Cellular Behavior on Epidermal Growth Factor (EGF)-Immobilized PCL/Gelatin Nanofibrous Scaffolds.
Nano-scaled poly(ε-caprolactone) (PCL) and PCL/gelatin fibrous scaffolds with immobilized epidermal growth factor (EGF) were prepared for the purpose of wound-healing treatments. The tissue scaffolds were fabricated by electrospinning and the parameters that affect the electrospinning process were optimized. While the fiber diameters were 488 ± 114 nm and 663 ± 107 nm for PCL and PCL/gelatin scaffolds, respectively, the porosities were calculated as 79% for PCL and 68% for PCL/gelatin scaffolds. Electrospun PCL and PCL/gelatin scaffolds were first modified with 1,6-diaminohexane to introduce amino groups on their surfaces, then EGF was chemically conjugated to the surface of nanofibers. The results obtained from Attenuated Total Reflectance Fourier Transform Infrared (ATR-FT-IR) spectroscopy and quantitative measurements showed that EGF was successfully immobilized on nanofibrous scaffolds. L929 mouse fibroblastic cells were cultivated on both neat and EGF-immobilized PCL and PCL/gelatin scaffolds in order to investigate the effect of EGF on cell spreading and proliferation. According to the results, especially EGF-immobilized PCL/gelatin scaffolds exerted early cell spreading and superior and rapid proliferation compared to EGF-immobilized PCL scaffolds and neat PCL, PCL/gelatin scaffolds. Consequently, EGF-immobilized PCL/gelatin scaffolds could potentially be employed as novel scaffolds for skin tissueengineering applications.


Income inequality and traumatic dental injuries in 12-year-old children: A multilevel analysis.
Contextual socio-economic factors have been associated with traumatic dental injuries (TDIs). However, evidence concerning the role of income inequality on TDIs in children is scarce. The aim of this study was to investigate the association between contextual income inequality over a 10-year period and TDIs in Brazilian children. The study population comprised a representative sample of 5027 children aged 12 years who participated in the Brazilian oral health survey in 2010. City-level Gini Index was used to measure contextual income inequality in the years 2000 and 2010, as well as the variation in income inequality between 2000 and 2010. Covariates were gender, ethnicity, family income, number of people per room and incisal overjet. Clinical examinations were used to assess TDIs. Multivariable multilevel ordered multinomial logistic regression was used to estimate cumulative Odds Ratio (OR) and 95% confidence intervals between income inequality and TDIs. The prevalence of children who had one tooth with TDI and two or more teeth with TDIs was 15.2% and 6.4%, respectively. The maxillary central and left lateral incisors were the teeth most affected by TDIs. Gini coefficient reduction between the years 2000 and 2010 decreased the odds of TDIs even after adjustment for demographic and socio-economic characteristics, and incisal overjet. The likelihood of more TDIs decreased 21% for each 0.05 unit decrease in the Gini coefficient between the years 2000 and 2010. Boys, brown skin colour, overcrowding and incisal overjet greater than 5 mm remained statistically associated with TDIs in the final model. The decrease in income inequality over a 10-year period was inversely associated with TDIs among Brazilian children aged 12 years.


Current reversals and synchronization in coupled ratchets.
Current reversal is an intriguing phenomenon that has been central to recent experimental and theoretical investigations of transport based on ratchet mechanism. By considering a system of two interacting ratchets, we demonstrate how the coupling can be used to control the reversals. In particular, we find that current reversal that exists in a single driven ratchet system can ultimately be eliminated with the presence of a second ratchet. For specific coupling strengths a current-reversal free regime has been detected. Furthermore, in the fully synchronized state characterized by the coupling threshold k(th), a specific driving amplitude a(opt) is found for which the transport is optimum.


Stereotactic radiosurgery for intracranial tumors: Puerto Rico experience.
Historically, the treatment for most intracranial pathologies has included medical management, surgery, radiotherapy and recently, stereotactic radiosurgery. Since its introduction, stereotactic radiosurgery has evolved from an investigational concept into a recognized neurosurgical procedure for the management of a wide variety of brain disorders. The goal of this research was to describe the experience in Puerto Rico using this technology and review the efficacy, safety, and role of radiosurgery in the treatment of the most common intracranial tumors treated today. Patients treated from 1999-2009 at Clinicas Las Americas were reviewed and medical literature databases were searched for articles pertaining to stereotactic radiosurgery performed in these intracranial tumor pathologies: meningiomas, gliomas, cerebral metastasis, vestibular schwannomas and pituitary adenomas. Each study was examined to determine the radiosurgical parameters, duration of follow-up review, tumor growth control rate and complications. A total of 50 peer-reviewed studies were examined. Radiosurgery in benign tumors resulted in the control of tumor size in 90% of treated patients. Unfortunately radiosurgery for malignant tumors is not curative, but has been effective in improving survival and quality of life. Although microsurgery remains the primary treatment modality in most cases, stereotactic radiosurgery offers both safe and effective treatment for much intracranial pathologies. Further refinements in the radiosurgical technique will likely lead to improved outcomes and make it a standard of care.


Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis.
In recent years, US patients have increasingly been the first to receive new medications, some of which are subsequently discovered to have suspected adverse drug reactions (SADRs). As a result, the challenge of early detection has largely shifted to the US postmarketing systems. To review the association between the use of cerivastatin sodium and the risk of rhabdomyolysis in an effort to illustrate the operation and limitations of the current US postmarketing safety-surveillance system. For the published literature, we used previous reviews and MEDLINE searches from all years through 2003. For the unpublished literature, we used internal company documents that have become part of the public record during a trial in Nueces County, Texas. In the published literature, cerivastatin was associated with much larger risks of rhabdomyolysis than other statins. Although only a small percentage of cerivastatin users also took gemfibrozil, approximately half of the case reports of rhabdomyolysis occurred in users of this combination therapy, and a cerivastatin-gemfibrozil interaction was supported by the results of a 3-day pharmacokinetic study. In internal company documents, multiple case reports suggested a drug-drug interaction within approximately 100 days of the launch in 1998; however, the company did not add a contraindication about the concomitant use of cerivastatin and gemfibrozil to the package insert for more than 18 months. Unpublished data available in July 1999 also suggested an increased risk of rhabdomyolysis associated with high doses of cerivastatin monotherapy. In late 1999 and early 2000, company scientists conducted high-quality analyses of the US Food and Drug Administration adverse event reporting system data. These analyses suggested that compared with atorvastatin calcium, cerivastatin monotherapy substantially increased the risk of rhabdomyolysis. To our knowledge, these findings were not disseminated or published. The company continued to conduct safety studies, some of them inadequately designed to assess the risk of rhabdomyolysis, until cerivastatin was removed from the market in August 2001. Despite limitations of the available data, the asymmetry between the information available to the company and the information available to patients and physicians seems striking. A subjective element is present in the effort to infer whether or not the occurrence of untoward outcomes in users of a particular drug was actually the consequence of the use of that drug, and, under the current system, a pharmaceutical company's appraisal of SADRs may be influenced by economic considerations. Such an appraisal would best be made by an independent group. The US Congress should mandate and provide adequate support for independent reviews and analysis of postmarketing data.


The nature of lexical knowledge.
This paper considers the nature of lexical knowledge and its role in language and information processing. The lexicon is the central component of language and plays a pivotal role in current linguistic theory [3, 4] and, increasingly, in natural language processing systems [5-7]. The lexicon embodies information about the lexical items of the language and serves as the foundation for morphologic, syntactic, and semantic processing. The differences as well as commonalities among dictionaries, thesauri, and lexicons are discussed, and distinctions between words, lexical items, and terms are drawn. Next, the scope and content of the SPECIALIST lexicon are presented, followed by a discussion of certain writing conventions that can be troublesome for text processing applications. One approach to handling orthographic and other lexical variation is discussed in a section that reports on the design and implementation of the SPECIALIST lexical programs. The paper concludes with a discussion of controlled terminologies for the medical domain. Throughout the discussion, examples are drawn from the SPECIALIST lexicon and from the other UMLS knowledge sources [8, 9].


High Dimensional Analyses of Circulating Immune Cells in Psoriatic Arthritis Detects Elevated Phosphorylated STAT3.
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, affecting up to 40% of patients with psoriasis. Constitutive expression by CD4+ T cells of an active form of STAT3, a signal transducer and transcription factor, has been shown to induce many of the major features of PsA in an animal model. We used high dimensional mass cytometry (CyTOF) to probe ex-vivo levels of phosphorylated STAT3 (pSTAT3) in circulating immune cell subpopulations from PsA patients during active and inactive states. We evaluated the frequency of 16 immune cell populations and the levels of the activated forms of STAT3 (pSTAT3) and, for comparison, STAT1 (pSTAT1) and Src (pSrc) in whole blood fixed shortly after collection. In addition to PsA patients, we studied active rheumatoid arthritis (RA) patients. Increased levels of pSTAT3 were found in all the CD4+ T cell subsets analyzed, specifically, Th1, Th2, Th17, T follicular helper (Tfh) and T regulatory (Treg) as well as in CD14+CD16- (classical) monocytes from active PsA patients compared to inactive patients. After correcting for body mass index (BMI), smoking and conventional disease modifying antirheumatic drugs (c-DMARDs), levels of pSTAT3 levels remained increased in Th1 and Tfh CD4+ T cells, and in CD14+CD16- monocytes from active patients compared to inactive patients. No differences between the patient groups were observed for pSTAT1 or pSrc. No differences were found between the active PsA and active RA groups after correction for multiple testing. During active PsA, circulating Th1 and Tfh CD4+ T cells, and CD14+CD16- monocytes expressing high levels of pSTAT3 may play a role in PsA pathophysiology, perhaps by migration to inflamed sites.


The similarity and frequency of proposals to reform US medical education. Constant concerns.
To identify the values and agendas underlying reports advocating the reform of medical education and to account for their similarity and repeated promulgation. Major reports regarding undergraduate medical education reform published between 1910 and 1993 were identified through a manual bibliographic search. Nineteen of a total of 24 reports met the two inclusion criteria: they directly addressed undergraduate medical education and contained a coherent body of recommendations. Content analysis of 19 reports. All the reports articulate a specifically social vision of the medical profession, in which medical schools are seen as serving society. The reports are remarkably consistent regarding the objectives of reform and the specific reforms proposed. Core objectives of reform include the following: (1) to better serve the public interest, (2) to address physician workforce needs, (3) to cope with burgeoning medical knowledge, and (4) to increase the emphasis on generalism. Proposed reforms have tended to suggest changes in manner of teaching, content of teaching, faculty development, and organizational factors. Reforms such as increasing generalist training, increasing ambulatory care exposure, providing social science courses, teaching lifelong and self-learning skills, rewarding teaching, clarifying the school mission, and centralizing curriculum control have appeared almost continuously since 1910. The similarity of the reports' objectives and reforms results not only from a similar body of problems, but also from the reaffirmation of similar values. The reports have two implicit agendas that transcend the reform of medical education: the affirmation of the social nature of the medical profession and self-regulation of the profession. These agendas help account for the reports' similarity and their repeated promulgation.


Human parotid saliva protein composition: dependence on physiological factors.
The relative concentrations of the major proteins in human parotid saliva as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis varied greatly between the six individuals included in this study but were remarkably constant for a given individual. Individual relative parotid protein concentrations differed in salivas collected under unstimulated and stimulated conditions but were at least partially independent from circadian and feeding effects. In addition, the relative concentrations of certain salivary proteins decreased with continued lemon-drop stimulation. A total of 29 different bands was composited from the six subjects. Five of the bands had mobilities corresponding with those of calibration proteins selected for their known occurrence in parotid saliva. Only those proteins comprising at least 0.75% of the total protein concentration were detected. Relative protein concentrations of parotid saliva samples collected 12 mo apart from given individuals were identical.


[Erectile dysfunction: prevalence and effect on the quality of life; Boxmeer study].
To assess the prevalence of erectile dysfunction (ED), and its influence on both the quality of life, and health care seeking behaviour. An age-stratified random sample was drawn from men aged 40-79 years in Boxmeer, the Netherlands (n = 1771), together with their partners. A questionnaire was mailed to the study population to collect data on ED, and the quality of life, both general and disorder related. The prevalence of ED was measured with the direct question 'Do you have problems getting an erection?'. The influence of ED on sexual function was measured with the Dutch version of the Sexual Function Inventory questionnaire. Seventy percent of all men (n = 1233) and 73% of their partners (n = 1071) responded to the questionnaire. The prevalence of ED increased with age class. To the question regarding problems to get an erection, 13% (95% confidence interval: 11-15%) of all men answered affirmatively (40-49 years: 6%; 50-59: 9%; 60-69: 22%; 70-79: 38%). All men aged 40-49 years of age with ED and 16% of men aged 70-79 with ED considered their ED as bothersome. Amongst 40 to 49 year old men with ED, 64% considered their ED as a big or rather a big problem. Amongst older men this percentage was much smaller: 50-59 years: 38%; 60-69: 37%, and 70-79: 27%. Thirty-four percent of all men with ED and 16% of their spouses were dissatisfied with their sex life. Twenty-five percent of men with ED consulted a doctor, with a mean delay of 13 months. ED bore a strong correlation with the general quality of life and comorbidity. ED was a common disorder within the population. Its prevalence was higher among older age groups, but they regarded ED as less of a problem than the younger age groups. Only a quarter of all men with ED consulted a physician.


Serum selenium levels in acute gastroenteritis of possible viral origin.
Selenium, as an essential micronutrient, is required for the proper functioning of the immune system and its deficiency affects the occurrence, virulence, or disease progression of some viral infections. We conducted a study to determine the serum selenium levels of children with acute gastroenteritis of possible viral origin and the effect of the serum selenium levels on the severity and the morbidity of the disease. The study was performed prospectively on 109 children aged 2-24 months with diarrhea of less than 8 days' duration admitted to the Diarrheal Disease Training and Treatment Unit. Blood samples were taken for selenium measurement on admission and 7-10 days after the end of the disease. Forty-three healthy children formed the control group. The mean serum selenium level on admission (62.41 +/- 13.06 microg/dl) was significantly lower than the mean of the second samples 7-10 days after the end of the diarrhea (81.73 +/- 17.10 microg/dl). The mean of the control group was 74.36 +/- 10.75 microg/dl, which was lower than the mean of the second samples but higher than the first sample. The frequency of vomiting and purging on admission and at the control visit, duration of diarrhea on admission, total duration of diarrhea, dehydration, breastfeeding, sex of the patients, and severity score of the disease did not alter the serum selenium levels. No correlation was detected between serum selenium levels and the parameters above. Further studies about the changes in selenium status during infectious diseases and the effect of selenium status on related mortality and morbidity are required to determine if there is need for supplementation.


The Development of a Postgraduate Orthopaedic Manual Therapy Residency Program in Nairobi, Kenya.
There are very few opportunities for long-term, comprehensive postgraduate education in developing countries because of fiscal and human resource constraints. Therefore, physiotherapists have little opportunity following graduation to advance their skills through the improvement of clinical reasoning and treatment planning and application. To address the need for sustainable advanced instruction in physiotherapy within the country, a postgraduate Residency program was initiated in Nairobi, Kenya in 2012. The mission of the program is to graduate advanced orthopedic practitioners who can lead their communities and local profession in the advancement of clinical care and education. Since its inception, six cohorts have been initiated for a total of 90 resident participants. In addition, six program graduates are being trained to continue the Residency program and are serving as teaching assistants for the on campus modules. This training will result in a self-sustaining program by 2020. The manual therapy Residency education model allowed for advancement of the participating physiotherapists professional development utilizing evidence-based practice. This was done without altering the current education system within the country, or accessing expensive equipment. The Residency program was developed and established with the cooperation of a local education institution and a non-profit corporation in the United States. This collaboration has facilitated the advancement of orthopedic clinical standards in the country and will, hopefully, one day serve an as a template for future programs.


Quantum dot labeling of butyrylcholinesterase maintains substrate and inhibitor interactions and cell adherence features.
Butyrylcholinesterase (BChE) is the major acetylcholine hydrolyzing enzyme in peripheral mammalian systems. It can either reside in the circulation or adhere to cells and tissues and protect them from anticholinesterases, including insecticides and poisonous nerve gases. In humans, impaired cholinesterase functioning is causally involved in many pathologies, including Alzheimer's and Parkinson's diseases, trait anxiety, and post stroke conditions. Recombinant cholinesterases have been developed for therapeutic use; therefore, it is important to follow their in vivo path, location, and interactions. Traditional labeling methods, such as fluorescent dyes and proteins, generally suffer from sensitivity to environmental conditions, from proximity to different molecules or special enzymes which can alter them, and from relatively fast photobleaching. In contrast, emerging development in synthesis and surface engineering of semiconductor nanocrystals enable their use to detect and follow molecules in biological milieus at high sensitivity and in real time. Therefore, we developed a platform for conjugating highly purified recombinant human BChE dimers (rhBChE) to CdSe/CdZnS quantum dots (QDs). We report the development and characterization of highly fluorescent aqueous soluble QD-rhBChE conjugates, present maintenance of hydrolytic activity, inhibitor sensitivity, and adherence to the membrane of cultured live cells of these conjugates, and outline their advantageous features for diverse biological applications.


Muscarinic stimulation of adenylate cyclase activity of rat olfactory bulb. I. Analysis of agonist sensitivity.
In rat olfactory bulb, stimulation of muscarinic receptors activates adenylate cyclase. In the present study we have examined a variety of muscarinic receptor stimulants to characterize the agonist profile of this response. Analysis of agonist concentration-response curves revealed the following rank order of potency: oxotremorine-M greater than oxotremorine greater than BM5 greater than acetylcholine greater than carbachol = methacholine greater than (+/-)muscarine greater than arecoline greater than pilocarpine greater than RS 86 greater than McN-A-343 greater than bethanechol. Acetylcholine, oxotremorine-M, carbachol, (+/-)muscarine and metacholine behaved as full agonists, whereas the other stimulants displayed lower efficacies. The slope values of the concentration-response curves were close or equal to 1, except those of the carbachol and pilocarpine curves, which showed values significantly lower than 1. Moreover, the slope of the pilocarpine curve was differentially changed by the M1 antagonist pirenzepine and the M2 antagonist AF-DX 116. The agonist profile of the muscarinic stimulation of adenylate cyclase in the olfactory bulb correlated well with that exhibited by the muscarinic inhibition of the enzyme activity in the striatum, suggesting that the two responses are mediated by a similar receptor subtype. Sodium ion modulated the agonist affinity for both adenylate cyclase-coupled receptor systems.


Steady-state hydrogen peroxide induces glycolysis in Staphylococcus aureus and Pseudomonas aeruginosa.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from human pathogens Staphylococcus aureus and Pseudomonas aeruginosa can be readily inhibited by reactive oxygen species (ROS)-mediated direct oxidation of their catalytic active cysteines. Because of the rapid degradation of H2O2 by bacterial catalase, only steady-state but not one-dose treatment with H2O2 rapidly induces glycolysis and the pentose phosphate pathway (PPP). We conducted transcriptome sequencing (RNA-seq) analyses to globally profile the bacterial transcriptomes in response to a steady level of H2O2, which revealed profound transcriptional changes, including the induced expression of glycolytic genes in both bacteria. Our results revealed that the inactivation of GAPDH by H2O2 induces metabolic levels of glycolysis and the PPP; the elevated levels of fructose 1,6-biphosphate (FBP) and 2-keto-3-deoxy-6-phosphogluconate (KDPG) lead to dissociation of their corresponding glycolytic repressors (GapR and HexR, respectively) from their cognate promoters, thus resulting in derepression of the glycolytic genes to overcome H2O2-stalled glycolysis in S. aureus and P. aeruginosa, respectively. Both GapR and HexR may directly sense oxidative stresses, such as menadione.


Loop-Mediated Isothermal Amplification Assay for Detecting Tumor Markers and Human Papillomavirus: Accuracy and Supplemental Diagnostic Value to Endovaginal MRI in Cervical Cancer.
To establish the sensitivity and specificity of a human papillomavirus (HPV) and tumor marker DNA/mRNA assay for detecting cervical cancer that is transferrable to a Lab-on-a-chip platform and determine its diagnostic benefit in early stage disease when used in conjunction with high-resolution endovaginal magnetic resonance imaging (MRI). Forty-one patients (27 with Stage1 cervical cancer [Group1] and 14 non-cancer HPV negative controls [Group2]) had DNA and RNA extracted from cervical cytology swab samples. HPV16, HPV18, hTERT, TERC/GAPDH and MYC/GAPDH concentration was established using a loop mediated isothermal amplification (LAMP) assay. Thresholds for tumor marker detection for Group1 were set from Group2 analysis (any hTERT, TERC/GAPDH 3.12, MYC/GAPDH 0.155). Group 1 participants underwent endovaginal MRI. Sensitivity and specificity for cancer detection by LAMP and MRI individually and combined was documented by comparison to pathology. Sensitivity and specificity for cancer detection was 68.8% and 77.8% if any tumor marker was positive regardless of HPV status (scenario1), and 93.8% and 55.8% if tumor marker or HPV were positive (scenario 2). Adding endovaginal MRI improved specificity to 88.9% in scenario 1 (sensitivity 68.8%) and to 77.8%% in scenario2 (sensitivity 93.8%). Specificity for cervical cancer detection using a LAMP assay is superior with tumor markers; low sensitivity is improved by HPV detection. Accuracy for early stage cervical cancer detection is optimal using a spatially multiplexed tumor marker/HPV LAMP assay together with endovaginal MRI.


Sexually transmitted infections among patients with herpes simplex virus at King Abdulaziz University Hospital.
Herpes simplex virus (HSV) infection is one of the commonest viral sexually transmitted infections (STIs). The aim of this study was to evaluate the prevalence of STIs among HSV positive patients at a tertiary hospital in Jeddah. Secondary objective of the study included the description of the demographic and clinical profile of patients with HSV and HIV co-infection. A retrospective chart review of the medical records was performed for HSV positive women who presented to the emergency room and outpatient department of King Abdulaziz University Hospital, Jeddah, Saudi Arabia between January 1, 2003 and August 30, 2011. Data were collected from the medical records of all the patients and analyzed using the Statistical Package for the Social Sciences. Three hundred forty-three HSV positive patients were included in this study. Co-infection with HIV was documented in 45 patients (13.1%). Other STIs included chlamydia (n = 43, 12.5%), gonorrhea (n = 44, 12.8%), hepatitis B infection (n = 8, 2.3%), and cytomegalovirus infection (n = 37, 10.8%). Nineteen patients (5.5%) had a total of 47 term pregnancies and five abortions post HSV diagnosis. Genital ulcer disease was diagnosed in 11 (57.9%) of the cases during labor. One newborn developed neonatal herpes infection and subsequently showed delayed psychomotor development during follow up. Genital herpes was diagnosed in one patient's partner; however, there was no documentation of screening for STIs in the partners of the other patients. Sexually transmitted infections are relatively common among HSV positive patients at King Abdulaziz University Hospital. Amongst these, HIV is the most common, with a prevalence of 13.1%. Further studies are warranted to evaluate STIs in Saudi Arabia. Health policy makers should adopt a protocol to screen for STIs in the partners of persons who are positive for any STI as early detection and appropriate treatment can improve the outcome.


Current trends in ophthalmic anesthesia. The Second Walter S. Atkinson Lecture.
General anesthesia permits surgery involving large operative fields without limit to time. It is essential in children and uncooperative adults and provides an immobile, quiet patient who does not recall the operative procedure. Local and regional anesthesia re indicated when the surgical field is limited in size and extent. Neuroleptanesthesia in ophthalmology usually involves the administration of droperidol followed by fentanyl followed in intubation, sometimes using a muscle relaxant, and maintenance of anesthesia with nitrous oxide. The terrifying dreams produced by ketamine may be minimized by preoperative administration of diazepam and a quiet recovery period. Attempts to eliminate the oculocardiac reflex are unpredictable and unreliable and, with careful monitoring of anesthesia, elimination does not seem essential. Malignant hyperthermia is an autosomal dominant disorder occurring mainly with the administration of halogenated fluoroethane and depolarizing muscle relaxants. It is often signaled by sudden and prolonged muscle spasm following the injection of the muscle relaxant. Treatment must be directed toward hyperventilation using oxygen, correction of the metabolic respiratory acidosis, and reduction of fever.


The endocannabinoid system: Novel targets for treating cancer induced bone pain.
Treating Cancer-induced bone pain (CIBP) continues to be a major clinical challenge and underlying mechanisms of CIBP remain unclear. Recently, emerging body of evidence suggested the endocannabinoid system (ECS) may play essential roles in CIBP. Here, we summarized the current understanding of the antinociceptive mechanisms of endocannabinoids in CIBP and discussed the beneficial effects of endocannabinoid for CIBP treatment. Targeting non-selective cannabinoid 1 receptors or selective cannabinoid 2 receptors, and modulation of peripheral AEA and 2-AG, as well as the inhibition the function of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have produced analgesic effects in animal models of CIBP. Management of ECS therefore appears to be a promising way for the treatment of CIBP in terms of efficacy and safety. Further clinical studies are encouraged to confirm the possible translation to humans of the very promising results already obtained in the preclinical studies.


[Malignant fibrous histiocytoma].
Malignant fibrous histiozytoma (MHF) is a pleomorphic sarcoma of ubiquituous origin. The clinical and radiological features of the tumor are illustrated by 23 patients with MFH of soft tissue and 4 MFH of bone. On conventional radiography MFH appears as a soft tissue tumor, sometimes with bone involvement; on sonography it is usually non-homogeneous and hypoechogenic with areas of necrosis. On CT the masses are homogeneous or inhomogeneous (10-60 HU.) containing areas of decreased density. Contrast enhancement was about 10-20 HU. Angiographically the tumor appears as hypo- or hypervascular with pathologic vessels. The morphology of MFH in diagnostic imaging including magnetic resonance tomography is discussed with the relevant literature.


Comparison of the kinetics of different Markov models for ligand binding under varying conditions.
We recently derived a Markov model for macromolecular ligand binding dynamics from few physical assumptions and showed that its stationary distribution is the grand canonical ensemble [J. W. R. Martini, M. Habeck, and M. Schlather, J. Math. Chem. 52, 665 (2014)]. The transition probabilities of the proposed Markov process define a particular Glauber dynamics and have some similarity to the Metropolis-Hastings algorithm. Here, we illustrate that this model is the stochastic analog of (pseudo) rate equations and the corresponding system of differential equations. Moreover, it can be viewed as a limiting case of general stochastic simulations of chemical kinetics. Thus, the model links stochastic and deterministic approaches as well as kinetics and equilibrium described by the grand canonical ensemble. We demonstrate that the family of transition matrices of our model, parameterized by temperature and ligand activity, generates ligand binding kinetics that respond to changes in these parameters in a qualitatively similar way as experimentally observed kinetics. In contrast, neither the Metropolis-Hastings algorithm nor the Glauber heat bath reflects changes in the external conditions correctly. Both converge rapidly to the stationary distribution, which is advantageous when the major interest is in the equilibrium state, but fail to describe the kinetics of ligand binding realistically. To simulate cellular processes that involve the reversible stochastic binding of multiple factors, our pseudo rate equation model should therefore be preferred to the Metropolis-Hastings algorithm and the Glauber heat bath, if the stationary distribution is not of only interest.


Distal convoluted tubule.
The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical practice.


Enhanced crossover SCRATCHY: construction and high-throughput screening of a combinatorial library containing multiple non-homologous crossovers.
SCRATCHY is a methodology for the construction of libraries of chimeras between genes that display low sequence homology. We have developed a strategy for library creation termed enhanced crossover SCRATCHY, that significantly increases the number of clones containing multiple crossovers. Complementary chimeric gene libraries generated by incremental truncation (ITCHY) of two distinct parental sequences are created, and are then divided into arbitrarily defined sections. The respective sections are amplified by skewed sets of primers (i.e. a combination of gene A specific forward primer and gene B specific reverse primer, etc.) allowing DNA fragments containing non-homologous crossover points to be amplified. The amplified chimeric sections are then subjected to a DNA shuffling process generating an enhanced crossover SCRATCHY library. We have constructed such a library using the rat theta 2 glutathione transferase (rGSTT2) and the human theta 1 glutathione transferase (hGSTT1) genes (63% DNA sequence identity). DNA sequencing analysis of unselected library members revealed a greater diversity than that obtained by canonical family shuffling or with conventional SCRATCHY. Expression and high-throughput flow cytometric screening of the chimeric GST library identified several chimeric progeny that retained rat-like parental substrate specificity.


Pentraxin 3: A promising Therapeutic Target for Cardiovascular Diseases.
Cardiovascular disease (CVD) is the primary global cause of death,and inflammation is a crucial factor in the development of CVDs. The acute phase inflammatory protein pentraxin 3 (PTX3) is a biomarker reflecting the immune response. Recent research indicates that PTX3 plays a critical role in CVDs and has been investigated as a possible biomarker for CVD in clinical settings. PTX3 is implicated in the progression of CVDs through mechanisms such as exacerbating vascular endothelial dysfunction, affecting angiogenesis, and regulating inflammation and oxidative stress. This review summarizes the structure and function of PTX3, focusing on its multifaceted effects on CVDs, such as atherosclerosis, myocardial infarction, and hypertension. This may help in explaining the varying PTX3 doses and usage, as well as in utilizing target organs to manage diseases. Moreover, elucidating the opposite role of PTX3 in the cardiovascular system will demonstrate the therapeutic and predictive potential in human diseases.


Understanding the interface between clinical and laboratory staff.
The interface between clinicians and laboratory staff is where the two meet and work together to provide quality care to their clients (patients). Effectiveness of the interface depends on the way the two groups of professionals relate to and communicate with each other. The number and type of tests requested and the use of the test results for clinical decision making can be influenced by the interface between clinicians and laboratory staff. A model to understand the factors and dynamics around the interface is lacking. To propose a new conceptual model to gain insight and analyse factors that influence the laboratory-clinical staff interface. To develop the conceptual model, a literature study was performed, regulatory guidelines and standards for laboratories were analysed and discussions were held with experts on the topic. A conceptual model and analytical framework provided good guidance in understanding and assessing the organisational and personal factors shaping the interface. The model was based on three elements: (1) the three phases of communication (pre-analytical, analytical and post-analytical); (2) the organisational and personal factors of interaction; and (3) the socio-political, economic and cultural context in which clinicians and laboratory staff operate. Assessment of the interface between clinicians and laboratory workers can be performed in a systematic way. Applying this model will provide information to managers of health institutions and heads of laboratories and clinical departments about what happens when clinicians and laboratory staff interact, thus aiding them in designing strategies to improve this interface.


Heart-specific isoform of tropomyosin4 is essential for heartbeat in zebrafish embryos.
Tropomyosin (Tpm) proteins, encoded by four Tpm genes (Tpm1-4), are associated with the stabilization of the F-actin filaments and play important roles in modulating muscle contraction. So far, little is known about Tpm4 function in embryonic heart development and its involvement in the cardiovascular diseases. In this study, we investigated functions of different isoforms of tpm4 in embryonic heartbeat in zebrafish. The transgenic zebrafish line, T2EGEZ8, was generated by insertion of a Tol2 transposon gene trap vector, and homozygous mutants (T2EGEZ8(m/m)) of this line showed failure of embryonic heartbeat without other detectable phenotypes. Observation by transmission electron microscopy revealed that the ventricular myocytes of mutant fish contained fewer, disorganized myofibrillar filaments. The transposon genome in T2EGEZ8 fish was found by thermal asymmetric interlaced-polymerase chain reaction (TAIL-PCR) and reverse transcription-polymerase chain reaction to have inserted into the ninth intron of the tpm4 locus, which resulted in production of Tpm4-GFP fusion proteins and loss of normal transcripts tpm4-tv1 and tpm4-tv2. Whole-mount in situ hybridization indicated that tpm4-tv1, encoding a peptide of 284 residues, is specifically expressed in the heart of zebrafish embryos, while tpm4-tv2, encoding a peptide of 248 residues, is mainly present in the vasculature but absent in the heart. Knockdown of tpm4-tv1 and tpm4-tv2 within wild-type embryos led to the failure of heartbeat, which could be rescued by coinjection with tpm4-tv1 mRNA but not with tpm4-tv2 mRNA. Tpm4-tv1 is a heart-specific isoform of Tpm4 and is essential for heartbeat in zebrafish embryos.


The EvMed Assessment: A test for measuring student understanding of core concepts in evolutionary medicine.
Universities throughout the USA increasingly offer undergraduate courses in evolutionary medicine (EvMed), which creates a need for pedagogical resources. Several resources offer course content (e.g. textbooks) and a previous study identified EvMed core principles to help instructors set learning goals. However, assessment tools are not yet available. In this study, we address this need by developing an assessment that measures students' ability to apply EvMed core principles to various health-related scenarios. The EvMed Assessment (EMA) consists of questions containing a short description of a health-related scenario followed by several likely/unlikely items. We evaluated the assessment's validity and reliability using a variety of qualitative (expert reviews and student interviews) and quantitative (Cronbach's α and classical test theory) methods. We iteratively revised the assessment through several rounds of validation. We then administered the assessment to undergraduates in EvMed and Evolution courses at multiple institutions. We used results from the pilot to create the EMA final draft. After conducting quantitative validation, we deleted items that failed to meet performance criteria and revised items that exhibited borderline performance. The final version of the EMA consists of six core questions containing 25 items, and five supplemental questions containing 20 items. The EMA is a pedagogical tool supported by a wide range of validation evidence. Instructors can use it as a pre/post measure of student learning in an EvMed course to inform curriculum revision, or as a test bank to draw upon when developing in-class assessments, quizzes or exams.


Cold Atmospheric Plasma Jet Irradiation Decreases the Survival and the Expression of Oncogenic miRNAs of Oral Carcinoma Cells.
Despite recent advancements, therapies against advanced oral squamous cell carcinoma (OSCC) remain ineffective, resulting in unsatisfactory therapeutic outcomes. Cold atmospheric plasma (CAP) offers a promising approach in the treatment of malignant neoplasms. Although the effects of CAP in abrogating OSCC have been explored, the exact mechanisms driving CAP-induced cancer cell death and the changes in microRNA (miRNA) expression are not fully understood. We fabricated and calibrated an argon-CAP device to explore the effects of CAP irradiation on the growth and expression of oncogenic miRNAs in OSCC. The analysis revealed that, in OSCC cell lines following CAP irradiation, there was a significant reduction in viability; a downregulation of miR-21, miR-31, miR-134, miR-146a, and miR-211 expression; and an inactivation of the v-akt murine thymoma viral oncogene homolog (AKT) and extracellular signal-regulated kinase (ERK) signals. Pretreatment with blockers of apoptosis, autophagy, and ferroptosis synergistically reduced CAP-induced cell death, indicating a combined induction of variable death pathways via CAP. Combined treatments using death inhibitors and miRNA mimics, alongside the activation of AKT and ERK following the exogenous expression, counteracted the cell mortality associated with CAP. The CAP-induced downregulation of miR-21, miR-31, miR-187, and miR-211 expression was rescued through survival signaling. Additionally, CAP irradiation notably inhibited the growth of SAS OSCC cell xenografts on nude mice. The reduced expression of oncogenic miRNAs in vivo aligned with in vitro findings. In conclusion, our study provides new lines of evidence demonstrating that CAP irradiation diminishes OSCC cell viability by abrogating survival signals and oncogenic miRNA expression.


Effects of creatine loading on electromyographic fatigue threshold in cycle ergometry in college-age men.
The purpose of this study was to examine the effects of 5 d of creatine (Cr) loading on the electromyographic fatigue threshold (EMG FT) in college-age men. Sixteen men (age 22.4 +/- 2.6 yr, height 177.4 +/- 6.8 cm, weight 79.5 +/- 10.6 kg; M +/- SD) participated in this double-blind study and were randomly placed into either placebo (Pl; 10 g of flavored fructose powder per packet; n = 8) or Cr (5 g dicreatine citrate plus 10 g of flavored fructose powder per packet; n = 8) loading groups. Each participant ingested 1 packet 4 times/d, totaling 20 g/d for 5 days (loading). Before and after loading, each participant performed a discontinuous cycle-ergometer test to determine his EMG FT, using bipolar surface electrodes placed on the vastus lateralis of the right thigh. Four 60-s work bouts (ranging from 200 to 400 W) were completed. Adequate rest was given between bouts to allow for the participants' heart rate (HR) to drop within 10 beats of their resting HR. The EMG amplitude was averaged over 5-s intervals for each 60-s work bout. Resulting slopes from each successive work bout were used to calculate EMG FT. A 2-way ANOVA, Group (Cr vs. Pl) x Time (pre vs. post), resulted in a nonsignificant (p > .05) interaction for supplement and time. In addition, a significant increase (p = .009) in weight was observed in the Cr group. These data suggest that there was a minimal influence of Cr loading on EMG FT for the participants in this study.


[The electric potential at the entrance of the amphotericin channel].
The dependence of the blockage of amphotericin B channel conductance on the concentration of inorganic anions is shown. A model of the interaction of amphotericin B channel with blocker ion is proposed. According to the model the blocker ion is bound to the charged groups of the channel entrance. The inorganic anions also interact with these groups and affect the blocker concentration near the channel entrance.


Small-scale grassland assembly patterns differ above and below the soil surface.
The existence of deterministic assembly rules for plant communities remains an important and unresolved topic in ecology. Most studies examining community assembly have sampled aboveground species diversity and composition. However, plants also coexist belowground, and many coexistence theories invoke belowground competition as an explanation for aboveground patterns. We used next-generation sequencing that enables the identification of roots and rhizomes from mixed-species samples to measure coexisting species at small scales in temperate grasslands. We used comparable data from above (conventional methods) and below (molecular techniques) the soil surface (0.1 x 0.1 x 0.1 m volume). To detect evidence for nonrandom patterns in the direction of biotic or abiotic assembly processes, we used three assembly rules tests (richness variance, guild proportionality, and species co-occurrence indices) as well as pairwise association tests. We found support for biotic assembly rules aboveground, with lower variance in species richness than expected and more negative species associations. Belowground plant communities were structured more by abiotic processes, with greater variability in richness and guild proportionality than expected. Belowground assembly is largely driven by abiotic processes, with little evidence for competition-driven assembly, and this has implications for plant coexistence theories that are based on competition for soil resources.


Applications of mass spectrometry to metabolomics and metabonomics: detection of biomarkers of aging and of age-related diseases.
Every 5 years or so new technologies, or new combinations of old ones, seemingly burst onto the science scene and are then sought after until they reach the point of becoming commonplace. Advances in mass spectrometry instrumentation, coupled with the establishment of standardized chemical fragmentation libraries, increased computing power, novel data-analysis algorithms, new scientific applications, and commercial prospects have made mass spectrometry-based metabolomics the latest sought-after technology. This methodology affords the ability to dynamically catalogue and quantify, in parallel, femtomole quantities of cellular metabolites. The study of aging, and the diseases that accompany it, has accelerated significantly in the last decade. Mutant genes that alter the rate of aging have been found that increase lifespan by up to 10-fold in some model organisms, and substantial progress has been made in understanding fundamental alterations that occur at both the mRNA and protein level in tissues of aging organisms. The application of metabolomics to aging research is still relatively new, but has already added significant insight into the aging process. In this review we summarize these findings. We have targeted our manuscript to two audiences: mass spectrometrists interested in applying their technical knowledge to unanswered questions in the aging field, and gerontologists interested in expanding their knowledge of both mass spectrometry and the most recent advances in aging-related metabolomics.


A step-by-step introduction to rule-based design of synthetic genetic constructs using GenoCAD.
GenoCAD is an open source web-based system that provides a streamlined, rule-driven process for designing genetic sequences. GenoCAD provides a graphical interface that allows users to design sequences consistent with formalized design strategies specific to a domain, organization, or project. Design strategies include limited sets of user-defined parts and rules indicating how these parts are to be combined in genetic constructs. In addition to reducing design time to minutes, GenoCAD improves the quality and reliability of the finished sequence by ensuring that the designs follow established rules of sequence construction. GenoCAD.org is a publicly available instance of GenoCAD that can be found at www.genocad.org. The source code and latest build are available from SourceForge to allow advanced users to install and customize GenoCAD for their unique needs. This chapter focuses primarily on how the GenoCAD tools can be used to organize genetic parts into customized personal libraries, then how these libraries can be used to design sequences. In addition, GenoCAD's parts management system and search capabilities are described in detail. Instructions are provided for installing a local instance of GenoCAD on a server. Some of the future enhancements of this rapidly evolving suite of applications are briefly described.


Type 1 aldosterone synthase deficiency presenting in a middle-aged man.
Aldosterone synthase deficiency due to mutations in the CYP11B2 gene usually presents in infancy with electrolyte abnormalities and failure to thrive, whereas affected adults are usually asymptomatic. We describe a patient who first came to medical attention in middle age when he developed hyperkalemia after preparation for a barium enema. Past medical history was notable for failure to thrive in infancy. He had elevated PRA with low serum and urinary levels of aldosterone and its metabolites and normal or slightly elevated levels of 18-hydroxycorticosterone. These findings suggested a diagnosis of type 1 aldosterone synthase deficiency. The patient had a homozygous duplication of six nucleotides at codon 143 in exon 3 of CYP11B2, leading to the insertion of two amino acid residues (Arg-Leu). When the corresponding mutant complementary DNA was expressed in cultured cells, the resulting enzyme was completely inactive, confirming the diagnosis. We conclude that aldosterone synthase deficiency represents an unusual cause of hyperreninemic hypoaldosteronism presenting in adult life, but it should be suspected if the past medical history is positive for failure to thrive in childhood or if the patient manifests no other recognized causes of hyperreninemic hypoaldosteronism.


Breast-feeding patterns, time to initiation, and mortality risk among newborns in southern Nepal.
Initiation of breast-feeding within 1 h after birth has been associated with reduced neonatal mortality in a rural Ghanaian population. In South Asia, however, breast-feeding patterns and low birth weight rates differ and this relationship has not been quantified. Data were collected during a community-based randomized trial of the impact of topical chlorhexidine antisepsis interventions on neonatal mortality and morbidity in southern Nepal. In-home visits were conducted on d 1-4, 6, 8, 10, 12, 14, 21, and 28 to collect longitudinal information on timing of initiation and pattern of breast-feeding. Multivariable regression modeling was used to estimate the association between death and breast-feeding initiation time. Analysis was based on 22,838 breast-fed newborns surviving to 48 h. Within 1 h of birth, 3.4% of infants were breast-fed and 56.6% were breast-fed within 24 h of birth. Partially breast-fed infants (72.6%) were at higher mortality risk [relative risk (RR) = 1.77; 95% CI = 1.32-2.39] than those exclusively breast-fed. There was a trend (P = 0.03) toward higher mortality with increasing delay in breast-feeding initiation. Mortality was higher among late (> or = 24 h) compared with early (< 24 h) initiators (RR = 1.41; 95% CI = 1.08-1.86) after adjustment for low birth weight, preterm birth, and other covariates. Improvements in breast-feeding practices in this setting may reduce neonatal mortality substantially. Approximately 7.7 and 19.1% of all neonatal deaths may be avoided with universal initiation of breast-feeding within the first day or hour of life, respectively. Community-based breast-feeding promotion programs should remain a priority, with renewed emphasis on early initiation in addition to exclusiveness and duration of breast-feeding.


Comparison of granule proteins from human polymorphonuclear leukocytes which are bactericidal toward Pseudomonas aeruginosa.
Killing of Pseudomonas aeruginosa by a 55-kDa bactericidal protein (BP 55), a 30-kDa protein (BP 30), cathepsin G, elastase, and proteinase 3 has been compared. P. aeruginosa was resistant to killing by elastase and proteinase 3. BP 55 at a 50% lethal dose (LD50) of 0.23 micrograms of protein per 5 x 10(6) bacteria per ml killed P. aeruginosa and was far more active than BP 30 and cathepsin G. The LD50s of BP 30 and cathepsin G were 16.9 and 28.3 micrograms of protein per 5 x 10(6) bacteria per ml, respectively. Preincubation of BP 55 or BP 30 with lipopolysaccharide (LPS) from P. aeruginosa inhibited bactericidal activity. The N-terminal amino acid sequence of BP 55 and BP 30 revealed no relationship between the two proteins. However, a monoclonal antibody (AHN-15) reacted with both proteins by Western immunoblot. The bactericidal activity of cathepsin G toward P. aeruginosa appeared to be dependent on the availability of the active site of the enzyme; bactericidal activity was inhibited by phenylmethylsulfonyl fluoride (PMSF) and by the specific cathepsin G inhibitor, Z-Gly-Leu-Phe-CH2Cl. The enzyme and bactericidal activities of cathepsin G were also inhibited by LPS from P. aeruginosa. LPS from P. aeruginosa was shown to be a competitive inhibitor of the enzyme activity of cathepsin G. Elastase enzyme activity was also inhibited noncompetitively by LPS, but the enzyme was not bactericidal. We have concluded that all three bactericidal proteins (BP 55, BP 30, and cathepsin G) may bind to the LPS of the outer membrane of P. aeruginosa. It appears that the enzyme active site must be available for cathepsin G to kill P. aeruginosa and that the active site may be involved in the binding of cathepsin G to P. aeruginosa.


[Antimicrobial effect of hydrazides and ilidenhydrazides of (quinoline-2-ilthio)carboxylic acids].
Antimicrobial activity of hydrazides and ilidenhydrazides of (quinoline-2-ilthio) carboxylic acids has been studied. It was shown, that the majority of compounds had moderate antimicrobial activity. It was established that beta-(5-nitrofuryl-2)allylidenhydrazides (4-methylquinoline-2-ilthio)acetic acid showed the expressed antibacterial activity with respect to gram-positive bacterial and Candida albicans; it also suppresses the growth of similar yeast fungus.


The economic burden of treating neonates in Intensive Care Units (ICUs) in Greece.
In a period when a public-private mix in Greece is under consideration and hospital budgets become restrained, economic assessment is important for rational decision making. The study aimed to estimate the hospitalization cost of neonates admitted to the ICUs and demonstrate discrepancies with reimbursement. Chosen methodology was based on the selection of medical records of all NICUs and intermediate care admissions within February to April 2004. Neonates (n = 99) were classified according to birthweight and gestational age. Mean cost per infant was estimated at euro5.485 while reimbursement from social funds arises to euro3.952. Costs per birthweight or gestational age show an inverse relationship. Personnel costs accounted for 59.9%, followed by enteral/parenteral feeding (16.14%) and pharmaceuticals expenses (11.10%) of all resources consumed. Sensitivity analysis increases the robustness of the results Neonatal intensive care in Greece is associated with significant costs that exceed reimbursement from social funds. Reimbursement should be adjusted to make neonatal intensive care economically viable to private hospitals and thus, increase capacity of the services provided.


Prognostic factors in glaucomatous visual field loss.
A retrospective review was conducted of 31 patients with bilateral elevations of intraocular pressure and unilateral glaucomatous visual field loss. Nine (29%) of the fellow eyes developed visual field loss during a three- to seven-year follow-up period. Of the 13 fellow eyes that had an initial intraocular pressure greater than 26 mm Hg, eight (62%) developed visual field loss, as opposed to one (6%) of the 18 eyes that had lower intraocular pressures. Of the 11 fellow eyes whose intraocular pressures exceeded 24 mm Hg, either treated or untreated, on more than 50% of the measurements, seven (64%) lost visual field, whereas in the 20 eyes whose intraocular pressures were lower, only two )10%) lost visual field.


Colonoscopy complications: experience with 8968 consecutive patients in a single institution.
to evaluate the incidence, epidemiological characteristics, diagnosis and evolution of patients who returned to the emergency care units of the Albert Einstein Hospital in São Paulo/SP with signs and symptoms suggestive of colonoscopy complications up to 30 days after the procedure. we conducted a retrospective, uni-institutional study of patients submitted to colonoscopy in 2014 who returned to the Emergency department (ED) within 30 days after the procedure. 8968 patients underwent colonoscopies, 95 (1.06%) of whom had complaints related to possible complications. Most of the procedures were elective ones. Minor complications (nonspecific abdominal pain/distension) were frequent (0.49%) and most of the patients were discharged after consultation at the ED. Severe complications were less frequent: perforation (0.033%), lower gastrointestinal bleeding (0.044%), and intestinal obstruction (0.044%). ED consultations in less than 24 hours after the procedure was associated with a higher index of normal colonoscopies (p=0.006), more diagnosis of fever (p=0.0003) and dyspeptic syndrome (p=0.043), and less diagnosis of colitis/ileitis (p=0.015). The observation of fever in patients treated at the ED was associated with the diagnosis of polyps at colonoscopy (p=0.030). the data corroborate the safety of the colonoscopy exam and points to a reduction in major complications rates.


Advances in Acupuncture Regulation on the Autonomic Nervous System from 2013 to 2022: A Bibliometric Analysis via CiteSpace.
To understand research advances and frontiers of acupuncture regulation on the autonomic nervous system (ANS) over the past decade through a bibliometric analysis. Publications related to acupuncture regulation on the ANS were retrieved from the Web of Science Core Collection (WoSCC) database. CiteSpace software was used to analyze the datasets and generate knowledge maps. A total of 445 relevant publications published between 2013 and 2022 were included in this bibliometric analysis. The number of annual publications fluctuated from 2013 to 2016 but increased gradually from 2016 to 2022. China produced the highest number of publications, while the USA established the most extensive cooperation relationships. China Academy of Chinese Medical Science was the most productive institution. Chen Jiande D.Z. was the most prolific author and Rong Peijing holds the most extensive cooperation network. Han Jisheng was the most co-cited author. Relevant research involved mechanism exploration and clinical efficacy research, and "anti-inflammatory effect" was the most active research topic, especially cholinergic anti-inflammatory mechanisms. The most cited references mainly focused on inflammation. Gastrointestinal and cardiovascular disorders were the most active medical conditions studied in this field. Research related to acupuncture regulation on the ANS mainly focused on anti-inflammation, and regulating gastrointestinal and cardiovascular function over the past decade. However, the mechanisms of the autonomic effects of acupuncture need further investigation. High-quality clinical studies are required to determine the optimal parameters of acupuncture for clinical application.


Acute effect of growth hormone to induce peripheral insulin resistance is independent of FFA and insulin levels in rats.
To examine whether growth hormone (GH) induces peripheral insulin resistance by altering plasma free fatty acid (FFA) or insulin levels, the effects of GH infusion on insulin-stimulated glucose fluxes were studied in conscious rats under two protocols. In study 1, either saline (n = 7) or human recombinant GH (21 microg. kg(-1). h(-1); n = 8) was infused for 300 min, and insulin-stimulated glucose fluxes were estimated during the final 150-min period of hyperinsulinemic euglycemic clamps. In study 2, hyperinsulinemic euglycemic clamps were first conducted for 150 min (to raise plasma insulin and suppress FFA levels), and saline or GH (n = 7 for each) was subsequently infused for the following 300-min clamp period. In study 1, GH infusion in the basal state did not significantly alter plasma FFA or insulin levels. In contrast, GH infusion decreased insulin-stimulated glucose uptake, glycolysis, and glycogen synthesis by 32, 27, and 40%, respectively (P < 0.05). In study 2, GH infusion during hyperinsulinemic euglycemic clamps did not alter plasma FFA or insulin levels (P > 0.05). GH infusion had no effect on insulin-stimulated glucose uptake during the initial 150 min but eventually decreased insulin-stimulated glucose uptake by 37% (P < 0. 05), similar to the results in study 1. These data indicate that GH induces peripheral insulin resistance independent of plasma FFA and insulin levels. The induction of insulin resistance was preceded by suppression of glycogen synthesis, consistent with the hypothesis that metabolic impairment precedes and causes development of peripheral insulin resistance.


Calcium flux across disk membranes. Studies with intact rod photoreceptors and purified disks.
Calcium accumulation by rod disks was studied in excised bullfrog retinas with 45Ca tracer-exchange methods. Ca uptake by disks is a necessary requirement if light-induced Ca releases from disks mediate photoreceptor excitation. In an hour-long incubation, disks exchanged less than or equal to 0.01 mole of Ca per mole of rhodopsin, or less than or equal to 10% of their total Ca. This corresponds to a unidirectional flux of less than or equal to 0.01 fmol/cm2 S, or less than or equal to 5 ions/disk-second across the disk membrane. Neither incubation in 10 mM Ca (which increases cytoplasmic activity 10--100-fold) nor photostimulation (which photoactivated up to 50% rhodopsin/h) had measurable effect on exchange rate, though an increase of several orders of magnitude would have been expected according to the hypothesis. The observed exchange could not be explained by: (a) 45Ca losses from disks before measurement (neither the net efflux nor the Ca-Ca exchange property of disks adequately explains such losses), (b) a limited pool of exchangeables Ca from strongly binding intradiskal sites, or (c) rate-limiting flux across the plasma membrane during incubation. For the study of the Ca efflux properties of disks, separate experiments were performed with 45Ca-loaded disks. Intradiskal activity could be estimated from the disks' hyperosmotically sensitive 45Ca pool and from their intradiskal volume (indirectly assayed by density). Ca-Ca exchange was undetectable (less than or equal to 0.1 fmol/cm2 S) in disks whose intradiskal activity was at least 0.3 mM. Net efflux was 0.2 fmol/cm2 S for an intradiskal activity of approximately 1 mM and is comparable to published fluxes for phospholipid vesicles. These results seem to exclude the internal space of disks as the source of Ca for photoreceptor excitation.


Influence analysis for high-dimensional time series with an application to epileptic seizure onset zone detection.
Granger causality is a useful concept for studying causal relations in networks. However, numerical problems occur when applying the corresponding methodology to high-dimensional time series showing co-movement, e.g. EEG recordings or economic data. In order to deal with these shortcomings, we propose a novel method for the causal analysis of such multivariate time series based on Granger causality and factor models. We present the theoretical background, successfully assess our methodology with the help of simulated data and show a potential application in EEG analysis of epileptic seizures.


Neurological complications of coronary artery bypass graft surgery: six month follow-up study.
As part of a major prospective study of the neurological complications of coronary artery bypass graft surgery patients were reviewed over six months to determine the clinical course and functional impact of early postoperative complications. One hundred and ninety one out of 312 (61%) patients had developed early postoperative disorders. At six months 165 of the 191 patients with early neurological complications were reviewed. Of the 165, 85 still had detectable neurological signs, but these were often minor and of little functional importance. Only 10 patients had neurological disability at six months, and this was major in only four patients, all of whom had suffered major perioperative stroke. No patient with non-disabling neurological complications in hospital became functionally impaired on returning home. Neurological disorders are not a major cause of failure to return to work by six months after coronary artery bypass surgery. Of 139 patients who were of working age and had not returned to work by six months, only four were prevented by neurological injury related to surgery. The long term prognosis for early neurological disorders after coronary artery bypass surgery is usually favourable, except in those patients who have sustained major perioperative stroke.


Gentamicin and methicillin resistant Staphylococcus aureus in Dublin hospitals: clinical and laboratory studies.
Strains of Staphylococcus aureus resistant to gentamicin and methicillin first appeared in Dublin hospitals in 1976, and rapidly became widely disseminated. The number of patients infected or colonised increased throughout the period of study, especially in 1979 and 1980. Most isolates were from burns, surgical wounds and traumatic skin lesions. During the 12 months after first isolation of these multiply antibiotic resistant strains, colonisation or minor infection was the usual event. Invasive infection such as bacteraemia, deep wound sepsis and osteomyelitis was rarely seen. Subsequently, as the number of patients from whom these organisms were isolated increased, bacteraemia and other severe infection became more common. The predominant phage type of S. aureus changed with the progression of the outbreak. Isolates of different phage type were sometimes found in a single lesion, or in different sites in one patient. By the second half of 1980, most isolates were untypable or typed only with an experimental phage.


Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4+ T cells with brain-homing capacity.
Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4+ T cells are assumed to be the first to cross the blood-central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4+ T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4+ memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3+ Eomes+ T-bet- enrichment in cerebrospinal fluid samples of treatment-naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6+ CXCR3+ CCR4-/dim ). Previously published CD28- CD4 T cells were characterized by a Runx3+ Eomes- T-bet+ phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme Khigh Th17.1 cells spontaneously passed the blood-brain barrier in vitro. This was only found for other subsets including CD28- cells when using inflamed barriers. Altogether, CD4+ T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood-brain barrier as a possible early event in MS.


Multistate Statistical Modeling: A Tool to Build a Lung Cancer Microsimulation Model That Includes Parameter Uncertainty and Patient Heterogeneity.
With the shift toward individualized treatment, cost-effectiveness models need to incorporate patient and tumor characteristics that may be relevant to treatment planning. In this study, we used multistate statistical modeling to inform a microsimulation model for cost-effectiveness analysis of individualized radiotherapy in lung cancer. The model tracks clinical events over time and takes patient and tumor features into account. Four clinical states were included in the model: alive without progression, local recurrence, metastasis, and death. Individual patients were simulated by repeatedly sampling a patient profile, consisting of patient and tumor characteristics. The transitioning of patients between the health states is governed by personalized time-dependent hazard rates, which were obtained from multistate statistical modeling (MSSM). The model simulations for both the individualized and conventional radiotherapy strategies demonstrated internal and external validity. Therefore, MSSM is a useful technique for obtaining the correlated individualized transition rates that are required for the quantification of a microsimulation model. Moreover, we have used the hazard ratios, their 95% confidence intervals, and their covariance to quantify the parameter uncertainty of the model in a correlated way. The obtained model will be used to evaluate the cost-effectiveness of individualized radiotherapy treatment planning, including the uncertainty of input parameters. We discuss the model-building process and the strengths and weaknesses of using MSSM in a microsimulation model for individualized radiotherapy in lung cancer.


Attenuation of exposure-response curves in occupational cohort studies at high exposure levels.
Numerous occupational cohort mortality studies have observed exposure-response curves to have an increasing slope at low exposure levels that attenuates or even turns negative at high exposure levels. Examples discussed in this paper include dioxin, silica, 1,3-butadiene, cadmium, beryllium, radon daughters, diesel fumes, nickel, arsenic, and hexavalent chromium. Possible explanations for this phenomenon include (i) bias introduced by the healthy worker survivor effect, (ii) a depletion of the number of susceptible people in the population at high exposure levels, (iii) a natural limit on the relative risk for diseases with a high background rate, (iv) mismeasurement or misclassification of exposures, (v) the influence of other risk factors that vary by the level of the main exposure, and (vi) the saturation of key enzyme systems or other processes involved in the development of disease.


The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture's disease.
Goodpasture's disease is a severe nephritis characterized by autoantibodies to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular basement membrane. The disease is very strongly associated with HLA-DR15, the affinities of alpha3(IV)NC1 peptides for DR15 are known, and elution experiments have identified major naturally processed sequences. Here, the fine specificity and cytokine profile of alpha3(IV)NC1-reactive T cells from patients with Goodpasture's disease is defined. Peripheral blood mononuclear cells from patients at diagnosis proliferated in response to significantly more peptides (chi(2) = 8.6, P = 0.004) from a panel spanning the sequence of alpha3(IV)NC1 than did those from control DR15-positive donors and were highly focused (P = 0.0002, binomial distribution) on two peptides, alpha3(71-90) and alpha3(131-150). Some peptides induced interferon-gamma, but none induced IL-4. Resolution of disease was accompanied by a striking deviation of the responses from proliferation to secretion of the T-regulatory cytokine IL-10, and addition of neutralizing antibody confirmed that such IL-10 production was suppressive. The affinity of the peptides for DR15 molecules was positively correlated (chi(2) = 14.6, P = 0.00067) with the ability to elicit proliferation. However, unlike foreign antigens, this hierarchy is not due to responses against the major naturally processed peptides, which rarely stimulated proliferation and which have only intermediate affinity for DR15 molecules. It is inferred that the helper response to alpha3(IV)NC1 in Goodpasture's disease is dominated by epitopes that are normally inefficiently presented because of processing constraints.


Microsatellite instability and the association with plasma homocysteine and thymidylate synthase in colorectal cancer.
The possible associations between microsatellite instability, homocysteine and thymidylate synthase were investigated in tumors and plasma from 130 patients with colorectal cancer. Other analyses included thymidylate synthase and 5,10-methylene-tetrahydrofolate reductase gene polymorphisms, carcinoembryonic antigen, vitamin B12, and folate. Microsatellite instability of tumors was associated with higher levels of plasma homocysteine (p = 0.008) and higher protein expression of thymidylate synthase (p < 0.001). Supplemental analyses ruled out that the finding could be explained by the other analyzed factors. CEA was not associated with neither homocysteine nor microsatellite instability. The data suggests that there is a more pronounced methyl unit deficiency in microsatellite instable tumors.


Malignant cancer mortality in Province of Taranto (Italy). Geographic analysis in an area of high environmental risk.
A geographic analysis of the causes of death is an important tool for assessing the effectiveness of Public Health initiatives. The aim of this study is to analyse the causes of death between 2000 and 2004, to discover any excess mortality from cancer in Province of Taranto, an area at high environmental risk. Mortality data from cancer were selected from the Puglia Regional Nominative Causes of Death Registry. Crude and standardized rates and Standardized Mortality Ratios (SMR) were calculated for the five Provinces of the Puglia Region, their capital cities and in four concentric rings around the industrial area located in Province of Taranto. . Even if the highest death rate for all tumours resulted in the Province of Lecce (24.9 x 10,000), in the cities of Lecce and Bari (29 x 10,000), the distribution of the SMRs in Province of Taranto showed an excess of mortality (+10%) in the ring next to industrial area. For lung cancer the highest rate was reported in city of Taranto (6 x 10,000) and the highest risk (+24%) in the ring next to industrial area. Moreover, in this area 9 (70%) of the 13 considered malignant tumours types presented an excess of mortality. The results uphold the data reported in the published literature. It is fundamental to intensify research into other risk factors (exposure at work and aberrant lifestyles). Moreover, there is an increasing need for a Regional Cancer Register.


Breast reduction in patients with prior breast irradiation: outcomes using a central mound technique.
Breast reduction in patients with a history of lumpectomy and irradiation is controversial because of a heightened risk of infection and wound healing complications. Persistent macromastia or asymmetry remains a problem in this patient population that is commonly not addressed. The authors studied the safety and efficacy of a central mound technique with minimal dissection for breast reduction or mastopexy in patients with a history of breast irradiation. A case-control study of all patients undergoing bilateral breast reduction mammaplasty between 2008 and 2013 at Memorial Sloan Kettering Cancer Center was conducted. Patients who had unilateral breast irradiation and bilateral reduction using the central mound technique were included. Each patient had a control breast and an irradiated breast. Complications and outcomes were analyzed. Thirteen patients were included for analysis. Their average age was 50.23 ± 9.9 years, and average time from irradiation to breast reduction mammaplasty was 41.3 ± 48.5 months (range, 9 to 132 months). The average specimen weight of irradiated breasts was less than that of control breasts; however, this failed to reach statistical significance (254.2 ± 173.5 g versus 386.9 ± 218.5 g; p = 0.099). One patient developed fat necrosis in the previously irradiated breast and underwent biopsy. There was no incidence of nipple necrosis or breast cancer in either irradiated or nonirradiated breasts. Breast reduction mammaplasty in patients who have had irradiation is feasible and can be performed safely in select cases. The central mound technique provides reliable and reproducible results and should be considered in patients with macromastia/asymmetry and a history of irradiation. Therapeutic, III.


Assessing the pathogenicity of RYR1 variants in malignant hyperthermia.
. Missense variants in the ryanodine receptor 1 gene ( RYR1 ) are associated with malignant hyperthermia but only a minority of these have met the criteria for use in predictive DNA diagnosis. We examined the utility of a simplified method of segregation analysis and a functional assay for determining the pathogenicity of recurrent RYR1 variants associated with malignant hyperthermia. . We identified previously uncharacterised RYR1 variants found in four or more malignant hyperthermia families and conducted simplified segregation analyses. An efficient cloning and mutagenesis strategy was used to express ryanodine receptor protein containing one of six RYR1 variants in HEK293 cells. Caffeine-induced calcium release, measured using a fluorescent calcium indicator, was compared in cells expressing each variant to that in cells expressing wild type ryanodine receptor protein. We identified 43 malignant hyperthermia families carrying one of the six RYR1 variants. There was segregation of genotype with the malignant hyperthermia susceptibility phenotype in families carrying the p.E3104K and p.D3986E variants, but the number of informative meioses limited the statistical significance of the associations. HEK293 functional assays demonstrated an increased sensitivity of RyR1 channels containing the p.R2336H, p.R2355W, p.E3104K, p.G3990V and p.V4849I compared with wild type, but cells expressing p.D3986E had a similar caffeine sensitivity to cells expressing wild type RyR1. . Segregation analysis is of limited value in assessing pathogenicity of RYR1 variants in malignant hyperthermia. Functional analyses in HEK293 cells provided evidence to support the use of p.R2336H, p.R2355W, p.E3104K, p.G3990V and p.V4849I for diagnostic purposes but not p.D3986E.


Primary appendiceal mucinous adenocarcinoma in two first-degree relatives: case report and review.
Carcinomas of the appendix are exceedingly rare tumors and have an annual age-adjusted incidence of around 0.4 cases per 100,000. Appendiceal adenocarcinoma accounts for < 0.5% of all gastrointestinal neoplasms and, of these, mucinous adenocarcinomas account for the majority. Published accounts of familial instances of primary appendiceal tumors are strikingly rare. We report two siblings who both developed primary mucinous adenocarcinomas. A genetics evaluation was conducted to determine if there was a recognizable underlying single gene disorder; no DNA mismatch repair defect was evident, and no other diagnosis was apparent. A review of appendiceal cancers seen at Mayo Clinic from l997 to the present was conducted to search for additional familial cases. Among 316 cases of primary appendiceal cancer of any histologic type, this sib pair was the only family reporting a second affected family member. The occurrence of appendiceal cancer in siblings may represent a random occurrence. An exceedingly rare predisposition syndrome cannot be ruled out.


Effects of a glyphosate-based herbicide in pejerrey Odontesthes humensis embryonic development.
Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Among them, the Roundup formulations are the most popular. Some aspects of GBH toxicity are well known, such as induction of oxidative stress. However, embryotoxicity is scarcely known. Therefore, the aim of the present study was to evaluate the effect of exposure to different Roundup Transorb R concentrations (0.36, 1.80, 3.62 and 5.43 mg glyphosate a.e./L) on Odontesthes humensis embryonic development. Embryos were sampled at three exposure times (48, 72 and 96 h). After 48 h, the stage of embryonic development and the number of somite pairs were analyzed; after 72 h, the percentage of pigmented embryos were evaluated and after 96 h, the eye diameter (ED) and the distance between eyes (DE) were measured. Mortality rates were daily calculated. Results show that Roundup exposure to all concentrations did not alter the endpoints evaluated at 48 and 72 h. On the other hand, exposure for 96 h to all concentrations induced a concentration-dependent reduction in ED and DE. Additionally, exposure to 5.43 mg a.e./L increased mortality. These findings indicate that Roundup has the potential to produce morphological alterations in fish embryos even at the lower and ecologically relevant concentration tested (0.36 mg a.e./L). This result corroborates the hypothesis that glyphosate alters the retinoic acid signaling pathway. Additionally, our findings indicate that exposure to high concentrations of Roundup (5.43 mg a.e./L) for 96 h causes high mortality rates of fish embryos. This is the first report of GBH embryotoxicity in an endemic fish of southern areas in South America.


Suppression of human lymphocyte responses in chronic renal failure mediated by adherent cells: analysis in serum-free media.
Concanavalin A (Con A)-induced proliferative responses by mononuclear leukocytes (MNCs) from patients with chronic renal failure (CRF) who were undergoing maintenance hemodialysis were studied with serum-free media to analyze leukocyte function independent of either uremic or normal serum factors. When we increased the number of cultured MNCs by 2.5- to fivefold over that normally used in microcultures and reduced the mitogen concentration, Con A induced proliferative responses 10- to 1000-fold higher than those in unstimulated cultures. In 12 of 15 patients with CRF observed, Con A-induced MNC responses were significantly depressed as compared with those in age- and sex-matched controls. Responses in 10 of these 12 patients with CRF improved significantly immediately after dialysis, but the improvement was only temporary. With MNCs from patients with CRF before dialysis, removal of adherent cells significantly improved their responses to Con A. Similar increases with adherent cell depletion were not found either in cultures of control MNCs or in patient MNCs after dialysis. Indomethacin, a cyclooxygenase inhibitor, added to unseparated MNCs from patients before dialysis, significantly increased responses in 13 of 15 patients. This effect of indomethacin was found less frequently in MNC cultures from normal persons or from patients with CRF after dialysis. Nonadherent lymphocytes from patients with CRF were not abnormally sensitive to inhibition by exogenously added prostaglandin E2. We conclude that MNCs from most patients with CRF have depressed reactivity when cultured without serum and that responses improve temporarily after dialysis. Adherent cells are largely responsible for inhibiting lymphocyte responses, and monocyte-released cyclooxygenase products appear to mediate much of this suppression.


Structure and function of the ovine type 1 corticotropin releasing factor receptor (CRF1) and a carboxyl-terminal variant.
Corticotropin releasing factor (CRF) is the major neuropeptide regulating the hypothalamo-pituitary-adrenocortical axis in most species. A pituitary receptor for CRF (designated CRF1) belonging to the seven-transmembrane helix, G-protein-coupled receptor superfamily has been cloned for human, rat, mouse and xenopus. Since ovine CRF shares only 84% identity to human/rat CRF (h/rCRF) we postulated that the sheep pituitary CRF1 receptor may have similarly diverged from the rodent and human CRF1. We report the molecular cloning of an ovine pituitary cDNA containing a 1245 bp open reading frame encoding a 415 amino acid sheep CRF1 receptor 78, 86, 94, and 95% homologous to xenopus, chicken, rat, mouse, and human CRF1, respectively. The divergence in primary structure between the sheep CRF1 and the other mammalian CRF1s is primarily localized to the extracellular amino terminal domain of the receptor (18 of 22 divergent residues, ovine vs human CRF1). A variant of the oCRF1 was also isolated (oCRF1var) with 133 bp deleted from nucleotide (nt) 1080 to nt 1213 of the open reading frame (ORF) resulting in a new ORF of 1176 nt predicting a 392 residue CRF1 variant receptor. The 133 bp deletion would cause a frame-shift at residue 358 within the carboxyl-third of the seventh transmembrane domain (TM7) resulting in a shortened cytoplasmic tail with a new amino acid sequence from residue 358 to 392. Scatchard analysis of saturation curves using membrane prepared from Cos 7 cells transfected with oCRF1 or oCRF1var indicated that both wild-type and variant receptors were expressed similarly (number of CRF binding sites) and both bound oCRF with high affinity [oCRF1 (Kd): 2.5 + 1.6 nM; oCRF1var: 5.1 + 2.3 nM]. The non-hydrolyzable GTP analogue (GTPgammaS) lowered the affinity of both wild-type and variant oCRF1 receptors to a similar extent (oCRF1: 18.2 nM; oCRF1var: 22.4 nM). Both wild-type and variant oCRF1 receptors exhibited approximately 10-fold greater selectivity for oCRF and sauvagine compared to h/rCRF or alpha-helical [9-41]oCRF. CRF effectively stimulated the accumulation of cAMP (EC50 = 51 pM) in Cos 7 cells transiently transfected with wild-type but not variant oCRF1 receptor. In Cos 7 cells transfected with oCRF1var, cAMP accumulation was only observed at the highest concentration of oCRF utilized (100 nM). Basal (unstimulated) levels of cAMP in Cos 7 cells transfected with oCRF1var (in the presence of 2 mM IBMX) were approximately 50% lower than for the wild-type oCRF1. Differences in cAMP accumulation could not be attributed to differences in receptor number since total binding sites in the transfected cells were not different between wild-type or variant oCRF1 receptors. Agonist-induced receptor internalization, determined as the percent of total [125I] Tyr0-oCRF bound located in the acid-resistant fraction of transfected Cos 7 cells, increased with time (0-60 min at 37 degrees C) for both wild-type and variant oCRF1. Wild-type CRF1 internalized approximately 2-fold greater percent of total [125I] Tyr0-oCRF bound compared to the variant receptor. In summary, an ovine CRF1 and a CRF1 cytoplasmic tail receptor variant displaying high affinity binding to oCRF as well as selectivity for oCRF vs h/rCRF, were cloned from an adult sheep pituitary cDNA library. GTPgammaS studies indicate that both variant and wild-type receptors couple efficiently to Galphas however, only the wild-type oCRF1 is capable of stimulating cAMP production at physiological levels of CRF. Agonist-induced internalization of the ovine CRF1var is also reduced compared to the wild-type CRF1 receptor. We suggest that the oCRF1var interacts efficiently with Galphas but is unable (post-hormonal binding) to effectively stimulate G-protein activation of adenylate cyclase, indicating that the cytoplasmic tail of the CRF1 can modulate receptor function related to signal transduction. (ABSTRACT TRUNCATED)


Rapid optimization method of the strong stray light elimination for extremely weak light signal detection.
The strong stray light has huge interference on the detection of weak and small optical signals, and is difficult to suppress. In this paper, a miniaturized baffle with angled vanes was proposed and a rapid optimization model of strong light elimination was built, which has better suppression of the stray lights than the conventional vanes and can optimize the positions of the vanes efficiently and accurately. Furthermore, the light energy distribution model was built based on the light projection at a specific angle, and the light propagation models of the vanes and sidewalls were built based on the Lambert scattering, both of which act as the bias of a calculation method of stray light. Moreover, the Monte-Carlo method was employed to realize the Point Source Transmittance (PST) simulation, and the simulation result indicated that it was consistent with the calculation result based on our models, and the PST could be improved by 2-3 times at the small incident angles for the baffle designed by the new method. Meanwhile, the simulation result was verified by laboratory tests, and the new model with derived analytical expressions which can reduce the simulation time significantly.


Racial/ethnic differences in the use of biologic disease-modifying antirheumatic drugs among California Medicaid rheumatoid arthritis patients.
To assess racial/ethnic differences in the use of biologic disease-modifying antirheumatic drugs (DMARDs) among California Medicaid (Medi-Cal) rheumatoid arthritis (RA) patients. Medi-Cal patient level data for 5,385 DMARD recipients between ages 18 and 100 years with at least 1 diagnosis of RA (International Classification of Disease, Ninth Revision, Clinical Modification code 714.xx) and the use of 1 DMARD between January 1, 1998 and December 31, 2005 were collected. The outcome of interest was the choice of either standard DMARDs (methotrexate, lefluonomide, hydroxychloroquine, and sulfasalazine) or biologic DMARDs (adalimumab, etanercept, anakinra, and infliximab). A univariate analysis and logistic regression model were applied to examine the association of the choice of DMARD among different racial/ethnic groups. In the univariate analysis, biologic DMARD use was significantly associated with race/ethnicity (P < 0.001). In the multivariate logistic regression model, after adjusting for age, sex, insurance coverage, 12 comorbid conditions, RA-related drug prescription, RA-related inpatient stay, and rehabilitation visits, African Americans had 53% lower odds of receiving biologic DMARDs as compared to whites, whereas Hispanics had 36% increased odds of receiving biologic DMARDs as compared to whites. In this Medi-Cal population, with its racial diversity and relatively homogenous socioeconomic status and health care benefits, racial/ethnic differences were found in RA patients receiving biologic DMARDs.


Hypertriglyceridemia. Examining its role in coronary heart disease.
If triglyceride-rich very-low-density lipoproteins (VLDLs) are a vehicle for transporting cholesterol into the arterial wall, they can be equated to low-density lipoproteins (LDLs) in estimating CHD risk and setting targets for therapy. Furthermore, the fate of cholesterol-rich VLDL (VLDL remnants) is similar to that of LDL; that is, both are removed from the circulation via LDL receptors. Thus, combining VLDL and LDL into a common category of atherogenic lipoproteins provides a rational framework for treatment of hypercholesterolemic patients with hypertriglyceridemia. A hydroxymethylglutaryl coenzyme A reductase inhibitor may be the best choice for treatment when both triglyceride and cholesterol levels are elevated, because these agents cause the greatest reduction in VLDL and LDL cholesterol levels. When hypertriglyceridemia is severe, a fibric acid or nicotinic acid is preferable, because these agents are more effective for lowering triglyceride levels and hence for reducing risk for acute pancreatitis.


Vena caval filters for the prevention of pulmonary embolism.
Pulmonary emboli (PE) can have potentially fatal consequences. Inferior vena caval filters (VCFs) are metal alloy devices that mechanically trap fragmented thromboemboli from the deep leg veins en route to the pulmonary circulation. Filters are designed to be introduced (and in the case of retrievable filters, removed) percutaneously. Although their deployment seems of theoretical benefit, their clinical efficacy and adverse event profile is unclear.This is an update of a Cochrane review first published in 2007. To examine evidence for the effectiveness of VCFs in preventing pulmonary embolism (PE). Secondary outcomes were mortality, distal (to filter) thrombosis, and filter-related complications. The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched October 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2009, Issue 4 for randomised or controlled clinical trials of VCFs for the prevention of PE. The authors contacted filter manufacturers for information. Controlled clinical trials (CCTs) and randomised controlled trials (RCTs) that examined the efficacy of filters in preventing PE. Two authors independently extracted information. Two studies were included involving a total of 529 people. One open quasi-randomised trial of 129 participants with traumatic hip fractures showed a reduction in PE but not mortality over a 34 day period in the filter group. The PREPIC (Prévention du Risque d'Embolie Pulmonaire par Interruption Cave) trial, was an open RCT of 400 participants with documented proximal deep vein thrombosis (DVT) or PE who received concurrent anticoagulation. Permanent VCFs prevented PE at eight years. No reduction in mortality was seen, but this reflected an older study population; the majority of deaths were due to cancer or cardiovascular causes. There was an increased incidence of (DVT) in the filter group. Adverse events were not reported. No recommendations can be drawn from the two studies. One study showed a reduction in PE rates but not mortality, but was subject to significant biases. The PREPIC study lacked statistical power to detect a reduction in PE over shorter and more clinically significant time periods. However, the trial demonstrated that permanent VCFs were associated with an increased risk of long term lower limb DVT.There is a paucity of VCFs outcome evidence when used within currently approved indications and a lack of trials on retrievable filters. Further trials are needed to assess vena caval filter safety and effectiveness.