Association Between Diabetic Retinopathy and Carotid Intima-Media Thickness.
Introduction Patients with diabetes having advanced stage of diabetic retinopathy (DR) may predict future risk of coronary artery disease. To predict cardiovascular outcomes carotid intima-media thickness (CIMT) is utilized in diabetic patients. The aim of our study was the evaluation of the relationship between retinopathy and CIMT as two valuable non-invasive methods for early detection of micro- and macrovascular complication of diabetes. Methods This comparative cross-sectional study was conducted in the internal medicine ward of tertiary care hospital in Pakistan from November 2020 to January 2021. Three hundred patients with type 2 diabetes mellitus and 300 control subjects were enrolled in the study after taking informed consent. Ophthalmological examination was done to screen patients for DR. CIMT was evaluated by a Doppler ultrasound for both carotid arteries. Results Carotid artery intimal thickness was more in patients with retinopathy compared to patients without retinopathy in both right (0.77 ± 0.16 vs. 0.66 ± 0.12; p-value: <0.0001) and left carotid artery (0.77 ± 0.15 vs. 0.65 ± 0.11; p-value: <0.0001). Conclusion In our study, there was a correlation between DR and CIMT. Screening for DR, which may be a potential early marker for complications, may help detect patients at risk of various macro and microvascular complications.


Statistically Analyzed Photoresponse of Elastically Bent CdS Nanowires Probed by Light-Compatible In Situ High-Resolution TEM.
We demonstrate that high resolution transmission electron microscopy (HRTEM) paired with light illumination of a sample and its electrical probing can be utilized for the in situ study of initiated photocurrents in free-standing nanowires. Morphology, phase and crystallographic information from numerous individual CdS nanowires is obtained simultaneously with photocurrent measurements. Our results indicate that elastically bent CdS nanowires possessing a wurtzite structure show statistically unchanged values of ON/OFF (photocurrent/dark current) ratios. Photocurrent spectroscopy reveals red shifts of several nanometers in the cutoff wavelength after nanowire bending. This results from deformation-induced lattice strain and associated changes in the nanowire band structure, as confirmed by selected area electron diffraction (SAED) analyses and density functional tight binding (DFTB) simulations. The ON/OFF ratio stabilities and photocurrent spectroscopy shift of bent CdS nanowires are important clues for future flexible electronics, optoelectronics, and photovoltaics.


Evaluation of atrial electromechanical delay and left atrial mechanical functions in patients with rheumatoid arthritis.
The aim of this study was to evaluate atrial electromechanical delay measured by tissue Doppler imaging (TDI) and left atrial (LA) mechanical functions in patients with rheumatoid arthritis (RA). The study included 68 patients (53 females, 15 males; mean age 43.7 years) with RA. Using TDI, atrial electromechanical coupling (PA) was measured from the lateral mitral annulus (PA lateral), septal mitral annulus (PA septum), and right ventricular tricuspid annulus (PA tricuspid). Left atrial volumes (maximal, minimal, and pre-systolic) were measured by the method of discs in the apical four-chamber view and were indexed to body surface area. Mechanical function parameters of the LA were calculated. The results were compared with those of 41 age- and gender-matched healthy volunteers (32 females, 9 males; mean age 41.9 years). Patients with RA had significantly prolonged PA lateral, PA septum, and intra- (PA septum-PA tricuspid) and interatrial (PA lateral-PA tricuspid) electromechanical delays compared to controls (p<0.0001, p=0.05, p<0.0001, and p<0.0001, respectively). Left atrial volumes were similar in the two groups (p>0.05). Left atrial passive emptying fraction was significantly decreased, LA active emptying volume and active emptying fraction were increased in RA patients (p=0.05, p=0.01, and p<0.0001; respectively). Interatrial electromechanical delay was correlated with systolic blood pressure (r=0.20, p=0.04), left ventricular mass index (r=0.22, p=0.02), C-reactive protein (CRP) (r=0.27, p=0.005), and LA active emptying fraction (r=0.29, p=0.002). In linear regression analysis, LA active emptying fraction and CRP were independent variables of interatrial electromechanical delay (beta=0.28, p=0.002 and beta=0.25, p=0.006, respectively). Prolonged electromechanical delays and impaired LA mechanical functions may be an early manifestation of subclinical cardiac involvement in RA patients.


Comparative morphological study of skeletal muscle weight among the red jungle fowl (Gallus gallus) and various fowl breeds (Gallus domesticus).
We examined the weight distribution of skeletal muscles of the red jungle fowl, then compared these values with those of domesticated populations to determine how muscle distribution has changed by selecting breeding. Sonia, Fayoumi, and Rhode Island Red were selected for comparison from livestock breeds, while Japanese Shamo and Thai fighting cocks were selected from cockfighting groups. Principal component analysis was applied using body size-free data. The mass distribution of muscles clearly differed between the wild, livestock, and cockfighting groups, demonstrating that muscle distribution has changed after selecting breeding, coupled with functional demands of each group. The red jungle fowl, which has the ability to fly, could be clearly distinguished from the flightless domesticated populations due to differences in flight pectoral muscle size. The cervical muscles in the wild population were smaller than in the domesticated groups; these do not contribute to flight. The gluteal muscles were larger in the fighting cock group, functionally coupled to their traditionally preferred upright posture. Wild bird populations typically exhibit reduced weight of their hind limbs, associated with flight, but as the red jungle fowl displays largely terrestrial behavior, these muscles are similar in arrangement and relative size to those of the livestock groups. We showed that the mass distribution pattern of skeletal muscles expresses selecting breeding strategy and clearly reflects the specific traits for each group.


Circumventing the Gastrointestinal Barrier for Oral Delivery of Therapeutic Proteins and Peptides (PPTS): Current Trends and Future Trajectories.
Therapeutic proteins and peptides (PPTs) have become one of the most important biological molecules for the management of many common and complex diseases due to their high specificity and high bioactivity. However, these biomolecules are mainly given by the hypodermic injection, which often leads to poor patient compliance due to the invasive nature of this route of administration. The oral route has been considered the most convenient and patient-friendly route for drug delivery relative to hypodermic injections. Despite the ease and simplicity conferred by oral administration, this drug delivery route suffers rapid peptide degradation in gastric fluid and low intestinal uptake. In order to circumvent these issues, several strategies, such as enzyme inhibitors, permeation enhancers, chemical modification, mucoadhesive and stimuli-responsive polymers, and specialised particulate formulation have been developed. Such strategies are designed with the aim of protecting PPTs from the harsh gastrointestinal environment as well as providing a strategy to enhance the uptake of the therapeutic across the gastrointestinal tract. This review aims to provide an overview of the current development in enteral drug delivery strategies for PPTs. The design of these drug delivery systems in overcoming physical and chemical barriers along the gastrointestinal tract while improving oral bioavailability will be highlighted and discussed.


Bring out your experts: The relationship between perceived expert causal understanding and pandemic behaviors.
In the complex modern world, people's understanding of how things work is often outsourced to other people. We explore how people's perceptions of expert causal understanding of the coronavirus disease (COVID-19) pandemic predicted their pandemic-related behaviors. As part of a larger longitudinal study, we collected data at four time points that measured participants' perceptions of experts' causal understanding of COVID-19, along with those participants' self-reported pandemic-related health behaviors. We found that perceiving experts to understand the causal mechanism of transmission was predictive of engaging in more social distancing, advice following, hand washing, and mask wearing. Believing experts could intervene and treat the symptoms or underlying cause of COVID-19 was negatively associated with these same behaviors, but to a lesser degree. These results held above and beyond political ideology and were overall similar for people who perceived themselves to be at high or low risk for COVID-19. This research provides new insights into how people's behaviors are guided by perceptions of others' understanding and highlights important implications for expert health-risk communication. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Are steroids a beneficial adjunctive therapy in the immunosuppressed patient with herpes simplex virus encephalitis?
Few reports describe the reactivation of latent herpes simplex virus causing encephalitis (HSVE) in patients undergoing brain radiation therapy and a concomitant steroid regimen. The role for steroid use in the treatment of patients with HSVE has not been fully elucidated. We report the case of a female patient immunosuppressed by steroids and brain radiation who developed HSVE and responded to acyclovir and dexamethasone.


High Blood miR-802 Is Associated With Poor Prognosis in HCC Patients by Regulating DNA Damage Response 1 (REDD1)-Mediated Function of T Cells.
miR-802 has been reported to be dysregulated in multiple tumors and contribute to tumor progression. However, its role in HCC was still largely unknown. The aim of this study is to investigate the function and mechanism of miR-802 in HCC progression. The results showed that miR-802 was upregulated in the peripheral blood and tumor tissue of HCC patients, and high levels of blood miR-802 predicted poor prognosis. miR-802 had no effect on the proliferation and migration of HCC cell lines. Interestingly, the levels of CD8/CD28 and regulated in development and DNA damage response 1 (REDD1) were declined along with the upregulation of miR-802 in vivo. Hence, it is speculated that miR-802 participated in the regulation of T-cell function in HCC patients. Furthermore, we demonstrated that mir-802 directly targets REDD1 and inhibited its expression. miR-802 increased the expression of programmed cell death protein 1 (PD-1) and decreased the expression of interferon-γ (IFN-γ) and CD8+CD28+ T-cell number. In conclusion, miR-802 was involved in T-cell exhaustion through posttranscriptionally suppressing REDD1, which might offer the suppressive effect of miR-802 on HCC progression.


Carbonyl-17O n.m.r. of amino acid and peptide carboxamide and methyl ester derivatives.
Specific carbonyl enrichment with 17O of amino acid OMe esters by up to 10(3) times over natural abundance was affected by treating [17O]-alpha-COOH amino acids with SOCl2 in MeOH. Carbonyl-[17O]-Gly-NH2, Gly-NHCH3 and Gly-N(CH3)2 were obtained from [17O]-Gly-OMe by (methyl)aminolysis with NH3, CH3NH2 and (CH3)2NH gases respectively. Peptide [17O]-carboxamides were prepared by (methyl)aminolysis of Z-Pro-Leu-[17O]-Gly-OMe followed by catalytic hydrogenation to remove the Z group. 17O chemical shifts of amino acid and peptide carboxamides in H2O, MeOH, CH3CN and DMSO were 260-324 p.p.m. downfield relative to H2O, depending on alpha-NH2 ionization, substitution on both amino groups and solvent H bonding, primarily to amide oxygen. Introduction of an amide-N methyl group usually caused upfield shifts (approx. -10 p.p.m.), attributed to elimination of one NH bond, while a second N methylation had the opposite effect. Amino acid and peptide OMe ester carbonyl-[17O] resonances appeared 326-359 p.p.m. downfield relative to H2O reflecting on side chain interactions, state of alpha-NH2 ionization and H-bonding with the solvent. Effective rotational correlation times for glycine and peptide carboxamide-[17O], calculated from T2 relaxation data, were of similar magnitude to values derived from solution properties and depended on the molecular weight and solvent viscosity.


A Novel COVID-19-Related Drug Discovery Approach Based on Non-Equidimensional Data Clustering.
The novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread all over the world. Since currently no effective antiviral treatment is available and those original inhibitors have no significant effect, the demand for the discovery of potential novel SARS-CoV-2 inhibitors has become more and more urgent. In view of the availability of the inhibitor-bound SARS-CoV-2 Mpro and PLpro crystal structure and a large amount of proteomics knowledge, we attempted using the existing coronavirus inhibitors to synthesize new ones, which combined the advantages of similar effective substructures for COVID-19 treatment. To achieve this, we first formulated this issue as a non-equidimensional inhibitor clustering and a following cluster center generating problem, where three essential challenges were carefully addressed, which are 1) how to define the distance between pairwise inhibitors with non-equidimensional molecular structure; 2) how to group inhibitors into clusters when the dimension is different; 3) how to generate the cluster center under this non-equidimensional condition. To be more specific, a novel matrix Kronecker product (p, m)-norm ⋅ p m ⊗ was first defined to induce the distance D p (A, B) between two inhibitors. Then, the hierarchical clustering approach was conducted to find similar inhibitors, and a novel iterative algorithm-based Kronecker product (p, m)-norm was designed to generate individual cluster centers as the drug candidates. Numerical experiments showed that the proposed methods can find novel drug candidates efficiently for COVID-19, which has provided valuable predictions for further biological evaluations.


[The German disability statistics 1906 to 1979 (author's transl)].
An analysis is presented of the total of 13 official surveys conducted between 1906 and 1979 of the number of disabled persons in the former German Reich and today's Federal Republic of Germany. The concept of disability was found to have been adapted to societal changes. From a helpless charge to be taken care of, the concept of the disabled changed into that of a person suffering from illness, to become that of the rehabilitee having a physical, sensory, mental, psychic, or educational handicap, who has a right to being accepted as a full and equal member of the community. As regards the method of data collection, the initial state surveys administered in an authoritarian manner (via official agencies) were followed by direct interviewing of those concerned; today the disabled are again registered via official agencies. All of the surveys are characterised by inconsistent use of almost any variable; this fact--besides the lack of comparability of the statistics with each other--warrants fundamental doubt in their usefulness as planning tools. In all surveys the number of disabled persons had been underestimated.


Properties of cells through life and death - an acoustic microscopy investigation.
Current methods to evaluate the status of a cell are largely focused on fluorescent identification of molecular biomarkers. The invasive nature of these methods - requiring either fixation, chemical dyes, genetic alteration, or a combination of these - prevents subsequent analysis of samples. In light of this limitation, studies have considered the use of physical markers to differentiate cell stages. Acoustic microscopy is an ultrahigh frequency (>100 MHz) ultrasound technology that can be used to calculate the mechanical and physical properties of biological cells in real-time, thereby evaluating cell stage in live cells without invasive biomarker evaluation. Using acoustic microscopy, MCF-7 human breast adenocarcinoma cells within the G1, G2, and metaphase phases of the proliferative cell cycle, in addition to early and late programmed cell death, were examined. Physical properties calculated include the cell height, sound speed, acoustic impedance, cell density, adiabatic bulk modulus, and the ultrasonic attenuation. A total of 290 cells were measured, 58 from each cell phase, assessed using fluorescent and phase contrast microscopy. Cells actively progressing from G1 to metaphase were marked by a 28% decrease in attenuation, in contrast to the induction of apoptosis from G1, which was marked by a significant 81% increase in attenuation. Furthermore late apoptotic cells separated into 2 distinct groups based on ultrasound attenuation, suggesting that presently-unidentified sub-stages may exist within late apoptosis. A methodology has been implemented for the identification of cell stages without the use of chemical dyes, fixation, or genetic manipulation.


[Continuous nursing education to improve the quality of health care].
Health care and today's medical and technical achievements and approved standards of treatment provide comprehensive quality, safety and traceability of medical procedures respecting the principles of health protection. Continuous education improves the quality of nursing health care and increases the effectiveness of patient care, consequently maintaining and enhancing patient safety. Patient health problems impose the need of appropriate, planned and timely nursing care and treatment. In providing quality nursing care, attention is focused on the patient and his/her needs in order to maintain and increase their safety, satisfaction, independence and recovery or peaceful death, so the health and nursing practices must be systematized, planned and based on knowledge and experience. Health and nursing care of patients at risk of developing acute and chronic wounds or already suffering from some form of this imply preventive measures that are provided through patient education, motivation, monitoring, early recognition of risk factors and causes, and reducing or removing them through the prescribed necessary medical treatment which is safe depending on the patient health status. Except for preventive measures, nursing care of patients who already suffer from some form of acute or chronic wounds is focused on the care and treatment of damaged tissue by providing appropriate and timely diagnosis, timely and proper evaluation of the wound and patient general status, knowledge and understanding of the wide range of local, oral and parenteral therapy and treatment, aiming to increase patient safety by preventing progression of the patient general condition and local wound status and reducing the possibility of developing infection or other complications of the underlying disease. In the overall patient management, through nursing process, medical interventions are implemented and aimed to maintain and optimize health status, prevent complications of existing diseases and conditions, provide appropriate wound treatment, increase satisfaction, reduce pain, increase mobility, reduce and eliminate aggravating factors, and achieve a satisfactory functional and aesthetic outcome. Many scientific researches and knowledge about the pathophysiological processes of wound formation and healing are currently available. Modern achievements can accelerate independence, reduce pain and encourage faster wound healing, thus it is important to continuously develop awareness, knowledge and experience, along with the treatment to achieve, maintain and enhance the quality of health care and patient safety.


The effects of alpha- and beta-adrenergic stimulation on contractility and prostaglandin (prostaglandins E2 and F2 alpha and 6-keto-prostaglandin F1 alpha) production of pregnant human myometrial strips.
The effects of catecholamines and alpha- and beta-adrenergic agonists and antagonists on the spontaneous contractility of superfused pregnant human myometrial strips are reported. Prostaglandins (prostaglandins E2 and F2 alpha and 6-keto-prostaglandin F1 alpha) were analyzed in the effluent of the superfusion medium by specific radioimmunoassays. Both epinephrine and norepinephrine dose-dependently (10 ng/ml to 1 microgram/ml) stimulated the contractility of the myometrial strips and significantly increased the synthesis of all prostaglandins assayed. alpha-Adrenergic blockers inhibited the catecholamine-induced increase in contractility. This was associated with decreased prostaglandins F2 alpha and E2 concentrations and a further increase in 6-keto-prostaglandin F1 alpha levels. Exclusive beta-adrenergic stimulation with beta-mimetic drugs had the same effect. Conversely, epinephrine stimulation together with beta-blockers resulted in a further increase in the prostaglandins F2 alpha and E2 release of the myometrial strips. This effect was even more pronounced with specific alpha-adrenergic stimulant drugs. Our results demonstrate the interrelationship of alpha- and beta-adrenergic stimulation and the prostaglandin system. alpha-Adrenergic stimulation increases myometrial contractility and the synthesis of prostaglandins F2 alpha and E2. beta-Adrenergic stimulation reduces contractility by further enhancing 6-keto-prostaglandin F1 alpha production.


Solution structure and dynamics of human hemoglobin in the carbonmonoxy form.
The solution structure of human adult carbonmonoxy hemoglobin (HbCO A) was refined using stereospecifically assigned methyl groups and residual dipolar couplings based on our previous nuclear magnetic resonance structure. The tertiary structures of individual chains were found to be very similar to the X-ray structures, while the quaternary structures in solution at low salt concentrations resembled the X-ray R structure more than the R2 structure. On the basis of chemical shift perturbation by inositol hexaphosphate (IHP) titration and docking, we identified five possible IHP binding sites in HbCO A. Amide-water proton exchange experiments demonstrated that αThr38 located in the α1β2 interface and several loop regions in both α- and β-chains were dynamic on the subsecond time scale. Side chain methyl dynamics revealed that methyl groups in the α1β2 interface were dynamic, but those in the α1β1 interface were quite rigid on the nanosecond to picosecond and millisecond to microsecond time scales. All the data strongly suggest a dynamic α1β2 interface that allows conformational changes among different forms (like T, R, and R2) easily in solution. Binding of IHP to HbCO A induced small structural and dynamic changes in the α1β2 interface and the regions around the hemes but did not increase the conformational entropy of HbCO A. The binding also caused conformational changes on the millisecond time scale, very likely arising from the relative motion of the α1β1 dimer with respect to the α2β2 dimer. Heterotropic effectors like IHP may change the oxygen affinity of Hb through modulating the relative motion of the two dimers and then further altering the structure of heme binding regions.


A Review on the Ethnomedicinal Usage, Phytochemistry, and Pharmacological Properties of Gentianeae (Gentianaceae) in Tibetan Medicine.
Gentianaceae is a large plant family and is distributed worldwide. As the largest tribe in Gentianaceae, Gentianeae contains 939-968 species, and the Qinghai-Tibet Plateau and adjacent areas are the main centers of diversity for Gentianeae. Species from the Gentianeae are widely used in traditional Tibetan medicine. In this review, a systematic and constructive overview of the information on botany, ethnomedicinal usage, phytochemistry, and pharmacological properties of Gentianeae in Tibetan medicine is provided. The results of this study are based on a literature search, including electronic databases, books, websites, papers, and conference proceedings. Botanical studies showed that Gentianeae includes the subtribe Gentianeae and Swertiinae, and several new genera and taxa have been identified. Approximately 83 species from Gentianeae were used in Tibetan medicine, among which Gentiana and Swertia constituted the largest number of species with 42 and 24 species, respectively. The species from Gentianeae are mainly used as Bangjian (སྤང་རྒྱན།), Jieji (ཀྱི་ལྕེ།), Dida (ཏིག་ཏ།), and Ganggaqiong (གང་གྰཆུང་།) in Tibetan medicine with different clinical applications. More than 240 formulas were found containing Gentianeae species with different attending functions. Phytochemical studies showed that the main active components of Gentianeae species are iridoids, xanthones, flavonoids, and triterpenoids. The bioactivities of plants from Gentianeae include hepatic protection, upper respiratory tract protection, joint and bone protection, glucose regulation, antibacterial, antioxidant, anticancer, and antiviral effects. This review will provide a reference for future research on natural resource protection, plant-based drug development, and further clinical investigation.


Emerging Roles of Strigolactones in Plant Responses to Stress and Development.
Our environment constantly undergoes changes either natural or manmade affecting growth and development of all the organisms including plants. Plants are sessile in nature and therefore to counter environmental changes such as light, temperature, nutrient and water availability, pathogen, and many others; plants have evolved intricate signaling mechanisms, composed of multiple components including several plant hormones. Research conducted in the last decade has placed Strigolactones (SLs) in the growing list of plant hormones involved in coping with environmental changes. SLs are carotenoid derivatives functioning as both endogenous and exogenous signaling molecules in response to various environmental cues. Initially, SLs were discovered as compounds that are harmful to plants due to their role as stimulants in seed germination of parasitic plants, a more beneficial role in plant growth and development was uncovered much later. SLs are required for maintaining plant architecture by regulating shoot and root growth in response to various external stimuli including arbuscular mycorrhizal fungi, light, nutrients, and temperature. Moreover, a role for SLs has also been recognized during various abiotic and biotic stress conditions making them suitable target for generating genetically engineered crop plants with improved yield. This review discusses the biosynthesis of SLs and their regulatory and physiological roles in various stress conditions. Understanding of detailed signaling mechanisms of SLs will be an important factor for designing genetically modified crops for overcoming the problem of crop loss under stressful conditions.


T1 lung cancer: prevalence of mediastinal nodal metastases and diagnostic accuracy of CT.
To determine the prevalence of mediastinal lymph node metastases in T1 non-small cell lung cancer and assess the sensitivity and specificity of computed tomography (CT) in detection of such metastases, the CT scans and surgical findings in 104 patients with T1 lesions were reviewed. Nodes longer than 10 mm on the short or long axis were considered abnormal. All patients underwent thorough mediastinal lymph node dissection at mediastinoscopy or thoracotomy. A total of 362 lymph nodes were sampled. Nodal metastases were present in 22 patients (21%). The sensitivity of CT for metastases to individual nodal stations was 41% for nodes measured on the short axis and 55% for those measured on the long axis. The specificity was 93% and 86%, respectively. When the adjacent nodal stations were included in the analysis, the sensitivity of CT was 59% for nodes measured on the short axis and 77% for those measured on the long axis; the specificity was 91% and 73%, respectively. T1 lung cancer has a higher prevalence of lymph node metastasis than previously reported, and CT is recommended in the preoperative staging of this disease.


The impact of dengue illness on social distancing and caregiving behavior.
Human mobility among residential locations can drive dengue virus (DENV) transmission dynamics. Recently, it was shown that individuals with symptomatic DENV infection exhibit significant changes in their mobility patterns, spending more time at home during illness. This change in mobility is predicted to increase the risk of acquiring infection for those living with or visiting the ill individual. It has yet to be considered, however, whether social contacts are also changing their mobility, either by socially distancing themselves from the infectious individual or increasing contact to help care for them. Social, or physical, distancing and caregiving could have diverse yet important impacts on DENV transmission dynamics; therefore, it is necessary to better understand the nature and frequency of these behaviors including their effect on mobility. Through community-based febrile illness surveillance and RT-PCR infection confirmation, 67 DENV positive (DENV+) residents were identified in the city of Iquitos, Peru. Using retrospective interviews, data were collected on visitors and home-based care received during the illness. While 15% of participants lost visitors during their illness, 22% gained visitors; overall, 32% of all individuals (particularly females) received visitors while symptomatic. Caregiving was common (90%), particularly caring by housemates (91%) and caring for children (98%). Twenty-eight percent of caregivers changed their behavior enough to have their work (and, likely, mobility patterns) affected. This was significantly more likely when caring for individuals with low "health-related quality of well-being" during illness (Fisher's Exact, p = 0.01). Our study demonstrates that social contacts of individuals with dengue modify their patterns of visitation and caregiving. The observed mobility changes could impact a susceptible individual's exposure to virus or a presymptomatic/clinically inapparent individual's contribution to onward transmission. Accounting for changes in social contact mobility is imperative in order to get a more accurate understanding of DENV transmission.


Nitric Oxide System and Bronchial Epithelium: More Than a Barrier.
Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved.


Personalised Medicine for Tuberculosis and Non-Tuberculous Mycobacterial Pulmonary Disease.
Personalised medicine, in which clinical management is individualised to the genotypic and phenotypic data of patients, offers a promising means by which to enhance outcomes in the management of mycobacterial pulmonary infections. In this review, we provide an overview of how personalised medicine approaches may be utilised to identify patients at risk of developing tuberculosis (TB) or non-tuberculous mycobacterial pulmonary disease (NTM-PD), diagnose these conditions and guide effective treatment strategies. Despite recent technological and therapeutic advances, TB and NTM-PD remain challenging conditions to diagnose and treat. Studies have identified a range of genetic and immune factors that predispose patients to pulmonary mycobacterial infections. Molecular tests such as nucleic acid amplification assays and next generation sequencing provide a rapid means by which to identify mycobacterial isolates and their antibiotic resistance profiles, thus guiding selection of appropriate antimicrobials. Host-directed therapies and therapeutic drug monitoring offer ways of tailoring management to the clinical needs of patients at an individualised level. Biomarkers may hold promise in differentiating between latent and active TB, as well as in predicting mycobacterial disease progression and response to treatment.


Estrogen enhancement of Ca-, Mg-, and Ca-Mg-stimulated adenosine triphosphatase activity in the chick shell gland.
The effect of 17 beta-estradiol (E2) on Ca-, Mg-, and Ca-Mg-ATPase activity was investigated in the shell gland of 6-week-old chicks. In the first study, each of 42 birds was implanted with three E2 (Compudose-200) pellets. An additional 6 sham-implanted birds served as controls for measurements of body weight and concentrations of E2 and Ca in plasma. The activities of Mg-, Ca-, and Ca-Mg-ATPase peaked coincident with maximum plasma E2 concentrations 8 days after implantation and then progressively declined in concert with the decline in plasma E2. By 29 days after implantation, the ATPase activities were similar to those measured in birds whose E2 pellets had been removed for 11 days. Concentrations of plasma E2 dropped from peak values of 1676 +/- 317 at Day 8 to 611 +/- 180 pg/ml at Day 29. When birds whose E2 pellets had been removed were reimplanted with three pellets per bird, plasma E2 again increased to 1637 +/- 227 pg/ml. ATPase activity in these reimplanted birds also was greater (P < 0.05) than activities measured in E2-removed or E2-maintained birds. In a second study the Ca-ATPase Km and Vmax were determined in E2-implanted chicks (three pellets per bird) and compared to E2-withdrawn chicks. Five days after reimplantation of chicks with E2, there was a significant increase in both Vmax (3.38 +/- 0.21 vs 2.37 +/- 0.28 micrograms Pi/mg protein/min; P < 0.05) and Km (0.31 +/- 0.02 vs 0.25 +/- 0.01 mM Ca; P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)


Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus.
Hepatoerythropoietic porphyria (HEP) is usually a severe form of cutaneous porphyria, characterized biochemically by an increased urinary excretion of polycarboxylated porphyrins. The disease is the result of a profound deficiency (<10% of normal activity) of uroporphyrinogen decarboxylase (UROD) activity. Hepatoerythropoietic porphyria is inherited as an autosomal recessive trait, whereas familial porphyria cutanea tarda is dominant. At least 30 different mutations of the UROD gene have been identified in patients with HEP and familial porphyria cutanea tarda, with 1 predominant missense mutation (glycine-to-glutamic acid substitution at codon 281) in Spanish patients with HEP. A 5-year-old patient with first-degree-related parents presented with HEP and mild symptomatology. We found low levels of UROD enzymatic activity and a new homozygous mutation of the UROD gene, a phenylanine-to-leucine substitution at codon 46 (F46L). Both parents were healthy carriers of the mutation. The mother had reduced UROD activity (50% of normal), whereas the father had normal UROD activity. Prokaryotic expression of the F46L mutation using a pGEX vector has been used to confirm the deleterious effect of the mutation. When the mother started a new pregnancy, a prenatal study showed the absence of F46L mutation in the fetus and no accumulation of porphyrins in the amniotic fluid. A new mutation in the UROD gene causes a mild HEP phenotype. A normal UROD enzymatic activity was observed in the father, despite the presence of the heterozygous mutation. To our knowledge, this observation is the first description of a prenatal exclusion of HEP.


[Effect of PCI-32765 and bortezomib on proliferation and apoptosis of B-cell tumor cell lines and its mechanisms].
This study was aimed to investigate the effect of Btk inhibitor PCI-32765 and the proteasome inhibitor bortezomib on Raji and Ramos cell proliferation, apoptosis, and its mechanisms. Raji and Ramos cells were treated with PCI-32765 and bortezomib alone and/or their combination. The cell proliferation and apoptosis were detected by CCK-8 and flow cytometry respectively, the expression level of Btk, NFκB, c-IAP1, Bcl-xL and caspase-3 protein were measured by Western blot. The results indicated that: (1) after Raji and Ramos cells were treated with PCI-32765 (0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 µmol/L) alone and bortezomib (10, 20, 30, 40, 50, 60, 80 nmol/L) alone and their combination for 48 h, the cell proliferation and vitality were inhibited in a dose-dependent manner and both had synergistic effect; (2) Raji and Ramos cells were treated with PCI-32765 (2.0 µmol/L) and bortezomib (20 nmol/L) alone and their combination for 8, 12, 24, 36, 48 and 72 h, the cell proliferation and vitality were inhibited in a time-dependent manner, the two drugs displayed a synergistic effects; (3) the Raji and Ramos cells were treated with PCI-32765 (2.0 µmol/L) and bortezomib (20 nmol/L) alone and their combination for 48 h, all these treatments could induce significant apoptosis of Raji and Ramos cells.In Raji cell experiment, the cell apoptosis rate in the control group, PCI-32765 group, bortezomib group and PCI-32765 and bortezomib combination group were 10.34 ± 0.53%, 24.26 ± 0.91%, 43.66 ± 1.08% and 74.06 ± 0.72% respectively, and the differences was statistically significant among the different groups (P < 0.05). In Ramos cell experiment, the cell apoptosis rate in the control group, PCI-32765 group, bortezomib group and PCI-32765 and bortezomib combination group are 15.16 ± 1.49%, 71.36 ± 0.82%, 75.32 ± 2.36% and 84.30 ± 0.91% respectively, the differences was statistically significant among the different groups (P < 0.05); (4) PCI-32765 and bortezomib could inhibit the expression level of intracellular Btk, NFκB, Bcl-xl and c-IAP1 proteins, but up-regulate the expression level of caspase-3. It is concluded that PCI-32765 and bortezomib can synergistically inhibit the proliferation and induce apoptosis of Raji and Ramos cells, the mechanism may be associated with inhibition of Btk and NFκB activity, down-regulation of anti-apoptotic proteins expression, such as Bcl-xl and c-IAP1, and increase of caspase-3 expression.


Progress and perspectives in computational neuroanatomy.
The tremendous increase in processing power of personal computers has recently allowed the construction of highly sophisticated models of neuronal function and behavior. Anatomy plays a fundamental role in supporting and shaping nervous system activity, yet to date most details of such a role have escaped the efforts of experimental and theoretical neuroscientists, mainly because of the problem's complexity. When accurate cellular morphologies are included in electrophysiological computer simulations, quantitative and qualitative effects of dendritic structure on firing properties can be extensively characterized. Complete models of dendritic morphology can be implemented to allow the computer generation of virtual neurons that model the anatomical characteristics of their real counterparts to a great degree of approximation. From a restricted and already available experimental database, stochastic and statistical algorithms can create an unlimited number of non-identical virtual neurons within several mammalian morphological classes, storing them in a compact and parsimonious format. When modeled neurons are distributed in three-dimensional and biologically plausible rules governing axonal navigation and connectivity are added to the simulations, entire portions of the nervous system can be "grown" as anatomically realistic neural networks. These computational constructs are useful to determine the influence of local geometry on system neuroanatomy, and to investigate systematically the mutual interactions between anatomical parameters and electrophysiological activity at the network level. A detailed computer model of a "virtual brain" that was truly equivalent to the biological structure could in principle allow scientists to carry out experiments that could not be performed on real nervous systems because of physical constraints. The computational approach to neuroanatomy is just at its beginning, but has a great potential to enhance the intuition of investigators and to aid neuroscience education. Anat Rec (New Anat): 257:195-207, 1999.


Transiently Pink-Tinged Serum in a Patient With Multiple Myeloma and Anemia Undergoing Lenalidomide Treatment.
While in vitro hemolysis is a preanalytical interferent, in vivo hemolysis is a pathologic process requiring investigation. We present a case of an anemic patient with multiple myeloma undergoing chemotherapy with lenalidomide who had multiple serum samples drawn before and after chemotherapy treatment. Some of these samples showed hemolysis. This triggered further investigations to differentiate the cause of the hemolysis. Various laboratory tests and additional investigations were necessary to establish the root of the hemolytic process. Multiple laboratory tests and a rigorous review of the samples, time of collection, and laboratory results revealed that only samples collected shortly after lenalidomide administration showed hemolysis. This indicates that the chemotherapeutic agent itself was most likely the proximate cause of the in vivo hemolysis in a non-immune-mediated manner. Upon administration, chemotherapeutic agents, such as lenalidomide, can immediately induce transient hemolysis, which can be visualized as transiently pink-tinged serum samples.


Functional mapping of thalamic nuclei and their integration into cortico-striatal-thalamo-cortical loops via ultra-high resolution imaging-from animal anatomy to in vivo imaging in humans.
The thalamus, a crucial node in the well-described cortico-striatal-thalamo-cortical circuits, has been the focus of functional and structural imaging studies investigating human emotion, cognition and memory. Invasive work in animals and post-mortem investigations have revealed the rich cytoarchitectonics and functional specificity of the thalamus. Given current restrictions in the spatial resolution of non-invasive imaging modalities, there is, however, a translational gap between functional and structural information on these circuits in humans and animals as well as between histological and cellular evidence and their relationship to psychological functioning. With the advance of higher field strengths for MR approaches, better spatial resolution is now available promising to overcome this conceptual problem. We here review these two levels, which exist for both neuroscientific and clinical investigations, and then focus on current attempts to overcome conceptual boundaries of these observations with the help of ultra-high resolution imaging.


[Advances in capture methods of circulating tumor cells].
Since circulating tumor cells (CTCs) in the blood carry the genetic and phenotypic information of tumor tissues, they are regarded as important markers for liquid biopsy, especially for the early diagnosis of cancer, determination of treatment options and evaluation of prognosis. However, the capture and detection of CTCs is challenging because of their extremely low concentration in blood. In this review, recent advances in capture methods of CTCs based on their biophysical properties, affinity, and artificial antibodies are summarized. The advantages and drawbacks of these methods are discussed from the aspects of capture efficiency, capture purity and maintenance of activity after release. Future trends in CTCs capture are also discussed.


Multi-level meta-workflows: new concept for regularly occurring tasks in quantum chemistry.
In Quantum Chemistry, many tasks are reoccurring frequently, e.g. geometry optimizations, benchmarking series etc. Here, workflows can help to reduce the time of manual job definition and output extraction. These workflows are executed on computing infrastructures and may require large computing and data resources. Scientific workflows hide these infrastructures and the resources needed to run them. It requires significant efforts and specific expertise to design, implement and test these workflows. Many of these workflows are complex and monolithic entities that can be used for particular scientific experiments. Hence, their modification is not straightforward and it makes almost impossible to share them. To address these issues we propose developing atomic workflows and embedding them in meta-workflows. Atomic workflows deliver a well-defined research domain specific function. Publishing workflows in repositories enables workflow sharing inside and/or among scientific communities. We formally specify atomic and meta-workflows in order to define data structures to be used in repositories for uploading and sharing them. Additionally, we present a formal description focused at orchestration of atomic workflows into meta-workflows. We investigated the operations that represent basic functionalities in Quantum Chemistry, developed the relevant atomic workflows and combined them into meta-workflows. Having these workflows we defined the structure of the Quantum Chemistry workflow library and uploaded these workflows in the SHIWA Workflow Repository.Graphical AbstractMeta-workflows and embedded workflows in the template representation.


[Construction of full-length cDNA library of erythrocytic stage Plasmodium vivax].
Blood samples were collected from vivax malaria patients without antimalarial drug therapy. After filtration through Plasmodipur filter to remove white blood cells, Plasmodium vivax-infected RBCs were enriched by Percoll. Total P. vivax in red blood cells was isolated. A full-length cDNA library of erythrocytic stage P. vivax was constructed by the SMART cDNA library construction kit. The volume and recombinant rate of the library were evaluated. The inserted fragments were identified by PCR amplification. The titer of cDNA library was 1.14 x 10(6). The length of inserted fragment ranged from 900 to 2 500 bp, and the recombination efficiency accounted for 97.2%.


Immunohistochemical and ultrastructural study of the immune cell system and epithelial surfaces of the respiratory organs in the bimodally breathing African sharptooth catfish (Clarias gariepinus Burchell, 1822).
Acetylcholine (Ach) represents the old neurotransmitter in central and peripheral nervous system. Its muscarinic and nicotinic receptors (mAChRs and nAChRs) constitute an independent cholinergic system that is found in immune cells and play a key role in the regulation of the immune function and cytokine production. Gas exchanging surfaces of the gills and air-breathing organs (ABOs) of the sharptooth catfish Clarias gariepinus were investigated using ultrastructural and confocal immunofluorescence techniques. This study was predominantly focused on the structure of the immune cell types, the expression of their neurotransmitters, including the antimicrobial peptide piscidin 1, and the functional significance of respiratory gas exchange epithelia. A network of immune cells (monocytes, eosinophils, and mast cells) was observed in the gill and the ABO epithelia. Eosinophils containing 5-hydroxytryptamine (5-HT) immunoreactivity were seen in close association with mast cells expressing acetylcholine (Ach), 5-HT, neuronal nitric oxide synthase, and piscidin 1. A rich and dense cholinergic innervation dispersing across the islet capillaries of the gas exchange barrier and the localization of Ach in the squamous pavement cells covering the capillaries were evidenced byVAChT antibodies. We report for the first time that piscidin 1 (Pis 1)-positive mast cells interact with Pis 1-positive nerves found in the epithelia of the respiratory organs. Pis 1 immunoreactivity was also observed in the covering respiratory epithelium of the ABOs and associated with a role in local mucosal immune defense. The above results anticipate future studies on the neuro-immune interactions at mucosal barrier surfaces, like the gill and the skin of fish, areas densely populated by different immune cells and sensory nerves that constantly sense and adapt to tissue-specific environmental challenges.


[Analysis of ferritin immunostaining in testicular tumors].
Localization of ferritin in testicular tumors was studied by the immunohistochemical method and the usefulness of ferritin was evaluated compared with the clinical course. Seven cases of seminoma and 9 cases of non-seminoma were used for the study. Formalin-fixed, paraffin-embedded tissue sections were stained by the avidin-biotin complex method. Commercial rabbit anti-human ferritin polyclonal antibody in 1/100 dilution was allowed to react at room temperature for one hour. In normal testicular tissues, the epithelium in germinal cells was not stained for ferritin. In seminomas, some tumor nests were stained for ferritin. Interstitial cells, especially histiocytes, were also stained for ferritin. In stained tumor cells, cytoplasm was stained uniformly. Necrotic cells were not stained. The same findings were obtained in non-seminomas. In metastatic lesions and tumor thrombi in the vessels, some tumor cells were stained as intensely as in the origin. A case was calculated positive if more than 5% of the tumor cells in the specimen were stained. The positive rate in ferritin immunostaining was significantly higher than that of human chorionic gonadotropin (beta-HCG), alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) immunostaining with the same materials. The specimens from cases with abnormally high serum ferritin level, were stained more intensely than those from cases with normal serum ferritin level. The result suggests that ferritin might be a useful tumor marker in some of testicular tumors.


B-SIDER: Computational Algorithm for the Design of Complementary β-Sheet Sequences.
The β-sheet is an element of protein secondary structure, and intra-/intermolecular β-sheet interactions play pivotal roles in biological regulatory processes including scaffolding, transporting, and oligomerization. In nature, a β-sheet formation is tightly regulated because dysregulated β-stacking often leads to severe diseases such as Alzheimer's, Parkinson's, systemic amyloidosis, or diabetes. Thus, the identification of intrinsic β-sheet-forming propensities can provide valuable insight into protein designs for the development of novel therapeutics. However, structure-based design methods may not be generally applicable to such amyloidogenic peptides mainly owing to high structural plasticity and complexity. Therefore, an alternative design strategy based on complementary sequence information is of significant importance. Herein, we developed a database search method called β-Stacking Interaction DEsign for Reciprocity (B-SIDER) for the design of complementary β-strands. This method makes use of the structural database information and generates target-specific score matrices. The discriminatory power of the B-SIDER score function was tested on representative amyloidogenic peptide substructures against a sequence-based score matrix (PASTA 2.0) and two popular ab initio protein design score functions (Rosetta and FoldX). B-SIDER is able to distinguish wild-type amyloidogenic β-strands as favored interactions in a more consistent manner than other methods. B-SIDER was prospectively applied to the design of complementary β-strands for a splitGFP scaffold. Three variants were identified to have stronger interactions than the original sequence selected through a directed evolution, emitting higher fluorescence intensities. Our results indicate that B-SIDER can be applicable to the design of other β-strands, assisting in the development of therapeutics against disease-related amyloidogenic peptides.


PARENTAL REGULATION OF INFANT SLEEP: ROUND-THE-CLOCK EFFORTS FOR SOCIAL SYNCHRONIZATION.
The sleep-cycle development of infants is influenced by familial and sociocultural conditions, but there is a lack of knowledge on how parental regulation of infant sleep is related to the specific life situation of a family. This article describes a context-sensitive study of parental regulation of infant sleep that includes the whole 24-hr day, parents' intentions, and familial and sociocultural conditions. The results are based on a longitudinal qualitative study in Norway of 51 families. Parents were interviewed in the infants' first year of life and approximately 18 months later. An interpretive analysis in four steps was conducted, informed by cultural psychological perspectives on development. The parents were found to perform five types of regulatory actions: facilitating sleep, letting sleep, letting be awake, keeping awake, and waking. These actions were performed continuously throughout the 24-hr day, each to different extents and at different hours in individual families, forming a regulation cycle. We describe patterns and variations in regulation cycles, changes over time as increased social synchronization, and how the regulation cycle is embedded in familial and sociocultural conditions. Finally, implications for clinical practice are discussed.


Global patterns of health care for acute coronary syndromes.
Despite similar guidelines, remarkable global differences exist in the management of acute coronary syndromes. This review describes recent insights in global patterns of patient baseline characteristics, treatment strategies, medication use, and outcome in acute coronary syndromes. Results from recent registries and randomized clinical trials suggest that the arrival of many novel medications and treatment options for acute coronary syndromes has led to interregional heterogeneity in the management and treatment of patients with acute coronary syndromes. These differences in health care and adherence to national and international guidelines appear to be influenced by geographical, social, cultural, and economic factors, resulting in regional variation in hospital characteristics, physician attitude, access to resources or advanced cardiovascular care, access to the literature, and the availability of drugs. Significant differences in diagnosis and treatment of acute coronary syndrome patients can be observed globally, despite similar guidelines based on the same randomized clinical trials. Guidelines are not adapted promptly worldwide, influencing outcome and health care expenditure.


Systemic hemodynamic and regional blood flow effects of LY141865, a selective dopamine receptor agonist.
Intravenous infusion of LY141865 (20 micrograms/kg) lowered systemic vascular resistance in anesthetized dogs resulting in a fall in mean arterial blood pressure. These effects require an intact nervous system and involve dopamine receptors as they were abolished by hexamethonium or sulpiride pretreatment. LY141865 does not appear to interact with adrenergic receptors because it did not increase diastolic blood pressure or cardiac rate of normal or hexamethonium-treated dogs, and yohimbine pretreatment did not antagonize its systemic vasodilator and hypotensive actions. Hemodynamic analysis demonstrated that infusion of LY141865 (20 and 100 micrograms/kg i.v.) resulted in persistent arterial hypotension due solely to reduced systemic vascular resistance; aortic blood flow index was maintained. LY141865 produced slight bradycardia and sustained increments in stroke volume index at the highest tested dose. Left ventricular filling pressure was unchanged by LY141865. Regional blood flows to heart, stomach, colon, small intestine, kidneys and marrow-laden bone were not changed during hemodynamic alterations produced by LY141865, although evidence of arteriovenous shunting of blood was observed in skin and skeletal muscle. Comparable systemic vasodilation and arterial hypotension induced by infusion of nitroglycerin reduced gastric and colonic blood flows, but did not produce detectable shunting. The composite data are interpreted to be a reflection of the ability of LY141865 to interact with DA2 dopamine receptors and thereby inhibit neurogenic release of norepinephrine. The present results and known oral efficacy of LY141865 lend further support for the development and use of dopamine receptor agonists for the treatment of cardiovascular disease.


Physical activity and lower limb lymphedema among uterine cancer survivors.
Physical activity (PA) is known to provide physical and mental health benefits to uterine cancer survivors. However, it is unknown if PA is associated with lower limb lymphedema (LLL), an accumulation of protein-rich fluid in the lower limbs. Therefore, we sought to examine the association between PA and LLL in uterine cancer survivors, with a focus on walking. We conducted a cross-sectional study using mailed surveys among uterine cancer survivors who received care at a university-based cancer center. We asked about PA, walking, and LLL symptoms using validated self-report questionnaires. PA was calculated using MET-hours per week, and walking was calculated using blocks per day. The response rate to our survey was 43%. Among the 213 uterine cancer survivors in our survey, 36% were classified as having LLL. Compared with participants who reported <3 MET · h · wk of PA, participants who reported ≥ 18.0 MET · h · wk of PA had an odds ratio of LLL of 0.32 (95% confidence interval, 0.15-0.69; P trend = 0.003). Stratified analyses suggested the association between PA and LLL existed only among women with body mass index (BMI) <30 kg · m (P trend = 0.007) compared with women with BMI ≥ 30 kg · m (P trend = 0.47). Compared with participants who reported <4.0 blocks per day of walking, participants who reported ≥ 12 blocks per day of walking had an odds ratio of LLL of 0.19 (95% confidence interval, 0.09-0.43; P trend < 0.0001). Stratified analyses suggested the association between walking and LLL was similar among women with BMI <30 kg · m (P trend = 0.007) and women with BMI ≥ 30 kg · m (P trend = 0.03). Participation in higher levels of PA or walking is associated with reduced proportions of LLL in dose-response fashion. These findings should be interpreted as preliminary and should be investigated in future studies.


Do chronic illnesses and poverty go hand in hand?
In the global context, the health and quality of life of people are adversely affected by either one or more types of chronic diseases. The chronic pain associated with diagnosed patients may include heavy medical expenditure along with the physical and mental suffering they undergo. Usually, unbearable amounts of medical expenses are incurred, to improve or sustain the health condition of the patient. Consequently, the heavy financial burden tends to push households from a comfortable or secure life, or even from bad to worse, towards the probability of becoming poor. Hence, this study is conducted to identify the impact chronic illnesses have on poverty using data from a national survey referred as the Household Income and Expenditure Survey (HIES), with data gathered by the Department of Census and Statistics (DCS) of Sri Lanka in 2016. As such, this study is the first of its kind in Sri Lanka, declaring the originality of the study based on data collected from the local arena. Accordingly, the study discovered that married females who do not engage in any type of economic activity, in the age category of 40-65, having an educational level of tertiary level or below and living in the urban sector have a higher likelihood of suffering from chronic diseases. Moreover, it was inferred that, if a person is deprived from access to basic education in the level of education, lives in the rural or estate sector, or suffers from a brain disease, cancer, heart disease or kidney disease, he is highly likely to be poor. Some insights concluded from this Sri Lankan case study can also be applied in the context of other developing countries, to minimise chronic illnesses and thereby the probability of falling into poverty.


Outcomes of unselected recipients of sirolimus-eluting stents: the Cypher stent U.S. post-marketing surveillance registry.
To examine the 1-year safety and clinical outcomes associated with the post-marketing early unselected use of sirolimus-eluting stents (SES) in the United States. The safety and effectiveness of SES has been assessed in selected patients enrolled in pivotal randomized trials. This PMS registry was initiated to examine the safety and effectiveness of SES in an unselected population. Consecutive patients who underwent implantation of > or = 1 SES at 38 participating U.S. centers were enrolled in this registry. Results were compared according to "off-" versus "on-label" use of SES. Multivariate regression analyses were carried out in search of predictors of 1- year MACE and stent thrombosis. The mean age of the 2,067 patients (3,367 treated lesions) was 63.7 years. The 12-month follow up was completed by 1,964 patients (95%). SES were implanted for "offlabel" indications in 1,173 patients (57%). The 12-month rates of MACE and TLR in that subgroup were 9.2% and 6.2% (p < 0.001 vs. "on-label" indications). Rate of definite/probable stent thrombosis was 1.6% ("off-label") vs. 0.6% ("on-label"), p = 0.026. The rates of MACE, TLR and stent thrombosis in 640 diabetics (31%) were 9.4%, 5.8% and 1.3% (p = 0.021, NS and NS vs. non-diabetics, respectively). Number of lesions, insulin-dependent diabetes and unstable angina were predictors of stent thrombosis. The "off-label" use of SES was associated with higher 1-year cumulative rates of MACE than "on-label" indications, although rates were similar to those seen in historical premarketing randomized trials. None of the "off-label" indications were independent predictors of MACE or stent thrombosis.


Spontaneous cerebrospinal fluid leaks: a variant of benign intracranial hypertension.
Previous reports indicate that elevated intracranial pressure (ICP) may cause spontaneous cerebrospinal fluid (CSF) leaks. In this study we examined the clinical diagnosis of benign intracranial hypertension (BIH) in this population using the modified Dandy criteria. We performed a retrospective review of clinical data and measurements of ICPs after surgical repair. Sixteen patients with spontaneous CSF leaks were surgically treated from 1996 to 2002. In 11 patients with CSF pressure measurements, strict adherence to the modified Dandy criteria definitively confirmed a diagnosis of BIH in 8 patients (72%) and a likely diagnosis in the 3 remaining patients. The mean ICP was 31.1 cm H20 (range, 17.3 to 52 cm H2O), and 81% of the patients were obese middle-aged women. Clinically, all patients had signs and/or symptoms of elevated ICP, such as headache (91%), pulsatile tinnitus (45%), hypertension (45%), balance problems (27%), and visual complaints (18%). Surgical repair was 100% successful in leak cessation over a mean follow-up of 14.1 months. Most patients with spontaneous CSF leaks fulfill the modified Dandy criteria; thus, this disorder appears to be a variant of BIH. Further investigation is needed to determine the exact cause of elevated CSF pressures in this group and whether medical or surgical treatments to correct the intracranial hypertension are warranted.


Stewardship of the seas.
Our seas offer food, beauty and fascination, and are fundamental in regulating our climate - but are we doing enough to protect them?


Role of inflammation in chemical-induced lung cancer.
Chemical-induced carcinogenesis has been in the focus of toxicological research for many decades. However, the mechanisms leading to tumor formation are only understood with certain substances. The intake of potential carcinogens by inhalation is a major route of exposure. Chemical-induced lung tumors are the final manifestation of a multistep pathway, resulting in an imbalance between cell proliferation and cell death by apoptosis. The impact of certain confounding factors e.g. extent of inflammatory response, type of genotoxic event, antagonizing principles and genetic background are discussed in this article. Finally, methods to assess the inflammatory potential of chemicals are referred to.


Rational design of Nd(3+)-sensitized multifunctional nanoparticles with highly dominant red emission.
Controlling excitation and emission wavelengths on demand is very significant in bioimaging. Up-conversion nanoparticles (UCNPs) emit visible light upon near-infrared (NIR) light excitation and are well studied in bioimaging. Red emission is usually preferred to green due to its higher tissue penetration depth in bioimaging. Herein, dominant red emission has been achieved under 808 nm excitation based on the designed α-NaYbF4:Mn(2+)/Er(3+)@NaLuF4:Mn(2+)/Yb(3+)@NaNdF4:Yb(3+)@NaGdF4 (C@S1@S2@S3) nanostructure. The rationally designed interlayer shell NaLuF4:Mn(2+)/Yb(3+) could efficiently filter unwanted energy back-transfer from Er(3+) to Nd(3+) and the outmost shell NaGdF4 could prevent excitation energy from surface-related quenching. The lifetime of (4)F9/2→(4)I15/2 transition of Er(3+) could be as high as 0.7 ms. Moreover, C@S1@S2@S3 UCNPs also possess effective contrast efficiency for both X-ray computed tomography (CT) and magnetic resonance (MR) imaging. The designed multifunctional UCNPs could be used as a potential multimodal bioprobe in bioimaging applications.


Spastic secondary contractile patterns identified by FLIP panometry in symptomatic patients with unremarkable high-resolution manometry.
Functional lumen imaging probe (FLIP) panometry can show spastic secondary contractile patterns of unclear significance in symptomatic patients who have no esophageal obstructive disorders, and no motility disorders on high-resolution manometry (HRM). We retrospectively analyzed non-obstructed, symptomatic patients with HRM findings of no motility disorder or ineffective esophageal motility (IEM) for whom spastic secondary contractile patterns identified by FLIP panometry were used to guide treatment. Symptoms were scored using the Brief Esophageal Dysphagia Questionnaire (BEDQ). We identified ten symptomatic patients treated at our medical center who met inclusion criteria (seven women; mean age 56 years; eight no motility disorder, two IEM). On FLIP panometry, seven had spastic secondary contractions at 60 ml, two at 40 ml, and one at both 40 ml and 60 ml balloon volumes. Eight patients (80%) had improvement in BEDQ scores with therapies that targeted the spastic secondary contractile patterns identified by FLIP (five botulinum toxin injection, two Esoflip dilation, and one Heller myotomy). Interestingly, review of HRM tracings revealed that all patients had a novel HRM finding of mid-vertical pressurization in at least 20% swallows, with seven exhibiting this finding in >50% of swallows. This case series demonstrates that treatments targeting spastic secondary contractions identified by FLIP panometry can result in symptomatic improvement in patients with no obstructive disorder and no diagnostic motility disorder on HRM. In such patients, we have identified the novel HRM finding of mid-vertical pressurization, which might be the manometric manifestation of spasm limited to the mid-esophagus.


The Specific Roles of Loss of Interest and Loss of Pleasure in Recent Suicidal Ideation.
Evidence suggests that recent changes in anhedonia may be more predictive of suicidal ideation than either state or trait anhedonia alone. However, the individual role that anhedonia symptoms play in suicidality is not yet well established. This study investigated whether state, trait, and recent changes in anhedonia predicted recent suicidal ideation, using cross-sectional data from two independent samples, one non-clinical (n = 2,138) and one clinical (n = 859), using binary logistic regression analyses. In Study 1, loss of interest in people and loss of pleasure were associated with recent suicidal ideation independent of other depression symptoms, state and trait anhedonia. In Study 2, loss of interest in people, loss of interest in sex, and work inhibition were associated with recent suicidal ideation. In both studies, recent changes in anhedonia was uniquely associated with recent suicidal ideation. These results indicate that recent changes in anhedonia and particularly the social aspect of the Loss of Interest in People item could be a significant risk factor in suicidal ideation.


Grief in family carers of people living with dementia: A systematic review.
Grief research in family carers of people with dementia has increased. We aimed to report the prevalence of pre-death and post-death grief and to synthesize associated factors and the relationship between pre-death factors and post-death grief and services used to manage grief. (Prospero protocol: CRD42020165071) We systematically reviewed literature from PsycINFO, MEDLINE, CINAHL, and ASSIA until April 2020. Effectiveness of intervention data and studies not written in English were excluded; qualitative studies were additionally excluded during study selection. Study quality was assessed using the Mixed Methods Appraisal Tool. Evidence was narratively summarized. Family non-paid carers of somebody with any dementia type. Validated measures of pre-death and/or post-death grief. We included quantitative data from 55 studies (44 rated as high quality). Most included solely spouse or adult child carers. Forty-one studies reported pre-death grief, 12 post-death grief, and 6 service use; eight were longitudinal. 17% met the Prolonged Grief Disorder criteria pre-death (n = 1) and 6-26% (n = 4) of participants met the Complicated Grief criteria post-death. Being a spouse, less educated, caring for somebody with advanced dementia, and greater burden and depression were associated with higher pre-death grief. Lower education level and depression were predictive of higher post-death grief. Pre-death factors found to influence post-death grief were grief and depression. Limited service use evidence was reported. Awareness of characteristics which increase the likelihood of higher grief can help identify those in need of support. Future research should focus on what supports or services are beneficial to grief experiences.


Electrophoretic deposition strategy for the fabrication of highly stable functionalized silica nanoparticle coatings onto nickel-titanium alloy wires for selective solid-phase microextraction.
A new strategy for the immobilization of phenyl-functionalized silica nanoparticles onto nickel-titanium alloy wires is presented. The homogeneous and compact silica nanoparticle coating was achieved on the hydrothermally treated nickel-titanium wires with large surface area by electrophoretic deposition, and followed by self-assembled modification of phenyltrichlorosilane. Coupled to high-performance liquid chromatography with ultraviolet detection, the extraction performance of the fabricated fiber was evaluated using typical aromatic compounds in direct-immersion mode of solid-phase microextraction. Due to its high extraction efficiency and good selectivity for ultraviolet filters, the novel fiber was employed to investigate the key factors affecting the extraction of ultraviolet filters. Under the optimized conditions, the proposed method presented linear ranges from 0.05 to 300 μg/L with correlation coefficients higher than 0.999 and limits of detection from 0.005 to 0.058 μg/L. Relative standard deviations were below 4.3 and 5.6% for intraday and interday analyses at the spiking level of 50 μg/L ultraviolet filters with the single fiber, respectively. The proposed method was successfully applied to the selective concentration and sensitive detection of target ultraviolet filters from environmental water samples. Furthermore, the developed fiber can be used at least 200 times, and fabricated in a precisely controllable manner.


Efficacy and safety of expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis.
Is expectant management (EM) of tubal ectopic pregnancy (EP) an effective and safe treatment strategy when compared to alternative interventions? There is insufficient evidence to conclude EM yields a difference in the resolution of tubal EP, the avoidance of surgery or time to resolution of tubal EP when compared to intramuscular methotrexate in stable patients with β-hCG <1500 IU/l. The utilisation of medical and surgical management for EP is well established. EM aims to allow spontaneous resolution of the EP without intervention. We performed a systematic review and meta-analysis, searching Ovid MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, OpenGrey.eu, Google Scholar, cross-referencing citations and trial registries to 15 December 2019. There were no limitations placed on language or publication date. Search terms included tubal EP and EM as well as variations of these terms. We considered studies that included patients with tubal EP, EM as a comparator, and that were randomised controlled trials (RCTs). The primary outcome was resolution of tubal EP. Secondary outcomes included avoidance of surgery and the time to resolution of EP. Two reviewers independently selected the studies, assessed bias and extracted data. Relative risk (RR) and mean difference with 95% CI were assessed using a random effects model. The certainty of evidence was scored according to Grading of Recommendations Assessment, Development and Evaluation guidelines. In total, 920 studies were screened. Five studies were eligible for inclusion in the systematic review. Two RCTs comparing methotrexate to EM were identified as being eligible for inclusion in meta-analysis. No RCTs comparing surgery to EM were identified. Compared with EM, there was insufficient evidence that methotrexate yields a difference on resolution of tubal EP (RR 1.04, 95% CI 0.88-1.23, P = 0.67; two RCTs, moderate-certainty evidence), avoiding surgery (RR 1.10, 95% CI 0.94-1.29, P = 0.25; two RCTs, low-certainty evidence) or the time to resolution of tubal EP (-2.56 days (favouring EM), 95% CI -7.93-2.80, P = 0.35; two RCTs, low-certainty evidence). Only two RCTs with a total of 103 patients were eligible for inclusion in this meta-analysis. Further RCTs comparing EM to medical and surgical management are needed and these should also report adverse events. Patient preference should also be evaluated. We found insufficient evidence of differences in terms of resolution, avoidance of surgery and time to resolution between expectant and medical management. Given the imprecision in the effect estimates as demonstrated by the wide CIs, resulting in the downgrading of certainty of evidence for all outcomes in this meta-analysis, larger RCTs comparing interventions for tubal EP are needed. Caution should be exercised when trying to decide between EM and methotrexate to treat tubal EP. There was no funding for this study. NICM receives funding from various sources; none specifically supported this research. M.L. reports grants from Australian Women and Children's Research Foundation, outside the submitted work. M.A.: As a medical research institute, NICM Health Research Institute receives research grants and donations from foundations, universities, government agencies and industry. Sponsors and donors provide untied and tied funding for work to advance the vision and mission of the Institute. This systematic review was not specifically supported by donor or sponsor funding to NICM. M.A. reports a partnership grant with Metagenetics outside the submitted work. G.C. reports grants from Australian Women and Children's Research Foundation, personal fees from Roche and GE Healthcare, outside the submitted work. The remaining authors report no conflicts of interest. CRD42020142736.


Two related phenolic antioxidants with opposite effects on vitamin E content in low density lipoproteins oxidized by ferrylmyoglobin: consumption vs regeneration.
Endogenous alpha-tocopherol of low density lipoprotein (LDL) particles exposed to ferrylmyoglobin (iron in the form of FeIV = O) vanishes as a function of myoglobin concentration. After alpha-tocopherol depletion, subsequent heavy lipid peroxidation is prevented by caffeic and p-coumaric acids, i.e., phenolic acids present in foods and beverages, by a mechanism involving the one-electron transfer reaction between the phenols and the ferrylmyoglobin, with formation of metmyoglobin and the corresponding phenoxyl radicals from caffeic and p-coumaric acids, as previously discussed. Caffeic acid delays alpha-tocopherol consumption when present before oxidation challenging and restores alpha-tocopherol when added halfway during the reaction. Conversely, p-coumaric acid accelerates the rate of alpha-tocopherol consumption when added either before or during the oxidation reaction. In LDL enriched with alpha-tocopherol, caffeic acid induces an inhibition period of oxidation longer than that expected from the sum of discrete periods characteristic of the phenolic acid and alpha-tocopherol. Surprisingly, p-coumaric acid decreases the peroxidation chain rate. Similar effects of these phenolic acids on alpha-tocopherol consumption were observed in a Triton X-100 micellar system, i.e., in the absence of a peroxidation chain reaction. Results suggest that caffeic acid acts synergistically with alpha-tocopherol, extending the antioxidant capacity of LDL by recycling alpha-tocopherol from the alpha-tocopherol radical (i.e., alpha-tocopheroxyl radical). By contrast, the phenoxyl radical from p-coumaric acid (produced by electron-transfer reaction between phenolic acid and ferrylmyoglobin) oxidizes alpha-tocopherol. However, in spite of alpha-tocopherol consumption, the exchange reaction recycling p-coumaric acid can still afford an antioxidant protection to LDL on basis of the chain-breaking activity of p-coumaric acid. These results emphasize the biological relevance of small structural modifications of phenols on the interaction with alpha-tocopherol in LDL. The significance of these results in the context of atherosclerosis is discussed.


Genome-wide prediction of splice-modifying SNPs in human genes using a new analysis pipeline called AASsites.
Some single nucleotide polymorphisms (SNPs) are known to modify the risk of developing certain diseases or the reaction to drugs. Due to next generation sequencing methods the number of known human SNPs has grown. Not all SNPs lead to a modified protein, which may be the origin of a disease. Therefore, the recognition of functional SNPs is needed. Because most SNP annotation tools look for SNPs which lead to an amino acid exchange or a premature stop, we designed a new tool called AASsites which searches for SNPs which modify splicing. AASsites uses several gene prediction programs and open reading frame prediction to compare the wild type (wt) and the variant gene sequence. The results of the comparison are combined by a handmade rule system to classify a change in splicing as "likely, probable, unlikely". Having received good results from tests with SNPs known for changing the splicing pattern we checked 80,000 SNPs from the human genome which are located near splice sites for their ability to change the splicing pattern of the gene and hereby result in a different protein. We identified 301 "likely" and 985 "probable" classified SNPs with such characteristics. Within this set 33 SNPs are described in the ssSNP Target database to cause modified splicing. With AASsites single SNPs can be checked for those causing splice modifications. Screening 80,000 known human SNPs we detected about 1,200 SNPs which probably modify splicing. AASsites is available at http://genius.embnet.dkfz-heidelberg.de/menu/biounit/open-husar using any web browser.


Quorum sensing and phenazines are involved in biofilm formation by Pseudomonas chlororaphis (aureofaciens) strain 30-84.
The biological control bacterium Pseudomonas chlororaphis (aureofaciens) strain 30-84 employs two quorum sensing (QS) systems: PhzR/PhzI regulates the production of the antibiotics phenazine-1-carboxylic acid, 2-hydroxy-phenazine-1-carboxylic acid, and 2-hydroxy-phenazine, whereas CsaR/CsaI regulates currently unknown aspects of the cell surface. Previously characterized derivatives of strain 30-84 with mutations in each QS system and in the phenazine biosynthetic genes were screened for their ability to form surface-attached biofilm populations in vitro, using microtiter plate and flow cell biofilm assays, and on seeds and roots. Results from in vitro, seed, and root studies demonstrated that the PhzR/PhzI and the CsaR/CsaI QS regulatory systems contribute to the establishment of biofilms, with mutations in PhzR/PhzI having a significantly greater effect than mutations in CsaR/CsaI. Interestingly, phenazine antibiotic production was necessary for biofilm formation to the same extent as the PhzR/PhzI QS system, suggesting the loss of phenazines was responsible for the majority of the biofilm defect in these mutants. In vitro analysis indicated that genetic complementation or AHL addition to the growth medium restored the ability of the AHL synthase phzI mutant to form biofilms. However, only phenazine addition or genetic complementation of the phenazine biosynthetic mutation in trans restored biofilm formation by mutants defective in the transcriptional activator phzR or the phzB structural mutant. QS and phenazine production were also involved in the establishment of surface-attached populations on wheat seeds and plant roots, and, as observed in vitro, the addition of AHL extracts restored the ability of phzI mutants, but not phzR mutants, to form surface attached populations on seeds. Similarly, the presence of the wild type in mixtures with the mutants restored the ability of the mutants to colonize wheat roots, demonstrating that AHL and/or phenazine production by the wild-type population could complement the AHL- and phenazine-deficient mutants in situ. Together, these data demonstrate that both QS systems are involved in the formation of surface-attached populations required for biofilm formation by P. chlororaphis strain 30-84, and indicate a new role for phenazine antibiotics in rhizosphere community development beyond inhibition of other plant-associated microorganisms.


The conserved dual phosphorylation sites of the Candida albicans Hog1 protein are crucial for white-opaque switching, mating, and pheromone-stimulated cell adhesion.
Candida albicans is an opportunistic human pathogen capable of causing life-threatening infections in immunocompromised patients. C. albicans has a unique morphological transition between white and opaque phases. These two cells differ in virulence, mating capability, biofilm formation, and host-cell interaction. Previous studies revealed that deletion of the SSK2, PBS2, or HOG1 gene resulted in 100% opaque cell formation and suppressed the mating response. Thr-174 and Tyr-176 of the Hog1 protein are important phosphoacceptors and can be activated in response to stimuli. In this study, we first demonstrated the importance of two conserved phosphorylation sites in white-opaque switching, mating, and pheromone-stimulated cell adhesion. Six Hog1 point-mutated strains were generated, including nonphosphorylated strains (Hog1(T174A), Hog1(Y176F), and Hog1(T174A,Y176F)) and negatively charged phosphorylated strains (Hog1(T174D), Hog1(Y176D), and Hog1(T174D,Y176D)). Point mutation on Thr-174, Tyr-176 or in combination with the Hog1 protein in C. albicans MTL homozygous strains stimulated opaque cell formation at a frequency of 100%. Furthermore, mating projections of point-mutated strains were significantly shorter and their mating efficiencies and pheromone-stimulated cell adhesive numbers were lower than those of the wild-type. By investigating the effects of Hog1 phosphorylation in ssk1Δ and sln1Δ, we also demonstrate that the phosphorylation intensity of Hog1p is directly involved in the white-opaque switching. Taken together, the results of our study demonstrate that dual phosphorylation sites of C. albicans are crucial for white-opaque transition, sexual mating, and pheromone-induced cell adhesion.


Sudden Dignity in the Act of Reading.
This essay argues that it is literature, and the serious reading of literature, which offers a sudden emotional experience of human dignity, realized anew through the care of its language. Case histories are provided from the work of The Reader, a charitable organization bringing live shared reading to hard-to-reach communities. The research was conducted by the Centre for Research into Reading, Literature and Society (CRILS), at the University of Liverpool. CRILS analysed the effect of literary texts on the heightened language of the participants themselves in the reading groups, revealing often neglected inner resources stirred by literature to bear the troubles and indignities of existence. These ordinary non-academic readers are able to register that emergent transformation from trouble into achievement not only vicariously through the texts they read at the time but also by seeing, later in interview, filmed excerpts of their own creative responses during the reading sessions.


Risk for Reinfection After SARS-CoV-2: A Living, Rapid Review for American College of Physicians Practice Points on the Role of the Antibody Response in Conferring Immunity Following SARS-CoV-2 Infection.
The strength and duration of immunity from infection with SARS-CoV-2 are important for public health planning and clinical practice. To synthesize evidence on protection against reinfection after SARS-CoV-2 infection. MEDLINE (Ovid), the World Health Organization global literature database, ClinicalTrials.gov, COVID19reviews.org, and reference lists. Longitudinal studies that compared the risk for reinfection after SARS-CoV-2 infection versus infection risk in individuals with no prior infection. Two investigators sequentially extracted study data and rated quality. Across 18 eligible studies, reinfection risk ranged from 0% to 2.2%. In persons with recent SARS-CoV-2 infection compared with unvaccinated, previously uninfected individuals, 80% to 98% of symptomatic infections with wild-type or Alpha variants were prevented (high strength of evidence). In the meta-analysis, previous infection reduced risk for reinfection by 87% (95% CI, 84% to 90%), equaling 4.3 fewer infections per 100 persons in both the general population (risk difference, -0.043 [CI, -0.071 to -0.015]) and health care workers (risk difference, -0.043 [CI, -0.069 to -0.016]), and 26.6 fewer infections per 100 persons in care facilities (risk difference, -0.266 [CI, -0.449 to -0.083]). Protection remained above 80% for at least 7 months, but no study followed patients after the emergence of the Delta or Omicron variant. Results for the elderly were conflicting. Methods to ascertain and diagnose infections varied. Before the emergence of the Delta and Omicron variants, persons with recent infection had strong protection against symptomatic reinfections for 7 months compared with unvaccinated, previously uninfected individuals. Protection in immunocompromised persons, racial and ethnic subgroups, and asymptomatic index case patients is unclear. The durability of protection in the setting of the Delta and Omicron variants is unknown. Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098).


Detection of allergen-specific antibody-secreting cells in dogs by ELISPOT.
Current laboratory tests are unable to distinguish healthy from allergic dogs. Unlike serum antibody responses, circulating antibody-secreting cells (ASC) are temporarily induced after each contact with the antigen. These ASC can be identified using ELISPOT and the observation of allergen-specific ASC might correlate with the causative allergens in dogs with an allergic dermatitis. In this study, blood was sampled from six privately-owned allergic dogs and six non-allergic laboratory beagles to determine the frequency of circulating allergen-specific ASC for common allergens. Blood IgE+, IgA + and IgG + cells were magnetically isolated to determine the number of allergen-specific ASC with ELISPOT for Dermatophagoides farinae, Dermatophagoides pteronyssinus, Alternaria alternata, birch, timothy grass, wheat, cow's milk, bovine, chicken and lamb meat. For IgA and IgG, allergen-specific spots were observed, however for IgE, no spots were detected for any of the allergens. ELISPOT could not differentiate allergic from non-allergic dogs. When the responses to the different allergens were compared, more IgA ASC for D. pteronyssinus were observed compared to some of the other allergens which was statistically significant for the non-allergic dogs and approached significance in the allergic dogs. These findings indicate that ELISPOT can be used to identify circulating allergen-specific IgA- and IgG-secreting cells. The technique did however not detect allergen-specific IgE ASC and was unable to distinguish allergic from non-allergic dogs. Only a small number of studies have studied allergen-specific IgA in dogs. The finding that dogs have higher numbers of D. pteronyssinus-specific IgA ASC points out that apart from IgE and IgG, it might be interesting to include IgA measurements for certain allergens to analyse the complete spectrum of both the protective and pro-allergic antibody responses.


Genome-wide association studies using single-nucleotide polymorphisms versus haplotypes: an empirical comparison with data from the North American Rheumatoid Arthritis Consortium.
The high genomic density of the single-nucleotide polymorphism (SNP) sets that are typically surveyed in genome-wide association studies (GWAS) now allows the application of haplotype-based methods. Although the choice of haplotype-based vs. individual-SNP approaches is expected to affect the results of association studies, few empirical comparisons of method performance have been reported on the genome-wide scale in the same set of individuals. To measure the relative ability of the two strategies to detect associations, we used a large dataset from the North American Rheumatoid Arthritis Consortium to: 1) partition the genome into haplotype blocks, 2) associate haplotypes with disease, and 3) compare the results with individual-SNP association mapping. Although some associations were shared across methods, each approach uniquely identified several strong candidate regions. Our results suggest that the application of both haplotype-based and individual-SNP testing to GWAS should be adopted as a routine procedure.


Mesenchymal Stem Cells Adaptively Respond to Environmental Cues Thereby Improving Granulation Tissue Formation and Wound Healing.
Granulation tissue formation constitutes a key step during wound healing of the skin and other organs. Granulation tissue concomitantly initiates regenerative M2 macrophages polarization, fibroblast proliferation, myofibroblast differentiation with subsequent contraction of the wound, new vessel formation, and matrix deposition. Impaired granulation tissue formation either leads to delayed wound healing or excessive scar formation, conditions with high morbidity and mortality. Accumulating evidence has demonstrated that mesenchymal stem cell (MSC)-based therapy is a promising strategy to ameliorate defects in granulation tissue formation and to successfully treat non-healing chronic wounds. In this review we give an updated overview of how therapeutically administered MSCs ensure a balanced granulation tissue formation, and furthermore discuss the cellular and molecular mechanisms underlying the adaptive responses of MSCs to cue in their direct neighborhood. Improved understanding of the interplay between the exogenous MSCs and their niche in granulation tissue will foster the development of MSC-based therapies tailored for difficult-to-treat non-healing wounds.


Societal costs of vascular cognitive impairment in older adults.
The construct of vascular cognitive impairment (VCI) includes many whose care is or will be costly. Nevertheless, estimates of these costs are not well described. We therefore set out to estimate the societal costs of VCI in elderly people. In a secondary analysis of the Canadian Study of Health and Aging, a representative cohort study, Canadian dollar costs using a societal perspective were estimated by standard methods. The total annual per-patient societal costs for VCI by severity were $15 022 for those with mild disease, $14 468 for those with mild to moderate disease, $20 063 for those with moderate disease, and $34 515 for those with severe disease. The most expensive component per individual was the cost of institutional long-term care. Although severe impairment was associated with higher costs, the extent of institutionalization at all levels of severity and less drug use among those more severely impaired mitigated a severity-cost gradient. The societal costs of VCI are not inconsiderable. In contrast to Alzheimer disease, there is no clear gradient relating cost to severity. Unpaid caregiver costs are an important aspect of societal costs, even in those with only mild impairment.


Prognostic factors in neonatal acute renal failure.
Sixteen infants, 2 to 35 days of age, had acute renal failure, a diagnosis based on serum creatinine concentrations greater than 1.5 mg/dL for at least 24 hours. Eight infants were oliguric (urine flow less than 1.0 mL/kg/h) whereas the remainder were nonoliguric. To determine clinical parameters useful in prognosis, urine flow rate, duration of anuria, peak serum creatinine, urea (BUN) concentration, and nuclide uptake by scintigraphy were correlated with recovery. Nine infants had acute renal failure secondary to perinatal asphyxia, three had acute renal failure as a result of congenital cardiovascular disease, and four had major renal anomalies. Four oliguric patients died: three of renal failure and one of heart failure. All nonoliguric infants survived with mean follow-up serum creatinine concentration of 0.8 +/- 0.5 (SD) mg/dL whereas that of oliguric survivors was 0.6 +/- 0.3 mg/dL. Peak serum creatinine concentration did not differ between those patients who were dying and those recovering. All infants who were dying remained anuric at least four days and revealed no renal uptake of nuclide. Eleven survivors were anuric three days or less, and renal perfusion was detectable by scintigraphy in each case. However, the remaining survivor (with bilateral renal vein thrombosis) recovered after 15 days of anuria despite nonvisualization of kidneys by scintigraphy. In neonates with ischemic acute renal failure, lack of oliguria and the presence of identifiable renal uptake of nuclide suggest a favorable prognosis.


[Tongdu Tiaoshen acupuncture combined with carotid endarterectomy for carotid artery stenosis: a randomized controlled trial].
To observe the clinical therapeutic effect of Tongdu Tiaoshen acupuncture combined with carotid endarterectomy (CEA) and simple CEA on carotid artery stenosis (CAS). A total of 60 patients with CAS were randomized into an observation group (30 cases, 2 cases dropped off) and a control group (30 cases, 3 cases dropped off). Both groups were treated with eversion CEA (eCEA). The conventional treatment of internal medicine and antiplatelet drugs i.e. aspirin enteric-coated tablet and clopidogrel hydrogen sulfate tablet were given in the control group for 4 weeks. On the basis of the treatment in the control group, Tongdu Tiaoshen acupuncture was applied at Baihui (GV 20), Fengfu (GV 16), Yamen (GV 15), cervical Jiaji (EX-B 2), Dazhui (GV 14), etc. in the observation group, once a day, 1-day rest was taken after 6-day treatment, 2 weeks were as one course and totally 2 courses were required. The carotid intima-media thickness (IMT) before and after treatment was detected by ultrasonic diagnostic apparatus, the TCM symptom score was compared before and after treatment and in the follow-up of 6 months after treatment, the clinical efficacy was evaluated in the two groups. The occurrence of endpoints within 1 year was recorded. After treatment, the carotid IMT and TCM symptom scores were decreased compared before treatment in the both groups (P<0.05), and the changes in the observation group were greater than the control group (P<0.05). In the follow-up, the TCM symptom scores were decreased compared before treatment in the both groups (P<0.05). The total effective rate was 96.4% (27/28) in the observation group, which was superior to 88.9% (24/27) in the control group (P<0.05). There were 1 case of stoke in the observation group and 2 cases of stroke in the control group within 1-year follow-up, and there was no significant difference in the number of endpoints between the two groups within 1 year (P>0.05). Tongdu Tiaoshen acupuncture combined with CEA can effectively reduce the IMT in patients with CAS, improve the TCM symptom score, the efficacy is superior to simple CEA treatment.