Activation of PPARbeta/delta inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release.
The infiltration of PMNs into tissues is a prominent feature in inflammation. The mechanism underlying PMN recruitment depends on the release of chemotactic mediators and CAM expression on endothelial cells. The nuclear receptor PPARbeta/delta is widely expressed in many tissues, including the vascular endothelium; however, its role in acute inflammation remains unclear. Using intravital microscopy in the mouse cremasteric microcirculation, we have shown that activation of PPARbeta/delta by its selective ligand GW501516 inhibits TNF-alpha-induced leukocyte rolling flux, adhesion, and emigration in a dose-dependant manner. Moreover, GW501516 reduced the expression of adhesion molecules such as ICAM-1, VCAM-1, and E-selectin in the cremasteric postcapillary venules. Similarly, rolling and adhesion of hPMNs under physiological flow on TNF-alpha-activated HUVECs were also inhibited markedly by GW501516. These inhibitory responses of GW501516 on activated endothelium were accompanied by a reduction in TNF-alpha-induced endothelial GRO-alpha release and VCAM-1, E-selectin, and ICAM-1 mRNA expression. Taken together, our results show that PPARbeta/delta modulates acute inflammation in vivo and in vitro under flow by targeting the neutrophil-endothelial cell interaction.


Influenza Testing and Treatment Among Patients Hospitalized With Community-Acquired Pneumonia.
Influenza is a leading cause of community-acquired pneumonia (CAP), and results of influenza tests can direct therapy. However, among adults hospitalized with CAP, little is known about the frequency and timing of influenza testing, treatment, and their associations with outcomes. In patients with CAP, is testing for influenza associated with antiviral treatment and shorter antibiotic courses, and is early treatment associated with better clinical outcomes? This study included adults admitted with pneumonia in 2010 to 2015 to 179 US hospitals contributing to the Premier database. We assessed influenza testing and compared antimicrobial utilization and the outcomes of test-positive, test-negative, and untested patients. Associations of early antiviral treatment (oseltamivir) with 14-day in-hospital mortality, hospital length of stay, and cost were studied. Among 166,268 patients with CAP, 38,703 (23.3%) were tested for influenza, of whom 11.5% tested positive. Testing increased from 15.4% to 35.6% from 2010 to 2015 and was 28.9% during flu season (October-May) vs 8.2% in June to September. Patients testing positive for influenza received antiviral agents more often and antibacterial agents less often and for shorter courses than patients testing negative (5.3 vs 6.4 days; P < .001). Influenza-positive patients receiving oseltamivir on hospital day 1 (n = 2,585) experienced lower 14-day in-hospital mortality (adjusted OR, 0.75; 95% CI, 0.59-0.96), lower costs (adjusted ratio of means, 0.88; 95% CI, 0.81-0.95), and shorter length of stay (adjusted ratio of means, 0.88; 95% CI, 0.84-0.93) vs patients receiving oseltamivir later or not at all (n = 1,742). Even during flu season, most patients with CAP in this study went untested for influenza. A positive influenza test result was associated with antiviral treatment, and early treatment was associated with lower mortality, suggesting that more widespread testing might improve patient outcomes.


A randomized, double-blind, placebo-controlled study of lorazepam as premedication for bronchoscopy.
To our knowledge, no study has clearly demonstrated the advantage of sedative premedication for bronchoscopy. In a double-blind study, we evaluated the efficacy of oral lorazepam as premedication for bronchoscopy. One hundred patients were randomly assigned to receive placebo (group A) or lorazepam (2 mg) (group B) approximately 1.5 h before bronchoscopy. Immediately after the procedure and the following day, a questionnaire addressing the patient's perception of the procedure was administered. Specifically, subjects were asked to grade the bronchoscopy as very easy, easy, difficult, or very difficult to tolerate and if they would agree to a second bronchoscopy if believed necessary. In addition, their recollection of the procedure was graded as clear, indistinct, or not at all. No difference was found between the two groups for age, duration of the bronchoscopy, and the answers to the questionnaire administered immediately after the procedure. Most patients from both groups found their level of sedation adequate. On the following day, however, group B reported with lower frequency that the technique was difficult or very difficult (38.0% vs 65.3% for group A; p < 0.005) and that they would be less reluctant to a repeated bronchoscopy (30.0% vs 57.1% for group A; p < 0.015). Moreover, their recollection of the procedure was now less precise than for those who had received the placebo (p < 0.005). This suggests that the difference observed between the two groups at 24 h was related to the amnesic effect of lorazepam. We conclude that lorazepam, by improving patient's perception of the bronchoscopy, is a useful premedication and may facilitate patient's investigation when a second bronchoscopy becomes necessary.


The effects of team-based learning techniques on nursing students' perception of the psycho-social climate of the classroom.
Background: Team-based learning is a structured type of cooperative learning that is becoming increasingly more popular in nursing education. This study compares levels of nursing students' perception of the psychosocial climate of the classroom between conventional lecture group and team-based learning group. Methods: In a quasi-experimental study with pretest-posttest design 38 nursing students of second year participated. One half of the 16 sessions of cardiovascular disease nursing course sessions was taught by lectures and the second half with team-based learning. The modified college and university classroom environment inventory (CUCEI) was used to measure the perception of classroom environment. This was completed after the final lecture and TBL sessions. Results: Results revealed a significant difference in the mean scores of psycho-social climate for the TBL method (Mean (SD): 179.8(8.27)) versus the mean score for the lecture method (Mean (SD): 154.213.44)). Also, the results showed significant differences between the two groups in the innovation (p<0.001), student cohesiveness (p=0.01), cooperation (p<0.001) and equity (p= 0.03) sub-scales scores (p<0.05). Conclusion: This study provides evidence that team-based learning does have a positive effect on nursing students' perceptions of their psycho-social climate of the classroom.


Harnessing a previously unidentified capability of bacterial allosteric transcription factors for sensing diverse small molecules in vitro.
A plethora of bacterial allosteric transcription factors (aTFs) have been identified to sense a variety of small molecules. Introduction of a novel aTF-based approach to sense diverse small molecules in vitro will signify a broad series of detection applications. Here, we found that aTFs could interact with their nicked DNA binding sites. Building from this new finding, we designed and implemented a novel aTF-based nicked DNA template-assisted signal transduction system (aTF-NAST) by using the competition between aTFs and T4 DNA ligase to bind to the nicked DNA. This aTF-NAST could reliably and modularly transduce the signal of small molecules recognized by aTFs to the ligated DNA signal, thus enabling the small molecules to be measured via various mature and robust DNA detection methods. Coupling this aTF-NAST with three DNA detection methods, we demonstrated nine novel biosensors for the detection of an antiseptic 4-hydroxybenzoic acid, a disease marker uric acid and an antibiotic tetracycline. These biosensors show impressive sensitivity and robustness in real-life analysis, highlighting the great potential of our aTF-NAST for biosensing applications.


Protease-deficient DegP suppresses lethal effects of a mutant OmpC protein by its capture.
The expression of assembly-defective outer membrane proteins can confer lethality if they are not degraded by envelope proteases. We report here that the expression of a mutant OmpC protein, OmpC(2Cys), which forms disulfide bonds in the periplasm due to the presence of two non-native cysteine residues, is lethal in cells lacking the major periplasmic protease, DegP. This lethality is not observed in dsbA strains that have diminished ability to form periplasmic disulfide bonds. Our data show that this OmpC(2Cys)-mediated lethality in a degP::Km(r) dsbA(+) background can be reversed by a DegP variant, DegP(S210A), that is devoid of its proteolytic activity but retains its reported chaperone activity. However, DegP(S210A) does not reverse the lethal effect of OmpC(2Cys) by correcting its assembly but rather by capturing misfolded mutant OmpC polypeptides and thus removing them from the assembly pathway. Displacement of OmpC(2Cys) by DegP(S210A) also alleviates the negative effect that the mutant OmpC protein has on wild-type OmpF.


Modulating retinoid X receptor with a series of (E)-3-[4-hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic acids and their 4-alkoxy isomers.
Rexinoids are ligands for the retinoid X receptor (RXR) that have great promise for both the prevention and treatment of cancer and metabolic diseases. In this regard, synthetic, functional, and structural investigations into the structure-activity relationships of derivatives of the potent RXR agonist (E)-3-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-hydroxyphenyl]acrylic acid (CD3254, 9) have been conducted. We recently reported on the characterization of a series of C3'-substituted alkyl ether analogues of 9 (10a-f), which display activities ranging from partial agonists to pure antagonists. The importance of the position of the alkoxy side chain for ligand activity has been further explored with the synthesis of C4'-substituted analogues (11a-f). Here we describe the synthesis of compounds 11a-f, which appear functionally different from their isomeric counterparts, as judged from transactivation assays and fluorescence anisotropy experiments. We also report on the 2.0 A resolution structure of RXR in complex with the parent compound 9, which helps understanding of the impact of the alkyl side chain location on ligand activity.


Death, sex, love, and neuroticism: why is sex such a problem?
Terror management theory posits that sex is a ubiquitous human problem because the creaturely aspects of sex make apparent our animal nature, which reminds us of our vulnerability and mortality. People minimize this threat by investing in the symbolic meaning offered by the cultural worldview. Because people high in neuroticism have difficulty finding or sustaining meaning, sex is a particular problem for them. In Study 1, mortality salience caused high-neuroticism participants to find the physical aspects of sex less appealing. Study 2 revealed that for such individuals thoughts of physical sex increase the accessibility of death-related thoughts. This finding was replicated in Study 3, which also showed that providing meaning by associating sex with love reduces the accessibility of death-related thoughts in response to thoughts of physical sex. These findings provide insight into why people high in neuroticism have conflicting thoughts about sexuality and why sexuality is so often regulated and romanticized.


Upper Limb Physical Rehabilitation Using Serious Videogames and Motion Capture Systems: A Systematic Review.
The use of videogames and motion capture systems in rehabilitation contributes to the recovery of the patient. This systematic review aimed to explore the works related to these technologies. The PRISMA method (Preferred Reporting Items for Systematic reviews and Meta-Analyses) was used to search the databases Scopus, PubMed, IEEE Xplore, and Web of Science, taking into consideration four aspects: physical rehabilitation, the use of videogames, motion capture technologies, and upper limb rehabilitation. The literature selection was limited to open access works published between 2015 and 2020, obtaining 19 articles that met the inclusion criteria. The works reported the use of inertial measurement units (37%), a Kinect sensor (48%), and other technologies (15%). It was identified that 26% used commercial products, while 74% were developed independently. Another finding was that 47% of the works focus on post-stroke motor recovery. Finally, diverse studies sought to support physical rehabilitation using motion capture systems incorporating inertial units, which offer precision and accessibility at a low cost. There is a clear need to continue generating proposals that confront the challenges of rehabilitation with technologies which offer precision and healthcare coverage, and which, additionally, integrate elements that foster the patient's motivation and participation.


Reduced Graphene Oxide and Polyaniline Nanofibers Nanocomposite for the Development of an Amperometric Glucose Biosensor.
The control of glucose concentration is a crucial factor in clinical diagnosis and the food industry. Electrochemical biosensors based on reduced graphene oxide (rGO) and conducting polymers have a high potential for practical application. A novel thermal reduction protocol of graphene oxide (GO) in the presence of malonic acid was applied for the synthesis of rGO. The rGO was characterized by scanning electron microscopy, X-ray diffraction analysis, Fourier-transform infrared spectroscopy, and Raman spectroscopy. rGO in combination with polyaniline (PANI), Nafion, and glucose oxidase (GOx) was used to develop an amperometric glucose biosensor. A graphite rod (GR) electrode premodified with a dispersion of PANI nanostructures and rGO, Nafion, and GOx was proposed as the working electrode of the biosensor. The optimal ratio of PANI and rGO in the dispersion used as a matrix for GOx immobilization was equal to 1:10. The developed glucose biosensor was characterized by a wide linear range (from 0.5 to 50 mM), low limit of detection (0.089 mM), good selectivity, reproducibility, and stability. Therefore, the developed biosensor is suitable for glucose determination in human serum. The PANI nanostructure and rGO dispersion is a promising material for the construction of electrochemical glucose biosensors.


Prosocial behavior toward estranged persons modulates the interaction between midline cortical structures and the reward system.
Good reputation enhances positive self-image, which motivates prosocial behavior, a phenomenon known as indirect reciprocity. Thus, good reputation should promote prosocial behavior toward estranged people to whom affective responses leading to direct reciprocity are suppressed. We predicted that such behaviors involve an interrelationship between self-image, processed in the medial prefrontal cortex (mPFC) and precuneus, and social reward, processed in the reward system. To test our hypothesis, we performed fMRI on 21 participants during a virtual ball-toss game after subjects formed negative impressions (estrangement) or neutral impressions of other players. During some blocks of the game, the other players did not receive tosses, and participants could increase tosses to them (i.e. engage in prosocial behavior). Participants significantly increased tosses to all isolated players; therefore, prosocial behavior occurred irrespective of estrangement. Prosocial behavior toward estranged players enhanced positive self-image and increased activation of the anterior mPFC and precuneus. The precuneus exhibited enhanced functional connectivity with the striatum. Thus, a positive self-image, represented by an interaction between the midline cortical structures and striatum, plays key roles in prosocial behavior toward estranged people.


Midazolam vs lorazepam and placebo as hypnotic premedication before surgery. A controlled, double-blind study.
The efficacy of midazolam vs lorazepam and placebo was studied in 60 patients in a comparative, double-blind study. Midazolam 15 mg and lorazepam 2.5 mg were given orally in a single dose the night before operation. Sleep latency was shortest on midazolam but the mean duration of sleep longest on lorazepam. Four patients on lorazepam complained of headache and one reported tinnitus. Three patients receiving midazolam complained of headache. Headache was observed also in one patient given placebo and another experienced tachycardia. Midazolam administered the night before surgery is a preferable hypnotic for transient insomnia caused by preoperative anxiety.


Inactivation of vanadium bromoperoxidase: formation of 2-oxohistidine.
The basis of the irreversible inactivation of the vanadium bromoperoxidase (V-BrPO) isolated from the marine alga Ascophyllum nodosum under turnover conditions at low pH (i.e., 15 to 100 mM H2O2, 0.1 KBr, ca. 15 nM V-BrPO in 0.1 M citrate, pH 4) has been investigated. Inactivation under these conditions was found to produce 2-oxohistidine as identified by HPLC using electrochemical detection. Formation of 2-oxohistidine requires all the components of turnover (i.e., bromide, hydrogen peroxide, and V-BrPO) as well as low pH; inactivation does not occur nor is significant 2-oxohistidine formed in the presence of hydrogen peroxide alone. The oxidation of histidine did not occur by singlet oxygen generated by V-BrPO, because neither 2-oxohistidine nor inactivation occur under the conditions in which singlet oxygen is produced quantitatively by V-BrPO. The addition of aqueous bromine to N alpha-benzoylhistidine at low pH formed N alpha-benzoyl-2-oxohistidine. cis-Dioxovanadium(V) (VO2+) in strong acid and MoO(O2)2(ox)2- (ox2- is oxalate) at pH 5, both of which are functional mimics of V-BrPO by oxidizing bromide by hydrogen peroxide, catalyzed the oxidation of N alpha-benzoylhistidine to N alpha-benzoyl-2-oxohistidine. Furthermore, when hypobromite was added to N alpha-benzoylhistidine in the presence of hydrogen peroxide at neutral pH, conditions under which HOBr would react first with H2O2 to produce singlet oxygen, no N alpha-benzoyl-2-oxohistidine was formed. Thus the oxidation of histidine in V-BrPO is proposed to occur via oxidized bromine species. Irreversible inactivation V-BrPO was also found to be accompanied by release of vanadium.


[Retroperitoneal Tumor: Neurofibroma.]
The neurofibroma is a benign tumor that grows from the sheath of the peripheral nerves, which is often localized on superficial tissues, especially in isolated forms. The neurofibromas can be of two types, localized or diffuse, the last one closely related to Von Recklinghausen disease or NF-1. We described a 37 years old male e patient, 37 years without symptoms, and the computed tomography scan (CT), and magnetic resonance imaging showed a tumor in proximity to the right kidney, the psoas muscle, the spine and compressing the cava vein, but cannot be accurately determinate the invasion of these structures. We review the differential diagnosis, therapeutic and the management of this disease in this clinical case.


APC promoter is frequently methylated in pancreatic juice of patients with pancreatic carcinomas or periampullary tumors.
Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome. The present authors previously demonstrated that DNA hypermethylation of adenomatous polyposis coli (APC), histamine receptor H2 (HRH2), cadherin 13 (CDH13), secreted protein acidic and cysteine rich (SPARC) and engrailed-1 (EN-1) promoters is frequently detected in pancreatic tumor cells. The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area. A total of 135 pancreatic juices obtained from 85 pancreatic cancer (PC), 26 ampullary carcinoma (AC), 10 intraductal papillary mucinous neoplasm (IPMN) and 14 chronic pancreatitis (CP) patients were analyzed. The methylation status of the APC, HRH2, CDH13, SPARC and EN-1 promoters was analyzed using methylation specific-melting curve analysis (MS-MCA). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were also tested with allele-specific quantitative polymerase chain reaction amplification. Out of the 5 promoters analyzed, APC (71%) and HRH2 (65%) were the most frequently methylated in PC juice. APC methylation was also detected at a high frequency in AC (76%) and IPMN (80%), but only occasionally observed in CP (7%). APC methylation had a high sensitivity (71-80%) for all types of cancer analyzed. The panel (where a sample scored as positive when ≥2 markers were methylated) did not outperform APC as a single marker. Finally, KRAS detection in pancreatic juice offered a lower sensitivity (50%) and specificity (71%) for detection of any cancer. APC hypermethylation in pancreatic juice, as assessed by MS-MCA, is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms.


[Angiotensin-converting enzyme: a protein conserved during evolution].
The Angiotensin-Converting Enzyme (ACE) is crucial for vascular homeostasis in mammals. Three isoforms are present in the human. the somatic ACE (sACE) generates the vasoactive angiotensin II. The testicular isoform (tACE) is required for male fertility. ACE2 was cloned from another gene and displays an antagonistic role. Several ACEs were cloned from insects, despite their lack of a closed circulatory system. Insect isoforms are implied in reproduction and development. No sequence in the C. elegans genome is able to encode a functional enzyme. Nevertheless, an active ACE was characterized in an even more distant organism, the leech, in which the enzyme is mainly expressed within the digestive tract. The presence of ACE is lophotrochozoans raises questions about the appearance and original functions of the enzyme. Besides, the recent availability of genomic data unraveled the putative presence of orthologues in even more distant phyla such as cnidaria, placozoa and even many procaryotes. Moreover, the characterization of an active ACE in a proteobacteria indicates that the ancestor isoform was already functional. Thus, ACE is present from bacteria to mammals and exhibits incredibly conserved molecular, biochemical as well as structural features. The absence of ACE in all eucaryotic bicounts could thus result from a secondary loss. Taken together, these data suggest that ACE appeared early during the course of evolution. Mammalian ACE features could thus be a result of the long evolutive specialization of an ancient protease whose physiological functions remain to be elucidated.


The development of small-molecule modulators for ClpP protease activity.
The global spread of antibiotic resistance among important human pathogens emphasizes the need to find new antibacterial drugs with a novel mode of action. The ClpP protease has been shown to demonstrate its pivotal importance to both the survival and the virulence of pathogenic bacteria during host infection. Deregulating ClpP activity either through overactivation or inhibition could lead to antibacterial activity, declaiming the dual molecular mechanism for small-molecule modulation. Recently, natural products acyldepsipeptides (ADEPs) have been identified as a new class of antibiotics that activate ClpP to a dysfunctional state in the absence of cognate ATPases. ADEPs in combination with rifampicin eradicate deep-seated mouse biofilm infections. In addition, several non-ADEP compounds have been identified as activators of the ClpP proteolytic core without the involvement of ATPases. These findings indicate a general principle for killing dormant cells, the activation and corruption of the ClpP protease, rather than through conventional inhibition. Deletion of the clpP gene reduced the virulence of Staphylococcus aureus, thus making it an ideal antivirulence target. Multiple inhibitors have been developed in order to attenuate the production of extracellular virulence factors of bacteria through covalent modifications on serine in the active site or disruption of oligomerization of ClpP. Interestingly, due to the unusual composition and activation mechanism of ClpP in Mycobacterium tuberculosis, mycobacteria are killed by ADEPs through inhibition of ClpP activity rather than overactivation. In this short review, we will summarize recent progress in the development of small molecules modulating ClpP protease activity for both antibiotics and antivirulence.


Molecular typing of Staphylococcus aureus from different sources by RAPD-PCR analysis.
Staphylococcus aureus is an opportunistic bacterium which is carried as a normal flora organism but has a major role in the epidemiology and pathogenesis of different staphylococcal infections in humans and animals. Fifty S. aureus isolated from banknotes, foods, human infections and bovine mastitis were subjected to DNA fingerprinting by randomly amplified polymorphic DNA (RAPD) analysis to examine their genotypic polymorphism and investigate the amount of genetic relatedness among these various isolates. At 100% RAPD profile similarity level, isolates were classified into four, five and seven groups of the same clone, according to the RAPDPCR with OLP6, OLP11 and OLP13 primers, respectively. Amplification of the isolates resulted in several polymorphic bands ranged from >50 to >1500 bp in size. Maximum number of bands was obtained by primer OLP13 which produced seven bands in bovine mastitis isolates. Most polymorphisms were observed in isolates of bovine mastitis and the lowest were associated with human infections isolates. There was no relationship between the RAPD patterns and the sources of isolates, except the three clusters which showed host specificity and only included the strains from the same sources. The results confirm the wide genotypic diversity of the studied S. aureus strains. RAPD-PCR technique can be a valuable tool for assessing the genetic relationship, detection of polymorphism in S. aureus and tracing the sources and management of S. aureus infections.


Maintenance of muscarinic tone after vagotomy in the lung periphery.
We developed a method for maintaining muscarinic tone in a small region of the lung periphery after vagotomy. A fiber-optic bronchoscope was wedged in a segmental airway of anesthetized male mongrel dogs and was used to deliver aerosols of distilled water (0.1 ml), neostigmine (0.022 mg), atropine (0.1 mg), and histamine (1.5 X 10(-4) mg). Measurements of resistance through the collateral system (Rcs) were used to monitor responses to these agents. Rcs increased 37.0 +/- 5.0% (mean +/- SE) after the administration of neostigmine and remained elevated for at least 50 min. The administration of neostigmine in vagotomized animals or in those where the obstructed lung segment was pretreated with atropine resulted in a small increase in Rcs that lasted only 2 min. When bilateral vagotomy was performed 10 min after neostigmine administration Rcs remained elevated for at least another 80 min. However, Rcs returned to baseline when atropine was administered 20 min after vagotomy, but increased when histamine was administered 50 min after atropine. We conclude that after neostigmine administration, parasympathetic tone, dependent on mediators released from the vagus nerve, can be maintained in the lung periphery after vagotomy.


A comparative study of the effects of yoga and clinical Pilates training on walking, cognition, respiratory functions, and quality of life in persons with multiple sclerosis: A quasi-experimental study.
The purpose was to investigate the effects of yoga and clinical Pilates training on walking, respiratory muscle strength, cognition, and quality of life and compare the effects of two popular exercise methods in persons with multiple sclerosis (pwMS). Twenty-eight pwMS (Pilates group = 16, yoga group = 12) received the program once a week for eight weeks in addition to home exercises. At baseline and the end of the training, participants underwent assessments. The outcome measures were walking speed, mobility, balance confidence, respiratory muscle strength, cognition, and quality of life. Following the program, there was no significant difference in mobility (p = 0.482), perceived walking quality (p = 0.325), respiratory muscle strength (maximum inspiratory pressure: p = 0.263, maximum expiratory pressure: p = 0.866), and cognition (Symbol Digit Modalities Test: p = 0.324, California Verbal Learning Test-II: p = 0.514, Brief Visuospatial Memory Test-Revised: p = 0.279) between the two groups. Improvements were higher in balance confidence (p = 0.006), walking speed (p = 0.004), and quality of life (p = 0.019) in the clinical Pilates group compared to the yoga group. This study showed positive effects in walking and respiratory aspects in pwMS who received yoga and clinical Pilates training. Pilates training was superior in improving walking speed, quality of life, and balance confidence compared to yoga training.


A prospective randomised controlled clinical trial comparing somatostatin and vasopressin in controlling acute variceal haemorrhage.
Twenty two patients were entered into a randomised controlled clinical trial comparing the efficacy of somatostatin and vasopressin in controlling acute variceal haemorrhage. Somatostatin was significantly more successful in controlling acute variceal haemorrhage than vasopressin (p = 0.003). Furthermore, no complications were observed during treatment with somatostatin.


Case Report: Aarskog-scott syndrome caused by FGD1 gene variation: A family study.
Aarskog-Scott syndrome is a rare genetic disorder characterized by short stature, abnormal facial features, and digital and genital deformities. FGD1 gene variation is the known cause of this disorder. This paper described a Chinese family study of Aarskog-Scott syndrome in which the main patients were two brothers. Then, the relationship between genotype and phenotype in Aarskog-Scott syndrome was investigated preliminarily. A new FGD1 gene variant was revealed in this study, providing insights into the link between phenotype and genotype variations in Aarskog-Scott syndrome as well as a foundation for its diagnosis and treatment.


Comparison of simple measures of insulin sensitivity in young girls with premature adrenarche: the fasting glucose to insulin ratio may be a simple and useful measure.
Insulin resistance is a strong predictor of the development of type 2 diabetes mellitus and cardiovascular disease. Girls with premature adrenarche (PA) or obesity may be at an increased risk for the development of insulin resistance. Recently, in prepubertal girls with PA, a fasting glucose to insulin ratio (FGIR) of less than 7 was found to be predictive of insulin resistance as determined by the frequently sampled iv glucose tolerance test. We sought to compare the FGIR with 2 insulin sensitivity measures, SiM (an adjusted mean measure of insulin sensitivity based on fasting and 2 h post glucose load insulin sensitivity measures) and the composite whole body insulin sensitivity index, ISI(comp), both derived from the 2-h oral glucose tolerance test in 2 groups of children at risk: girls with PA and obese girls. We studied 25 prepubertal girls with PA and/or obesity and further classified them as insulin resistant (IR) or insulin sensitive (IS) based on the FGIR. Four simple measures of insulin sensitivity [FGIR, quantitative insulin sensitivity check index (QUICKI), fasting insulin resistance index, and fasting insulin] were compared with SiM and ISI(comp). Additionally, we characterized the subjects in terms of risk factors associated with insulin resistance according to their insulin resistance status based on the FGIR. In our subjects the strongest correlations overall appeared to be between FGIR and SiM, FGIR and ISI(comp), QUICKI and SiM, and QUICKI and ISI(comp) [correlations (r) ranged from 0.81--0.84]. Furthermore, the IR group had higher body mass index and body mass index z-scores and triglyceride levels than the IS group and were over 3 times more likely to have triglycerides greater than the 95th percentile compared with national norms. We conclude that the FGIR and QUICKI are highly correlated with oral glucose tolerance test measures of insulin sensitivity. An FGIR less than 7 in young girls with PA or obesity may be helpful in the early identification of children at risk for complications of insulin resistance.


Differential effects of excitatory and inhibitory heterogeneity on the gain and asynchronous state of sparse cortical networks.
Recent experimental and theoretical studies have highlighted the importance of cell-to-cell differences in the dynamics and functions of neural networks, such as in different types of neural coding or synchronization. It is still not known, however, how neural heterogeneity can affect cortical computations, or impact the dynamics of typical cortical circuits constituted of sparse excitatory and inhibitory networks. In this work, we analytically and numerically study the dynamics of a typical cortical circuit with a certain level of neural heterogeneity. Our circuit includes realistic features found in real cortical populations, such as network sparseness, excitatory, and inhibitory subpopulations of neurons, and different cell-to-cell heterogeneities for each type of population in the system. We find highly differentiated roles for heterogeneity, depending on the subpopulation in which it is found. In particular, while heterogeneity among excitatory neurons non-linearly increases the mean firing rate and linearizes the f-I curves, heterogeneity among inhibitory neurons may decrease the network activity level and induces divisive gain effects in the f-I curves of the excitatory cells, providing an effective gain control mechanism to influence information flow. In addition, we compute the conditions for stability of the network activity, finding that the synchronization onset is robust to inhibitory heterogeneity, but it shifts to lower input levels for higher excitatory heterogeneity. Finally, we provide an extension of recently reported heterogeneity-induced mechanisms for signal detection under rate coding, and we explore the validity of our findings when multiple sources of heterogeneity are present. These results allow for a detailed characterization of the role of neural heterogeneity in asynchronous cortical networks.


Effects of supplemental fat concentration on feeding logistics, animal performance, and nutrient losses of heifers fed finishing diets based on steam-flaked corn and sorghum-based distiller's grains.
The use of distiller's grains (DG) in beef cattle finishing diets is a common practice. However, the effects of supplemental fat on performance and nutrient losses of cattle fed diets containing DG are not known. Therefore, we fed 398 crossbred yearling heifers (initial BW = 373.5 kg) for 106 d to determine the effects of dietary fat concentration and sorghum-based wet distiller's grains with solubles (SWDGS) on performance, carcass characteristics, and nutrient losses of finishing cattle. Treatments included two 92% concentrate, steam-flaked corn (SFC)-based diets with 0% or 3% added fat from yellow grease and 3 SFC-based diets with 15% SWDGS (DM basis) that contained either 0%, 1.5%, or 3% added fat (8 pens per treatment) in a randomized block design. Overall DMI and ADG were 5% to 6% greater (P < 0.01) for heifers fed 15% SWDGS than for those fed 0% SWDGS. Among heifers fed 15% SWDGS, DMI was greatest (P = 0.04; quadratic effect) and ADG tended (P = 0.12; quadratic effect) to be greatest for heifers fed 1.5% fat. The ADG:DMI did not differ between 0% SWDGS with 0% or 3% fat, and was not altered by replacing a portion of SFC with SWDGS (P > 0.36). However, ADG:DMI tended to increase as more fat was added to diets with 15% SWDGS (P = 0.06). Average hot carcass weight (HCW) was 5 kg greater (P = 0.05) when SWDGS was fed, but HCW tended to be greatest for heifers fed 15% SWDGS with 1.5% fat (P = 0.09, quadratic effect). Heifers fed 0% SWDGS with 0% fat tended to have a lower marbling score, less rib fat, lower average yield grade (P < 0.08), and more (P < 0.01) yield grade 1 carcasses than heifers fed 0% SWDGS with 3% fat. Averaged across fat levels, heifers fed 15% SWDGS had more rib fat and a higher yield grade (P < 0.03) than heifers fed 0% SWDGS. Feeding 15% SWDGS did not alter carcass quality grade distribution compared to feeding 0% SWDGS, but 15% SWDGS produced fewer yield grade 3 carcasses (P = 0.03) than 0% SWDGS. The calculated NEg of SWDGS (1.36 Mcal/kg) was 91% of the tabular value for dry rolled corn (1.50 Mcal/kg) and 84% of the tabular value for SFC (1.62 Mcal/kg). Nitrogen intake, and N excretion were greater (P < 0.05) in heifers fed 15% SWDGS than in heifers fed the 0% SWDGS diets, but N loss as a % of N intake was less (P < 0.05). Our results suggest adding 1.5% fat to diets containing 15% SWDGS may improve beef cattle performance; however, feeding logistics need to be considered when pricing wet DG.


Skin Vaccination against Rotavirus Using Microneedles: Proof of Concept in Gnotobiotic Piglets.
Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P[8]) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P[8] human RV. Three doses of 5 μg IRV when administered intradermally and 5 μg IRV formulated with aluminum hydroxide [Al(OH)3] when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route.


Cholecystokinin receptor antagonist MK-329 blocks intestinal fat-induced inhibition of meal-stimulated gastric acid secretion.
MK-329, a selective type A cholecystokinin (CCK) receptor antagonist, was given to dogs to test the hypothesis that CCK is one of the principal physiological enterogastrones mediating fat-induced decreases in gastric acid secretion. Gastric acid secretion in response to 300 mL 8% peptone meals was measured by intragastric titration to pH 5.5 in six awake dogs with chronic gastric, duodenal, and jejunal fistulas. Gastric emptying was measured by a dye-dilution technique. During the last hour of peptone stimulation, the intestine was perfused with either control solution or 20% lipid (Intralipid; Kabi Vitrum, Alamedo, CA) intraduodenally or intrajejunally. Compared with control perfusions, mean gastric acid outputs were decreased significantly after lipid perfusion of the duodenum (47% of control) and jejunum (24% of control). Similarly, mean gastric emptying rates were significantly less after lipid perfusion of the duodenum (56%) and jejunum (26%). Oral pretreatment with MK-329 (1 mg/kg) significantly reversed the inhibition of gastric acid output caused by lipid perfusion of the duodenum and jejunum, but fat-induced inhibition of gastric emptying was not significantly affected. These studies provide evidence for an important inhibitory role for CCK as an enterogastrone but do not implicate CCK as being important in fat-induced delayed gastric emptying of a liquid meal in dogs.


Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain.
Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.


Pathological significance of first-trimester fetal nuchal oedema.
The pathological mechanism that causes the transient phenomenon sonographically defined as "nuchal translucency' is still poorly understood. Seven pregnancies in which the fetuses clearly presented this ultrasonic sign at 10-14 weeks' gestation were terminated because of an abnormal fetal karyotype. The pathological specimens, compared by morphometric analysis with normal fetuses of the same gestational age, showed oedema and dilatation of lymphatic capillary vessels. No particular relationship was found with any structural abnormality. We speculate that nuchal oedema is a transient non-specific phenomenon which is probably related to an early disarrangement of lymphatic connections.


Diabetic ulcer healing preparations from the skin of the Arabian Gulf catfish (Arius bilineatus Val.): a novel and effective treatment.
A novel and simple treatment for healing of infected diabetic foot ulcers in uncontrolled diabetes mellitus patients was devised. The preparations which involve aqueous extracts from the skin of the Arabian Gulf catfish are enriched with different fractions from the same source and with catfish lipids. Eight patients with non-healing foot ulcers and two with wet gangrene were treated. It was found that the ulcers were completely healed. The gangrenic feet noticeably improved in 48 h. The treatment resulted in natural debridation of the necrotic tissues. The ulcer site was invaded by angiogenesis and granulation tissues. Sensation returned to the otherwise neuropathic extremity. The rate of growth of new tissues was proportional to the amount of healing material applied, and its effect ceased shortly after the interruption of the treatment. No. atrophy of the skin lesions was noted and no side-effects were detected.


Development of a swine animal model for the study of sudden infant death syndrome.
An animal model with selective cardiac autonomic denervation was developed in neonatal swine for the purpose of future studies concerning the possible role of abnormal cardiac innervation in the etiology of sudden infant death syndrome. Twenty-six 4- to 8-day old piglets were randomly assigned to one of the following treatment groups: right stellate ganglionectomy (RSG), left stellate ganglionectomy (LSG), right cardiac vagotomy (RCV), and sham-operated control group. Piglets were anesthetized with Saffan and mechanically ventilated on room air. The thoracic wall was opened, and the sternum was divided, permitting exposure of pleura, heart, and lungs. After completion of one of these operative procedures, the thoracic wall was closed in layers. On successful recovery from anesthesia and extubation, piglets were returned to their sows. Postoperative administration of antibiotics was performed during the first week. Electrocardiograms were recorded once a week over an 8-week period. The sham-operated control group had a postnatal increase in QTc and decrease in heart rate. The RSG group had significantly longer QTc than the sham-operated control group QTc, whereas the RCV group had significantly shorter QTc interval than sham-operated controls. Surgical complications caused the death of two piglets (hemorrhage in one and aspiration in the other), infection caused the death of one piglet 2 weeks after surgery, and three died of unknown causes (one from the RSG group and two from the RCV group). The cause of death for these three animals could not be determined (necropsy was not revealing) because they were not monitored at the time of their demise.(ABSTRACT TRUNCATED AT 250 WORDS)


Next-generation sequencing of custom amplicons to improve coverage of HaloPlex multigene panels.
Next-generation sequencing (NGS) of multigene panels performed for genetic clinical diagnostics requires 100% coverage of all targeted genes. In the genetic diagnostics laboratory, coverage gaps are typically filled with Sanger sequencing after NGS data are collected and analyzed. Libraries prepared using the hybridization-based custom capture HaloPlex method are covered at ~98% and include gaps in coverage because of the location of the restriction enzyme sites used for fragmentation and differences in the designed and actual library insert size. We describe a method for improving the coverage of HaloPlex libraries by generating a set of amplicons spanning known low-coverage regions that are pooled, indexed by sample, and sequenced together with the HaloPlex libraries. This approach reduces the number of post-NGS Sanger sequencing reactions required and complements any NGS library preparation method when complete gene coverage is necessary.


Rationale and protocol of the StayFitLonger study: a multicentre trial to measure efficacy and adherence of a home-based computerised multidomain intervention in healthy older adults.
In older adults, multidomain training that includes physical and cognitive activities has been associated with improvement of physical and cognitive health. The goal of the multisite StayFitLonger study is to assess a home-based computerised training programme, which combines physical exercises, stimulating cognitive activities and virtual coaching. One hundred twenty-eight cognitively healthy older adults will be recruited from the community in Switzerland, Canada and Belgium. The study will comprise (1) a 26-week double-blind randomized controlled efficacy trial and (2) a 22-week pragmatic adherence sub-study. In the efficacy trial, participants will be randomly assigned to an experimental or an active control intervention. In the experimental intervention, participants will use the StayFitLonger programme, which is computerised on a tablet and provides content that combines physical activities with a focus on strength and balance, as well as divided attention, problem solving and memory training. Outcomes will be measured before and after 26 weeks of training. The primary efficacy outcome will be performance on the "Timed-Up & Go" test. Secondary outcomes will include measures of frailty, cognition, mood, fear of falling, quality of life, and activities of daily living. Age, sex, education, baseline cognition, expectation, and adherence will be used as moderators of efficacy. Following the 26-week efficacy trial, all participants will use the experimental programme meaning that participants in the control group will 'cross over' to receive the StayFitLonger programme for 22 weeks. Adherence will be measured in both groups based on dose, volume and frequency of use. In addition, participants' perception of the programme and its functionalities will be characterised through usability, acceptability and user experience. This study will determine the efficacy, adherence and participants' perception of a home-based multidomain intervention programme and its functionalities. This will allow for further development and possible commercialization of a scientifically validated training programme. ClinicalTrials.gov , NCT04237519 Registered on January 22, 2020 - Retrospectively registered.


High glucose promotes Aβ production by inhibiting APP degradation.
Abnormal deposition of neuriticplaques is the uniqueneuropathological hallmark of Alzheimer's disease (AD).Amyloid β protein (Aβ), the major component of plaques, is generated from sequential cleavage of amyloidβ precursor protein (APP) by β-secretase and γ-secretase complex. Patients with diabetes mellitus (DM), characterized by chronic hyperglycemia,have increased risk of AD development.However, the role of high blood glucose in APP processing and Aβ generation remains elusive. In this study, we investigated the effect of high glucose on APP metabolism and Aβ generation in cultured human cells. We found that high glucose treatment significantly increased APP protein level in both neuronal-like and non-neuronal cells, and promoted Aβ generation. Furthermore, we found that high glucose-induced increase of APP level was not due to enhancement of APP gene transcription but resulted from inhibition of APP protein degradation. Taken together, our data indicated that hyperglycemia could promote AD pathogenesis by inhibiting APP degradation and enhancing Aβ production. More importantly, the elevation of APP level and Aβ generation by high glucose was caused by reduction of APP turnover rate.Thus,our study provides a molecular mechanism of increased risk of developing AD in patients withDMand suggests thatglycemic control might be potentially beneficial for reducing the incidence of AD in diabetic patients and delaying the AD progression.


COVID-19 classification by CCSHNet with deep fusion using transfer learning and discriminant correlation analysis.
: COVID-19 is a disease caused by a new strain of coronavirus. Up to 18th October 2020, worldwide there have been 39.6 million confirmed cases resulting in more than 1.1 million deaths. To improve diagnosis, we aimed to design and develop a novel advanced AI system for COVID-19 classification based on chest CT (CCT) images. : Our dataset from local hospitals consisted of 284 COVID-19 images, 281 community-acquired pneumonia images, 293 secondary pulmonary tuberculosis images; and 306 healthy control images. We first used pretrained models (PTMs) to learn features, and proposed a novel (L, 2) transfer feature learning algorithm to extract features, with a hyperparameter of number of layers to be removed (NLR, symbolized as L). Second, we proposed a selection algorithm of pretrained network for fusion to determine the best two models characterized by PTM and NLR. Third, deep CCT fusion by discriminant correlation analysis was proposed to help fuse the two features from the two models. Micro-averaged (MA) F1 score was used as the measuring indicator. The final determined model was named CCSHNet. : On the test set, CCSHNet achieved sensitivities of four classes of 95.61%, 96.25%, 98.30%, and 97.86%, respectively. The precision values of four classes were 97.32%, 96.42%, 96.99%, and 97.38%, respectively. The F1 scores of four classes were 96.46%, 96.33%, 97.64%, and 97.62%, respectively. The MA F1 score was 97.04%. In addition, CCSHNet outperformed 12 state-of-the-art COVID-19 detection methods. : CCSHNet is effective in detecting COVID-19 and other lung infectious diseases using first-line clinical imaging and can therefore assist radiologists in making accurate diagnoses based on CCTs.


Fabrication of nanostructured poly(3-thiophene methyl acetate) within poly(vinylidene fluoride) matrix: new physical and conducting properties.
Nanostructured poly(3-thiophene methyl acetate) (PTMA) within the poly(vinylidene fluoride) (PVDF) matrix is achieved by reactive blending technique under melt-cooled condition. The nanoparticles are almost spherical showing a minimum size with 5% (w/w) PTMA concentration (PTMA5), and they become agglomerated at > or = 25% (w/w) PTMA concentration. Different phase separation mechanisms are used to explain the above variation of nanoparticle size. The lower size nanophase in the PTMA5 blend is attributed to spinodal decomposition, while the larger size nanophases are produced from binodal decomposition. The TGA study indicates increasing thermal stability of PVDF in the nanoblends. DSC study shows increasing melting and crystallization temperature of the nanoblends; the former is due to the attractive forces of PTMA nanostructure, and the latter is for the nucleating effect of nanophase PTMA. The long distance, lamellar distance, and amorphous overlayer distance decrease to different extents. The pi-pi* transition band of UV-vis spectra shows a red shift with increasing PTMA concentration, but the photoluminescence spectra of the nanoblends show a blue shift. The former is attributed to intrachain aggregation of PTMA, while the latter is caused from "static excimer" formation at the ground state. PTMA1 and PTMA3 show approximately 8 times increase in PL intensity except PTMA5 where interconnectivity between the nanodomains makes the nonradiative decay similar to bulk PTMA. The temperature variation of conductivity indicates a conformational transition of PTMA chain with increasing temperature facilitating better charge transport. The I-V characteristic curves are really interesting; the nanoblends show a negative hysterisis, but PTMA5 shows a memory effect attributed to the electrical bistability originated from the interconnected nanophases arising from spinodal decomposition.


Neck web and congenital heart defects: a pathogenic association in 45 X-O Turner syndrome?
This study explores the association between neck web and congenital heart disease in patients with Turner syndrome. Of 193 cases with documented 45 X-O karyotype, 106 (55%) had a web neck and 87 (45%) had a normal neck. The incidence of congenital heart disease was significantly different between these two groups, occurring in 30% of those with web neck and 9% of those with normal neck (x2 = 12.82, P less than .0005). The difference was most striking in coarctation of the aorta for which the prevalence was 25% with web neck and 3% with normal neck (X2 = 17.65, P less than .0001). The association between web neck and congenital heart disease suggests a pathogenic relationship exists between the two. The following hypothesis is proposed to explain the association. Increased lymphatic pressure associated with jugular lymphatic sac obstruction distends the thoracic ducts, which compress the ascending aorta altering intracardiac blood flow. Redirection of intracardiac blood flow produces coarctation of the aorta and other defects in the spectrum of left heart obstruction. This proposed mechanism is an example of a teratogenic event remote from the heart, which alters cardiovascular morphology.


[Deep intrauterine insemination in cattle].
Most of the artificial inseminations in cattle nowadays are being performed in the uterine body with a rigid insemination device. Uterotubal junction insemination can only be performed in cattle with a device which is rigid enough to pass the cervix and flexible enough to follow the curvature of the uterine horns. At the Faculty of Veterinary Medicine in Ghent, a new insemination device has been developed for semen deposition near the utero-tubal junction in cattle and other animals. In a first field trial the feasibility of the newly developed Ghent device was evaluated. Four thousand sixty-four dairy cows were inseminated by 12 inseminators with a standard insemination dose (10-15 million of frozen-thawed spermatozoa). Three insemination methods were compared; group 1: insemination in the uterine body with the conventional insemination device, group 2: insemination in the uterine body with the Ghent device, and group 3: insemination in the tip of both uterine horns with the Ghent device. In a second field trial insemination of dairy cows with the Ghent device was compared with the conventional insemination technique to evaluate the effect on pregnancy rates. The insemination dose was lowered to eight million (trial 1), four million (trial 2), and finally to two million frozen-thawed spermatozoa (trial 3). In each field trial, cows were divided into three groups: the first group was inseminated with a full insemination dose (12 x 10(6)) in the uterine body with the conventional insemination device, the second group with a lowered insemination dose in the uterine body with the conventional insemination device, and the third group with a lowered insemination dose in the tip of both uterine horns with the Ghent device. It can be concluded that decreasing the insemination dose from 12 to four million frozen-thawed spermatozoa had no effect on pregnancy rate in our experiments, neither with the conventional insemination device, nor with the Ghent device. The device is made of disposable materials and has been tested to be non-toxic for bovine spermatozoa, can be used by one person and is adapted for application in the field. In the near future, similar field trials will be performed with even lower doses of semen. It is only in these cases that we truly hope to show a positive effect of uterotubal junction insemination by using low quality semen or by using sexed semen.


The tail wagging the dog: insights into catalysis in R67 dihydrofolate reductase.
Plasmid-encoded R67 dihydrofolate reductase (DHFR) catalyzes a hydride transfer reaction between substrate dihydrofolate (DHF) and its cofactor, nicotinamide adenine dinucleotide phosphate (NADPH). R67 DHFR is a homotetramer that exhibits numerous characteristics of a primitive enzyme, including promiscuity in binding of substrate and cofactor, formation of nonproductive complexes, and the absence of a conserved acid in its active site. Furthermore, R67's active site is a pore, which is mostly accessible by bulk solvent. This study uses a computational approach to characterize the mechanism of hydride transfer. Not surprisingly, NADPH remains fixed in one-half of the active site pore using numerous interactions with R67. Also, stacking between the nicotinamide ring of the cofactor and the pteridine ring of the substrate, DHF, at the hourglass center of the pore, holds the reactants in place. However, large movements of the p-aminobenzoylglutamate tail of DHF occur in the other half of the pore because of ion pair switching between symmetry-related K32 residues from two subunits. This computational result is supported by experimental results that the loss of these ion pair interactions (located >13 Å from the center of the pore) by addition of salt or in asymmetric K32M mutants leads to altered enzyme kinetics [Hicks, S. N., et al. (2003) Biochemistry 42, 10569-10578; Hicks, S. N., et al. (2004) J. Biol. Chem. 279, 46995-47002]. The tail movement at the edge of the active site, coupled with the fixed position of the pteridine ring in the center of the pore, leads to puckering of the pteridine ring and promotes formation of the transition state. Flexibility coupled to R67 function is unusual as it contrasts with the paradigm that enzymes use increased rigidity to facilitate attainment of their transition states. A comparison with chromosomal DHFR indicates a number of similarities, including puckering of the nicotinamide ring and changes in the DHF tail angle, accomplished by different elements of the dissimilar protein folds.


The P300 component in patients with Alzheimer's disease and their biological children.
There are few studies examining P300 in the biological children of patients with Alzheimer's disease (AD). In addition to examining P300 in patients with AD, the current study examined the utility of P300 as a preclinical marker in the offspring of AD patients. P300 was elicited from an AD group, their biological children, and two age- and gender-matched control groups using the auditory oddball paradigm. Each group consisted of 20 subjects each. ERPs recorded from sites Fz, Cz, and Pz were analysed using analysis of variance. Amplitudes were significantly smaller in the AD group when compared to controls. Both amplitude and latency values in the FH+ group were significantly impaired when compared to its control group. These findings replicate previous P300 amplitude abnormalities found in patients with AD. Further, participants with a family history of AD demonstrate possible preclinical evidence at the electrophysiological level. Comparisons with other findings and theoretical implications are discussed.


Increasing Rate of Pulmonary Embolism in Trauma Patients at a Level One Trauma Center: An Opportunity for Quality Improvement?
Introduction Pulmonary embolism (PE) is the most common cause of preventable hospital death in trauma patients, with 100,000 patients dying from PE annually. A steadily increasing PE rate was observed over seven years in the trauma population at a single level one trauma center. Our study seeks to analyze this trend by examining risk factors and searching for targets for improvement. We hypothesized that a change in one or more modifiable risk factors was associated with the increased PE rate. Methods This retrospective cohort study considered trauma patients admitted to our trauma center between 2012 and 2018. The change in PE rate over time and correlation with various risk factors were examined using logistic regression. The study population was divided into two cohorts: early (2012-2015), and late (2016-2018). Data were collected from a prospectively maintained trauma database. More detailed information was obtained from individual patient charts for 533 patients worked up for PE. Risk factors were evaluated using both univariate and multivariate analysis. Results A total of 14,986 trauma patients were included in the study, of which 132 were diagnosed with PE. The PE rate was 1.11% in the late group compared to 0.67% in the early group (p=.004). We detected no association between the PE rate and preventive measures such as screening for and treating deep venous thrombosis (DVT), placing inferior vena cava (IVC) filters, and patterns of chemical DVT prophylaxis. We did not observe a distal migration of the anatomic distribution of PEs on CT pulmonary angiogram (CTPA). There were nonsignificant trends between PE rate and changes in population demographics and injury patterns, increased frequency of major surgery, and increased tranexamic acid (TXA) use. Of known risk factors for PE, units of packed red blood cells (PRBC) (p=0.041), units of fresh frozen plasma (FFP) (p=.037), and the number of patients receiving transfusion (p=0.043) were all significantly greater in the later period. Conclusion Change in hemostatic resuscitation practices (use of balanced ratios of blood products) is most likely to have contributed to the increased PE rate at our institution. However, PE in trauma is multifactorial, and the increased rate cannot be attributed to any single factor. We did not observe a lapse in preventive measures commonly considered indices of quality of care. Caution is advised against overreliance on PE rate as a measure of quality.


Removal by a Trace of Sodium of the Period Lengthening of the Potassium Uptake Rhythm Due to Lithium in Lemna gibba G3.
The effect of Li(+) on the period of the K(+) uptake rhythm in the flow medium culture of the duckweed (Lemna gibba G3) was investigated under various ionic conditions. In the presence of Li(+) at 0.2 millimolar or higher concentrations, the period was longer than the normal level of 25.4 hours by 2 hours. Li(+) also lowered the amplitude of the rhythm. Although Na(+) itself did not change any parameter of the rhythm, simultaneous application of Na(+) at a very low concentration (20 micromolar) almost completely removed the effects of 0.5 millimolar Li(+) on both the period and the amplitude. However, divalent cations (Ca(2+) and Mg(2+)) or Rb(+) did not remove the Li(+) action on the period. The effect of Li(+) and its removal by Na(+) corresponded to intracellular Li(+) and Na(+) levels. The period was prolonged when the duckweed contained more Li(+) than 5 micromoles/gram fresh weight. But the Li(+) effect was cancelled when the in vivo Na(+) level was greater than one-fifth that of Li(+), even if the Li(+) level exceeded over 5 micromoles/gram fresh weight.


The cost of quantum locality.
It has been more than 20 years since Deutsch and Hayden demonstrated that quantum systems can be completely described locally-notwithstanding Bell's theorem. More recently, Raymond-Robichaud proposed two other approaches to the same conclusion. In this paper, all these means of describing quantum systems locally are proved formally equivalent. The cost of such descriptions is then quantified by the dimensionality of their underlining space. The number of degrees of freedom of a single qubit's local description is shown to grow exponentially with the total number of qubits considered as a global system. This apparently unreasonable cost to describe such a small system in a large Universe is nonetheless shown to be expected. Finally, structures that supplement the universal wave function are investigated.


Wireless capsule endoscopic detection of Meckel's diverticulum after nondiagnostic surgery.
A patient aged 26 was investigated for recurrent severe gastrointestinal bleeding. Over a 4-year period, he was transfused more than 400 units of blood. Multiple investigations included three negative Meckel's scans. A right hemicolectomy for supposed angiodysplasia failed to control his bleeding. Wireless capsule endoscopy demonstrated the presence of a Meckel's diverticulum. At a repeat laparotomy, the ulcerated Meckel's diverticulum was identified and resected. The patient had no further bleeding and had a normal haemoglobin level on repeat blood tests up to 12 months after surgical excision of the diverticulum.


High SRC-1 and Twist1 expression predicts poor prognosis and promotes migration and invasion by inducing epithelial-mesenchymal transition in human nasopharyngeal carcinoma.
Steroid receptor coactivator 1 (Src-1) and Twist1 are aberrantly upregulated in a variety of tumors and play an important role in tumor progression. However, the exact role of Src-1 and Twist1 in nasopharyngeal carcinoma (NPC) is uncertain. In this study, we investigated the possible prognostic value and biological effect of Src-1 and Twist1 in NPC. Src-1 and Twist1 expression was detected in a cohort of NPC patients (n = 134) by qRT-PCR. Kaplan-Meier survival analysis was used comparing overall survival (OS) and progression-free survival (PFS). Multivariate analysis was performed using the Cox proportional hazard regression model. Biologic effect of Src-1 and Twist1 in NPC cell lines was evaluated by western blot, colony formation assay, soft agar assay, scratch wound healing assay, transwell invasion assay and tumor xenografts growth. We have found that Src-1 and Twist1 were aberrantly upregulated in human NPC tissues, and associated with advanced tumor stage, distant metastasis and unfavorable prognosis. Knockdown of Src-1 or Twist1 in human NPC cell line CNE-1 suppressed colony formation, anchorage-independent growth, cell migration, invasion and tumor xenografts growth, while enforced expression of Src-1 or Twist1 in human NPC cell line HNE-2 promotes anchorage-independent growth, cell migration and invasion. In addition, Src-1 and Twist1 could suppress E-cadherin expression and increase Vimentin expression, thus suggested that Src-1 and Twist1 enhanced the malignant behaviors of NPC cells via inducing epithelial-mesenchymal transition (EMT). Our data indicated that Src-1 and Twist1 could be possible prognostic biomarkers and potential therapy targets for patients with NPC.


Emodin alleviates myocardial ischemia/reperfusion injury by inhibiting gasdermin D-mediated pyroptosis in cardiomyocytes.
Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury. Pyroptosis is a proinflammatory programmed cell death that is related to many diseases. The present study investigated the effect of emodin on pyroptosis in cardiomyocytes. Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups. I/R model was subjected to 30 minutes' ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion. Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours. The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA. The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment. Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis. Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins. This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro. The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, emodin may provide an alternative treatment for myocardial I/R injury.


Occurrence of a Novel Strain of Moroccan Watermelon Mosaic Virus Infecting Pumpkins in Kenya.
The Potyvirus Moroccan watermelon mosaic virus (MWMV) naturally infects and severely threatens production of cucurbits and papaya. In this study, we identified and characterized MWMV isolated from pumpkin (Cucurbita moschata) intercropped with MWMV-infected papaya plants through next-generation sequencing (NGS) and Sanger sequencing approaches. Complete MWMV genome sequences were obtained from two pumpkin samples through NGS and validated using Sanger sequencing. The isolates shared 83.4 to 83.7% nucleotide (nt) and 92.3 to 95.1% amino acid (aa) sequence identities in the coat protein and 79.5 to 79.9% nt and 89.2 to 89.7% aa identities in the polyprotein with papaya isolates of MWMV. Phylogenetic analysis using complete polyprotein nt sequences revealed the clustering of both pumpkin isolates of MWMV with corresponding sequences of cucurbit isolates of the virus from other parts of Africa and the Mediterranean regions, distinct from a clade formed by papaya isolates. Through sap inoculation, a pumpkin isolate of MWMV was pathogenic on zucchini (Cucurbita pepo), watermelon (Citrullus lanatus), and cucumber (Cucumis sativus) but not on papaya. Conversely, the papaya isolate of MWMV was nonpathogenic on pumpkin, watermelon, and cucumber, but it infected zucchini. The results suggest the occurrence of two strains of MWMV in Kenya having different biological characteristics associated with the host specificity.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


Making memories that last a lifetime: heritable functions of self-renewing memory CD8 T cells.
Clonal expansion of virus-specific naive T cells during an acute viral infection results in the formation of memory CD8 T cells that provide the host with long-term protective immunity against the pathogen. Memory CD8 T cells display enhanced effector functions compared with their naive precursors, allowing them to respond more rapidly and effectively to antigen re-encounter. The enhanced functions of memory CD8 T cells are mediated by heritable changes in gene regulation. Expression of select transcription factors along with locus-specific epigenetic modifications are coupled to and are essential in the formation of memory-specific gene expression patterns. Here, we will review the changes in gene expression that accompany development of memory CD8 T cells and discuss chromatin modifications as a potential means for heritable propagation of these changes during homeostatic cell division of self-renewing memory CD8 T cells. Also, we will discuss therapies that manipulate heritable gene regulation as a potential mechanism to restore function to non-functional memory CD8 T cells to combat chronic viral infection.


Laparoscopic Management of Gallbladder Duplication: A Case Report.
Laparoscopic cholecystectomy has become one of the most commonly performed abdominal surgeries worldwide. Several anatomic variations and congenital malformations in the gallbladder and biliary anatomy have been described. We reported the case of a middle-aged woman who presented with jaundice and abdominal pain. Her laboratory investigations revealed an elevated bilirubin level (mainly the direct component). The patient showed an improvement in the clinical and laboratory parameters after conservative management. Then, the patient was prepared for a laparoscopic cholecystectomy which revealed a duplication of the gallbladder with two distinct cystic ducts draining independently to the common bile duct. The procedure was completed uneventfully. This type of gallbladder duplication is among the least common types. The case highlights the importance of having a meticulous intraoperative evaluation of the biliary anatomy to avoid potential complications and injuries.


[Leflunomide--a new drug for pharmacological immunomodulation].
The novel immunomodulatory agent leflunomide exhibits a strong anti-inflammatory action. This isoxazole derivative is chemically unrelated to any hitherto applied immunosuppressants. As a prodrug leflunomide is completely converted to its active metabolite A 77 1726 (M1) which blocks the dihydroorotate dehydrogenase, a key enzyme of the pyrimidine de novo synthesis. Drug-related adverse effects are mild, dose-related and reversible, characterising leflunomide as a safe immunosuppressant. While up to now leflunomide has just been approved for therapy of rheumatoid arthritis, its mechanism of action affects multiple inflammatory pathways, thereby suggesting it to be a potent therapeutic agent in autoimmune diseases, graft rejection, and tumour therapy. First dermatological experience has been gained in psoriasis and bullous pemphigoid. The role of leflunomide in the dermatologist's therapeutic armamentarium will evolve during the next years.


Cutting edge: differential chemokine production by myeloid and plasmacytoid dendritic cells.
To examine the different roles of myeloid dendritic cells (M-DCs) and plasmacytoid dendritic cells (P-DCs) in the induction and regulation of immune response, we have studied chemokine secretion by freshly isolated DC subsets in response to bacterial, viral, and T cell-derived stimuli. M-DCs selectively produced very high levels of the homeostatic chemokines CC chemokine ligand (CCL)17 and CCL22, while P-DCs produced very little if any. In contrast, the proinflammatory chemokine CCL3 was secreted mostly by P-DCs, whereas CCL4 and CXC chemokine ligand 8 were produced by both subsets. The selective production of CCL17 and CCL22 by M-DCs but not P-DCs was confirmed in vivo by immunohistology on human reactive lymph node sections. The high production of CCR4 ligands by M-DCs suggests their capacity to selectively recruit at sites of inflammation T cells with regulatory properties or with a Th2 phenotype, whereas P-DCs, by preferentially secreting CCR1/CCR5 ligands, would mostly recruit effector T cells and, in particular, Th1-type cells.


[The possibilities for gender determination based on the specific anatomical features of the human cricoid cartilage].
Is to establish the morphometric features of the human cricoid cartilage structure using anthropometric research. Cricoid cartilage was examined from 37 men and 30 women. Using an electronic caliper and scales, 17 metric parameters and the mass of the cricoid cartilage were established, and a statistical analysis of the results obtained was carried out. It was found that the greatest relationship with the gender had the following dimensions: the distance from the upper outer edge of the plate to the outer edge of the arch and the height of the cricoid cartilage plate, the distance between the arytenoid articular surfaces, and the mass of cricoid cartilage. The data obtained confirmed the gender dimorphism of the cricoid cartilage. The data of this study can be used in expert practice for forensic medical identification of a person.


Comparison and Prognostic Analysis of Adjuvant Radiotherapy versus Salvage Radiotherapy for Treatment of Radically Resected Locally Advanced Esophageal Squamous Cell Carcinoma.
Objective. To compare adjuvant radiotherapy and salvage radiotherapy after radical resection for treatment of esophageal squamous cell carcinoma (ESCC). Methods. Data from 155 patients with locally advanced ESCC who underwent radical resection and received postoperative radiotherapy from 2005 to 2011 were reviewed. Seventy-nine patients received adjuvant radiotherapy and 76 received salvage radiotherapy after locoregional recurrence. Results. The median disease-free survival (DFS) and overall survival (OS) were significantly higher in the adjuvant radiotherapy group than the salvage radiotherapy group (DFS 25.73 months versus 10.73 months, P < 0.001; OS 33.33 months versus 26.22 months, P = 0.006). The independent prognostic factors for DFS were performance status (PS) before radiotherapy and pathological stage in the adjuvant radiotherapy group, compared with lymph node metastasis, tumor location, and adjuvant chemotherapy in the salvage radiotherapy group. The independent prognostic factors for OS were age and PS in both groups. No differences in median DFS and OS between the groups were observed in patients aged > 65 years or with PS ≥ 2. Conclusion. Compared to salvage radiotherapy, postoperative adjuvant radiotherapy can prolong DFS and OS for patients with radically resected local advanced ESCC but cannot improve survival for patients aged > 65 years or with PS ≥ 2.


A Combination Approach in Inhibiting Type 2 Diabetes-Related Enzymes Using Ecklonia radiata Fucoidan and Acarbose.
Although there are chemotherapeutic efforts in place for Type 2 diabetes mellitus (T2DM), there is a need for novel strategies (including natural products) to manage T2DM. Fucoidan, a sulphated polysaccharide was extracted from Ecklonia radiata. The integrity of the fucoidan was confirmed by structural analysis techniques such as FT-IR, NMR and TGA. In addition, the fucoidan was chemically characterised and tested for cell toxicity. The fucoidan was investigated with regards to its potential to inhibit α-amylase and α-glucosidase. The fucoidan was not cytotoxic and inhibited α-glucosidase (IC50 19 µg/mL) more strongly than the standard commercial drug acarbose (IC50 332 µg/mL). However, the fucoidan lacked potency against α-amylase. On the other hand, acarbose was a more potent inhibitor of α-amylase (IC50 of 109 µg/mL) than α-glucosidase. Due to side effects associated with the use of acarbose, a combination approach using acarbose and fucoidan was investigated. The combination showed synergistic inhibition (>70%) of α-glucosidase compared to when the drugs were used alone. The medicinal implication of this synergism is that a regimen with a reduced acarbose dose may be used, thus minimising side effects to the patient, while achieving the desired therapeutic effect for managing T2DM.


Oxacalix[3]arene complexes with the ReI(CO)3 fragment.
Oxacalix[3]arenes p-methyloxacalix[3]arene (L(1)), p-isopropyloxacalix[3]arene (L2), and p-ethoxycarbonyloxacalix[3]arene (L3) are able to bind the Re(I)(CO)3 moiety with two of their three phenol-O atoms and one of their ether-O atoms. The monoanionic complexes were isolated in the salts (DBUH)[Re(CO)3(L1H-2)].L1 (1) and (NEt4)[Re(CO)3(L2H-2)].L2.0.5 MeCN (2) (DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene). Over the course of its reaction with (NEt4)(2)[Re(CO)3Br(3)] and DBU, p-ethoxycarbonyloxacalix[3]arene decomposes to form [{Re(CO)3(L4H-2)}2] (3) {L4 = 1-(5-ethoxycarbonyl-2-hydroxy-3-hydroxymethyl-benzyl)-2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepin-1-ium. The expected monoanion [Re(CO)3(L3H-2)]- (4) was identified by 13C NMR and mass spectra.


The efficacy and safety of warming acupuncture and moxibustion on rheumatoid arthritis: A protocol for a systematic review and meta-analysis.
Rheumatoid arthritis (RA), as an autoimmune disease, can eventually lead to joint deformity and loss of function, seriously reduce the quality of life of patients and increase economic burden. As a traditional Chinese therapy, warming acupuncture and moxibustion is safe, economical, and has few side effects. At present, some studies have shown that warming acupuncture and moxibustion has a certain effect on RA, but there is no evidence of evidence-based medicine. The purpose of this study was to evaluate the efficacy and safety of warming acupuncture and moxibustion in the treatment of rheumatoid arthritis. Randomized controlled trials of warming acupuncture and moxibustion treating RA will be searched in the databases including PubMed, EMBASE, the Cochrane library, Web of science, China National Knowledge Infrastructure (CNKI), WanFang, the Chongqing VIP Chinese Science and Technology Periodical Database (VIP), and China biomedical literature database (CBM) from inception to July, 2020. In addition, Baidu, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry will be searched to obtain the gray literature and relevant data that have not yet been published. Two qualified researchers will extract data and assess the risk of bias from included studies independently. Statistical analysis is performed in RevMan 5.3 software. The primary outcome is symptom evaluation including morning stiffness, pain, and joint swelling. The number of joints affected by RA, Rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), anti-cyclic peptide containing citrulline (A-CCP), and adverse effects, will be evaluated as secondary outcomes. This study will compare the efficacy and safety of warming acupuncture and moxibustion with common acupuncture in the treatment of RA, providing reliable evidence for clinical application. DOI 10.17605/OSF.IO/C8RY9.


[Cardiac pacemaker for the treatment of obstructive hypertrophic cardiomyopathy, a concept which is gaining ground].
Pacing reduces the sub-aortic pressure gradient in hypertrophic obstructive cardiomyopathy. This phenomenon was described long ago but only recently, with the development of sophisticated pacemakers, has it become possible to use pacemakers for the long term treatment of this disease. The acute hemodynamic improvement with pacemaker treatment is well documented. The reason for this acute and chronic improvement is of multiple origin. Pacing modulates the activation sequence of the left ventricle, reduces contractility, reduces subaortic flow velocities, influences mitral valve movement and leads to remodeling of the ventricle in the long term. All these factors together explain the clinical and hemodynamic improvement in patients suffering from hypertrophic obstructive cardiomyopathy.


[Effect of needle suspension on continence mechanisms].
To compare the separation in time of urethral and bladder pressure pulses and urodynamic parameters after successful and unsuccessful anterior colporrhaphy and needle suspension of the bladder neck in patients with stress urinary incontinence. Retrospective evaluation of urethral pressure profiles at rest and under stress in 10 successfully and 10 unsuccessfully operated patients. In the successfully treated group, the onset of the urethral pressure increase preceded that of the bladder pressure by an average of 300 ms. Pressure transmission ratios in the 3 proximal quartiles of the urethra were significantly improved after successful surgery. Women who remained incontinent showed neither an advanced onset of the urethral pressure pulse during stress nor improved pressure transmission ratios. Successful anterior repair and needle suspension of the bladder neck support the bladder neck and thus improve the pressure transmission to the urethra. Improved pressure transmission is associated with the finding that pressure increases in the urethra precede those in the bladder in continent women.


Dolichyl phosphate-dependent glycosyltransferases utilize truncated cofactors.
Synthetic truncated dolichyl phosphates of chain lengths from four to thirteen isoprene units (Jaenicke L. and Siegmund H.-U., Chem. Phys. Lipids 51 (1989) 159-170) were assayed for their cofactor activity in the enzymatic transfer of hexoses and hexosamines. The enzymes were microsomal preparations from the green alga Volvox carteri, baker's yeast, and mammalian liver cells. Under saturating conditions, the acceptor activities of the truncated dolichyl phosphates increased from zero to full strength as compared to the mixture of long-chain dolichyl phosphates from natural sources with growing chain length from five to nine isoprene units. Km determinations confirmed the results. Of the geometric isomers of dolichyl 7-phosphate (35 carbon atoms), the 14-trans compound has unchanged acceptor activity; all-trans dolichyl 7-phosphate, however, was almost inactive. The data suggest that hydrophobicity may be an important, but not the only criterion for the binding of the isoprene moiety to the active sites of the transferase enzyme(s) and that the geometry of more than only one double bond in the dolichols is recognized.


Impeded eruption rate of the rat maxillary incisor during exposure to different simulated altitudes.
Female rats weighing about 200 g each were separated into normoxic and hypoxic groups. The former were maintained at sea-level conditions. The hypoxic groups were placed in an altitude chamber and maintained at the equivalent of 1850 m, 4100 m, or 7100 m over a period of two weeks. Hematocrit, body weight, body length, and impeded eruption rate were recorded once a week. Food intake was recorded every day. Exposure to 1850 m did not significantly alter hematocrit, body weight and body length gains, food intake, and impeded eruption rate. Nevertheless, exposure to 4100 m and 7100 m decreased body weight and body length gains, food intake, and impeded eruption rate, and increased hematocrit value. These parameters varied as a function of altitude. In spite of the lack of conclusive evidence, this work affords further insight into the particular significance of polycythemia on the eruption rate.


Transgenic techniques to delineate cell-specific effects of beta2-adrenergic receptors in the lung.
Many, if not most, of the different cell types within the lung have been shown to express beta(2)-adrenergic receptors (beta(2)ARs) on the cell surface. beta(2)ARs have thus been implicated in the regulation of many aspects of lung function. However, the physiologic and therapeutic relevance for many of these cell-specific responses has been difficult to establish because of confounding effects that result from the simultaneous activation of receptors on multiple cell types in an in vivo environment. It has been recognized in in vitro models that overexpression of G-protein-coupled receptors such as the beta(2)ARs can increase the number of spontaneously active receptors (R*) and thereby promote autonomous signal transduction or enhanced agonist sensitivity. With transgenic techniques, high levels of receptor expression and activation can also be attained in vivo. By further using cell-specific promoters to direct expression, it is possible to express beta(2)ARs in select cell types of a heterogeneous organ such as the lung. In this manner, activation of receptor signaling is limited to the targeted cell. Promoter-directed transgenesis can therefore be a useful tool to delineate cell-specific beta(2)AR-mediated effects in the lung.


Depletion of intracellular zinc from neurons by use of an extracellular chelator in vivo and in vitro.
The membrane-impermeable chelator CaEDTA was introduced extracellularly among neurons in vivo and in vitro for the purpose of chelating extracellular Zn(2+). Unexpectedly, this treatment caused histochemically reactive Zn(2+) in intracellular compartments to drop rapidly. The same general result was seen with intravesicular Zn(2+), which fell after CaEDTA infusion into the lateral ventricle of the brain, with perikaryal Zn(2+) in Purkinje neurons (in vivo) and with cortical neurons (in vitro). These findings suggest either that the volume of zinc ion efflux and reuptake is higher than previously suspected or that EDTA can enter cells and vesicles. Caution is therefore warranted in attempting to manipulate extracellular or intracellular Zn(2+) selectively.


Economic outcomes in patients diagnosed with systemic lupus erythematosus with versus without nephritis: results from an analysis of data from a US claims database.
Based on a literature search, there are limited data on the economic burden of systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis. The objective of this study was to compare health care resource utilization and direct medical care costs over a period of 12 months in patients with a history of SLE with or without nephritis. Patients aged >or=18 years with >or=1 claim for an immunosuppressive/disease-modifying antirheumatic drug, antimalarial agent, NSAID/cyclooxygenase-2 inhibitor, or other SLE-related treatment (eg, opioid and combination analgesic, antianxiety agent, antihyperlipidemic agent, antihypertensive agent, bisphosphonate, vitamin D) dated between January 1, 2007, and December 31, 2007, were identified using a nationally representative, US commercial insurance claims database. The date of the first dispensation of the treatment represented the index date. Patients were required to have >or=2 claims containing a diagnosis of SLE during a 6-month preindex period through 3 months postindex and to have continuous health plan enrollment for 6 months before and 12 months after the index date. Patients with >or=1 claim containing a diagnosis of nephritis during the preindex period were identified. Health care resource utilization and direct medical care cost data were assessed over a period of 12 months; paid amounts were used as a proxy for costs and were expressed in year-2008 US dollars. A total of 15,590 patients with SLE were identified (13,828 women, 1762 men; mean age, 48 years); 1068 (6.9%) had a history of nephritis. The mean age of patients with SLE without nephritis was significantly greater compared with the group with nephritis (47.9 vs 46.5 years, respectively; P < 0.001), and a greater proportion of this group were women (89.0% vs 84.7%; P < 0.001). Over a period of 12 months, 30.3% of patients with nephritis were hospitalized compared with 13.6% of those without nephritis (P < 0.001); the mean lengths of hospital stays were 16.52 and 9.69 days (P < 0.001) in patients with and without nephritis, respectively. Patients with nephritis also underwent more outpatient laboratory tests (mean, 64.42 vs 30.96; P < 0.001) and had a significantly higher mean number of intravenous infusions (mean, 1.7 vs 1.1; P < 0.001), and total 12-month follow-up costs were significantly greater in patients with nephritis compared with those without nephritis (mean, $30,652 vs $12,029; P < 0.001). Costs associated with inpatient and outpatient care were 252% and 146% higher in patients with SLE with nephritis, respectively. Outpatient costs were associated with approximately half of the total costs in patients with or without nephritis; pharmacy costs accounted for 20% of the total costs in patients with SLE and nephritis and 27% of total costs among those without nephritis. Significantly higher costs also were found in patients with nephritis when only SLE-related costs were assessed and after differences in patient characteristics and comorbidities were adjusted through multivariate analyses (all, P < 0.05). The present data analysis found that patients with SLE with nephritis consumed significantly more health care resources, with >2.5-fold the costs, compared with those without nephritis. The majority (84%) of added costs were attributable to inpatient hospitalizations and outpatient services, and 16% were attributable to pharmacy services.


Ultrafast Pockels cells for the infrared.
The design and performance of a 2.25-cm(2)-aperture Pockels cell system for 10-mum radiation is described. Pulses as short as 90 ps can be reliably generated with this device.


Interest in a stepped approach model (SAM): identification of recruitment strategies for university alcohol programs.
This study evaluates interest in a stepped approach model (SAM) of service delivery and identifies variables to enhance recruitment to alcohol programs. Subjects were 2,443 college student drinkers (1,420 men and 1,023 women) at a large midwestern university (selected by stratified systematic sampling) who completed a questionnaire on drinking behavior and interest in five intervention steps. Results indicated that there was more interest in interventions that required less time, which supports predictions of SAM. Overall lack of interest peaked at 67% for men and 65% for women and did not change significantly across the last three steps of SAM, which included traditional interventions of group and individual counseling. The data suggest that the stepped approach is more viable than conventional approaches, recruitment is unquestionably an exigent research priority because of the overwhelming lack of interest in alcohol programs, and specific variables that were identified may be important for recruiting particular subgroups.


[Analysis of chloramphenicol in shrimps by gas chromatography tandem mass spectrometry].
A sensitive method based on isotope dilution gas chromatography tandem mass spectrometry is described for the determination of the antibiotic chloramphenicol (Cap) in shrimp tissue. Homogenized shrimp samples spiked with an isotopically labeled internal standard (d5-Cap) were extracted with ethyl acetate extraction, defatted with hexane, followed by a clean-up step on a SPE C18 cartridge, and then the elute was evaporated and derivatized with Sylon BFT {N,O-bis (trimethylsily) trifluoroacetamide[BSTFA]-trimethylchlorosilane [TMCS] ,99 + 1}. Analyzes were determined by GC/MS-MS in MRM mode. Internal calibration curves obtained for Cap/ d5-Cap in the 5 to 500 pg range were linear with correlation coefficients of 0.9958. Limit of quantitation (LOQ) was 0.3ng/g. Shrimp tissues were fortified with Cap at 0.3, 0.5, 1.0 ng/g level, average recoveries were 104%, 111% and 95% , respectively. The proposed method allows the detection, quantitation and confirmation of Cap in shrimps with high accuracy and sensitivity.


Comparative Evaluation of 3 Commercial Mouthwash Formulations on Clinical Parameters of Chronic Gingivitis.
BACKGROUND Chlorhexidine (CHX) is not prescribed as a mouthwash for long-term use; therefore, probiotic/herbal mouthwashes are being investigated. This study compared the effect of 3 commercial mouthwashes on plaque index (PI), gingival index (GI), and bleeding index (BI) in patients with chronic gingivitis. MATERIAL AND METHODS Forty-five patients (all with moderate plaque) were randomly allocated into 3 groups (Gp): Gp 1 (CHX), Gp 2 (Manuka), and Gp 3 (Pro-Dental). Three periodontal clinical parameters - PI, GI, and BI - were recorded at baseline and on days 7, 14, and 28. An oral hygiene maintenance program was followed by a double-blinded intervention (coded bottle containing mouthwash). Both inter-group and intra-group comparisons were made using analysis of variance (ANOVA) with multiple t tests. All probable values were considered to have various levels of significance at P<0.05 or below. RESULTS All indices for all groups showed higher values (mean) at baseline, which were lower on days 7, 14, and 28. No differences in any clinical parameter at any point of time existed between Gp 1 and Gp 2. There were, however, significant differences (P<0.05) between Gp 1/Gp 3 and Gp 2/Gp 3 for all clinical parameters at all observed time periods (days 7, 14, 28). Intra-group comparison for all groups demonstrated highly significant differences between baseline values and other time points. CONCLUSIONS For managing chronic gingivitis, Manuka mouthwash is as effective as a CHX mouthwash, as there were no differences observed in any clinical parameters at any point points.


A diurnally regulated dehydrin from Avicennia marina that shows nucleo-cytoplasmic localization and is phosphorylated by Casein kinase II in vitro.
Dehydrins have a key role in protecting plants from dehydration stress. We report here the isolation of two cDNAs coding for the same dehydrin, AmDHN1 and AmDHN1a from salt stressed leaves of Avicennia marina (Forsk.) Vierh. by EST library screening. AmDHN1 was found to contain a retained intron that was absent in AmDHN1a. AmDHN1 expression in the context of various environmental stresses was investigated. In leaves, AmDHN1 shows a diurnal pattern of regulation and is induced only by mannitol application. In roots, AmDHN1 is rapidly induced by salinity (NaCl) and dehydration stress (PEG and mannitol). A fragment of 795 bp corresponding to the 5' upstream region of AmDHN1 was isolated by TAIL-PCR. In silico analysis of this sequence reveals the presence of putative stress regulatory elements (ABRE, DRE, MYB and MYC binding sequences). Putative phosphorylation sites for Casein kinase II were identified in the AmDHN1a ORF. In vitro phosphorylation of Escherichia coli expressed Trx-AmDHN1a by Casein kinase II was observed that was reversed by Shrimp Alkaline Phosphatase treatment. A putative nuclear targeting domain was identified in the translated AmDHN1a ORF and stably transformed AmDHNIa-GFP was found to show nucleo-cytoplasmic localization in tobacco guard cells. As observed for maize Rab 17, the phosphorylation of AmDHN1a may contribute to its nuclear localization.