The globus pallidus sends reward-related signals to the lateral habenula.
As a major output station of the basal ganglia, the globus pallidus internal segment (GPi) projects to the thalamus and brainstem nuclei thereby controlling motor behavior. A less well known fact is that the GPi also projects to the lateral habenula (LHb) which is often associated with the limbic system. Using the monkey performing a saccade task with positionally biased reward outcomes, we found that antidromically identified LHb-projecting neurons were distributed mainly in the dorsal and ventral borders of the GPi and that their activity was strongly modulated by expected reward outcomes. A majority of them were excited by the no-reward-predicting target and inhibited by the reward-predicting target. These reward-dependent modulations were similar to those in LHb neurons but started earlier than those in LHb neurons. These results suggest that GPi may initiate reward-related signals through its effects on the LHb, which then influences the dopaminergic and serotonergic systems.


Economic evaluation of nivolumab as a second-line treatment for advanced renal cell carcinoma from US and Chinese perspectives.
Nivolumab is a new standard of care for patients with metastatic renal cell carcinoma (mRCC) and provides an overall survival benefit of 5.40 months in comparison with everolimus. This study evaluated the cost-effectiveness of nivolumab for the second-line treatment of mRCC from the perspective of US payers and identified the range of drug costs for which the addition of nivolumab to standard therapy could be considered cost-effective from a Chinese perspective. A partitioned survival model was constructed to estimate lifetime costs, life-years, and quality-adjusted life-years (QALYs). Costs were estimated for the US and Chinese health care systems. One-way and probabilistic sensitivity analyses were performed. Nivolumab provided an additional 0.29 QALYs at a cost of $151,676/QALY in the United States. The probabilistic sensitivity analysis showed that at a willingness-to-pay threshold of $100,000/QALY, at the current cost of nivolumab, the chance of nivolumab being cost-effective was 3.10%. For China, when nivolumab cost less than $7.90 or $9.70/mg, there was a nearly 90% likelihood that the incremental cost-effectiveness ratio for nivolumab would be less than $22,785 or $48,838/QALY, respectively. For the United States, nivolumab is unlikely to be a high-value treatment for mRCC at the current price, and a price reduction appears to be justified. In China, value-based prices for nivolumab are $7.90 and $9.70/mg for the country and Beijing City, respectively. This study could and should inform the multilateral drug-price negotiations in China that may be upcoming for nivolumab. Cancer 2017;123:2634-41. © 2017 American Cancer Society.


A stand-alone fiber-coupled single-photon source.
In this work, we present a stand-alone and fiber-coupled quantum-light source. The plug-and-play device is based on an optically driven quantum dot delivering single photons via an optical fiber. The quantum dot is deterministically integrated in a monolithic microlens which is precisely coupled to the core of an optical fiber via active optical alignment and epoxide adhesive bonding. The rigidly coupled fiber-emitter assembly is integrated in a compact Stirling cryocooler with a base temperature of 35 K. We benchmark our practical quantum device via photon auto-correlation measurements revealing g(2)(0) = 0.07 ± 0.05 under continuous-wave excitation and we demonstrate triggered non-classical light at a repetition rate of 80 MHz. The long-term stability of our quantum light source is evaluated by endurance tests showing that the fiber-coupled quantum dot emission is stable within 4% over several successive cool-down/warm-up cycles. Additionally, we demonstrate non-classical photon emission for a user-intervention-free 100-hour test run and stable single-photon count rates up to 11.7 kHz with a standard deviation of 4%.


Histoplasmosis in a dog from New Brunswick.
A young dog was presented with a history of chronic diarrhea, anorexia, and weight loss. Histoplasma capsulatum was suspected, based on cytologic examination of lymph node aspirates and peritoneal fluid, and confirmed by fungal culture. To our knowledge, this is the first case of histoplasmosis diagnosed in a dog in Atlantic Canada.


Components of Goutengsan in Rat Plasma by Microdialysis Sampling and Its Protection on Aβ1-42-Induced PC12 Cells Injury.
Goutengsan, a Chinese herbal formula, potential protection on Alzheimer's disease (AD) has been less reported. In current study, we investigated the protection of Goutengsan on Aβ1-42-induced pheochromocytoma-derived cells (PC12). Furthermore, the components from Goutengsan in rat plasma were identified by microdialysis (MD) for in vivo sampling. Meanwhile, the protection of components identified was also verified. At last, we found that Goutengsan has a potential protective effect on Aβ1-42-induced PC12 cells via reducing cells damage and increasing cells vitality as well as six components (pachymic acid, liquiritin, rhynchophylline, isorhynchophylline, corynoxeine, and isocorynoxeine) which may be effective components. This study helps to understand the treatment of Goutengsan for AD and would facilitate the clinical and further studies for this formula.


Analysis of the CODIS autosomal STR loci in four main Colombian regions.
Genotype polymorphism studies at the 13 loci STRs included in the combined DNA index system [CODIS and PCR-based short tandem repeat loci, in: Proceedings of the Second European Symposium on Human Identification, Promega Corporation, Madison, WI, 1998, pp. 73-88; J. Forensic Sci. 46 (2001) 453] (CODIS: D3S1358, HUMvWA31, HUMFGA, D8S1179 D21S11, D18S51, D5S818, D13S317, D7S820, HUMTH01, HUMTPOX, HUMCSF1PO and D16S539) were carried out in a sample of 1429 unrelated Colombian individuals belonging to 25 different departments. As many other countries in Latino-America, Colombia shows an important admixture component, basically integrated by Amerindians, European-descendants and African-descendants. Due to the fact that only partial population analyses have been carried out in the country, the main aim of the present analysis is to establish a database of forensic interest based on the widely used CODIS systems covering the main Colombian regions.


The Association of Independent Living/Transitional Living Program Services to Educational Attainment among Older Foster Youth.
Among a sample of 312 older youth transitioning from foster care in the state of Missouri, this study examined whether participating in independent living (IL) classes and living in an IL or transitional living program (TLP) is associated with completing high school with a diploma or GED and entering college. Most of the youth reported participating in IL classes (80%), with 25% having lived in an IL/TLP between ages 17-19. Results of multinomial logistic regression analysis indicated that having lived in any type of IL/TLP was associated with greater odds of completing high school with a diploma or GED as well as entering college. Participating in IL classes was not associated with high school completion. but completion of IL classes was associated with greater odds of high school graduation with a diploma or GED. These findings lend support for the positive role that living in an IL/TL setting, or the completion of IL classes can play in the academic achievement of older youth transitioning from foster care. Future evaluation research is needed that elucidates specific components of IL services and transitional living programs that successfully address the academic needs of older foster youth and contribute to greater educational attainment.


Pharmacodynamics of carbapenems for the treatment of Pseudomonas aeruginosa ventilator-associated pneumonia: associations with clinical outcome and recurrence.
This study was designed to evaluate the pharmacodynamics of doripenem, imipenem and meropenem as a predictor of clinical success, mortality, 28 day recurrence and development of resistance in patients treated for Pseudomonas aeruginosa ventilator-associated pneumonia (VAP). Previously published demographic and outcome data derived from patients treated for P. aeruginosa VAP with doripenem, imipenem or meropenem were utilized. Patient-specific data were used in conjunction with published population pharmacokinetic models to construct concentration-time profiles for each patient. Etest MICs were used to determine pharmacodynamic profiles. Classification and regression tree (CART) analysis was utilized to partition pharmacodynamics based on outcomes with P values of 0.05. Eighty-six patients were included in the analysis. Initial carbapenem MICs ranged from 0.03 to 32 mg/L. VAP recurred in 28 patients; of these, 17 patients were initially infected with susceptible organisms, and 14 of them developed resistance. CART fT>MIC partitions identified for clinical success and survival were 19.2% (P = 0.016) and 47.9% (P < 0.001), respectively. No statistically significant partitions for fT>MIC were identified for recurrence or resistance development. We identified fT>MIC cut-offs for positive clinical outcomes in patients with P. aeruginosa VAP that were similar to those observed in animal models of infection for stasis (∼20%) and 1 log decreases in cfu (∼40%). Although in vitro studies have suggested a link between drug exposure and development of resistance, we were unable to identify such a relationship clinically.


Phylogeography of the South China field mouse (Apodemus draco) on the southeastern Tibetan Plateau reveals high genetic diversity and glacial refugia.
The southeastern margin of the Tibetan Plateau (SEMTP) is a particularly interesting region due to its topographic complexity and unique geologic history, but phylogeographic studies that focus on this region are rare. In this study, we investigated the phylogeography of the South China field mouse, Apodemus draco, in order to assess the role of geologic and climatic events on the Tibetan Plateau in shaping its genetic structure. We sequenced mitochondrial cytochrome b (cyt b) sequences in 103 individuals from 47 sampling sites. In addition, 23 cyt b sequences were collected from GenBank for analyses. Phylogenetic, demographic and landscape genetic methods were conducted. Seventy-six cyt b haplotypes were found and the genetic diversity was extremely high (π = 0.0368; h = 0.989). Five major evolutionary clades, based on geographic locations, were identified. Demographic analyses implied subclade 1A and subclade 1B experienced population expansions at about 0.052-0.013 Mya and 0.014-0.004 Mya, respectively. The divergence time analysis showed that the split between clade 1 and clade 2 occurred 0.26 Mya, which fell into the extensive glacial period (EGP, 0.5-0.17 Mya). The divergence times of other main clades (2.20-0.55 Mya) were congruent with the periods of the Qingzang Movement (3.6-1.7 Mya) and the Kun-Huang Movement (1.2-0.6 Mya), which were known as the most intense uplift events in the Tibetan Plateau. Our study supported the hypothesis that the SEMTP was a large late Pleistocene refugium, and further inferred that the Gongga Mountain Region and Hongya County were glacial refugia for A. draco in clade 1. We hypothesize that the evolutionary history of A. draco in the SEMTP primarily occurred in two stages. First, an initial divergence would have been shaped by uplift events of the Tibetan Plateau. Then, major glaciations in the Pleistocene added complexity to its demographic history and genetic structure.


Frequent loss of heterozygosity on chromosome 10p14-p15 in esophageal dysplasia and squamous cell carcinoma.
High frequencies of loss of heterozygosity (LOH) on chromosome 10p14-p15 have been reported in various tumors, including glioma, pulmonary carcinoid and cervical, hepatic and prostatic carcinomas. These findings suggest the presence of a tumor suppressor gene at the loci. However, analysis of LOH on chromosome 10p14-p15 in esophageal tumors has not been reported. Therefore, we examined LOH on chromosome 10p14-p15 in 88 esophageal squamous cell carcinomas (SCC) (35 superficial- and 53 advanced-types) and 44 dysplasias by microsatellite assay. Five oligonucleotide primer sets for microsatellite loci D10S191, D10S501, D10S559, D10S558 and D10S249 were used. In dysplasias, frequent LOH was detected with markers D10S191 (26%) and D10S249 (33%). In superficial esophageal SCCs, frequent LOH was detected with markers D10S191 (26%), D10S559 (50%), D10S558 (29%) and D10S249 (33%). In advanced esophageal SCCs, we found frequent LOH was detected with markers D10S191 (38%), D10S501 (25%) and D10S559 (30%). There were no significant correlations between LOH on chromosome 10p14-p15 and clinicopathologic features, including patient age, sex, tumor location, depth of invasion and lymph node metastasis. These data suggest that a putative tumor suppressor gene for esophageal carcinogenesis may be located on chromosome 10p14-p15 and that malfunction of this gene may be involved in the development but not progression of esophageal tumors.


More 'crop per drop': constraints and opportunities for precision irrigation in European agriculture.
Dwindling water supplies, increasing drought frequency and uncertainties associated with a changing climate mean Europe's irrigated agriculture sector needs to improve water efficiency and produce more 'crop per drop'. This paper summarizes the drivers for change, and the constraints and opportunities for improving agricultural water management through uptake of precision irrigation technologies. A multi-disciplinary and integrated approach involving irrigation engineers, soil scientists, agronomists and plant physiologists will be needed if the potential for precision irrigation within the field crop sector is to be realized.


State-of-the-Art on Brain-Computer Interface Technology.
This paper provides a comprehensive overview of the state-of-the-art in brain-computer interfaces (BCI). It begins by providing an introduction to BCIs, describing their main operation principles and most widely used platforms. The paper then examines the various components of a BCI system, such as hardware, software, and signal processing algorithms. Finally, it looks at current trends in research related to BCI use for medical, educational, and other purposes, as well as potential future applications of this technology. The paper concludes by highlighting some key challenges that still need to be addressed before widespread adoption can occur. By presenting an up-to-date assessment of the state-of-the-art in BCI technology, this paper will provide valuable insight into where this field is heading in terms of progress and innovation.


Bulk phase proton fluxes during the generation of membrane potential in rat liver mitochondria.
The addition of oxygen to anaerobic rat liver mitochondria incubated at 15 degrees C in the absence of permeant cations produced negligible rapid H+ ejection, monitored spectroscopically with phenol red, which corresponded kinetically to the rise in delta psi, as monitored by merocyanine 540. Slow H+ translocation was observed under these conditions during the aerobic phase, the extent of which was proportional to the amount of oxygen added and the rate dependent on the rate of counter-ion movement. Measurement of H+ disappearance in the mitochondrial matrix, as monitored by neutral red, likewise showed little or no rapid H+ change in the absence of counter-ion movements. In the presence of permeant cations, the H+ disappearance in the matrix was readily measured. This observation argues against the importance of the mitochondrial outer membrane and intermembrane space in masking H+ movements. The H+ translocation required in the generation of maximal or static head delta psi was determined by following the spectral response of merocyanine to increasing oxygen additions. The amount of oxygen giving maximal Delta psi corresponds to an extrusion of 2-3 ng ions of H+ . mg of protein-1. The absence of H+ movement of near this magnitude during the development of the Delta psi argues against the Delta psi-driven backflow of H+ ions as the sole explanation of these observations.


Time-resolved immunofluorometric assay for thyrotropin improved for enhanced functional sensitivity and clinical discrimination.
Modification of a new commercial time-resolved immunofluorometric assay for thyrotropin (DelfiaR hTSH Ultra) by prediluting samples, reducing tracer concentration, and increasing total reaction volume offered improved functional sensitivity of 0.005 mIU l-1 (20% between-assay CV) over the functional sensitivity limit of 0.014 mIU l-1 of the unmodified TSH assay. Serum TSH concentrations of 50 hyperthyroid patients and 24 clinically euthyroid patients with serum TSH < 0.1 mIU l-1 by a second generation immunoradiometric assay were analysed by both the original and modified TSH-IFMA method. The discrimination was better with the modified method, according to ROC-analysis (p = 0.027). In conclusion, these modifications enhanced functional sensitivity and improved the discriminatory power of the assay in separating hyperthyroid patients from euthyroid subjects with low TSH concentrations.


Infective endocarditis-experience in Nigeria.
Ninety cases of infective endocarditis seen over a 10-year-period at University College Hospital, Ibadan, are reviewed. The peak incidence was in the third decade and rheumatic heart disease was the commonest pre-existing lesion in 59 cases with subacute endocarditis. In most cases the source of infection was not known. In 41 of the 90 cases (44%) the diagnosis was made only at autopsy. The bacterial isolation rate was low, the commonest organisms being staphylococci, streptococci, micrococci and gramnegative bacilli. The overall mortality was 70%. A plea is made for increasing awareness of the disease and prompt institution of effective treatment.


Prospective assessment of suicidal ideation and behavior: an internet survey of pharmaceutical sponsor practices.
To survey the current approaches of clinical trial sponsors in prospective suicidal ideation and behavior assessments and challenges encountered. An internet-based survey. Inclusion of prospective assessments of suicidal ideation and behavior in industry-sponsored clinical studies were required following the release of the September 2010 United States Federal Drug Administration draft guidance. The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Workgroup conducted an online survey to understand industry practices and experiences in implementing suicidal ideation and behavior assessments in clinical trials. The survey was sent to 1,447 industry employees at 178 pharmaceutical companies. A total of 89 evaluable responses, representing 39 companies, were obtained. A 30-item internet survey was developed asking about potential challenges and issues in implementing prospective suicidal ideation and behavior assessments. Common factors in deciding whether to include suicidal ideation and behavior assessments in a clinical trial were psychiatric or neurologic drug product (95%); central nervous system activity (78%); disease (74%) and patient population (71%); and regulatory announcements and policies (74%). The most common challenges in implementing suicidal ideation and behavior assessments included cross-cultural differences in acceptance of SIB assessments (40%); obtaining adequate baseline history (36.8%); obtaining translations (35%); investigator/rater discomfort with asking about suicidal ideation and behavior (32%); and inadequate training of raters to administer suicidal ideation and behavior ratings (30%). Among sponsors surveyed, the implementation rate of suicidal ideation and behavior assessment in central nervous systems studies is very high. Most have used the Columbia-Suicide Severity Rating Scale. Challenges regarding standardization of retrospective assessment timeframes and differing approaches to summarizing and analyzing suicidal ideation and behavior-related study data were frequently reported. These results suggest that inconsistent reports of suicidal ideation and behavior within study datasets may occur and that integration of data across studies remains a concern.


Annexin A5 haplotypes in familial hypercholesterolemia: lack of association with carotid intima-media thickness and cardiovascular disease risk.
Annexin A5 (ANXA5) has been suggested to possess antiatherogenic properties. We investigated whether ANXA5 genetic variations and plasma ANXA5 levels were associated with carotid atherosclerosis and contributed to cardiovascular disease (CVD) risk in patients with familial hypercholesterolemia (FH). We sequenced the promoter region and exon 2 of ANXA5 in 284 FH patients from the ASAP (Atorvastatin versus Simvastatin on Atherosclerosis Progression) trial. Common haplotypes (H) were constructed based on seven single nucleotide polymorphisms (SNPs). We studied whether plasma ANXA5 levels or ANXA5 haplotypes were associated with the extent of atherosclerosis (evaluated by carotid intima-media thickness (IMT). The association between ANXA5 haplotypes and the risk for CVD events was investigated in 1730 FH patients from the GIRaFH (Genetic Identification of Risk factors in Familial Hypercholesterolemia) study. In ASAP, individuals carrying the ANXA5 haplotype H2 exhibited lower plasma ANXA5 levels, whereas H4 carriers had increased levels of circulating ANXA5 compared to non-carriers. Plasma ANXA5 levels were not associated with carotid IMT. None of the four ANXA5 haplotypes correlated with the age-related IMT progression (ASAP study) or contributed to CVD risk (GIRaFH cohort). Both ANXA5 haplotypes and plasma ANXA5 levels were not associated with carotid IMT progression or CVD risk in FH patients.


High Seroprevalence of Toxoplasmosis Detected by RDT among the Residents of Seokmo-do (Island) in Ganghwa-Gun, Incheon City, Korea.
Seroprevalence of Toxoplasma gondii infection among the residents of Seokmo-do (Island) in Ganghwa-gun, Incheon, Korea was surveyed for 4 years by a rapid diagnostic test (RDT) using recombinant fragment of major surface antigen (SAG1), GST-linker-SAG1A. Sera from 312, 343, 390, and 362 adult residents were collected on a yearly basis from 2010 to 2013, respectively. Total positive seroprevalence regardless of gender was 29.2, 35.3, 38.7, and 45.3% from 2010 to 2013, respectively. Positive seroprevalence in male adults was 43.9, 48.2, 45.4, and 55.3%, which was far higher than that of the corresponding female adults which was 20.7, 29.2, 33.9, and 38.9%, from 2010 to 2013, respectively. This high seroprevalence of toxoplasmosis in Seokmo-do may have been caused in part by peculiar changes in the toxoplasmic environment of the island as it is a relatively isolated area preserving its natural habitat while also being connected by a bridge to the mainland. Further study is necessary to find out symptomatic patients and to confirm the risk factors.


Traditional Chinese Medicine Compounds Containing Lonicera japonica, Chrysanthemum morifolium, and Siraitia grosvenorii Inhibits the Growth of Streptococcus mutans.
Postoperative sore throat (POST) is one of the common complications after endotracheal intubation under general anesthesia. This work attempted to design and screen out the traditional Chinese medicine (TCM) compounds containing Lonicera japonica Thunb., Chrysanthemum morifolium Ramat., and Siraitia grosvenorii (Swingle) C. Jeffrey ex A. M. Lu et Z. Y. Zhang, and further explored its antibacterial effect on POST. The antibacterial activities of Lonicera japonica, Chrysanthemum morifolium, and Siraitia grosvenorii on Streptococcus mutans (S. mutans) UA159 was measured. Lonicera japonica (40 mg/mL), Chrysanthemum morifolium (10 mg/mL), and Siraitia grosvenorii (10 mg/mL) effectively inhibited the growth of S. mutans. Then, 5 different TCM compounds were designed using the U5 (53) uniform design experimentation method. TCM compound C3 (50 mg/mL Lonicera japonica, 10 mg/mL Chrysanthemum morifolium, and 15 mg/mL Siraitia grosvenorii) significantly promoted the inhibition zone and inhibited the biofilm formation of S. mutans. In addition, TCM compound C3 exerted great antibacterial effects on S. mutans and had the least effect on cell viability of primary human pharyngeal epithelial cells. In conclusion, this work demonstrated that TCM compound containing Lonicera japonica, Chrysanthemum morifolium, and Siraitia grosvenorii inhibited the growth of S. mutans. Thus, this study provides a theoretical basis for screening out the optimal compatibility of effective components in TCM mouthwash for relieving POST.


Palmitic acid decreases cell migration by increasing RGS2 expression and decreasing SERCA expression.
Palmitic acid, the main saturated fatty acid, is related with a wide range of metabolic disorders such as obesity, type 2 diabetes and heart disease. It is known that palmitic acid disturbs the expression of some important proteins for cell homeostasis such as SERCA and RGS2, however, the role of this lipid at the molecular level in these disorders is not completely elucidated. Thus, our aim was to determinate the effect of palmitic acid in a relevant cell process as it is cell migration and the participation of SERCA and RGS2 in this response. We found that palmitic acid reduces cell migration (determined by the Boyden chamber method) in an epithelial cell line (HEK293) and this effect is modulated by SERCA and RGS2 differential protein expression (measured by western blot). Also, overexpression of individual proteins, RGS2 and SERCA, produced a decrease and an increase on cell migration, respectively. Taken together, these data suggest that the expression of regulatory proteins is affected by high concentrations of saturated fatty acids and in consequence cell migration is diminished in epithelial cells.


MicroRNA Intercellular Transfer and Bioelectrical Regulation of Model Multicellular Ensembles by the Gap Junction Connectivity.
We have studied theoretically the microRNA (miRNA) intercellular transfer through voltage-gated gap junctions in terms of a biophysically grounded system of coupled differential equations. Instead of modeling a specific system, we use a general approach describing the interplay between the genetic mechanisms and the single-cell electric potentials. The dynamics of the multicellular ensemble are simulated under different conditions including spatially inhomogeneous transcription rates and local intercellular transfer of miRNAs. These processes result in spatiotemporal changes of miRNA, mRNA, and ion channel protein concentrations that eventually modify the bioelectrical states of small multicellular domains because of the ensemble average nature of the electrical potential. The simulations allow a qualitative understanding of the context-dependent nature of the effects observed when specific signaling molecules are transferred through gap junctions. The results suggest that an efficient miRNA intercellular transfer could permit the spatiotemporal control of small cellular domains by the conversion of single-cell genetic and bioelectric states into multicellular states regulated by the gap junction interconnectivity.


Misconceptions and limitations of locus of control and the I-E scale.
Since 1966, locus of control as measured by the I-E scale has been shown predictive of many different dependent variables in both health and nonhealth situations. In hundreds of articles, expectancies have been reported to mediate perceptual, cognitive, and motivational processes. However, in many other investigations, locus of control has failed to predict the dependent variable being studied. Therefore, it is clear there are limitations to the predictive power of the construct. In recent years published research highlighting these limitations has resulted in a decrease in research about locus of control and the use of the I-E scale. Yet many investigators do not know or perhaps choose to ignore the criticisms published in recent years. Nurses who are interested in locus of control are encouraged to understand the construct and the frequent misapplications of it which occur, to realize the limitations of the I-E scale when considering instrumentation, and to consider multidimensional attribution theory as more appropriate to understanding behavior than locus of control.


Impact of highly active antiretroviral therapy on the morbidity and mortality in Spanish human immunodeficiency virus-infected children.
Highly active antiretroviral therapy (HAART) slows the progression of HIV disease and lowers mortality and morbidity in adults. The impact on the disease course in children has not been still completely elucidated. Furthermore the effect of HAART on organ-specific complications of HIV is unknown. To assess the effect of HAART on the progression of HIV infection, mortality, organ-specific complications, number of infections and hospitalizations in HIV-1-infected children. Records of HIV-1-infected children were reviewed in a large referral pediatric hospital. Patients were divided into three groups: children who did not receive antiretroviral therapy (Group 1); children who received mono- or bitherapy (Group 2); and patients who received HAART (Group 3). Endpoints analyzed were progression to AIDS and mortality among AIDS patients and overall. One hundred seven children have been evaluated. Actuarial survival at 5 years of age was 33% in Groups 1 and 2 compared with 100% in Group 3 (P < 0.01). At 5 years of age, the proportion of children progressing to AIDS was 76% in Groups 1 and 2, compared with 26% in Group 3 (P < 0.01). At 5 years of follow-up, there were 45 cases of organ-specific complications in patients without HAART. No children without organ-specific complications when HAART was started have developed them after 5 years (P < 0.01). In patients without HAART there were 9 cases of lymphoid interstitial pneumonia, and there was none in Group 3 (P < 0.01). The incidence rates of infections and hospitalizations were 2.83 and 0.52 per patient-year, respectively, in children who did not receive HAART and 0.75 and 0.17 when they were managed with HAART (relative risk, 0.26 and 0.32). HAART is associated with a marked decline in the progression to AIDS, improved survival in HIV-1-infected children, reduced incidence of infections and hospitalizations and decreased incidence of some organ-specific complications of HIV.


Is the common carotid artery intima-media thickness associated with functional outcome after acute ischaemic stroke?
Common carotid artery intima-media thickness (CCA-IMT) is an independent and early marker of generalised atherosclerosis. Brain affected by atherosclerosis may be more vulnerable to an ischaemic insult. To investigate the association between CCA-IMT and functional outcome after an acute ischaemic stroke. Prospective cohort analysis. 284 consecutive patients (mean (SD) age, 68.7 (12.7) years, 126 (44%) female) with an acute ischaemic stroke had carotid ultrasonography, carried out by a single operator. Demographic data, vascular risk factors, initial stroke severity, and brain imaging findings were recorded. Outcome was assessed at seven days from stroke onset, at discharge from hospital, and at one year post-stroke. CCA-IMT was not significantly associated with adverse short or long term functional outcome in univariate analysis, or after adjustment in a multivariate logistic regression analysis for demographic data, initial stroke severity, conventional vascular risk factors, and the characteristics of the ischaemic lesion. Age and initial stroke severity were the only independent predictors of outcome. CCA-IMT was not associated with adverse functional outcome after an ischaemic stroke. Adding CCA-IMT in a prediction model for stroke outcome would probably not improve the power of the model.


Hydrogen-bonding patterns in pyrimethaminium dinitrate.
The title compound, 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidine-1,3-diium dinitrate, C12H15ClN42+.2NO3-, contains two crystallographically independent pyrimethamine (PMN) molecules, which differ in the relative orientations of the pyrimidine and benzene rings and of the ethyl substitutents. In both pyrimethamine molecules, all the pyrimidine N atoms are protonated, unlike most related compounds, in which only one pyrimidine N atom is protonated. The two pyrimethamine moieties are bridged by a variety of N-HO(nitrate) interactions, including some three-centre hydrogen bonds.


Pyrolyzable Nanoparticle Tracers for Environmental Interrogation and Monitoring.
Environmental tracing applications require materials that can be detected in complex fluids composed of multiple phases and contaminants. Moreover, large libraries of tracers are necessary in order to mitigate memory effects and to deploy multiple tracers simultaneously in complex oil fields. Herein, we disclose a novel approach based on the thermal decomposition of polymeric nanoparticles comprised of styrenic and methacrylic monomers. Polymeric nanoparticles derived from these monomers cleanly decompose into their constituent monomers at elevated temperatures, thereby maximizing atom economy wherein the entire nanoparticle mass contributes to the generation of detectable units. A total of ten unique single monomer particles and three dual-monomer particles were synthesized using semicontinuous monomer starved addition polymerization. The pyrolysis gas chromatography-flame ionization detection/mass spectrometry (GC-FID/MS) behavior of these particles was studied using high-pressure mass spectrometry. The programmable nature of our methodology permits simultaneous removal of contaminants and subsequent identification and quantification in a single analytical step.


[Pancreatic and duodenal metastases from renal cell carcinoma 13 years after radical nephrectomy: a case report].
A 52-year-old male was admitted to our hospital complaining of orthostatic vertigo, fatigue and weight loss, who underwent right total nephrectomy for renal cell carcinoma(RCC) with curative operation 13 years ago (in 1992). Endoscopic examination revealed a submucosal tumor with erosion in the duodenum. The diagnosis made from the biopsy specimens was metastatic RCC in the duodenum. Abdominal CT scan revealed that his metastasis has spread to the pancreas. Five million units of interferon a was administered intramuscularly three times a week for 1 month. He received blood transfusions and palliative care. He died 5 months later because of disease progression. Metastases of RCC have been often reported in the lungs, the liver, and the bones, but rarely in the gastrointestinal tract. This is a very rare case of metastatic RCC in the duodenum, which was diagnosed 13 years after curative right nephrectomy. Since late recurrence is characteristic of renal cell carcinoma, careful long-term follow-up is needed. To our knowledge, this is the 19th case of duodenal metastasis from RCC reported in the literature.


Detection of a novel specificity (CTLA-4) in ATG/TMG globulins and sera from ATG-treated leukemic patients.
T-cell costimulation has been shown to provide positive signals for T-cell activation and generation of effector activity. In this study, we analyzed the presence of antibodies (Abs) against the T-lymphocyte costimulatory molecules CD28, CTLA-4, CD80, and CD86 in anti-T-lymphocyte (ATG) and antithymocyte (TMG) globulin preparations to address their mechanism of action. We focused our attention on the role of CTLA-4-specific Abs in the immunosuppressive effect of ATG/TMG, because anti-CTLA-4 agonistic Abs may suppress T-cell proliferation and nonagonistic Abs may lead to T-cell depletion through an Ab-dependent cell cytotoxicity mechanism. ATG/TMG and patients' sera were tested for binding to recombinant human costimulatory molecules by ELISA techniques. CTLA-4 specificity was also analyzed by cytoplasmic immunofluorescence staining of a CTLA-4 transfectant by competitive inhibition immunofluorescence and by cell proliferation assay in allogeneic mixed lymphocyte reaction (MLR). Either ATG or TMG predominantly contained anti-CTLA-4 Abs, with higher reactivity in ATG followed by anti-CD86 and -CD28 Abs, whereas anti-CD80 Abs were found only in ATG. Anti-CTLA-4 Abs present in ATG/TMG recognized the native form of CTLA-4 molecule, and their removal reduced the effect of ATG in an allogeneic MLR. Kinetic studies indicated that such Abs were present in the sera of 12 ATG-treated leukemic patients up to 21 days after ATG administration. These data suggest that the novel anti-CTLA-4 Abs found in ATG may greatly contribute to its immunosuppressive effect, thus accounting for the absence of rejection and exceptionally low incidence of graft-versus-host disease in the group of patients analyzed.


Beauvericin, a cyclic peptide, inhibits inflammatory responses in macrophages by inhibiting the NF-κB pathway.
Beauvericin (BEA), a cyclic hexadepsipeptide produced by the fungus Beauveria bassiana, is known to have anti-cancer, anti-inflammatory, and anti-microbial actions. However, how BEA suppresses macrophage-induced inflammatory responses has not been fully elucidated. In this study, we explored the anti-inflammatory properties of BEA and the underlying molecular mechanisms using lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. Levels of nitric oxide (NO), mRNA levels of transcription factors and the inflammatory genes inducible NO synthase (iNOS) and interleukin (IL)-1, and protein levels of activated intracellular signaling molecules were determined by Griess assay, semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), luciferase reporter gene assay, and immunoblotting analysis. BEA dose-dependently blocked the production of NO in LPS-treated RAW264.7 cells without inducing cell cytotoxicity. BEA also prevented LPS-triggered morphological changes. This compound significantly inhibited nuclear translocation of the NF-κB subunits p65 and p50. Luciferase reporter gene assays demonstrated that BEA suppresses MyD88-dependent NF-κB activation. By analyzing upstream signaling events for NF-κB activation and overexpressing Src and Syk, these two enzymes were revealed to be targets of BEA. Together, these results suggest that BEA suppresses NF-κB-dependent inflammatory responses by suppressing both Src and Syk.


Efficacy and safety of a once-daily extended-release formulation of pramipexole switched from an immediate-release formulation in patients with advanced Parkinson's disease: results from an open-label study.
This study aimed to evaluate the efficacy and safety of an extended-release tablet formulation of pramipexole (PPX-ER) given once daily when switched from an immediate-release tablet formulation (PPX-IR) given 3 times daily. This open-label study included 29 patients with idiopathic Parkinson's disease (PD) who were followed for 8 weeks. Primary endpoints were Unified Parkinson's Disease Rating Scale (UPDRS) part III score, a physician evaluation of motor symptoms; nocturnal and early morning symptoms (NEMS) score, based on the results for 4 items in the Parkinson's Disease Sleep Scale and the Movement Disorder Society - sponsored revision of the UPDRS; and patients' formulation preference, determined through questionnaires. Secondary endpoints were nocturnal sleep disturbance, evaluated using the revised version of the Parkinson's Disease Sleep Scale (PDSS-2); quality of life, evaluated using the 39-item Parkinson's Disease Questionnaire (PDQ-39); Clinical Global Impression-Improvement (CGI-I) score; Patient Global Impression-Improvement (PGI-I) score; and caregiver formulation preference. UPDRS part III score (mean ± SD) was significantly decreased after 4 weeks (13.9 ± 7.3; P=0.030) and 8 weeks (12.2 ± 7.3; P<0.001) from baseline (15.3 ± 7.0). However, no significant change was found in NEMS scale, PDSS-2 or PDQ-39 scores. After 8 weeks, the responder rates based on CGI-I and PGI-I scores were 27.6% and 20.7%, respectively. As a result of the questionnaire, 63.0% of patients and 58.8% of their caregivers preferred PPX-ER. A non-serious drug-related adverse event (diarrhea) was observed in one patient. In conclusion, PPX-ER can be considered as a useful treatment option when PPX-IR needs to be switched to other dopamine agonists.This study is registered with UMIN-CTR (UMIN000006521).


A follow-up and treatment model for pediatric eating disorders: examination of the clinical variables of a child and adolescent psychiatry eating disorder outpatient clinic.
Anorexia nervosa and other eating disorders are common in children and adolescents and are characterized by symptoms such as food restriction, efforts to lose weight, fear of gaining weight and impaired body image. Anorexia nervosa is a life-threatening psychiatric disorder and its management in the outpatient setting can be challenging for clinicians. The aim of this study was to introduce the subunit service model developed for the multidisciplinary diagnosis and management of eating disorders in the outpatient setting and to evaluate the clinical follow-up of patients. The medical records of 37 patients who were followed up by the eating disorders team at our clinic between 2018 and 2022 were reviewed. The study was designed as retrospective case study. A diagnosis was made according to DSM-5 and a treatment plan was developed for each case. Body mass index (BMI), Clinic Global Impression (CGI) scale scores, duration of follow-up, number of interviews and other scale scores (The Turgay Attention Deficit Hyperactivity Disorder Scale and the Autism Spectrum Screening Questionnaire Scale) of 37 patients aged 12-17 years diagnosed with an eating disorder and followed up in our clinic were statistically compared. The Eating Disorder Follow-up Model developed and applied in our clinic had a positive effect on patients BMI scores, a significant improvement in CGI scores was observed. Conclusion: We believe that this multidisciplinary system will serve as a model for other mental health centers by raising awareness and guiding mental health professionals in the follow-up and treatment of eating disorders.


Characteristics associated with the availability of therapeutic acupuncture in substance use disorder treatment facilities in the United States.
We examine the characteristics associated with the availability of therapeutic acupuncture in substance use disorder (SUD) treatment facilities in the United States (US). This study utilizes data from the 2018 National Survey of Substance Abuse Treatment Services (N-SSATS). Multivariable logistic regression was performed. Only 5.5% (n = 814) of all SUD treatment facilities offered acupuncture therapy. Facilities operating an opioid treatment program (OTP) were 1.60 times more likely to offer therapeutic acupuncture than non-OTP facilities. Facilities that offered oral naltrexone pharmacotherapy or buprenorphine with naloxone pharmacotherapy were 1.63 and 1.37 times more likely to offer therapeutic acupuncture, respectively, compared to facilities that did not offer these pharmacotherapies. Federal government facilities were over four times more likely to offer acupuncture than those operated by state governments and had triple the odds of having acupuncture than private nonprofit organizations. Tribal facilities were over five times more likely than state government-operated facilities to offer acupuncture. Facilities located in the Western region of the US were 1.59, 1.39, and 1.30 times more likely than Northeastern, Midwestern, and Southern US regions, respectively, to offer acupuncture therapy. Although complementary and holistic approaches such as acupuncture are accepted adjunct methods to treat persons with SUD, the findings suggest that their utilization in SUD treatment facilities in the US is minimal. Results, however, highlight that facilities operated by tribal and federal governments, those that are located in the Western region of the US, and non-hospital facilities have the highest odds of incorporating therapeutic acupuncture as treatment for SUD. Supplemental data for this article is available online at https://doi.org/10.1080/10550887.2022.2056401 .


Recent progress in the treatment of adult acute leukemia.
In 3 studies for adult acute myelogenous leukemia (AML) treated with BHAC-DMP, BHAC-DMP(II) and M-85 from 1979 to 1987, intensive induction resulted in a higher cure rate, since reduction of the blasts in bone marrow at 2 weeks after the initiation of therapy to less than 20% was the most significant prognostic factor to predict the long complete remission (CR), followed by initial WBC counts (less than 60,000/cmm) and achievement of CR within 50 days or by one course of induction therapy. However, it seemed impractical to give very intensive chemotherapy during the induction because of the high frequency of complications due to prolonged myelosuppression. Consolidation should be as intensive as possible. Non-cross resistant drugs will theoretically produce better results. In M-85 protocol, 71% of 41 adult AML achieved CR. The predicted 3.5-year survival and CR length of CR cases are 74 and 56%; respectively. The preliminary results of JALSG-AML87 and -ALL87 were also reviewed.


Antigenic cross-reaction between the alpha types of human and mouse interferon.
Cross-neutralization of the alpha and beta types of human and mouse interferons was tested using antibodies directed against the heterologous types of interferons. The alpha type of mouse interferon (MuIFN-alpha) prepared from L cells was found to be completely neutralizable by high-titered antibody against human alpha-type interferon (HuIFN-alpha), although the titers were much lower than those obtained in neutralization reactions with the homologous interferon. MuIFN-alpha from virus-induced lymphocytes, as well as non-glycosylated MuIFN-alpha from L cells, reacted similarly. The cross-reaction was also observed by the binding of anti-HuIFN-alpha antibody to a column of immobilized MuIFN-alpha. The binding experiment indicated that only a small fraction of the anti-HuIFN-alpha antibody population is heterologous reactive. Reciprocally, HuIFN-alpha from L cells, again with relatively low antibody titers, and the antibody responsible for the heterologous reaction was shown to be the anti-MuIFN-alpha and not anti-MuIFN-beta type. It is concluded that the alpha types of human and mouse interferon bear an antigenic homology. On the other hand, no significant antigenic cross-reactivity has been detected between the beta types of human and mouse interferons.


Multimodality Imaging Trials Evaluating the Impact of Omega-3 Fatty Acids on Coronary Artery Plaque Characteristics and Burden.
Treatment of established risk factors, especially low-density lipoprotein (LDL) cholesterol, is the cornerstone of preventing atherosclerotic coronary artery disease. Despite reducing LDL cholesterol, there remains a significant risk of cardiovascular disease. Inflammatory and metabolic pathways contribute to recurrence of cardiovascular events, and are often missed in clinical practice. Eicosapentaenoic acid (EPA) may play a crucial role in reducing residual risk of cardiovascular disease. In this review we discuss the clinical applications of omega-3 fatty acids (OM3FAs), their mechanism of action, the difference between pure EPA and docosahexaenoic acid components, and the latest cardiovascular outcome trials and imaging trials evaluating coronary plaque. PubMed and EMBASE were searched to include all the remarkable clinical trials investigating OM3FAs and cardiovascular disease. Beyond statins, additional medications are required to reduce the risk of cardiovascular disease. EPA has shown cardiovascular benefit in addition to statins in large outcome trials. Additionally, multiple serial-imaging studies have demonstrated benefits on plaque progression and stabilization. Due to its pleotropic properties, icosapent ethyl outperforms other OM3FAs in decreasing cardiovascular disease risk in both patients with and without high triglycerides, and is currently recommended as an adjunct to statins. To further strengthen the current evidence, additional research is required to elucidate the inconsistencies between the effects of pure EPA and EPA plus docosahexaenoic acid.


Simultaneous estimation of levodopa and carbidopa by RP-HPLC using a fluorescence detector: its application to a pharmaceutical dosage form.
A reverse-phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated for the simultaneous estimation of levodopa and carbidopa in bulk and pharmaceutical formulations. Chromatographic separation was achieved by using a C18 reverse-phase column and a mixture of an aqueous phase (10 mM potassium dihydrogen phosphate buffer, pH4.0) and methanol (90:10 v/v) as the mobile phase. Quantitative analysis of levodopa and carbidopa was performed using a fluorescence detector at an excitation wavelength of 280 nm and an emission wavelength of 310 nm. The method was linear between 5 and 500 ng/mL for both levodopa and carbidopa. The detection limits for levodopa and carbidopa were 0.30 and 0.60 ng/mL, respectively, whereas the quantitation limit was 0.80 ng/mL for levodopa and 1.2 ng/mL for carbidopa. The method demonstrated good and consistent recoveries (99.63-100.80% for levodopa and 98.97-100.94% for carbidopa) with low interday and intraday relative standard deviation. The validated method was successfully applied to quantify levodopa and carbidopa simultaneously in a pharmaceutical formulation. The method was found to be precise, sensitive and accurate for the simultaneous determination levodopa and carbidopa in bulk and pharmaceutical formulations.


[125I]Leu31, Pro34-PYY is a high affinity radioligand for rat PP1/Y4 and Y1 receptors: evidence for heterogeneity in pancreatic polypeptide receptors.
Cloned receptors for the PP-fold peptides are subdivided into Y1, Y2, PP1/Y4, Y5 and Y6. NPY and PYY have similar affinity for Y1, Y2, Y5 and Y6 receptors while PP has highest affinity for PP1. Pro34-substituted analogs of NPY and PYY have selectivity for Y1 and Y1-like receptors over Y2 receptors. In the present study, we found the putative Y1-selective radioligand, [125I]Leu31, Pro34-PYY, also binds with high affinity to the rat PP1 receptor in cell lines expressing the receptor. However, in rat brain sections, [125I]Leu31, Pro34-PYY does not appear to bind to the interpeduncular nucleus, a brain region containing a high density of [125I]-bPP binding sites. Therefore, it appears there is additional heterogeneity in receptors recognizing PP.


Vulnerability of long-term care facility residents to Clostridium difficile infection due to microbiome disruptions.
Aging presents a significant risk factor for Clostridium difficile infection (CDI). A disproportionate number of CDIs affect individuals in long-term care facilities compared with the general population, likely due to the vulnerable nature of the residents and shared environment. Review of the literature cites a number of underlying medical conditions such as the use of antibiotics, proton pump inhibitors, chemotherapy, renal disease and feeding tubes as risk factors. These conditions alter the intestinal environment through direct bacterial killing, changes to pH that influence bacterial stabilities or growth, or influence nutrient availability that direct population profiles. In this review, we examine some of the contributing risk factors for elderly associated CDI and the toll they take on the microbiome.


White Matter Structural Connectivity Is Not Correlated to Cortical Resting-State Functional Connectivity over the Healthy Adult Lifespan.
Structural connectivity (SC) of white matter (WM) and functional connectivity (FC) of cortical regions undergo changes in normal aging. As WM tracts form the underlying anatomical architecture that connects regions within resting state networks (RSNs), it is intuitive to expect that SC and FC changes with age are correlated. Studies that investigated the relationship between SC and FC in normal aging are rare, and have mainly compared between groups of elderly and younger subjects. The objectives of this work were to investigate linear SC and FC changes across the healthy adult lifespan, and to define relationships between SC and FC measures within seven whole-brain large scale RSNs. Diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) data were acquired from 177 healthy participants (male/female = 69/108; aged 18-87 years). Forty cortical regions across both hemispheres belonging to seven template-defined RSNs were considered. Mean diffusivity (MD), fractional anisotropy (FA), mean tract length, and number of streamlines derived from DTI data were used as SC measures, delineated using deterministic tractography, within each RSN. Pearson correlation coefficients of rs-fMRI-obtained BOLD signal time courses between cortical regions were used as FC measure. SC demonstrated significant age-related changes in all RSNs (decreased FA, mean tract length, number of streamlines; and increased MD), and significant FC decrease was observed in five out of seven networks. Among the networks that showed both significant age related changes in SC and FC, however, SC was not in general significantly correlated with FC, whether controlling for age or not. The lack of observed relationship between SC and FC suggests that measures derived from DTI data that are commonly used to infer the integrity of WM microstructure are not related to the corresponding changes in FC within RSNs. The possible temporal lag between SC and FC will need to be addressed in future longitudinal studies to better elucidate the links between SC and FC changes in normal aging.


Acute respiratory distress syndrome in paediatric scrub typhus.
Acute respiratory distress syndrome is a life-threatening complication of scrub typhus; we sought to describe its mortality and associated factors, namely eschar, hepatomegaly and severe thrombocytopenia, in a retrospective study in India of 65 children.


High-Nuclearity Chiral 3 d-4 f Heterometallic Clusters Ln6Cu24 and Ln6Cu12.
Based on the anion template and chiral ligand inducting role, two series of high-nuclearity 3 d-4 f heterometallic clusters with formulas [NO3@Ln6Cu24(μ3-OH)30(μ2-OH)3(OAc)6( R/ S-L)12(H2O)24](NO3)14· x(H2O) (Ln = Dy, x = 30 for 1a( R-L) and 1b( S-L); Ln = Tb, x = 40 for 2a( R-L) and 2b( S-L)) and (Et3NH)4[Ln6Cu12(μ3-OH)14(μ2-Cl)6Cl12( R/ S-L)12]Cl2· x(H2O) (Ln = Dy, x = 28 for 3a( R-L) and 3b( S-L); Ln = Tb, x = 33 for 4a ( R-L) and 4b( S-L); HL = ( R/ S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), have been synthesized and characterized. Structural analysis reveals that the metal skeleton of compounds 1 and 2 display a Ln6Cu12 octahedral inner core encapsulated by six outer Cu2 units. In the Ln6Cu12 octahedron, 6 Ln3+ ions located at the six vertices and 12 inner Cu2+ ions located at the 12 edges of octahedron, and one NO3- locates in the center of the octahedron. The metal core of compounds 3 and 4 can be viewed as a Ln6 octahedron encapsulated by six Cu2 units. It is interesting that the different inorganic anions involved in the reaction result in the difference in the structures of 1 to 2 and 3 to 4. Circular dichroism spectra of 1-4 display obvious mirror symmetry effect at 600-800 nm of d-d transition of Cu2+, suggesting that the chirality transferred from chiral R- and S-ligand to Cu2+ ions in this system. Notably, the CD peak at the Cu2+ d-d transition position of Ln6Cu12 cluster is obviously blue-shifted compared with that of Ln6Cu24 due to the different coordinated environments of Cu2+. Magnetic studies indicate that 1a and 2a show weak ferromagnetic interactions, while 3a and 4a display antiferromagnetic interactions.


Molecular mechanisms of pulmonary carcinogenesis by polycyclic aromatic hydrocarbons (PAHs): Implications for human lung cancer.
Lung cancer has the second highest incidence and highest mortality compared to all other cancers. Polycyclic aromatic hydrocarbon (PAH) molecules belong to a class of compounds that are present in tobacco smoke, diesel exhausts, smoked foods, as well as particulate matter (PM). PAH-derived reactive metabolites are significant contributors to lung cancer development. The formation of these reactive metabolites entails metabolism of the parent PAHs by cytochrome P4501A1/1B1 (CYP1A1/1B1) and epoxide hydrolase enzymes. These reactive metabolites then react with DNA to form DNA adducts, which contribute to key gene mutations, such as the tumor suppressor gene, p53 and are linked to pulmonary carcinogenesis. PAH exposure also leads to upregulation of CYP1A1 transcription by binding to the aryl hydrocarbon receptor (AHR) and eliciting transcription of the CYP1A1 promoter, which comprises specific xenobiotic-responsive element (XREs). While hepatic and pulmonary CYP1A1/1B1 metabolize PAHs to DNA-reactive metabolites, the hepatic CYP1A2, however, may protect against lung tumor development by suppressing both liver and lung CYP1A1 enzymes. Further analysis of these enzymes has shown that PAH-exposure also induces sustained transcription of CYP1A1, which is independent of the persistence of the parent PAH. CYP1A2 enzyme plays an important role in the sustained induction of hepatic CYP1A1. PAH exposure may further contribute to pulmonary carcinogenesis by producing epigenetic alterations. DNA methylation, histone modification, long interspersed nuclear element (LINE-1) activation, and non-coding RNA, specifically microRNA (miRNA) alterations may all be induced by PAH exposure. The relationship between PAH-induced enzymatic reactive metabolite formation and epigenetic alterations is a key area of research that warrants further exploration. Investigation into the potential interplay between these two mechanisms may lead to further understanding of the mechanisms of PAH carcinogenesis. These mechanisms will be crucial for the development of effective targeted therapies and early diagnostic tools.


Reduction of renal ischemia-reperfusion injury in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton.
The role of 5-lipoxygenase (5-LOX) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Here we investigate the effects of 1) the 5-LOX inhibitor zileuton and 2) 5-LOX gene knockout (5-LOX(-/-)) mice on renal dysfunction and injury caused by I/R of the kidney in mice. Wild-type mice treated with zileuton (3 mg/kg i.v.) or 5-LOX(-/-) mice were subjected to bilateral renal artery occlusion (30 min) followed by reperfusion (24 h). Plasma urea, creatinine, and aspartate aminotransferase (AST) were measured as markers of renal dysfunction and reperfusion injury. Kidneys were used for histological evaluation of renal injury. Renal myeloperoxidase activity was measured and used as an indicator of polymorphonuclear leukocyte (PMN) infiltration and renal expression of intercellular adhesion molecule-1 (ICAM-1) was determined using immunohistochemistry. Administration of zileuton before I/R significantly reduced the degree of renal dysfunction (urea, creatinine) and injury (AST, histology). In addition, zileuton reduced the expression of ICAM-1 and the associated PMN infiltration caused by I/R of the mouse kidney. Compared with wild-type mice, the degree of renal dysfunction, injury, and inflammation caused by I/R in 5-LOX(-/-) mice was also significantly reduced, confirming the pathophysiological role of 5-LOX in the development of renal I/R injury. We propose that 1) endogenous 5-LOX metabolites enhance the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules, and 2) inhibitors of 5-LOX may be useful in the treatment of conditions associated with I/R of the kidney.


Control of astigmatism in cataract surgery.
A study is reported on cataract surgery, with intraocular lens implant, with measurement of the preoperative astigmatism and of the postoperative astigmatism over 28 weeks. Nine interrupted 10/0 nylon sutures are used to close a limbal section. Preoperative astigmatism is compensated for in the method of suturing by the placement of additional sutures. Postoperatively sutures are cut in line with the plus cylinder axis in eyes showing excessive astigmatism with the rule. Final postoperative astigmatism is controlled within 2.25 D cyl. 68% of cases lie within 1.0 D cyl with the rule to 1.0 D cyl against the rule. The average case in which sutures are not cut is one having 1.51 D cyl with the rule at one week postoperatively, declining to zero at approximately 12 weeks, and having a final value of 0.17 D cyl against the rule. No significant change in cylinder is seen after 10 weeks. The final postoperative astigmatism is only weakly correlated with the preoperative astigmatism, showing that the surgical method is effective. The spherical equivalent error is shown to shift in the direction of myopia in the postoperative period.


Modular pharmacology: the next paradigm in drug discovery.
Effective regulation of abnormal targets of disease requires the alteration of either the topological structure or dynamic characteristics of modules in a given target network. In order to disturb the complex direct and indirect target hubs, new approaches in adaptive pharmacology should be developed to regulate target loops using module-based designs. This review discusses the formation in disease-associated structural networks with multiple drug targets and the optimization of a multi-objective system of modules. On the basis of these concepts, modular pharmacology (MP) has emerged as a method that can balance multiple outcomes by regulating the response of property modules on the basis of the benefits and risks of diversified modules and drugs, thereby allowing novel approaches for drug discovery. Further research of pharmacological mechanisms underlying diversity interactions between multiple modules is necessary for a better understanding of the basic therapeutic processes.


Solute exclusion from cellulose in packed columns: process modeling and analysis.
In this investigation, process modeling and analysis were used to explore the behavior of solute exclusion from cellulose in packed columns. The study focused on modeling the effects of dispersion, mass transport, and pore diffusion. Three mathematical models were used to predict the behavior of the columns: an equilibrium model, a mass transfer model, and a combined mass transfer and pore diffusion model. Computer implementations of these models were tested against experimental conditions where cellulose particle size and solution velocity were used to either amplify or minimize dispersion or skewness in the elution curves. For small cellulose particles (200-300 mesh), all three models accurately predicted the shape of the elution curve and the particle porosity. For larger particles (45-60 mesh), the mass transfer model and the combined mass and pore diffusion model best represented the behavior of the column. At high solution velocities (0.63 cm(3) min(-1)) and large particles, only the combined mass transfer and pore diffusion model accurately represent the column behavior. Sensitivity analysis revealed that the mass transfer coefficient had little effect on the elution curves for the range of values (10(-6)-10(-3) cm s(-1)) calculated from the experimental data. The combined mass transfer and pore diffusion model presented in this article can be used to design solute exclusion measurement experiments for the larger cellulose particles found in a commercial cellulose-to-ethanol plant.


Fungi from industrial tannins: potential application in biotransformation and bioremediation of tannery wastewaters.
Tannins are a complex family of polyphenolic compounds, widely distributed in the plant kingdom where they act as growth inhibitors towards many microorganisms including bacteria, yeasts, and fungi. Tannins are one of the major components of tannery wastewaters and may cause serious environmental pollution. In the present study, four different tannins (the hydrolysable chestnut ellagitannin and tara gallotannin and the condensed quebracho and wattle tannins) were characterized from a mycological point of view with the aim of selecting fungal strains capable of growing in the presence of high tannin concentration and thus potentially useful in industrial biotransformations of these compounds or in the bioremediation of tannery wastewaters. A total of 125 isolates of filamentous fungi belonging to 10 species and four genera (Aspergillus, Paecilomyces, Penicillium, and Talaromyces) were isolated from the tannin industrial preparations. Miniaturized biotransformation tests were set up with 10 fungal strains and the high-performance liquid chromatography (HPLC) analysis pointed out a strong activity of all the tested fungi on both chestnut and tara tannins. Two strains (Aspergillus tubingensis MUT 990 and Paecilomyces variotii MUT 1125), tested against a real tannery wastewater, were particularly efficient in chemical oxygen demand (COD) and tannin removal (> 60%), with a detoxification above 74%. These results indicate that these fungi are potentially exploitable in the treatment of tannery wastewaters.


Abuse of a fire-extinguishing agent and sudden death in adolescents.
Two cases of abuse of bromochlorodifluoromethane (BCF - a fire-extinguishing agent) by inhalation are reported. In the first case, a 15-year-old youth presented in ventricular fibrillation; the second youth was dead on arrival at hospital. Port-mortem toxicological investigations confirmed BCF inhalation in the latter patient. Management of the surviving patient included cardioversion, controlled mandatory hyperventilation, intravenous infusions of mannitol, and barbiturate protection against cerebral ischaemia. He had completely recovered after eight days. Community agencies report that BCF inhalation occurs frequently on the Gold Coast, Queensland. This behaviour can be associated with sudden death from ventricular arrhythmias after cardiac sensitization to endogenous adrenaline. The "lone sniffer" is at greatest risk, and identification of such individuals may prevent a fatal outcome.


Pure right ventricular infarction.
A 76-year-old man with chest pain was admitted to hospital where electrocardiography (ECG) showed ST-segment elevation in leads V1-4, indicative of acute anterior myocardial infarction. ST-segment elevation was also present in the right precordial leads V4R-6R. Emergency coronary angiography revealed that the left coronary artery was dominant and did not have significant stenosis. Aortography showed ostial occlusion of the right coronary artery (RCA). Left ventriculography showed normal function and right ventriculography showed a dilated right ventricle and severe hypokinesis of the right ventricular free wall. Conservative treatment was selected because the patient's symptoms soon ameliorated and his hemodynamics was stable. 99mTc-pyrophosphate and 201Tl dual single-photon emission computed tomography showed uptake of 99mTc-pyrophosphate in only the right ventricular free wall, but no uptake of 99mTc-pyrophosphate and no perfusion defect of 201Tl in the left ventricle. The peak creatine kinase (CK) and CK-MB were 1,381 IU/L and 127 IU/L, respectively. His natural course was favorable and the chest pain disappeared under medication. Two months after the onset, the ECG showed poor R progression in leads V1-4 indicating an old anterior infarction. Coronary angiography confirmed the ostial stenosis of the hypoplastic RCA. This was a case of pure right ventricular free wall infarction because of the occlusion of the ostium of the hypoplastic RCA, but not of the right ventricular branch. Because the electrocardiographic findings resemble those of an acute anterior infarction, it is important to consider pure right ventricular infarction in the differential diagnosis.


Substance P-like immunoreactivity in the intramural nerve plexuses of the guinea-pig ureter: a light and electron microscopical study.
Immunofluorescence and immunoperoxidase techniques were used to study the distribution of substance P-like immunoreactivity in the intramural nerve plexuses of the guinea-pig ureter. In light microscopical preparations, immunoreactivity was observed in plexuses related to the muscle coat as well as in plexuses in the submucosa and beneath the epithelium. Ultrastructural examination showed that the immunoreactivity was located primarily in axons in the nerves. In perfusion-fixed specimens, there was evidence of its presence both in axons with terminals containing mainly large dense-cored vesicles and in axons with terminals containing mainly small vesicles. The presence of substance P-like immunoreactivity in axons with terminals containing mainly large dense-cored vesicles was supported by examination of specimens treated in vitro with capsaicin. In these specimens, the axons were dilated and showed a number of other changes in fine structure. There was also a substantial reduction in the amount of immunoreactivity in the nerve plexuses and the dilated axons contained little if any reaction product. The possibility that axons which contained large amounts of reaction product after treatment with capsaicin represented axons with terminals containing mainly small vesicles was discussed. Comparison of the distribution of the different types of small vesicle-containing terminal identified in glutaraldehyde-fixed material with that of axons containing reaction product suggested that the immunoreactivity present in such axons was located in those in which the small vesicles in the terminals were clear rather than those in which the vesicles contained dense material.


Entinostat for the treatment of breast cancer.
Breast cancer accounts for 29% of malignant tumors. It is an heterogenous disease covering a spectrum of different molecular subtypes. Epigenetic aberrations may affect gene expression through DNA and histone proteins modifications thus promoting tumor progression and resistance to anti- tumor treatment. Area covered: This article explores the potential role of entinostat in the treatment of breast cancer. The clinical trials evaluating entinostat are discussed, highlighting preclinical data and early-phase clinical studies results. The emerging activity of entinostat in several clinical settings is evaluated by focusing on endocrine-resistant, HER2 positive and triple-negative breast cancer with promising activity in boosting the immune-system. Expert opinion: Entinostat, a synthetic benzamide derivative class I histone deacetylases (HDACs) inhibitor, inhibits cell proliferation and promotes apoptosis in breast cancer. Several results from clinical trials demonstrate that the addition of an epigenetic therapy to antiestrogen therapy may be an effective approach to targeting resistance pathways in breast cancer, particularly in hormone-positive disease. Agents such as entinostat may have a role in immunogenic modulation. Genetic and pharmacological inhibition studies identified HDAC as a key determinant in the reversal of carcinoma immune escape. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines.


Four-week "living high training low" program enhances 3000-m and 5000-m time trials by improving energy metabolism during submaximal exercise in athletes.
This study aimed to determine the effect of a 4-week living high training low (LHTL) versus a living low training low (LLTL) program on energy metabolism during submaximal exercise and 3000-m and 5000-m time trial (TT) in athletes. Male athletes (n = 20) were randomly assigned to the LLTL (n = 10, living at 1000 m and training at 700-1330 m) and LHTL (n = 10, living at simulated 3000 m and training at 700-1330 m) groups. We compared energy metabolisms during submaximal exercise on a treadmill and aerobic exercise performance (3000 m and 5000 m TT) before and after 4 weeks of training. As expected, the LHTL group demonstrated enhanced energy metabolism during submaximal exercise via significant interaction (time × group) in heart rate, oxygen consumption, and carbon dioxide excretion; these variables were significantly decreased in the LHTL group compared with the LLTL group. Additionally, both training groups revealed significantly decreased blood lactate levels during submaximal exercise, 3000 m TT, and 5000 m TT but significant interactions (time × group) in the 3000 m and 5000 m TT. Thus, the LHTL group demonstrated greater improvements in 3000 m and 5000 m TT than the LLTL group via significant interactions. Our results suggest that 4-week LHTL intervention enhances 3000 m and 5000 m TT by improving energy metabolism during submaximal exercise. The proposed LHTL intervention in this study is a novel and effective method for improving aerobic exercise performance in male athletes.


Childhood intussusception in a regional hospital.
This study reviews all childhood intussusceptions treated over a 6 year period in a regional centre with six visiting general surgeons and two paediatricians. Clinical presentation, management, complications and outcomes were noted and an attempt was made to follow up all cases. There were 20 patients, with a median age of 6 months (range 10 weeks to 17 months). Only one patient had all four classical features of intussusception (pain, vomiting, 'red currant jelly' stools and abdominal mass). Seven patients were managed successfully by barium enema reduction, but 14 required operation, four following failed radiological reduction. There was one intestinal perforation due to attempted barium enema reduction and one patient required a reoperation for ileal gangrene following operative reduction. There were no deaths and there have been no subsequent recurrent intussusceptions although three cases were lost to follow up. There was a delay in diagnosis in some cases (average duration from onset to diagnosis was 34 h). Although delay was incurred by parents in some cases and in peripheral hospitals in others, there is a need for greater awareness by surgeons of the significance of subtle features such as pallor and lethargy in a child with persistent vomiting. Delay in diagnosis is likely to lead to an increased need for primary surgical intervention. Adverse features (age > 3 months or < 2 years; symptoms > 24 h; small bowel obstruction; dehydration > 5%) were predictive of an increased likelihood of surgical resection, and may help avoid inappropriate attempts at radiological reduction.(ABSTRACT TRUNCATED AT 250 WORDS)


Relating Chain Conformations to Extensional Stress in Entangled Polymer Melts.
Nonlinear extensional flows are common in polymer processing, but they remain challenging theoretically because dramatic stretching of chains deforms the entanglement network far from equilibrium. Here, we present coarse-grained simulations of extensional flows in entangled polymer melts for Rouse-Weissenberg numbers Wi_{R}=0.06-52 and Hencky strains ε≥6. Simulations reproduce experimental trends in extensional viscosity with time, rate, and molecular weight. Studies of molecular structure reveal an elongation and thinning of the confining tube with increasing Wi_{R}. The rising stress is quantitatively consistent with the decreasing entropy of chains at the equilibrium entanglement length. Molecular weight dependent trends in viscosity are related to a crossover from the Newtonian limit to a high rate limit that scales differently with chain length.


A categorical structure-activity relationship analysis of GPR119 ligands.
The categorical structure-activity relationship (cat-SAR) expert system has been successfully used in the analysis of chemical compounds that cause toxicity. Herein we describe the use of this fragment-based approach to model ligands for the G protein-coupled receptor 119 (GPR119). Using compounds that are known GPR119 agonists and compounds that we have confirmed experimentally that are not GPR119 agonists, four distinct cat-SAR models were developed. Using a leave-one-out validation routine, the best GPR119 model had an overall concordance of 99%, a sensitivity of 99%, and a specificity of 100%. Our findings from the in-depth fragment analysis of several known GPR119 agonists were consistent with previously reported GPR119 structure-activity relationship (SAR) analyses. Overall, while our results indicate that we have developed a highly predictive cat-SAR model that can be potentially used to rapidly screen for prospective GPR119 ligands, the applicability domain must be taken into consideration. Moreover, our study demonstrates for the first time that the cat-SAR expert system can be used to model G protein-coupled receptor ligands, many of which are important therapeutic agents.


Survival outcome of patients with screening versus symptomatically detected colorectal cancers.
The national Bowel Cancer Screening Programme has been rolled out nationwide following pilot screening in two health authorities in the UK. The aim of this study was to define overall 5-year survival of screen detected cancers and to compare the overall survival outcome of screened vs symptomatic patients over a 10-year period. All patients with colorectal cancer treated at one trust in patients of screening age (50-69 years) during the pilot screening programme (2000-2008) were analysed. Patients were defined as screen detected or symptomatically detected. Disease pathology and recurrence data were obtained from the hospital's computerized results reporting system and mortality was cross-matched with data from the West Midlands Cancer Intelligence Network. In all, 633 patients aged 50-69 were identified in the study period; 155 patients had a screen detected cancer and 478 did not. A log-rank test completed on survival outcomes indicated that survival was significantly worse in the symptomatic group. This difference persisted if only patients treated with curative intent were considered. Survival outcome was significantly better in the screened vs the symptomatic population in all groups and also in those treated for curative intent. There was a trend towards better survival for screen detected cancer when compared stage for stage.


Somatic changes during human prenatal life.
A twofold synopsis is presented on human developmental anatomy prior to birth. The first portion of the paper focuses on conceptual perspective and the second part on factual understanding. Section 1 gives an overview of the wide assortment of somatic changes manifested in the prenatal segment of human ontogeny; it illustrates alterations occurring in number, kind, location, size, and shape of body components. Section 2 presents a chronological panorama of human anatomical modifications during prenatal life; it traces somatic changes from "zygote to embryo", from "embryo to fetus", and during "the fetal period".


Identification and characterization of middle ear vascular leakage sites in experimental otitis media.
The site of leakage in middle ear vessels was determined and characterized in experimental otitis media in rats. Middle ear effusion was induced by intravenous administration or local application in the tympanic bulla of substance P (SP), acetylcholine, and histamine. In another experiment, a 14 degrees C airstream was blown into the external auditory canal. Colloidal carbon was used to trace leakage sites at the light and electron microscopic levels. All mediators tested and the 14 degrees C airstream resulted in an increased number of leaking vessels in the pars flaccida and the middle ear mucosa. The leakage sites were restricted to capillaries and postcapillary venules. Increased numbers of degranulated pars flaccida mast cells were observed for SP only. Interendothelial gaps formed in leakage vessels after administration of mediators and stimulation of the external auditory canal with a 14 degrees C airstream. Also, cytoplasmic vesicle-like structures within the endothelial cells increased in number following SP and histamine treatment, suggesting that an increased permeability in experimental otitis media does not occur exclusively through interendothelial gaps.


Ghrelin Alleviates MDMA-Induced Disturbance of Serum Glucose and Lipids Levels in the Rat.
Hepatotoxicity is one of the clinically adverse effects of ecstasy (3, 4-methylenedioxymethamphetamine; MDMA) consumption. The detoxification tissue, liver, plays a central role in maintaining circulating levels of glucose and lipid. Hypoglycemia and hypotriglyceridemia have been reported due to ecstasy abuse. Ghrelin is a 28-amino-acid peptide secreted predominantly from the stomach. It has been demonstrated that ghrelin has hepatoprotective effects and is able to increase blood glucose concentration. In the current study, we explored the effect of hepatotoxic dose of MDMA and therapeutic use of exogenous ghrelin on the serum levels of glucose and lipids in four groups of rats. MDMA caused a severe and transient reduction in circulating levels of glucose and triglyceride and increased serum LDL. However, cholesterol and HDL levels remained unchanged. Meanwhile, altered hepatic architecture was observed with intracellular vacuolation that may indicate intracellular accumulation of lipid droplets. In addition, following ghrelin administration, the blood sugar levels improved and LDL levels returned to the baseline value, and ghrelin treatment did not improve triglycerides levels. These results showed that MDMA causes hypoglycemia, hypotriglyceridemia, and hyper LDL-cholesterolemia. To our knowledge, this is the first report showing ghrelin administration could improve hypoglycemia and normalize LDL levels induced by MDMA and partially restore hepatic architecture.


[Chronic pancreatitis. A recent national experience with its surgical management].
The prevalence of chronic pancreatitis in Chile is not known and there is no local information about the surgical treatment of this disease. To review retrospectively the results of surgical treatment of chronic pancreatitis. The charts of 17 patients (12 male), aged 7 to 65 years old, with chronic pancreatitis that were operated in three different Chilean regions, were reviewed. Seven patients had previous endoscopic therapeutic procedures (papillotomy in 4 and stent placing in 3). Seven patients had been subjected to previous biliary surgical procedures. Indications for surgery were severe pain in 14 patients, the suspicion of a pancreatic carcinoma in 4 patients, an infected pseudocyst in one and massive bleeding of multiple pseudo-aneurysms in a pseudocyst in one patient. Twelve patients were subjected to decompressions and 5 to pancreatic resections. There was no operative mortality and one transient pancreatic fistula. After an average follow up of 22 months, pain improved in 94% of cases, pancreatic cancer was diagnosed in one patient and 79% of subjects gained weight. One patient became insulin dependent, one increased his insulin requirements and one had transient steatorrhea, since she could not afford pancreatic enzyme replacement therapy. The multidisciplinary approach of patients with chronic pancreatitis, with selective use of surgery, may greatly improve their quality of life.


Compendium of unpublished phase III trials in oncology: characteristics and impact on clinical practice.
Many phase III trials presented at annual meetings of the American Society of Clinical Oncology (ASCO) remain unpublished. The results of these unpublished trials, if more generally known, might have an impact on clinical practice. Abstracts of large phase III trials evaluating systemic cancer treatment were identified from conference proceedings of the 1989 to 2003 ASCO annual meetings. PubMed, Medline, and Embase were searched for corresponding publications. A compendium of unpublished phase III trials was assembled. Clinical significance of nonpublication was determined by disease site-specific oncology experts from two academic cancer centers in Canada. A total of 709 phase III trials were identified of which 66 (9.3%) remain without a subsequent publication at a minimum of 6.5 years of follow-up and 94 (13%) were published after a delay of ≥ 5 years from their initial presentation. Of the unpublished trials, 48% were presented as oral sessions at an ASCO meeting, and 71% of the abstracts reported negative results. The experts judged that 70% of the unpublished trials addressed an important question and 59% might have had clinical impact if their results had been published promptly. A substantial number of cancer clinical trials with potential influence on clinical practice remain unpublished and many other trials are published after a substantial delay. Nonpublication of clinical trials breaks an implicit contract with participants, institutional review boards, and sponsors.


Applications of computational toxicology methods at the Agency for Toxic Substances and Disease Registry.
In its efforts to provide consultations to state and local health departments, other federal agencies, health professionals, and the public on the health effects of environmental pollutants, the Agency for Toxic Substances and Disease Registry relies on the latest advances in computational toxicology. The computational toxicology laboratory at the agency is continually engaged in developing and applying models for decision-support tools such as physiologically based pharmacokinetic (PBPK) models, benchmark dose (BMD) models, and quantitative structure-activity relationship (QSAR) models. PBPK models are suitable for connecting exposure scenarios to biological indicators such as tissue dose or end point response. The models are used by the agency to identify the significance of exposure routes in producing tissue levels of possible contaminants for people living near hazardous waste sites. Additionally, PBPK models provide a credible scientific methodology for route-to-route extrapolations of health guidance values, which are usually determined from a very specific set of experiments. Also, scientists at the computational toxicology laboratory are using PBPK models for advancing toxicology research in such areas as joint toxicity assessment and child-based toxicity assessments. With BMD modeling, all the information embedded in an experimentally determined dose-response relationship is used to estimate, with minimum extrapolations, human health guidance values for environmental substances. Scientists in the laboratory also rely on QSAR models in the many cases where consultations from the agency are reported for chemicals that lack adequate experimental documentation.


Protective roles of adenosine A1, A2A, and A3 receptors in skeletal muscle ischemia and reperfusion injury.
Although adenosine exerts cardio-and vasculoprotective effects, the roles and signaling mechanisms of different adenosine receptors in mediating skeletal muscle protection are not well understood. We used a mouse hindlimb ischemia-reperfusion model to delineate the function of three adenosine receptor subtypes. Adenosine A(3) receptor-selective agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IBMECA; 0.07 mg/kg ip) reduced skeletal muscle injury with a significant decrease in both Evans blue dye staining (5.4 +/- 2.6%, n = 8 mice vs. vehicle-treated 28 +/- 6%, n = 7 mice, P < 0.05) and serum creatine kinase level (1,840 +/- 910 U/l, n = 13 vs. vehicle-treated 12,600 +/- 3,300 U/l, n = 14, P < 0.05), an effect that was selectively blocked by an A(3) receptor antagonist 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; 0.05 mg/kg). The adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 0.05 mg/kg) also exerted a cytoprotective effect, which was selectively blocked by the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.2 mg/kg). The adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.07 mg/kg)-induced decrease in skeletal muscle injury was selectively blocked by the A(2A) antagonist 2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e] [1,2,4]triazolo[1,5-C]pyrimidin-5-amine (SCH-442416; 0.017 mg/kg). The protection induced by the A(3) receptor was abrogated in phospholipase C-beta2/beta3 null mice, but the protection mediated by the A(1) or A(2A) receptor remained unaffected in these animals. The adenosine A(3) receptor is a novel cytoprotective receptor that signals selectively via phospholipase C-beta and represents a new target for ameliorating skeletal muscle injury.


Site-specific initiation of a DNA fragment: nucleotide sequence of the bacteriophage G4 negative-strand initiation site.
The synthesis of the bacteriophage G4 negative strand is an example of the de novo initiation of a polynucleotide chain. This initiation is performed by the Escherichia coli replication protein dna G which selects a unique site on 5400-base positive-strand template. In this paper we present the nucleotide sequence of the G4 negative-strand initiation site. This is the template element recognized by the dna G priming protein. In conjunction with the sequence of the nascent negative strand, obtained by Bouché, Rowen, and Kornberg [Bouché, J.-P., Rowen, L. & Kornberg, A. (1978) J. Biol. Chem. 253, 765-769], the present data provide a description of a dna G-dependent origin of replication in which one knows the place at which polymerization starts at the nucleotide level.


Biological and mechanical characterization of chitosan-alginate scaffolds for growth factor delivery and chondrogenesis.
Chitosan-alginate (Ch-Al) natural polysaccharide blends have been used for wound healing, tissue engineering, and drug delivery due to their ability to form pH-dependent ionic chain-chain interactions. Yet, the biomechanical properties and growth factor (GF) release kinetics of Ch-Al, which are important in controlling the microenvironment during tissue regeneration, have not been fully explored. This study examines the compressive elastic modulus of many Ch-Al scaffold formulations and crosslinking conditions, and also the strain recovery after compressive deformation of Ch-Al scaffolds, both of which make Ch-Al an attractive composite for reproducing articular cartilage's resistance to and resiliency under compression. Cell viability, proliferation, and in vitro cartilaginous matrix production (collagen type II, glycosaminoglycans, aggrecan) without supplemental GFs are also investigated, demonstrating the polymer blend's inherent chondrogenic properties. Additionally, this study explores the ability of Ch-Al chain functional groups to control and extend GF delivery and minimize GF burst release, using model proteins BSA and histone at high loading dose and chondrogenic protein TGF-β1 at low loading dose in complete media. Expedited cartilaginous matrix synthesis on Ch-Al with low dose TGF-β1 release is evaluated, with Ch-Al supporting homogeneous matrix deposition and lacunae formation as early as 3 weeks due to Ch-Al's maintenance of GF bioactivity and sustained GF delivery. These results illustrate the potential to focus the formulational range of Ch-Al to provide enhanced mechanical performance and controlled, bioactive GF release to cooperatively promote cartilage regeneration. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 272-282, 2017.


The same rat Delta6-desaturase not only acts on 18- but also on 24-carbon fatty acids in very-long-chain polyunsaturated fatty acid biosynthesis.
The recently cloned Delta6-desaturase is known to catalyse the first step in very-long-chain polyunsaturated fatty acid biosynthesis, i.e. the desaturation of linoleic and alpha-linolenic acids. The hypothesis that this enzyme could also catalyse the terminal desaturation step, i.e. the desaturation of 24-carbon highly unsaturated fatty acids, has never been elucidated. To test this hypothesis, the activity of rat Delta6-desaturase expressed in COS-7 cells was investigated. Recombinant Delta6-desaturase expression was analysed by Western blot, revealing a single band at 45 kDa. The putative involvement of this enzyme in the Delta6-desaturation of C(24:5) n-3 to C(24:6) n-3 was measured by incubating transfected cells with C(22:5) n-3. Whereas both transfected and non-transfected COS-7 cells were able to synthesize C(24:5) n-3 by elongation of C(22:5) n-3, only cells expressing Delta6-desaturase were also able to produce C(24:6) n-3. In addition, Delta6-desaturation of [1-(14)C]C(24:5) n-3 was assayed in vitro in homogenates from COS-7 cells expressing Delta6-desaturase or not, showing that Delta6-desaturase catalyses the conversion of C(24:5) n-3 to C(24:6) n-3. Evidence is therefore presented that the same rat Delta6-desaturase catalyses not only the conversion of C(18:3) n-3 to C(18:4) n-3, but also the conversion of C(24:5) n-3 to C(24:6) n-3. A similar mechanism in the n-6 series is strongly suggested.


[Changes in bone mineral content in kidney deficiency].
Bone mineral determination (BMD) of ulna and radius in 184 patients with and without Kidney Deficiency (KD) were assayed. (BMD) in KD patients was apparently lower than that without KD as well as normal group, no difference between the patients without KD and the normal group, but there was a significant difference between the patients who had same disease with and without KD. The study indicated that BMD in patients with KD had characteristic change. It revealed also the objectivity of Syndrome in TCM.


Role of the twin-arginine translocase (tat) system in iron uptake in Listeria monocytogenes.
The twin-arginine translocase (Tat) complex is a unique system that translocates folded proteins across the cytoplasmic membrane. In this study, the Tat transporter system in Listeria monocytogenes was characterized to determine the role of Tat in the iron uptake pathway. A putative tatAC operon, containing conserved Fur-binding sequences in the promoter region, has been predicted to encode Tat-translocase components. Another operon, fepCAB, with a putative Fur-binding sequence in the promoter, close to TatAC, was identified in the complementary strands of L. monocytogenes. Electrophoretic mobility shift assay showed that the listerial Fur-repressor binds to the promoter of the tatAC operon, suggesting that tat is under Fur regulation. Using a heterologous system in a reporter assay, FepB was translocated across the membrane. Mutations in tatC and fepB were constructed to determine the roles of Tat and FepB, respectively. In a whole-cell ferric reductase assay, the fepB and tatC mutants were found to have reduced levels of ferric reductase activities compared with those of the isogenic parent strain. Although ferric reductase activity has been demonstrated in Listeria, a conventional ferric reductase encoding sequence does not appear to be present in its genome. Hence, we propose that fepB encodes a ferric reductase enzyme, which is translocated by the Tat-translocase system onto the bacterial cell surface, and plays an important role in the reductive iron uptake process in L. monocytogenes.


Sound absorption estimation of finite porous samples with deep residual learninga).
This work proposes a method to predict the sound absorption coefficient of finite porous absorbers using a residual neural network and a single-layer microphone array. The goal is to mitigate the discrepancies between predicted and measured data due to the finite-size effect for a wide range of rectangular absorbers with varying dimensions and flow resistivity and for various source-receiver locations. Data for training, validation, and testing are generated with a boundary element model consisting of a baffled porous layer on a rigid backing using the Delany-Bazley-Miki model. In effect, the network learns relevant features from the array pressure amplitude to predict the sound absorption as if the porous material were infinite. The method's performance is quantified with the error between the predicted and theoretical sound absorption coefficients and compared with the two-microphone method. For array distances close to the porous sample, the proposed method performs at least as well as the two-microphone method and significantly better than it for frequencies below 400 Hz and small absorber sizes (e.g., 20 × 20 cm2). The significance of the study lies in the possibility of measuring sound absorption on-site in the presence of strong edge diffraction.


A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts.
We have examined the effect of a synthetic low-molecular-weight matrix metalloproteinase inhibitor, [4-(N-hydroxyamino)-2R-isobutyl-3S- (thiopen-2-ylthiomethyl)-succinyl]-L-phenylalanine-N-meth yla mide (BB-94), on human ovarian carcinoma xenografts growing in nude mice. The xenografts grew as thick intraperitoneal mucinous ascites containing free-floating tumor cell clumps. The ascites increased in volume, causing death approximately 3 weeks after introduction. Treatment with BB-94 caused resolution of ascitic disease. Tumor burden was dramatically reduced, and survival increased 5-6-fold. The increase in survival was dose dependent. The effects observed with BB-94 appeared to be due to its matrix metalloproteinase inhibiting effects, inasmuch as its inactive diastereoisomer had no effect on tumor biology. Following treatment with BB-94, free-floating clumps of tumor cells became surrounded by a capsule of host cells. These clumps of tumor cells typically formed one small (approximately 8 mm) avascular tumor of bright white appearance loosely attached to fat in the peritoneum. Tumor cells within these capsules often appeared to be necrotic. Gel substrate analysis demonstrated that activated Mr 92,000 type IV collagenase was present in the xenografts. We propose that inhibition of this enzyme causes the transition of ascites to solid tumors, concomitantly slowing tumor cell growth and allowing the development of tumor stroma.