FEES is likely to be significant since specificity is high. FEES negative for aspiration may be interpreted taking into account, the aspiration risk of the subject and/or other endoscopic risk factors (penetration, weak/absent LAR & glottic secretions), if VFSS is not a viable alternative.


Spondylocostal dysostosis and urinary tract anomaly: definition and review of an entity.
A two-year-old girl with spondylocostal dysostosis and urinary tract anomalies is described. Genetic counselling to the healthy non-consanguineous parents is based on the hypothesis of autosomal recessive inheritance. At birth this type of spondylocostal dysostosis can be differentiated radiographically from related conditions by the severe and generalized anomaly of the entire vertebral column, and by the typical configuration of the posteriorly-fused ribs. Only the cardinal clinical features of a short trunk and a short, immobile neck are consistently present in all patients. In one group of patients the severe thoracic malformation and lordosis contribute to cardiopulmonary problems with a fatal outcome in early infancy. The roentgenographic changes are less marked in other patients, whose subsequent clinical course is usually without major problems but remains at present insufficiently known.


The demonstration of cells bearing Fc receptors in the metrial gland of the pregnant rat uterus.
Cells obtained by collagenase treatment of metrial gland tissue from rats of day 12, 13, 14 and 15 of pregnancy were examined for the presence of surface membrane receptors for immunoglobulin (Fc receptors). Using an EA rosetting technique in which sheep red blood cells (SRBC) were sensitized with a rabbit anti-SRBC immunoglobulin preparation, Fc receptors were found on a proportion of the cells. The majority of the granulated metrial gland cells were not included in the rosetting cell population, suggesting that they do not possess the type of Fc receptor detected by this method. A comparison was made between results obtained when cells were counted in suspension and those obtained from cell counts on sections of fixed material. Both methods were found to yield similar results.


Antibody deposition in the pleura: a finding in drug-induced lupus.
Pleural tissues from a group of 36 consecutive patients comprised of 15 malignancies, 3 tuberculous, 2 rheumatoid arthritis, 3 procainamide-induced systemic lupus erythematosus (SLE) syndromes, 1 infectious mononucleosis, and 12 nonspecific pleural effusions undergoing needle biopsy were studied by immunofluorescent techniques for antibody deposition. Specific nuclear fluorescence was detected only in procainamide-induced SLE and was characterized by in vivo staining with either IgG, IgM, and in one case, also C3. C1q could not be detected. Two other patients who had antinuclear antibodies (ANA) in their peripheral blood did not have detectable in vivo antinuclear staining in their pleural tissue. The presence of in vivo fixation of ANA in the pleura may be of etiologic and diagnostic significance in procainamide-induced SLE syndrome.


Sonication, osmosonication and vacuum-assisted osmosonication pretreatment of Ghanaian garlic slices: Effect on physicochemical properties and quality characteristics.
This work aimed to assess the impact of sonication (US), osmosonication (US + OD) and vacuum-assisted osmosonication (V + US + OD) pretreatments on the quality of Ghanaian garlic prior to relative humidity convective drying. Hence, slices of fresh garlic subjected to US, US + OD and V + US + OD pretreatments were dried and the following assessed: antioxidant activities, total phenolic content (TPC), total flavonoid content (TFC), polyphenol oxidase (PPO) enzyme inactivation, rehydration ratio (RR), drying kinetics, energy consumption, chromatographic fingerprinting, allicin content and Fourier-transform infrared (FT-IR) spectroscopy. V + US + OD pretreatment gave the best results for antioxidant activities, TPC, TFC, RR and PPO enzyme inactivation. It also recorded the shortest drying time and was more energy efficient. Finally V + US + OD pretreatment maintained the chemical integrity of the finished product and recorded the highest content of allicin. A general trend was however observed for all quality parameters assessed for the various pretreatment methods as: V + US + OD > US + OD > US.


Computed vs. film-based radiographs' contour artifacts influence diagnosis of secondary caries.
To test local grey-scale changes on dental bitewing radiographs near filling margins for image acquisition. Forty approximal preparations in caries-free amalgam filled teeth and bitewing radiographs were acquired under standardized conditions applying four techniques. Film-based analog radiographs were digitized using flat-bed scanner (FDR). Phosphor-plate computed radiographs (PCR) were directly acquired by scanning VistaScan imaging plates. Image quality was tested using Preset Filter (PF) or manually applied IntraOral Fine Filter (IF) to enhance digital images. Local changes from digital imaging processing were assessed by comparing the margin-near (MN) and margin-far (MF) zone by a multivariate repeated measurements analysis. All images were acquired with 8-bit depth (256 shades). Dentine was displayed in 79 shades for FDR and 54 shades for PCR. PF or IF locally modify bitewing radiographs by darkening marginal dentine by 8 or 29 shades, respectively. The sharpest display of the margin (shades per pixel) from dentine to filling was found for IF (26.2), followed by FDR (23.2), PF (15.3) and PCR (8.3). Computed radiography with phosphor plates generate more homogeneous images compared to flatbed-digitized film-based radiographs. The filling margin was sharpest represented with the IF filter at the detriment of an artificial darkening of the dentine near the margin of the filling. Contour artifacts by filters have the potential to confound diagnosis of secondary caries. Algorithms and filters for sensor data processing, causing local changes above 2% of the dynamic range by non-continuous mathematical functions, should only be applied with caution, manually when diagnosing and reversibly.


Helicobacter and gastric malignancies.
Over the past year Helicobacter pylori has been confirmed as the most important risk factor for non-cardia gastric adenocarcinomas and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Eradication therapy has been proven to be beneficial when given prior to the development of intestinal metaplasia, but is less efficacious when administered later. However, the best data from clinical trials indicate that H. pylori eradication alone will have only a moderate effect on gastric cancer incidence worldwide. The mechanisms responsible for H. pylori-associated gastric carcinogenesis continue to be dissected. Accumulating evidence suggests that some H. pylori may be able to invade through the gastric epithelial barrier, though pro-carcinogenic effects may also be related to the complex and evolving pathways of altering signal transduction pathways within gastric epithelial cells that are stimulated by adherence and translocation of H. pylori products through its type IV secretory system. Determinants of the host response to H. pylori infection continue to focus on polymorphisms in genes related to the innate and acquired immune responses, including NOD2, COX-2, and TLR-4. H. pylori eradication is indicated for low-grade gastric B-cell MALT lymphoma and may even provide "cure" in some apparently H. pylori-negative cases. How and why does H. pylori promote lymphomagenesis? Some evidence from human and murine models points to specific chromosomal translocations and host genetic polymorphisms as relating to the outcome of infection. Finally, Helicobacter hepaticus infection has been linked to both intestinal and breast tumorigenesis in susceptible strains of female mice - a provocative and novel finding warranting further investigation.


Spatial distribution data of cultural sites from the Paleolithic to Bronze Age in Xinjiang, China.
The published map recording cultural sites in Xinjiang shows that there is a lack of data collection on the distribution of sites in the area, and no relevant data sets have been released. Existing written materials indicate that there are more cultural sites in this area. For this reason, we have collected and sorted out information. Our cultural site database provides the geographic location and corresponding geographic environment of each site in Xinjiang from the Paleolithic to the Bronze Age. The data record the human development and settlement process, settlement environment landscape characteristics, scale, type, quantity, and spatial distribution in Xinjiang in prehistoric China. These data not only are the basis for further understanding the spatial distribution of prehistoric humans in Xinjiang, but also provide references for understanding prehistoric human behavior and prehistoric man-land relationship, and the exchange of eastern and western civilizations. It is of great significance to modern social planning, site protection, and resource utilization.


Gestational age-dependent reference values for pH in umbilical cord arterial blood at term.
Despite a change of fetal physiologic and biochemical functions with gestational age, stationary umbilical cord acid-base reference values are used as measures of obstetric care quality. The aim of this study was to assess the risk of low Apgar score relative to low pH when using stationary versus gestational age-adjusted reference values. Umbilical artery pH was determined in 24,390 term singleton vaginal deliveries with a 5-minute Apgar score of 9 or greater. Low pH was defined as less than 7.10 as a stationary cutoff value, whereas pH less than (mean - 2 standard deviations [SDs]) was used when gestational age was considered. The 5-minute Apgar score less than 7 at low pH was studied in 44,978 term deliveries. A significant negative correlation was found between gestational age and umbilical artery pH. The odds ratio (OR) for pH less than 7.10 was continuously increasing, from 0.6 at 37 weeks to 1.5 at 42 weeks. In contrast, the OR for pH less than (mean - 2 SDs) was steady until 42 weeks, whereafter it increased (OR 1.24; 95% confidence interval 1.05, 1.47). A linear decrease of the association between Apgar score less than 7 and pH less than 7.10 with increasing pregnancy duration was found (P =.097), but for pH less than (mean - 2 SDs) there was no such association. We found a physiologic linear decline of umbilical artery pH with gestational age at term. Gestational age-adjusted umbilical cord artery pH reference values result in fewer diagnoses of cord acidemia than a stationary cutoff of pH less than 7.10.


Lung protective ventilatory strategies in very low birth weight infants.
Respiratory distress syndrome (RDS) is the most common respiratory diagnosis in preterm infants. Surfactant therapy and mechanical ventilation using conventional or high-frequency ventilation have been the standard of care in the management of RDS. Bronchopulmonary dysplasia (BPD) continues to remain as a major morbidity in very low birth weight infants despite these treatments. There is no significant difference in pulmonary outcome when an optimal lung volume strategy is used with conventional or high-frequency ventilation. Lung injury is directly related to the duration of invasive ventilation via the endotracheal tube. Studies using noninvasive ventilation, such as nasal continuous positive airway pressure and noninvasive positive pressure ventilation, have shown to decrease postextubation failures as well as a trend toward reduced risk of BPD. Lung protective ventilatory strategy may involve noninvasive ventilation as a primary therapy or following surfactant administration in very preterm infants with RDS. Initial steps in the management of preterm infants may also include sustained inflation to establish functional residual capacity, followed by noninvasive ventilation to minimize lung injury and subsequent development of BPD.


Ultrafast Ultrasound Localization Microscopy by Conditional Generative Adversarial Network.
Ultrasound localization microscopy (ULM) overcomes the acoustic diffraction limit and enables the visualization of microvasculature at subwavelength resolution. However, challenges remain in ultrafast ULM implementation, where short data acquisition time, efficient data processing speed, and high imaging resolution need to be considered simultaneously. Recently, deep learning (DL)-based methods have exhibited potential in speeding up ULM imaging. Nevertheless, a certain number of ultrasound (US) data ( L frames) are still required to accumulate enough localized microbubble (MB) events, leading to an acquisition time within a time span of tens of seconds. To further speed up ULM imaging, in this article, we present a new DL-based method, termed as ULM-GAN. By using a modified conditional generative adversarial network (cGAN) framework, ULM-GAN is able to reconstruct a superresolution image directly from a temporal mean low-resolution (LR) image generated by averaging l -frame raw US images with l being significantly smaller than L . To evaluate the performance of ULM-GAN, a series of numerical simulations and phantom experiments are both implemented. The results of the numerical simulations demonstrate that when performing ULM imaging, ULM-GAN allows ∼ 40 -fold reduction in data acquisition time and ∼ 61 -fold reduction in computational time compared with the conventional Gaussian fitting method, without compromising spatial resolution according to the resolution scaled error (RSE). For the phantom experiments, ULM-GAN offers an implementation of ULM with ultrafast data acquisition time ( ∼ 0.33 s) and ultrafast data processing speed ( ∼ 0.60 s) that makes it promising to observe rapid biological activities in vivo.


Electrokinetic characteristics of HSA dimer and its monolayers at mica.
Human serum albumin (HSA) dimer was synthesized in a reaction of the monomer with 1,6-bis(maleimido)hexane (BMH) cross-linker. Thorough physicochemical characteristics of the dimer were performed. They comprised the diffusion coefficient, hydrodynamic diameter, electrophoretic mobility as a function of pH, isoelectric point and electrokinetic charge. The adsorption of the dimer molecules at mica was studied using the atomic force microscopy (AFM) and in situ streaming potential measurements. The kinetics of adsorption was determined by a direct AFM imaging of single molecules over various substrate areas and interpreted in terms of the random sequential adsorption model. These results were consistent with streaming potential measurements carried out for the parallel-plate channel flow. It was also shown by these measurements that the desorption of the monomer under flow conditions was negligible. In this way, the amount of irreversibly bound dimer was quantitatively evaluated to be 0.5 mgm(-2) for ionic strength of 0.01 and pH 3.5 that is similar that to previous result obtained for the albumin monomer. This indicates that the dimer adsorption occurs mostly in the side-on orientation. Finally, the electrokinetic characteristics of the dimer monolayers on mica were performed by the streaming potential method. It was observed that for lower pHs the zeta potential of monolayers is much lower than the bulk zeta potential of the dimer molecules. This was attributed to a heterogeneous charge distribution. It was concluded that the well-characterized HSA dimer monolayers can be used for quantitatively determining ligand and drug binding that has an essential practical significance.


Theoretical and experimental aspects of erythrocyte filterability testing; flow acceleration and systemic resistance.
Blood cell filterability is an established method in blood rheology. The dynamics at flow onset and its relevance to the data interpretation is, however, not fully known. This paper aims to investigate what controls the length and slope of flow acceleration as the medium accelerates to reach the steady state, and how this phenomenon may interfere with the data output. The acceleration time was not constant. With buffer the steady-state flow showed a logarithmic correlation (p<0.05) versus acceleration time and a linear correlation (p<0.001) versus acceleration slope. With 5% erythrocyte resuspension the steady-state flow instead demonstrated a linear relationship versus acceleration time (p<0.001) and no correlation versus acceleration slope. A cut-off timing of 0.6s is suggested to avoid artifacts associated with flow acceleration. The possible influence on data interpretation from the flow channel systemic resistance was also addressed, and found to significantly underestimate measurable changes in erythrocyte properties from unprocessed flow curves. This was despite the traditional correction for blank filtration flow. Both acceleration and effects from systemic resistance do probably have minor influence on the historic data interpretation but could perhaps be considered in the methodology to sharpen the data output.


T-bet over-expression regulates aryl hydrocarbon receptor-mediated T helper type 17 differentiation through an interferon (IFN)γ-independent pathway.
Various transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen-induced arthritis was suppressed in T-bet transgenic (T-bet Tg) mice, and T-bet seemed to suppress Th17 differentiation through an interferon (IFN)-γ-independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T-bet over-expression, and we found the new relationship between T-bet and aryl hydrocarbon receptor (AHR). Both T-bet Tg mice and IFN-γ-/- -over-expressing T-bet (T-bet Tg/IFN-γ-/- ) mice showed inhibition of retinoic acid-related orphan receptor (ROR)γt expression and IL-17 production by CD4+ T cells cultured under conditions that promote Th-17 differentiation, and decreased IL-6 receptor (IL-6R) expression and signal transducer and activator of transcription-3 (STAT-3) phosphorylation in CD4+ T cells. The mRNA expression of ahr and rorc were suppressed in CD4+ T cells cultured under Th-17 conditions from T-bet Tg mice and T-bet Tg/IFN-γ-/- mice. CD4+ T cells of wild-type (WT) and IFN-γ-/- mice transduced with T-bet-expressing retrovirus also showed inhibition of IL-17 production, whereas T-bet transduction had no effect on IL-6R expression and STAT-3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4+ T cells with T-bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)-17 production from CD4+ T cells by the addition of AHR ligand with Th17 conditions was cancelled by T-bet over-expression. Our findings suggest that T-bet over-expression-induced suppression of Th17 differentiation is mediated through IFN-γ-independent AHR suppression.


Use and acceptance of the "Paper Pill" among an urban clinic population.
A randomized, crossover study comparing the acceptability of two presentations of the same oral contraceptive, a paper formulation and the conventional tablet, was carried out among two-hundred-and-seventy women attending two urban family planning clinics in Mexico City. During the first three cycles of use, the percentage of women discontinuing the medication for side effects was almost identical in the two groups. Although the paper formulation failed to demonstrate any major advantage in terms of continuation or acceptability, it was preferred by a majority of the women who began oral contraception with its use.


Population changes in a biofilm reactor for phosphorus removal as evidenced by the use of FISH.
Induction of denitrification was investigated for a lab-scale phosphate removing biofilm reactor where oxygen was replaced with nitrate as the electron acceptor. Acetate was used as the carbon source. The original biofilm (acclimatised with oxygen) was taken from a well-established large-scale reactor. During the first run, a decrease in the denitrifying bio-P activity was observed after 1 month following a change in the anaerobic phase length. This was initially interpreted as a shift in the microbial population caused by the changed operation. In the second run, biomass samples were regularly collected and analysed by fluorescent in situ hybridisation (FISH) and confocal laser scanning microscopy (CLSM). Concurrently, samples were taken from the original reactor with oxygen as electron acceptor in order to investigate natural microbial fluctuations. A similar decrease in the activity as in the first run was seen after one month, although the phase lengths had not been varied. Hence, the decrease after 1 month in the first and second run should be seen as a start-up phenomenon. FISH could detect a noticeable shift in the microbial population mainly within the first 2 weeks of operation. Almost all bacteria belonging to the alpha subclass disappeared and characteristic clusters of the beta and gamma subclasses were lost. Small clusters of gram-positive bacteria with a high DNA G + C content (GPBHGC) were gradually replaced by filamentous GPBHGC. Most of the bacteria in the denitrifying, phosphate removing biofilm belonged to the beta subclass of Proteobacteria. The applied set of gene probes had been selected based on existing literature on biological phosphate removing organisms and included a recently published probe for a Rhodocyclus-like clone. However, none of the specific probes hybridised to the dominant bacterial groups in the reactors investigated. No noticeable changes were detected in the aerobic bench-scale reactor during this period, indicating that the observed changes in the lab-scale reactor were caused by the changed environment.


Effect of ionizing radiation on transcription of colorectal cancer MDR1 gene of HCT-8 cells.
To discuss effect of ionizing radiation on transcription of colorectal cancer multidrug resistance (MDR) 1 gene of HCT-8 cells. Total RNA was extracted by guanidine thiocyanate one-step method. Northern blot was applied to detect transcription level of MDR1 gene. The expression of P-gp protein was detected by flow cytometry. The expression of MDR1 of normal colorectal cancer HCT-8 cells was low. It was increased by 8.35 times under stimulus with 2 Gy. When treated with low doses in advance, high expressed MDR was decreased significantly under 0.05, 0.1 Gy, which was 69.00%, 62.89% in 2 Gy group and 5.77 times, 5.25 times in sham irradiation group. No obvious difference was detected between (0.2+2) Gy group and 2 Gy group. Compared with sham irradiation group, the percentage of P-gp positive cells after radiation of a high 2 Gy dose was increased significantly (P<0.01). When treated with high radiation dose following low radiation dose (0.05 Gy, 0.1 Gy) in advance, the percentage of P-gp positive cells were also increased significantly. The percentage of P-gp positive cells were increased obviously in 0.2 Gy and 2 Gy groups. Compared with simple high radiation 2 Gy group, the percentage of P-gp positive cells was decreased significantly (P<0.05). Low radiation dose can reverse multidrug resistance of colorectal cancer cells caused by high radiation dose.


Aggressive surgery for pancreatic duct cell cancer: feasibility, validity, limitations.
Pancreatic duct cell cancer is characterized by a low resectability rate and a low long-term survival rate. Between September 1974 and December 1992 in our institution, 149 (59%) of the 253 patients with this cancer underwent resection. The operative procedures were pancreatoduodenectomy in 105 patients, total pancreatectomy in 36, and distal pancreatectomy in 8. The tumor was extirpated with extensive dissection of the lymph nodes and excision of the nerve plexus in the retroperitoneum. Of the 149 patients, 79 (53%) underwent combined resection of the pancreas and the portal vein; 16 of the 79 patients also underwent resection of the adjacent arteries. Three patients died within 30 days after surgery, and 17 other patients succumbed within 2 to 7 months. The mortality among patients undergoing pancreatectomy and resection of the portal vein (9.5%) was similar to that of patients with pancreatectomy alone (10%). Curative resection was necessary for long-term survival. The 5-year survival rate in 61 patients with the curative resection was 15%. Ten patients lived more than 5 years. Even patients with lymph node metastases and cancer invasion of the portal vein had a prolonged survival. Intraoperative irradiation was carried out in 35 patients to improve the survival rate, but without success. Infusion chemotherapy with 5-fluorouracil via the portal vein was tried in 25 patients, resulting in a decrease in liver metastasis. We have made some progress in the first step toward improving treatment, although we are far from the goal and it is necessary to conduct additional trials.


Health behaviors in adolescent survivors of cancer: An integrative review.
Adolescent survivors of cancer face an increased risk of chronic health conditions that can be improved by healthy behaviors. The purpose of this review is to synthesize the extent/prevalence of health behaviors (physical activity [PA], diet, human papillomavirus [HPV] vaccination, alcohol use, smoking, marijuana use, and unprotected sex) compared to age-matched peers and factors associated with those behaviors. Four databases (PubMed, EMBASE, PsycINFO, and CINAHL) were searched for peer-reviewed primary studies published since 2000 including adolescents aged 11-20 years-old, who had completed cancer treatments. Studies reporting at least one behavior were included. Of 1979 articles reviewed, 27 studies reporting any of the following health behaviors were included: PA, diet, HPV vaccination, alcohol use, smoking, marijuana use, or unprotected sex. Adolescent survivors of cancer engaged less in health risk behaviors (alcohol use, smoking, marijuana use, and unprotected sex) or health-promoting behaviors (PA, healthy diet, and HPV vaccination) compared to age-matched peers. Their health behaviors were associated with psychosocial factors including emotional discomfort (e.g., feeling depressed or nervous) and influence of others (family, friends, and healthcare providers). Although health risk behaviors in adolescent survivors of cancer are not as prevalent as in their peers, the survivors' low engagement in health-promoting behaviors including PA, diet, and HPV vaccination is concerning. More research is needed to develop and evaluate interventions to improve health-promoting behaviors in adolescent survivors of cancer by strengthening or facilitating psychosocial resources.


Lower partial pubicectomy for postoperative complicated posterior urethral stricture.
To report the experience of partial inferior pubicectomy in the treatment of complex posterior urethral stricture after trauma. A total of 46 patients with post-traumatic posterior urethral stricture admitted to the Department of Urology of our Hospital from January 2013 to September 2021 were selected as the research objects and underwent urethroplasty (including nine patients who had failed previous perineal repair surgery and adopted partial inferior pubicectomy approach). Retrograde urethrograph (RUG) and urine flow measurement were performed at 1, 3, 12 and 18 months after operation, and follow-up was performed when necessary. The clinical data during treatment were statistically analyzed. All 46 patients underwent urethroplasty successfully, of which nine were treated with partial pubicectomy, accounting for 19.57% of the total. The causes of the disease were motor vehicle accident in 4 cases, falling collision injury in 2 cases, and rolling injury of military exercise tank in 3 cases. Among the 9 patients, 2 were children (22.22%), aged 8 and 12 years, and 7 were adults (77.78%), aged 19-44 (28.42 ± 1.56) years. Among the 9 patients, 6 had erectile dysfunction, accounting for 66.67%. The length of posterior urinary tract stenosis was (5.12 ± 0.57) cm. The operation time was (290.34 ± 12.35) min from anesthesia induction to skin closure. Five patients received 2 U blood transfusion during operation and three patients received 3 U blood transfusion after operation. The average hospital stay was 12-16 (14.24 ± 1.25) days, and the follow-up was 12-24 (18.24 ± 1.35) months. After surgery, one patient developed HIP abscess, which was successfully treated conservatively. One patient had dysuria 1 month after operation and was successfully treated by transurethral dilatation. One case had postoperative infection and recovered after intravenous administration of potent antibiotics. Cystourethrography was performed 3 months after operation, and there was no difference between patients with wide, long or short anastomotic stretch defects. All patients met the criteria for surgical success. Partial inferior pubicectomy is a good surgical procedure for the repair of complicated posterior urethral stricture after operation. It is safe and reliable, can better display the prostatic apex and surgical field, shorten the length of reconstructed urethra, and has good postoperative effect. It has no direct or long-term effect on the stability of pelvis or bladder. However, further studies in a larger cohort of patients with complex posterior urethral strictures after repair are needed to demonstrate the specific indications for partial pubicectomy.


A modified random walk door-to-door recruitment strategy for collecting social and biological data relating to mental health, substance use, addiction, and violence problems in a Canadian community.
To describe a modified "random walk" door-to-door recruitment strategy used to obtain a random community sample for participation in a study relating to mental health, substance use, addiction, and violence (MSAV) problems and involving the collection of both self-report and biological (hair and saliva) data. This paper describes study protocols, response rates for the study and for the provision of biological data, and possible further applications for this data collection method. A two-stage cluster sample was derived from the 2006 Canadian census sampling frame for a small Ontario community, based on the random selection of city blocks as the primary sampling units and households as the secondary sampling units. A small city in Ontario, Canada. A general population sample of 92 participants selected randomly from households using Kish tables. A computerized questionnaire was administered to obtain self-report data on MSAV problems. Saliva was collected to study genetic vulnerabilities to MSAV problems, and hair was collected to examine stress levels (via the hormone cortisol) as they relate to MSAV problems. The study showed a response rate of 50% and a high rate of provision of biological samples (over 95%). Modified random walk methodologies involving face-to-face recruitment may represent a useful approach for obtaining general population samples for studies of MSAV problems, particularly those involving the collection of biological samples. Further studies are needed to assess whether this approach leads to better response rates and improved estimates compared to other survey methods used in research on substance use.


The assessment and management of deep neck space infections in adults: A systematic review and qualitative evidence synthesis.
To summarise current practices in the diagnosis and management of deep neck space infections (DNSIs). To inform future studies in developing a framework in the management of DNSIs. This review was registered on PROSPERO (CRD42021226449) and reported in line with PRISMA guidelines. All studies from 2000 that reported the investigation or management of DNSI were included. The search was limited to English language only. Databases searched included AMED, Embase, Medline and HMIC. Quantitative analysis was undertaken with descriptive statistics and frequency synthesis with two independent reviewers. A qualitative narrative synthesis was conducted using a thematic analysis approach. Secondary or tertiary care centres that undertook management of DNSIs. All adult patients with a DNSI. The role of imaging, radiologically guided aspiration and surgical drainage in DNSIs. Sixty studies were reviewed. Thirty-one studies reported on imaging modality, 51 studies reported treatment modality. Aside from a single randomised controlled trial, all other studies were observational (n = 25) or case series (n = 36). Computer tomography (CT) was used to diagnose DNSI in 78% of patients. The mean percentage of management with open surgical drainage was 81% and 29.4% for radiologically guided aspiration, respectively. Qualitative analysis identified seven major themes on DNSI. There are limited methodologically rigorous studies investigating DNSIs. CT imaging was the most used imaging modality. Surgical drainage was commonest treatment choice. Areas of further research on epidemiology, reporting guidelines and management are required.


3D-QSAR studies of azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives as anti-AChE and anti-AD agents by the CoMFA method.
In the present study, a series of novel azaoxoisoaporphine derivatives were reported and their inhibitory activities toward acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Aβ aggregation were evaluated. The new compounds remained high inhibitory potency on Aβ aggregation, with inhibitory activity from 29.42% to 89.63% at a concentration of 10μM, but had no action on AChE or BuChE, which was very different from our previously reported oxoaporphine and oxoisoaporphine derivatives. By 3D-QSAR studies, we constructed a reliable CoMFA model (q(2)=0.856 and r(2)=0.986) based on the inhibitory activities toward AChE and discovered key information on structure and anti-AChE activities among the azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives. The model was further confirmed by the test-set validation (q(2)=0.873, r(2)=0.937, and slope k=0.902) and Y-randomization examination. The statistically significant and physically meaningful 3D-QSAR/CoMFA model provided better insight into understanding the inhibitory behaviors of those chemicals, which may provide useful information for the rational molecular design of azaoxoisoaporphine derivatives anti-AChE and anti-AD agents.


Use of 13C/12C to trace dissolved and particulate organic matter utilization by populations of an aquatic invertebrate.
The 13C/12C of limnephilid caddisfly larvae (Clistoronia magnifica) grown in the presence of red alder leaf particulate organic matter (POM) and alder leaf leachate was found to be identical to the 13C/12C of larvae grown on alder POM, but with isotopically contrasting grass leachate substituted for the above alder leachate. The isotopic similarity between these insects and the alder POM common in both treatments indicates that grass leachate was not a source of insect carbon. In contrast to these results, the 13C/12C of larvae grown on grass POM and leachate was markedly different from the 13C/12C of larvae raised on grass POM and alder leachate. The relative 13C depletion found in larvae from the latter treatment could be accounted for only if a significant amount of carbon derived from alder leachate had been incorporated into insect biomass. Significant differences in yield of insect biomass among the above treatments also were found.


Digital redesign of analog smith predictor for systems with input time delays.
This paper presents a new methodology for digitally redesigning an existing analog Smith predictor control system, such that the cascaded analog controller with input delay can be implemented with a digital controller. A traditional analog Smith predictor system is reformulated into an augmented system, which is then digitally redesigned using the predicted intersampling states. The paper extends the prediction-based digital redesign method from a delay free feedback system to an input time-delay cascaded system. A tuning parameter v is optimally determined online such that in any sampling period, the output response error between the original analogously controlled time-delay system and the digitally controlled sampled-data time-delay system is significantly reduced. The proposed method gives very good performance in dealing with systems with delays in excess of several integer sampling periods and shows good robustness to sampling period selection.


A protocol for visualization of murine in situ neurovascular interfaces.
Mapping cranial vasculature and adjacent neurovascular interfaces in their entirety will enhance our understanding of central nervous system function in any physiologic state. We present a workflow to visualize in situ murine vasculature and surrounding cranial structures using terminal polymer casting of vessels, iterative sample processing and image acquisition, and automated image registration and processing. While this method does not obtain dynamic imaging due to mouse sacrifice, these studies can be performed before sacrifice and processed with other acquired images. For complete details on the use and execution of this protocol, please refer to Rosenblum et al.1.


Death associated with asymptomatic carotid artery stenosis: long-term clinical evaluation. VA Cooperative Study 167 Group.
As part of a prospective clinical trial on the efficacy of carotid endarterectomy in patients with asymptomatic carotid artery stenosis, we studied the risk factors for death in 444 male patients. At entry to the trial, patients were judged to be healthy enough to be randomized to operative intervention and were judged to be free of any disease that would preclude a minimal 5-year life expectancy after randomization. Patients were treated with aspirin and optimal medical care and were monitored for an average of 4 years. Combined mortality rate was 37% (9% per year) for the medical group (38%) and surgical group (35%). Eight factors were identified that were significantly associated with increased mortality rates: coronary artery disease (p = 0.044), history of angina (p = 0.047), congestive heart failure (CHF) (p = 0.012), abnormal electrocardiography results at entry (p = 0.005), peripheral vascular disease (p = 0.019), claudication (p = 0.044), diabetes (p = 0.008), and history of hypertension (p = 0.044). The increase in risk indicated by the odds ratios (OR) were moderate (OR < 2.00) for each of the clinical risk factors except for CHF. Sixteen of 27 patients (59%) with a history of CHF at entry to the study died during follow-up (OR = 2.67). Arteriographic predictors of increased mortality rates included bilateral carotid artery stenosis and intracranial vascular disease (ICVD). With bilateral stenosis, 42% (80 of 190 patients) died compared with 33% (83 of 252 patients) with unilateral stenosis (p = 0.062). With ICVD, 43% (56 of 130 patients) died compared with 34% (107 of 314 patients) of those without ICVD (p = 0.073). Multivariate analysis demonstrated that three risk factors were significantly associated with an increased risk of death: diabetes, abnormal electrocardiography results, and claudication. Patients with two or three of these risk factors demonstrated annual mortality rates of 11.3% and 13%, respectively. This was significantly higher than patients with none of these risks (OR = 2.95 and OR = 4.06, respectively). Adult male patients with high-grade asymptomatic carotid artery stenosis demonstrate a mortality rate of 37% at a mean follow-up of 4 years. Although age was not a risk for increased mortality rates in this population, diabetes, abnormal electrocardiography results, and claudication were significant. Patients with two or three of these risk factors were at high risk of death and may require aggressive treatment of their concurrent medical diseases.


The impact of distal aortic perfusion and somatosensory evoked potential monitoring on prevention of paraplegia after aortic aneurysm operation.
Temporary distal aortic perfusion and somatosensory evoked potential monitoring were attempted prospectively in 198 patients to prevent neurologic complications from occurring after operation for descending thoracic and thoracoabdominal aortic aneurysm. These 198 patients were divided into two groups. Group 1 consisted of 99 (50%) patients in whom adequate (60 mm Hg) distal bypass was achieved and combined with somatosensory evoked potential monitoring. Group 2 consisted of 99 (50%) in whom this could not be achieved. Of the latter, four patients were excluded because of operative death in one and preexisting neurologic deficits in three. The rates of early and delayed neurologic complications were 8% and 12%, respectively, in the former and 7% and 8%, respectively, in the latter. Using the logistic regression method of statistical analysis, adjusting for the difference in patient mix, we found no statistical difference in the incidence of neurologic complications in the two groups. The incidence of false negative somatosensory evoked potential response was 13% and false positive response 67%. Localization of critical spinal arteries for reattachment was not possible. Thus, the method had no significant impact upon the prevention of neurologic deficits, which varied from mild or transient to severe and which either occurred during the operation or were delayed from 12 hours to 21 days.


Ligand binding to a humanized anti-cocaine mAb detected by non-reducing SDS-PAGE.
Monoclonal antibodies are very useful tools in experimental biology, as well as being valuable and effective therapeutic drugs. They can be targeted against proteins with varied functions, or against small molecules of interest to both researchers and clinicians, such as drugs of abuse, including cocaine. Since there is no currently FDA approved pharmacological treatment for cocaine abuse, our laboratory has developed an anti-cocaine mAb for the treatment of cocaine use disorders. This humanized anti-cocaine antibody, named h2E2, has been thoroughly characterized both functionally and structurally, in preparation for the start of clinical development. We previously showed that this mAb could be characterized by sequential thermal unfolding of antibody domains using non-reducing SDS-PAGE. We also demonstrated that ligand-induced protein stabilization can be used to quantitatively measure cocaine and cocaine metabolite binding to the h2E2 mAb, utilizing differential scanning fluorimetry. Here, we demonstrate the utility of non-reducing SDS-PAGE for the qualitative assessment of binding of cocaine and some of its metabolites, both to the intact mAb, as well as to fragments containing the antigen binding site (Fab and F(ab')2 fragments). These results clearly show a ligand concentration dependence of the stabilization of the cocaine binding domain in non-reducing SDS-PAGE, as well as visually differentiating the relative binding affinities of various cocaine metabolites. Thus, non-reducing SDS-PAGE is a simple and widely available technique that is useful as a measure of binding of cocaine and its metabolites to the h2E2 mAb, and it is likely that this technique will also be applicable to other small molecule-directed mAbs.


Long-term outcome of renal function and proteinuria in kidney transplant donors.
Ten to eighteen years after donor uninephrectomy (UN) there was no evidence for deterioration of renal function. The mean urinary albumin excretion was slightly increased. There was a positive correlation between the assessed protein intake at investigation and the glomerular filtration rate (GFR).


Age related change in the frequency of ara C-induced chromosome aberrations in human peripheral blood lymphocytes.
1-beta-D-Arabinofuranosylcytosine (ara C) has been known to inhibit repair replication in the G1 phase of cell cycle and to convert certain types of DNA damage into chromosome-type exchanges: e.g., dicentric or ring chromosomes. It is then considered to be a useful cytogenetic method to investigate the frequency of ara C-induced dicentric and ring chromosomes (dic and ring) for estimating cellular DNA damage or capacity to repair it. Peripheral blood lymphocytes from donors ranging from newborn to 91 years old were treated with 10 microM ara C in their G1 phase and the resulting disc and ring were observed to investigate whether age-related change in peripheral lymphocytes would be present in the amount of spontaneous DNA damage or in the capacity to repair it. Chromatid-type (Ct) aberrations and sister chromatid exchanges (SCEs) were also scored for additional cytogenetic indices of DNA damage in the lymphocytes. The results showed that the frequency of dic and ring had a negatively linear correlation with the logarithm of the age of the blood donors, but that the frequencies of Ct aberrations and SCEs were not influenced by the age. The present study suggests the presence of age-related change in the amount or in the capacity to repair certain types of DNA damage in the G1 phase of human peripheral lymphocytes. Other possible explanations for the present results are also discussed.


[Pathobiology of deficiencies of the nervous system: apropos of cobalt and copper metalloprotein deficiency].
The Author debate a new concept and classification of neurologic nutritional disorders, according with pathobiological data. Cobalt and copper nutritional syndroms are exposed.


Effect of selenium on blood pressure, urinary sodium excretion and plasma aldosterone in cadmium-treated male rats.
The present study was carried out to help elucidate the possible mechanisms underlying the effect of Cd and the interaction of Se with Cd on blood pressure. Male Wistar rats were divided into four groups: control, Cd-treated, Se-treated, Se-and Cd-treated. Cd and Se were administered at doses of 1.0 mg/kg body weight by subcutaneous injection of aqueous solutions of CdCl2 X 2 X 1/2 H2O and Na2SeO3, respectively. Injections were made either alone or in the Cd + Se treated group, simultaneously at 12-h intervals for 7 consecutive days. All animals were then maintained without further treatment for an additional period of 18 days. Treatment with Cd and Se separately lowered the blood pressure on days 3 and 8, but these levels increased and were significantly higher than that in control rats by day 26. Plasma aldosterone concentrations increased and urinary Na excretion decreased from day 1 to 3 in rats treated with Cd and Se separately. Thereafter, increased water retention precedes the onset of increased blood pressure. From these findings, we suggest that in rats treated with Cd and Se separately the increase in plasma aldosterone is a main factor for decreased urinary Na excretion and increased retention of water, and these factors may be associated with an increase in blood pressure. The treatment with Cd and Se simultaneously decreased urinary Na excretion and increased the plasma aldosterone concentration and water retention before the onset of increased blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical Outcome From Oxaliplatin Treatment in Stage II/III Colon Cancer According to Intrinsic Subtypes: Secondary Analysis of NSABP C-07/NRG Oncology Randomized Clinical Trial.
Oxaliplatin added to fluorouracil plus leucovorin therapy for patients with colon cancer has been shown to provide significant but modest absolute benefit for disease-free survival. However, acute and chronic neurotoxic effects from this regimen underscore the need for markers that predict oxaliplatin benefit. To test our hypothesis that molecular subtypes of colon cancer would be associated with differential prognosis and benefit from oxaliplatin added to fluorouracil plus leucovorin therapy. Participants in the NSABP C-07 trial were divided into discovery (n = 848) and validation (n = 881) cohorts based on the order of tissue block submission. A reestimated centroid using 72 genes was used to determine Colorectal Cancer Assigner subtypes and their association with oxaliplatin benefit in the discovery cohort. The validation cohort was examined with a locked-down algorithm for subtype classification and statistical analysis plan. Post hoc analysis included examination of the entire cohort with Colorectal Cancer Assigner, Colorectal Cancer Subtype (CCS), and Consensus Molecular Subtype (CMS) methods. Fluorouracil plus leucovorin with or without oxaliplatin. Percent recurrence-free survival. Among 1729 patients, 744 (43%) were female and mean (SD) age was 58 (11) years. Although C-07 participants with stage III disease with an enterocyte subtype showed a statistically significant benefit from oxaliplatin in the discovery cohort (hazard ratio, 0.22 [95% CI, 0.09-0.56]; P = .001 [N = 65]), no statistically significant benefit was observed in the validation cohort (hazard ratio, 0.53 [95% CI, 0.22-1.24]; P = .14 [N = 70]). The stemlike subtype was associated with poor prognosis and lack of benefit from oxaliplatin treatment (HR, 0.99 [95% CI, 0.73-1.34]; P = .96 [N = 367]). Examination of the different subtyping methods shows that all 3 methods robustly identified patients with poor prognosis (stemlike, CCS-3, and CMS-4) in both stage II and III. Patients with stemlike tumors may be appropriate for clinical trials testing experimental therapies because stemlike tumors were robustly identified and associated with a poor prognosis regardless of stage or chemotherapy regimen. The clinical utility of using subtyping for the identification of patients for treatment with oxaliplatin requires validation in independent clinical trial cohorts. clinicaltrials.gov Identifier: NCT00004931.


Modulation of steroid affinity for the androgen receptor by sucrose.
The effects of sucrose on androgen binding to its receptor were investigated. Sucrose decreased the rate of thermal inactivation of unoccupied and occupied androgen receptor (AR) and the rates of [3H]5 alpha-dihydrotestosterone [( 3H]DHT) dissociation from both activated and nonactivated AR complexes. Binding of [3H]DHT to AR in vivo, or in intact cells at 37 degrees C, caused reduction of [3H]DHT dissociation from cytosolic and nuclear complexes, as compared to in vitro labeled receptor complexes. Further, exposure of these complexes to sucrose at 0 degrees C caused an additional reduction of dissociation rates. Thus, the decrease of [3H]DHT dissociation induced by sucrose is independent of the reaction that reduces DHT dissociation from activated and transformed AR. Sucrose also reduced the ability of mersalyl acid to inactivate AR complexes. This effect of sucrose was markedly diminished in the presence of 2M urea. Sucrose did not significantly affect the association rate, sedimentation properties, or nuclear binding ability of AR complexes, but it did decrease the equilibrium dissociation constant. Other monosaccharides and disaccharides also stabilized AR. These data suggest that sucrose induces conformational changes in the steroid binding domain of androgen receptor, thereby reducing the rates of inactivation, steroid dissociation, and the accessibility of sulfhydryl groups to mersalyl.


Relationship between serum lipoproteins and hemostatic parameters in men with prostatic cancer.
Serum lipoprotein concentrations were related to hemostatic parameters in a group of 31 men before and during three different hormone treatment regimens for prostate cancer in an attempt to analyse to what extent the changes in these two systems correlate. In a correlation matrix the number of significant relationships at the 5% and 1% level corresponded to what could be expected by chance. The study thus failed to demonstrate any consistent relationship between any lipoprotein lipid concentration and the hemostatic parameters in men treated for prostate cancer. Most significant relationships were found for HDL-TG versus plasminogen, but the clinical significance of this observation is not clear.


Thin film nanoarchitectonics of layer-by-layer assembly with reduced graphene oxide on intraocular lens for photothermal therapy of posterior capsular opacification.
Due to development of surgical techniques and intraocular lens (IOL) implants, vision can often be restored in cataracts patients. However, posterior capsular opacification (PCO) has become the most common and challenging complication in cataracts surgery. While various approaches such as surface modification and drug prophylaxis have been investigated to prevent PCO development, there is no standard treatment that is sufficiently safe and effective to meet clinical demands. Near-infrared (NIR) light-triggered photothermal therapy is an attractive noninvasive treatment for PCO prophylaxis. We fabricated a new type of IOL with excellent biocompatibility, stability, and photothermal conversion property. Polyethyleneimine (PEI) and graphene oxide (GO) were layer-by-layer assembled on model polymethylmethacrylate and IOL substrates, and the thickness, surface roughness, and wettability of the substrates with different numbers of bilayers were evaluated. After the reduction of GO to reduced GO (rGO), a rGO/PEI multilayer thin film with good stability and photothermal conversion capability was obtained. The rGO/PEI multilayer coating was able to induce apoptosis in lens epithelium cells under 808-nm NIR laser irradiation in vitro. Finally, rGO@IOL was implanted into rabbit eyes, and the biocompatibility and ability to prevent PCO were evaluated for 5 weeks. The rGO@IOL implant exhibited excellent PCO prevention ability with the assistance of NIR irradiation and did not induce obvious pathological effects in surrounding healthy tissues. The rGO@IOL implant with good biocompatibility, good physicochemical stability, and excellent photothermal conversion property shows promise for clinical application in PCO prophylaxis.


The Effect of Pollution on the Spread of COVID-19 in Europe.
This study investigates empirically how air pollution in earlier periods as measured by three air pollutants, namely N O 2, P M 10, and P M 2.5 may have affected the spread and fatality of COVID-19 in 31 European countries. Using panel data with fixed effects to examine the relationship between previous exposure to air pollution and COVID-19 new cases and COVID-19 deaths, we find that previous air pollution levels have both acted as an important factor in explaining the COVID-19 spread and its high fatality rate. This result may explain the negative impact that these pollutants may have on health and in particular on the respiratory functions that are mainly attacked by the virus. The online version contains supplementary material available at doi:10.1007/s41885-021-00099-y.


Water regulation in Barmer goat of the Rajasthan desert.
The different body fluid compartments in normally watered and 4-day water-deprived goats of Rajasthan desert, India, were measured in autumn. The goats maintained plasma volume and extracellular fluid volume, but lost gut and cell water considerably under the experimental conditions; indicating that the maintenance of the fluidity of the blood has priority over the body's other fluid requirements in this desert-adapted species during water deprivation.


A brief review of the use and utility of growth hormone stimulation testing in the NCGS: do we need to do provocative GH testing?
True growth hormone deficiency (GHD) in childhood, while rare, has major clinical consequences. GHD is often associated with other pituitary hormone deficiencies, so these children may require multiple hormonal replacement and close clinical follow-up to optimize their outcome. Growth hormone stimulation testing (GHST), as currently conducted, is not a reliable diagnostic tool. Both changes in growth hormone assay methodologies and increases in the diagnostic threshold contribute to the incorrect labeling of a substantial proportion of normal children as having idiopathic GHD. Fortunately, newer imaging technologies and laboratory tests form a more rational basis to diagnose true GHD. The use of GHST among GH-naive subjects (<20 years of age) enrolled in the National Cooperative Growth Study has declined over the past two decades, from a high of 89% between 1987 and 1989 to only 52% in 2002. Given that GH stimulation testing does not meaningfully aid in distinguishing those few children with true growth hormone deficiency from the much more common short normal child and that alternatives are now available, it is time to discontinue the routine use of GHST in children.


Induction of Ca2+-Dependent Exocytotic Processes by Laser Ablation of Endothelial Cells.
Ca2+ regulates a variety of cellular processes that are essential to maintain cell integrity and function. Different methods have been used to study these processes by increasing intracellular Ca2+ levels. Here, we describe a protocol to initiate Ca2+-dependent membrane-related events, using laser ablation by near-infrared irradiation. This creates a rupture in the plasma membrane that allows the extracellular Ca2+ to enter the cell and thereby induce a receptor-independent Ca2+ increase. We report laser ablation protocols to study two different Ca2+-induced processes in human endothelial cells-membrane resealing and exocytosis of secretory granules called Weibel-Palade bodies (WPBs). Thus, laser ablation represents a technique that permits the analysis of different Ca2+-regulated processes at high spatiotemporal resolution in a controlled manner.


Factors influencing the decision to seek treatment for symptoms of acute myocardial infarction: an evaluation of the Self-Regulatory Model of illness behaviour.
The aim of this study was to determine the usefulness of the Self-Regulatory Model (SRM) of illness behaviour [Leventhal J, Meyer D, Nerenz D. The common-sense representation of illness danger. In: Rachman S, editor. Medical psychology. New York (NY): Pergamon, 1980, pp. 27-30.] as a framework for explaining prehospital delay in patients with acute myocardial infarction (AMI). Data were collected from 61 patients with confirmed AMI regarding demographics, clinical history, distance from hospital and components of the SRM. The median time from onset of symptoms to arrival at Accident and Emergency (A&E) was 4 h 4 min. A hierarchical multiple regression revealed that the components of the SRM explained 37% of the variance in prehospital patient delay. Males who viewed a heart attack as having serious consequences and who adopted an active-cognitive and problem-focused coping response to their symptoms had the shortest delay times. The SRM is a useful framework for partially explaining patient delay. There are, however, complex interactions between the physical manifestation of pain and symptomatology and patient response. Patients' perceptions of the severity of the consequences of an AMI appear to override the effects of an individual's emotional response to the acute event. Interventions should teach patients the skills associated with active-cognitive and problem-focused coping and take account of gender differences in their design.


Are there clinically useful predictors and early warning signs for pending relapse?
Despite the availability of effective long-term treatment strategies in schizophrenia, relapse is still common. Relapse prevention is one of the major treatment objectives, because relapse represents burden and costs for patients, their environment, and society and seems to increase illness progression at the biological level. Valid predictors for relapse are urgently needed to enable more individualized recommendations and treatment decisions to be made. Mainly recent evidence regarding predictors and early warning signs of relapse in schizophrenia was reviewed. In addition, data from the first-episode (long-term) study (FES; Gaebel et al., 2007, 2011) performed within the German Research Network on Schizophrenia were analyzed. On the basis of FES data, premorbid adjustment, residual symptoms and some side effects are significant predictors. Although a broad spectrum of potential parameters has been investigated in several other studies, only a few and rather general valid predictors were identified consistently. Data of the FES also indicated that predictive power could be enhanced by considering interacting conjunctions, as suggested by the Vulnerability-Stress-Coping model. Prospective studies, however, are rare. In addition, prodromal symptoms as course-related characteristics likewise investigated in the FES add substantially to early recognition of relapse and may serve as early warning signs, but prognosis nevertheless remains a challenge. Comprehensive and well-designed studies are needed to identify and confirm valid predictors for relapse in schizophrenia. In this respect, broadly accepted and specifically defined criteria for relapse would greatly facilitate comparison of results across studies.


Profiling the human intestinal environment under physiological conditions.
The spatiotemporal structure of the human microbiome1,2, proteome3 and metabolome4,5 reflects and determines regional intestinal physiology and may have implications for disease6. Yet, little is known about the distribution of microorganisms, their environment and their biochemical activity in the gut because of reliance on stool samples and limited access to only some regions of the gut using endoscopy in fasting or sedated individuals7. To address these deficiencies, we developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. Collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease.


Involvement of angiotensin-(1-7) in the neuroprotection of captopril against focal cerebral ischemia.
Accumulating evidence suggests that brain angiotensin-converting enzyme (ACE)/angiotensin II/angiotensin II type I receptor axis is activated and thus contributes to the neuronal injury during ischemic stroke. Conversely, inhibition of this axis using centrally active ACE inhibitor captopril was proven neuroprotective in rodents with focal cerebral ischemia. Interestingly, captopril was able to increase angiotensin-(1-7) [Ang-(1-7)] levels in the peripheral organs. As the main component of the alternative renin-angiotensin system axis in the brain, Ang-(1-7) was revealed to protect against focal cerebral ischemia via a MAS1 receptor-dependent manner. Based on this evidence, we hypothesized that Ang-(1-7) might contribute to the neuroprotection of captopril during ischemic stroke. In this study, we evaluated this hypothesis using a rat model of focal cerebral ischemia. We revealed that brain ACE2 activity and Ang-(1-7) levels were significantly elevated following captopril treatment in rats with focal cerebral ischemia. More importantly, we showed that the neuroprotection provided by captopril was partially reversed by A-779, an antagonist for Ang-(1-7) receptor MAS1, indicating that Ang-(1-7) was involved in the neuroprotection of captopril. These findings have uncovered new mechanisms by which captopril protects against focal cerebral ischemia and further suggest that captopril may have practical clinical use for stroke prevention and treatment in addition to its antihypertensive effect.


Association of Perceived Stress With Incident Heart Failure.
The relationship between psychological stress and heart failure (HF) has not been well studied. We sought to assess the relationship between perceived stress and incident HF. We used data from the national REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a large prospective biracial cohort study that enrolled community-dwellers aged 45 years and older between 2003 and 2007, with follow-up. We included participants free of suspected prevalent HF who completed the Cohen 4-item Perceived Stress Scale (PSS-4). Our outcome variables were incident HF event, HF with reduced ejection fraction events, and HF with preserved ejection fraction events. We estimated Cox proportional hazard models to determine if PSS-4 quartiles were independently associated with incident HF events, adjusting for sociodemographics, social support, unhealthy behaviors, comorbid conditions, and physiologic parameters. We also tested interactions by baseline statin use, given its anti-inflammatory properties. Among 25,785 participants with a mean age of 64 ± 9.3 years, 55% were female and 40% were Black. Over a median follow-up of 10.1 years, 1109 ± 4.3% experienced an incident HF event. In fully adjusted models, the PSS-4 was not associated with HF or HF with reduced ejection fraction. However, PSS-4 quartiles 2-4 (compared with the lowest quartile) were associated with incident HF with preserved ejection fraction (Q2 hazard ratio 1.37, 95% confidence interval 1.00-1.88; Q3 hazard ratio 1.42, 95% confidence interval 1.03-1.95; Q4 hazard ratio 1.41, 95% confidence interval 1.04-1.92). Notably, this association was attenuated among participants who took a statin at baseline (P for interaction = .07). Elevated perceived stress was associated with incident HF with preserved ejection fraction but not HF with reduced ejection fraction.


In vivo profiling of DPP4 inhibitors reveals alterations in collagen metabolism and accumulation of an amyloid peptide in rat plasma.
Dipeptidyl peptidase 4 (DPP4) inhibitors represent a novel class of oral anti-hyperglycemic agents. The complete pharmacological profile of these protease inhibitors remains unclear. In order to gain deeper insight into the in vivo effects caused by DPP4 inhibition, two different DPP4 inhibitors (vildagliptin and AB192) were analyzed using differential peptide display. Wistar rats were treated with the DPP4 inhibitors (0.3mgkg(-1); 1mgkg(-1) or 3mgkg(-1) body weight) and DPP4 activity was measured before and at the end of the experiment. One hour after compound administration, blood plasma samples were collected to generate peptide displays and to subsequently identify differentially regulated peptides. A dose-dependent decrease in blood plasma DPP4 activity was measured for both inhibitors. DPP4 inhibition influenced collagen metabolism leading to depletion of collagen derived peptides (e.g. collagen alpha 1 (III) 521-554) and accumulation of related N-terminally extended collagen derived peptides (e.g. collagen alpha 1 (III) 519-554). Furthermore, the intact amyloid rat BRI (1-23) peptide was detected in plasma following in vivo DPP4 inhibition. DPP4 catalyzed cleavage kinetics of the BRI peptide were determined in vitro. The k(cat) and K(m) for cleavage by DPP4 were 5.2s(-1) and 14microM, respectively, resulting in a specificity constant k(cat)/K(m) of 0.36 x 10(6)s(-1)M(-1). Our results demonstrate that differential peptide analysis can be applied to monitor action of DPP4 inhibition in blood plasma. For the first time effects on basal collagen metabolism following DPP4 inhibition in vivo were demonstrated and the BRI amyloid peptide was identified as a novel DPP4 substrate.


Motivationally neutral stimulation of the nucleus basalis induces specific behavioral memory.
The cholinergic system has been implicated in learning and memory. The nucleus basalis (NB) provides acetylcholine (ACh) to the cerebral cortex. Pairing a tone with NB stimulation (NBstm) to alter cortical state induces both associative specific tuning plasticity in the primary auditory cortex (A1) and associative specific auditory behavioral memory. NB-induced memory has major features of natural memory that is induced by pairing a tone with motivational reinforcers, e.g., food or shock, suggesting that the cholinergic system may be a "final common pathway" whose activation promotes memory storage. Alternatively, NB stimulation might itself be motivationally significant, either rewarding or punishing. To investigate these alternatives, adult male rats (n=7) first formed a specific NB-induced memory (CS=8.0kHz, 2.0s paired with NBstm, ISI=1.8s, 200 trials), validated by post-training (24h) frequency generalization gradients (1-15kHz) of respiration interruption that were specific to the CS frequency. Thereafter, they received the same level of NBstm that had induced memory, while confined to one quadrant of an arena, and later tested for place-preference, i.e., avoidance or seeking of the quadrant of NBstm. This NBstm group exhibited neither preference for nor against the stimulated quadrant, compared to sham-operated subjects (n=7). The findings indicate that specific associative memory can be induced by direct activation of the NB without detectable motivational effects of NB stimulation. These results are concordant with a memory-promoting role for the nucleus basalis that places it "downstream" of motivational systems, which activate it to initiate the storage of the current state of its cholinergic targets.