Cooling interventions for athletes: An overview of effectiveness, physiological mechanisms, and practical considerations.
Exercise-induced increases in core body temperature could negative impact performance and may lead to development of heat-related illnesses. The use of cooling techniques prior (pre-cooling), during (per-cooling) or directly after (post-cooling) exercise may limit the increase in core body temperature and therefore improve exercise performance. The aim of the present review is to provide a comprehensive overview of current scientific knowledge in the field of pre-cooling, per-cooling and post-cooling. Based on existing studies, we will discuss 1) the effectiveness of cooling interventions, 2) the underlying physiological mechanisms and 3) practical considerations regarding the use of different cooling techniques. Furthermore, we tried to identify the optimal cooling technique and compared whether cooling-induced performance benefits are different between cool, moderate and hot ambient conditions. This article provides researchers, physicians, athletes and coaches with important information regarding the implementation of cooling techniques to maintain exercise performance and to successfully compete in thermally stressful conditions.


The application of graph theory and percolation analysis for assessing change in the spatial configuration of pond networks.
Pond networks support high levels of biodiversity when compared to other freshwater ecosystems such as rivers, lakes and streams. The persistence of species in these small, sometimes ephemeral, aquatic habitats depends on the dispersal of individuals among ponds in the landscape. However, the number of ponds across the landscape is at a historical low as urbanisation and intensified agricultural practices have led to a substantial loss of ponds (nodes in the pond network) over more than a century. Here, we examine the extent and drivers of pond loss in a heavily urbanised landscape (Birmingham, UK) over 105 years and determine how pond loss influences key structural properties of the pond network using graph theoretic approaches. Specifically, we calculated minimum spanning trees (MST) and performed percolation analyses to determine changes in both the spatial configuration and resilience of the pond network through time. Pond numbers declined by 82% between ca1904 and 2009, such that pond density decreased from 7.1 km-2 to 1.3 km-2. The MST analyses revealed increased distance between ponds in the network (i.e. edge length increased) by up to 49% over the 105-year period, indicating that ponds in the modern landscape (2009) were considerably more isolated, with fewer neighbours. This study demonstrates that graph theory has an excellent potential to inform the management of pond networks in order to support ecological communities that are less vulnerable to environmental change.


Host Immune Response to Influenza A Virus Infection.
Influenza A viruses (IAVs) are contagious pathogens responsible for severe respiratory infection in humans and animals worldwide. Upon detection of IAV infection, host immune system aims to defend against and clear the viral infection. Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. The adaptive immunity is mediated by B cells and T cells, characterized with antigen-specific memory cells, capturing and neutralizing the pathogen. The humoral immune response functions through hemagglutinin-specific circulating antibodies to neutralize IAV. In addition, antibodies can bind to the surface of infected cells and induce antibody-dependent cell-mediated cytotoxicity or complement activation. Although there are neutralizing antibodies against the virus, cellular immunity also plays a crucial role in the fight against IAVs. On the other hand, IAVs have developed multiple strategies to escape from host immune surveillance for successful replication. In this review, we discuss how immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs. In addition, we highlight how IAVs antagonize different immune responses to achieve a successful infection.


Gynaecotyla squatarolae (Digenea: Microphallidae) from rats experimentally infected with metacercariae from the shore crab, Macrophthalmus dilatatus.
Metacercariae of Gynaecotyla squatarolae (Digenea: Microphallidae) were discovered from the shore crab, Macrophthalmus dilatatus, purchased at a market in a coastal town of Taean-Eup, Chungcheongnam-do, Republic of Korea. Their adult flukes were confirmed by experimental infection of rats. The metacercariae of G. squatarolae were elliptical (391.1 x 362.5 micrometer), and the excysted metacercariae had progenetic genital organs, including the ovary and testes. To obtain adult flukes, 6 Sprague-Dawley rats were fed 500 metacercariae each, and killed at days 2, 4, and 6 post-infection. The adult flukes were identified as G. squatarolae (Yamaguti, 1934) Yamaguti, 1939, based on morphological characters, including 2 ventral suckers (1 large and 1 small), a large genital atrium equipped with the cirrus and the metraterm, separated male and female genital pores, a transversely long cirrus pouch, and extensive vitelline follicles. In the present study, it has been first proven that the shore crab M. dilatatus is a second intermediate host for G. squatarolae in the Republic of Korea.


Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.
Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins. We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins. The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events. Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).


Mortality among Parkinson patients treated with L-dopa combined with a decarboxylase inhibitor.
Since L-dopa in combination with a decarboxylase inhibitor is currently the most effective therapy available for treatment of Parkinson's disease, the authors compare the actual causes of death in a large series of treated Parkinson patients with a normal population and with previous studies. This investigation shows that the mortality of correctly treated Parkinson patients lies within the range of the expected mortality of a group of a normal population comparable in age and sex. The risk of death for a Parkinson patient is therefore no longer higher than for the normal population.


Fine-Mapping and Analysis of Cgl1, a Gene Conferring Glossy Trait in Cabbage (Brassica oleracea L. var. capitata).
Cuticular waxes covering the outer plant surface impart a whitish appearance. Wax-less cabbage mutant shows glossy in leaf surface and plays important roles in riching cabbage germplasm resources and breeding brilliant green cabbage. This is the first report describing the characterization and fine-mapping of a wax biosynthesis gene using a novel glossy Brassica oleracea mutant. In the present paper, we identified a glossy cabbage mutant (line10Q-961) with a brilliant green phenotype. Genetic analyses indicated that the glossy trait was controlled by a single recessive gene. Preliminary mapping results using an F2 population containing 189 recessive individuals revealed that the Cgl1 gene was located at the end of chromosome C08. Several new markers closely linked to the target gene were designed according to the cabbage reference genome sequence. Another population of 1,172 recessive F2 individuals was used to fine-map the Cgl1 gene to a 188.7-kb interval between the C08SSR61 simple sequence repeat marker and the end of chromosome C08. There were 33 genes located in this region. According to gene annotation and homology analyses, the Bol018504 gene, which is a homolog of CER1 in Arabidopsis thaliana, was the most likely candidate for the Cgl1 gene. Its coding and promoter regions were sequenced, which indicated that the RNA splice site was altered because of a 2,722-bp insertion in the first intron of Bol018504 in the glossy mutant. Based on the FGENESH 2.6 prediction and sequence alignments, the PLN02869 domain, which controls fatty aldehyde decarbonylase activity, was absent from the Bol018504 gene of the 10Q-961 glossy mutant. We inferred that the inserted sequence in Bol018504 may result in the glossy cabbage mutant. This study represents the first step toward the characterization of cuticular wax biosynthesis in B. oleracea, and may contribute to the breeding of new cabbage varieties exhibiting a brilliant green phenotype.


Clinical Application of Shock Wave in the Treatment of Avascular Necrosis of the Femoral Head in the Early and Middle Stages.
In order to observe the clinical efficacy of shock waves in the treatment of avascular necrosis of the femoral head in the early and middle stages, a clinical application method of a shock wave in the treatment of avascular necrosis of the femoral head in the early and middle stages was proposed. The method combines the CT image segmentation technology to further segment the hip joint image, thereby speeding up the treatment speed and achieving a better treatment effect. Experimental results show that CT image segmentation takes 10.9 hours with an average time of 8 seconds, which is faster than other methods. The shock wave is an effective treatment method for early avascular necrosis of the femoral head, and this method will become one of the main methods for the clinical treatment of this kind of disease.


Treatment Experiences of Women with Reproductive Cancers in Odisha, India: A Qualitative Exploration of Enablers and Barriers
Introduction: Cancer continues to be a major menace to our Indian society notwithstanding significant progress in diagnosis and treatment. In India cancer mortality rates in women are high compared to other countries, despite efforts to improve survival through the development of effective detection techniques and increased numbers of viable treatment options. Indian women's advanced stage of disease at diagnosis is largely attributable to delay in seeking treatment. The present qualitative inquiry was conducted with the aim of capturing the treatment experiences of patients with gynecology cancer at a tertiary care hospital and understanding the barriers, enablers, stress and apprehension they experience during the treatment phases. Methods: Twenty-one in-depth interviews were conducted with women diagnosed with gynecological cancers and undergoing at least one treatment intervention in the Inpatient Department (IPD). Theme guides were developed with a review of the literature and consultation with experts in the field. Data were collected by trained investigators who were well versed with the local language and analyzed using an inductive approach. Results are presented in the form of core- and sub-themes evolved during this process. Results: Out of the 21 respondents, 19 were married and 2 were widows. Nineteen had attained more than secondary qualifications. Nearly all women described themselves as 'housewives'. Amongst participants, 13 were diagnosed with breast cancer, 5 with ovarian cancer and 3 with cervical cancer. Thematic framework analysis of the transcripts yielded six key themes: 1) best and worst experiences during the treatment process; 2) financial and emotional stress; 3) care giving and social support; 4) satisfaction with the medical staff; 5) preferences for a female gynecologist and female gynecology ward; and 6) prompt and free treatment. Quotable quotes were presented in the table against every theme. Conclusion: Strengths in the Indian health care delivery system need to be built upon, while attention should be paid to developing effective psychosocial interventions, with a robust financial protection plan for patients and their involvement in decision making. Counselling of patients should be made part of a routine protocol.


Analysis of case-only studies accounting for genotyping error.
The case-only design provides one approach to assess possible interactions between genetic and environmental factors. It has been shown that if these factors are conditionally independent, then a case-only analysis is not only valid but also very efficient. However, a drawback of the case-only approach is that its conclusions may be biased by genotyping errors. In this paper, our main aim is to propose a method for analysis of case-only studies when these errors occur. We show that the bias can be adjusted through the use of internal validation data, which are obtained by genotyping some sampled individuals twice. Our analysis is based on a simple and yet highly efficient conditional likelihood approach. Simulation studies considered in this paper confirm that the new method has acceptable performance under genotyping errors.


The polarization anisotropy of vibrational quantum beats in resonant pump-probe experiments: Diagrammatic calculations for square symmetric molecules.
By analogy to the Raman depolarization ratio, vibrational quantum beats in pump-probe experiments depend on the relative pump and probe laser beam polarizations in a way that reflects vibrational symmetry. The polarization signatures differ from those in spontaneous Raman scattering because the order of field-matter interactions is different. Since pump-probe experiments are sensitive to vibrations on excited electronic states, the polarization anisotropy of vibrational quantum beats can also reflect electronic relaxation processes. Diagrammatic treatments, which expand use of the symmetry of the two-photon tensor to treat signal pathways with vibrational and vibronic coherences, are applied to find the polarization anisotropy of vibrational and vibronic quantum beats in pump-probe experiments for different stages of electronic relaxation in square symmetric molecules. Asymmetric vibrational quantum beats can be distinguished from asymmetric vibronic quantum beats by a pi phase jump near the center of the electronic spectrum and their disappearance in the impulsive limit. Beyond identification of vibrational symmetry, the vibrational quantum beat anisotropy can be used to determine if components of a doubly degenerate electronic state are unrelaxed, dephased, population exchanged, or completely equilibrated.


Endogenous MLC2 phosphorylation and Ca(2+)-activated force in mechanically skinned skeletal muscle fibres of the rat.
A method has been developed for measuring the level of phosphorylation of myosin regulatory light chains (MLC2) by the endogenous myosin light chain kinase in mechanically skinned skeletal muscle fibres. The method was used to characterize the endogeous MLC2 phosphorylation capacity of single fast-twitch fibres from the rat and to investigate the relationship between the endogenous MLC2 phosphorylation and the Ca(2+)-activated force. The results show that (1) about 50% of MLC2 were 32P-phosphorylated after activation of the skinned fibre preparation by 30 microM [Ca2+] for longer than 30 s, but that there was variability between fibres; (2) most of the endogenous phosphorylating system diffused out of the skinned fibre preparation after 5 min exposure to an aqueous solution; (3) the MLC2 phosphorylation by the endogenous phosphorylating system followed with a delay of the order of 1-2 s after the sudden rise in [Ca2+] from below 10 nM to 30 microM; and (4) the sensitivity of the contractile apparatus to Ca2+ was markedly increased when the MLC2 were phosphorylated by the endogenous phosphorylating system following a rise in [Ca2+]. The Kd for MgATP of the endogenous MLC2 phosphorylating system was estimated to be less than 300 microM. These results unequivocally demonstrate that prolonged activation of the fast-twitch muscle fibre leads to increased Ca2+ sensitivity of the contractile apparatus and that mechanically skinned fibres can be successfully used to study the regulation of the endogenous MLC2 phosphorylation capacity at single muscle fibre level.


Effect of Spreader Graft on Nasal Functions in Septorhinoplasty Surgery.
The authors aimed to investigate the effect of spreader grafts on nasal function in septorhinoplasty (SRP). A prospective randomized double-blind study was conducted. Thirty patients who underwent SRP operation between October 2011 and January 2013 were divided into 2 equal groups randomly. Fifteen patients underwent SRP surgery without spreader graft technique (Group I) and 15 patients underwent SRP surgery with spreader grafts (Group II). Preoperative and postoperative evaluation included visual analog score (VAS) and acoustic rhinometry test. Visual analog scores and acoustic rhinometry measurements of Group I and Group II patients were compared. Statistically significant difference was found for VAS scores of both the sides of the nasal cavity (both before and after topical decongestion) (P < 0.05), except for the VAS on the right side of the nasal cavity before decongestion (P > 0.05). On acoustic rhinometry test the difference was statistically significant for minimal cross-sectional area (MCA) and volumetric values (VOL)-MCA1, MCA2, VOL1, VOL2 values on the left side of the nasal cavity (both before and after topical decongestion) (P < 0.05) but not on the right side of the nasal cavity (P > 0.05). Performing spreader graft technique in SRP surgery can prevent the narrowing of the internal nasal valve area after surgery and maintain adequate airway for respiration.


INCOMPLETE BEHAVIORAL ISOLATION BETWEEN TWO DISTANTLY RELATED DROSOPHILA SPECIES.
Two sympatric, distantly related Drosophila species, D. affinis and D. melanogaster, interact sexually in the laboratory and in the field. When mature males from one species are tested with females or sexually attractive males from the other species, the mature males perform courtship that, in most cases, is indistinguishable from the courtship that attractive conspecific flies elicit. Moreover, some of the D. affinis females that elicit courtship from D. melanogaster males copulate with them.


Controlled Oxygenated Rewarming of Cold Stored Livers Prior to Transplantation: First Clinical Application of a New Concept.
Abrupt temperature shift from hypothermia to normothermia incurred on reperfusion of organ grafts has been delineated as a genuine factor contributing to reperfusion injury and graft dysfunction after transplantation. In a first clinical series of 6 patients, cold-stored livers, all allocated by the rescue offer mechanism by Eurotransplant, were subjected to machine-assisted slow controlled oxygenated rewarming (COR) for 90 minutes before engrafting. A historical cohort of 106 patients basically similar in graft (all rescue offer organs) and recipient factors was used for comparison. The clinical benefit of COR was documented by a significant reduction by approximately 50% in peak serum transaminases after transplantation compared to untreated controls (AST 563.5 vs. 1204 U/L, P = 0.023). After 6 months graft survival was 100% in the COR group and 80.9% in the controls (P = 0.24). Respective patient survival was 100% and 84.7% (P = 0.28). Real-time assessment of glucose concentration in the perfusion solution correlated well with postoperative synthetic graft function (r = 0.78; P < 0.02). All treated recipients had normal liver function after a 6-month follow-up and are well and alive. This first clinical application suggests that controlled graft rewarming after cold storage is a feasible and safe method in clinical praxis and might become an adjunct in organ preservation.


Tributyl phosphate assisted hollow-fiber liquid-phase microextraction of short-chain fatty acids in microbial degradation fluid using capillary electrophoresis-contactless coupled conductivity detection.
A tributyl phosphate assisted hollow-fiber liquid-phase microextraction coupled with capillary electrophoresis-contactless coupled conductivity detection (HF-LPME/CE-C4D) method has been developed for trace analysis of common short-chain fatty acids (SCFAs) without derivatization. Under the optimum conditions, ten SCFAs including a pair of isomers were well separated from their homologous FAs and the main coexisting inorganic anions within 40 min. Tributyl phosphate assisted HF-LPME produced excellent purification and enrichment for the model sample with high-salt matrix, microbial degradation fluid, and the limits of detection could reach 0.072-0.67 ng/mL (S/N = 3). Owing to its high sensitivity, good linearity, and acceptable recovery, this proposed method provided a sensitive and environment-friendly alternative for trace analysis of SCFAs in complicated samples.


Innate lymphoid cells and tumor-derived lactic acid: novel contenders in an enduring game.
Aerobic glycolysis, also known as the Warburg effect, has for a prolonged period of time been perceived as a defining feature of tumor metabolism. The redirection of glucose utilization towards increased production of lactate by cancer cells enables their rapid proliferation, unceasing growth, and longevity. At the same time, it serves as a significant contributor to acidification of the tumor microenvironment, which, in turn, imposes substantial constraints on infiltrating immune cells. Here, we delve into the influence of tumor-derived lactic acid on innate lymphoid cells (ILCs) and discuss potential therapeutic approaches. Given the abundance of ILCs in barrier tissues such as the skin, we provide insights aimed at translating this knowledge into therapies that may specifically target skin cancer.


Quantitative determination of human aqueous proteins by crossed immunoelectrophoresis.
Crossed immunoelectrophoresis having high resolving power and sensitivity was applied to the human aqueous humor, in an attempt to determine which of the following is the most appropriate parameter for detecting the concentration of protein components: 1) the height of the precipitation line, 2) the length of the line itself or 3) the area under the precipitation line. Furthermore, the concentrations of several proteins were determined in the aqueous humor from normal subjects. Although it has been reported that the area under the precipitation line was proportional to the concentration of the protein, the present study showed that both the height and the length of the precipitation line are also equally valid for concentration determinations. The amount of protein antigens in 100 ml of the normal human aqueous humor were prealbumin 0.31-0.41 mg, albumin 5.4-6.5 mg, alpha 1-acid glycoprotein 0.05-0.17 mg and transferrin 1.3-1.7 mg.


Real-world heart failure management in 10,910 patients with chronic heart failure in the Netherlands : Design and rationale of the Chronic Heart failure ESC guideline-based Cardiology practice Quality project (CHECK-HF) registry.
Data from patient registries give insight into the management of patients with heart failure (HF), but actual data from unselected real-world HF patients are scarce. Therefore, we performed a cross sectional study of current HF care in the period 2013-2016 among more than 10,000 unselected HF patients at HF outpatient clinics in the Netherlands. In 34 participating centres, all 10,910 patients with chronic HF treated at cardiology centres were included in the CHECK-HF registry. Of these, most (96%) were managed at a specific HF outpatient clinic. Heart failure was typically diagnosed according to the ESC guidelines 2012, based on signs, symptoms and structural and/or functional cardiac abnormalities. Information on diagnostics, treatment and co-morbidities were recorded, with specific focus on drug therapy and devices. In our cohort, the mean age was 73 years (SD 12) and 60% were male. Frequent co-morbidities reported in the patient records were diabetes mellitus 30%, hypertension 43%, COPD 19%, and renal insufficiency 58%. In 47% of the patients, ischaemia was the origin of HF. In our registry, the prevalence of HF with preserved ejection fraction was 21%. The CHECK-HF registry will provide insight into the current, real world management of patient with chronic HF, including HF with reduced ejection fraction, preserved ejection fraction and mid-range ejection fraction, that will help define ways to improve quality of care. Drug and device therapy and guideline adherence as well as interactions with age, gender and co-morbidities will receive specific attention.


Breast cancer: new technologies for risk assessment and diagnosis.
In the US, one in every eight women will develop breast cancer in her lifetime. Despite the advances made in treating breast cancer, the causal mechanisms underlying this disease have yet to be fully elucidated; 85% of breast cancer cases occur sporadically without any known genetic mutation. Too little is known about the pathogenesis of breast cancer for primary prevention to be feasible in the near- to mid-term. Secondary prevention through screening offers an alternative that has been widely adopted. For decades, breast self-examination has been touted as a technique for the early identification of breast cancer. However, it has been recently suggested that this technique is a waste of time and resources for both doctors and patients. Mammography finds breast cancer earlier than breast self-examination, and will reduce the risk of death from breast cancer by approximately 30% in women over 50 years old. Mammography is limited in that cancer, like breast tissue, appears white on the x-ray; therefore lesions may be difficult to detect in women with very dense breasts, and a tumor may not cast a significant shadow until it is quite large. Some cancers are so aggressive that they can spread quickly, before routine screening can detect them. Despite these limitations, mammography is still viewed as the best tool currently available for screening and early diagnosis. Improved methods to detect and diagnose breast cancer early, when it is most curable, are required if a significant impact on morbidity and mortality from breast cancer is to be made. Various new and innovative technologies are being investigated for improving the early detection and diagnosis of breast cancer. About 85% of breast cancers begin in the milk ductal system of the breast. As cancer develops in the breast, abnormalities occur, including atypical hyperplasia, ductal carcinoma in situ, and invasive breast carcinoma. Thus, the early screening of ductal cells can provide a parallel benefit to the 'Pap' smear, which is used virtually universally to identify the abnormal cells that can lead to cervical cancer. Two technologies to monitor for atypical ductal epithelial cells are Cytyc Corporation's FirstCyte Ductal Lavage system and Nastech Pharmaceutical Company's Mammary Aspiration Cytology Test. Matritech, Inc. is searching for biomarkers linked to breast cancer. Researchers at Matritech have detected the presence of nuclear matrix protein (NMP) in the blood of women at the early stage of breast cancer, which is absent in the blood of healthy women, as well as those with fibroadenoma, a benign breast disease. NMP66 has been selected as a marker for further development and clinical trials of a test for use in the detection and monitoring of women with, or at risk for, breast cancer have been initiated. Technologies developed by the US Department of Defense are under investigation as breast cancer screening. Advanced Image Enhancement, Inc. has licensed naval sonar technology for digital image enhancement of mammograms. New thermography applications are also being investigated in two separate projects sponsored by the US Department of Defense using military thermal surveillance tools adapted for cancer detection. Both are enhancements of older thermal imaging technology based on the principle that heat equates to unwanted activity, in the case of breast cancer, abnormal cell proliferation.


Human MHC-II with Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands-Relation to Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder of unknown etiology, which is characterized by inflammation in the synovium and joint damage. Although the pathogenesis of RA remains to be determined, a combination of environmental (e.g., viral infections) and genetic factors influence disease onset. Especially genetic factors play a vital role in the onset of disease, as the heritability of RA is 50-60%, with the human leukocyte antigen (HLA) alleles accounting for at least 30% of the overall genetic risk. Some HLA-DR alleles encode a conserved sequence of amino acids, referred to as the shared epitope (SE) structure. By analyzing the structure of a HLA-DR molecule in complex with Epstein-Barr virus (EBV), the SE motif is suggested to play a vital role in the interaction of MHC II with the viral glycoprotein (gp) 42, an essential entry factor for EBV. EBV has been repeatedly linked to RA by several lines of evidence and, based on several findings, we suggest that EBV is able to induce the onset of RA in predisposed SE-positive individuals, by promoting entry of B-cells through direct contact between SE and gp42 in the entry complex.


Lack of C-erbB-2 protein expression in pulmonary carcinoid tumours.
To determine if amplification of the C-erb-B2 proto-oncogene could be correlated with prognosis in carcinoid tumours, 49 pulmonary carcinoid tumours (26 typical, 23 atypical) were examined using a polyclonal antibody to the C-terminal peptide of the C-erb-B2 protein sequence. No C-erb-B2 gene product could be shown: the demonstration of C-erb-B2 does not seem to help, therefore, in determining diagnosis or prognosis in pulmonary carcinoid tumours.


[A CASE REPORT: LITHIASIS OF THE LEFT ECTOPIC PELVIC KIDNEY].
We report a case of lithiasis of the left ectopic pelvic kidney. A 70-year-old man was admitted to our department for left lower back pain. He has been aware of gross hematuria since three or four years before. Computed tomography demonstrated the left ectopic pelvic kidney with a 16-mm stone and a 5-mm stone in the renal pelvis which was accompanied by hydronephrosis. Ten days later, the renal pelvic stones moved to the renal calices and the symptoms disappeared. Though a pyeloureteral junction obstruction was not evident, renogram showed a obstruction pattern of the left kidney. He had been followed up for six years, then the stone was impacted in the renal pelvis and hydronephrosis worsened. Open pyelolithotomy was performed. His clinical course was uneventful and no evidence of recurrence has been observed.


Area per lipid and cholesterol interactions in membranes from separated local-field (13)C NMR spectroscopy.
Investigations of lipid membranes using NMR spectroscopy generally require isotopic labeling, often precluding structural studies of complex lipid systems. Solid-state (13)C magic-angle spinning NMR spectroscopy at natural isotopic abundance gives site-specific structural information that can aid in the characterization of complex biomembranes. Using the separated local-field experiment DROSS, we resolved (13)C-(1)H residual dipolar couplings that were interpreted with a statistical mean-torque model. Liquid-disordered and liquid-ordered phases were characterized according to membrane thickness and average cross-sectional area per lipid. Knowledge of such structural parameters is vital for molecular dynamics simulations, and provides information about the balance of forces in membrane lipid bilayers. Experiments were conducted with both phosphatidylcholine (dimyristoylphosphatidylcholine (DMPC) and palmitoyloleoylphosphatidylcholine (POPC)) and egg-yolk sphingomyelin (EYSM) lipids, and allowed us to extract segmental order parameters from the (13)C-(1)H residual dipolar couplings. Order parameters were used to calculate membrane structural quantities, including the area per lipid and bilayer thickness. Relative to POPC, EYSM is more ordered in the ld phase and experiences less structural perturbation upon adding 50% cholesterol to form the lo phase. The loss of configurational entropy is smaller for EYSM than for POPC, thus favoring its interaction with cholesterol in raftlike lipid systems. Our studies show that solid-state (13)C NMR spectroscopy is applicable to investigations of complex lipids and makes it possible to obtain structural parameters for biomembrane systems where isotope labeling may be prohibitive.


A critical approach to the malignant transformation of human breast epithelial cells with chemical carcinogens.
This work was undertaken with the purpose of clarifying the factors that modulate the transformation of human breast epithelial cells. For accomplishing this goal, it was necessary to establish the adequate culture conditions for maintaining primary cultures of breast tissue for their treatment with genotoxic agents. It also was determined whether primary cultures generated from these tissues maintained the basic biological properties of the host. In this work we have been able to show that the in vivo developmental stage of the gland is important in the expression of an early transformation phenotype after treatment with chemical carcinogens in vitro; furthermore, that the culture conditions, mainly the calcium concentration in the medium, are important in the selection of that specific phenotype. Four carcinogens, 7,12-dimethylbenz(a)anthracene (DMBA), benzo(a)pyrene (BP), methyl-N-nitro-nitrosoguanidine (MNNG), and N-methyl-N-nitrosourea (NMU) were used for treating primary human breast epithelial cell (HBEC) cultures. Ten out of 20 samples tested expressed survival efficiency in agar methocel. The immortalized human breast epithelial cell line MCF-10 was treated with the same chemical carcinogens, which induced point mutations in codons 12 and 61 and the expression of malignant phenotypes in treated cells. MCF-10 cells transfected with the mutated c-Ha-ras gene exhibited the same malignant phenotypes shown by carcinogen-treated cells, mainly tumorigenesis in SCID mice. It was concluded that both chemical carcinogens and mutated ras gene induce malignant transformation of immortalized HBEC, which suggests that the critical point in the transformation pathway is the immortalization of the cell.


A new method for managing emergency calls.
Available methods for managing territorial medical emergencies are nowadays very effective. Nevertheless, resources are limited, and such methods are far from being perfect. It could be difficult, sometimes, to ensure adequate and prompt medical care to the community when emergency is taking place in such short times as those recommended for cardiocirculatory arrest or a trauma. The major intent of this project is to implement some drawbacks of the current management of medical rescue on the territory improving overall response times to emergencies and providing the delivery of qualified pre-hospital patient care. This may include (but not be limited to) the institution of a database, on a voluntary basis, for trained personnel. Such database should include resuscitation specialists, physicians, but also anyone who has undergone recognized training. Upon receiving a medical emergency call, an off-duty operator can be selected from the database (in a cooperative, non-competitive manner with the dedicated emergency services), based on current position of his/her cellular phone and his/her training profile. Finally, the operator who is both closest to and best prepared for the emergency is contacted via cellular phone. If the operator is available he/she can precede or join the mobile unit on site, managing the emergency according to his/her profile, possibly in cooperation with the ambulance personnel and even up to hospital admission.


Molecular Detection of Equine Herpesvirus Types 1 and 4 Infection in Healthy Horses in Isfahan Central and Shahrekord Southwest Regions, Iran.
This study was undertaken to investigate molecularly the occurrence of EHV-1 and EHV-4 infection among equine population in regions, Iran. Blood samples from 53 and 37 randomly selected horses settled in Isfahan and Shahrekord, Iran, respectively, were collected. Detection of EHV-1 and EHV-4 genes in the blood samples was done using polymerase chain reaction (PCR). Out of 53 and 37 samples from Isfahan and Shahrekord, 4 (18.18%) and 3 (8.10%) were positive for PCR of EHV-1, respectively. Nine (16.98%) and 6 (16.21%) were positive for PCR of EHV-4, while 6 (11.32%) and 3 (8.10%) were positive for PCR of both EHV-1 and EHV-4, in Isfahan and Shahrekord, respectively. Of the 7 blood samples positive for EHV-1, 4 (16.66%) and 3 (8.10%) were from horses >3 years old while 2 (18.18%) and 1 (16.66%) were from 2-3 years old horses, in Isfahan and Shahrekord, respectively. Out of the 7 and 3 samples positive for PCR of EHV-1 in Isfahan and Shahrekord, 4 (22.2%) and 1 (7.69%) were Standardbred, while 3 (14.28%) and 2 (13.33%) were Thoroughbreds, respectively. EHV-4 was detected in blood of 4 (22.22%) and 2 (15.83%) Standardbreds and from 4 (19.04%) and 4 (26.66%) Thoroughbred horses in Isfahan and Shahrekord, respectively. This study has shown that horses settled in Isfahan central and Shahrekord southwest regions, Iran, are infected by EHV-1 and EHV-4 and thus serve as potential reservoirs and disseminators of the viruses.


Surgical management of the lacrimal drainage system.
The physiology of normal tear drainage has been better defined in recent years. Some of the refined techniques developed in the fields of anaesthesia and surgery have been applied to the lacrimal drainage system. The combination of these advances has resulted in more rational and successful treatment of lacrimal drainage abnormalities. A review of these advances is presented with a discussion on the treatment of lacrimal drainage abnormalities.


Revealing cytokine-induced changes in the extracellular matrix with secondary ion mass spectrometry.
Cell-secreted matrices (CSMs), where extracellular matrix (ECM) deposited by monolayer cell cultures is decellularized, have been increasingly used to produce surfaces that may be reseeded with cells. Such surfaces are useful to help us understand cell-ECM interactions in a microenvironment closer to the in vivo situation than synthetic substrates with adsorbed proteins. We describe the production of CSMs from mouse primary osteoblasts (mPObs) exposed to cytokine challenge during matrix secretion, mimicking in vivo inflammatory environments. Time-of-flight secondary ion mass spectrometry data revealed that CSMs with cytokine challenge at day 7 or 12 of culture can be chemically distinguished from one another and from untreated CSM using multivariate analysis. Comparison of the differences with reference spectra from adsorbed protein mixtures points towards cytokine challenge resulting in a decrease in collagen content. This is supported by immunocytochemical and histological staining, demonstrating a 44% loss of collagen mass and a 32% loss in collagen I coverage. CSM surfaces demonstrate greater cell adhesion than adsorbed ECM proteins. When mPObs were reseeded onto cytokine-challenged CSMs they exhibited reduced adhesion and elongated morphology compared to untreated CSMs. Such changes may direct subsequent cell fate and function, and provide insights into pathological responses at sites of inflammation.


Determinants of prognosis in patients with heart failure.
Heart failure is now the single most common inpatient diagnosis for patients 65 years of age and older and is growing. As decisions regarding heart transplantation are contemplated in an era of fixed resources, determination of prognosis becomes a critically important process. No single factor can be used to predict survival in this complex clinical syndrome, but a number of factors, which are highly interactive, can be deduced from laboratory studies. Left ventricular ejection fraction, exercise tolerance, and heart size are the most consistent and reliable measures of prognosis, but other variables are also useful. Despite the availability of numerous high technology measurements, determination of prognosis remains largely an art form.


Protective effect of spin trap agent, N-tert-butyl-alpha-phenylnitrone on hyperoxia-induced oxidative stress and its potential as a nitric oxide donor.
We have previously suggested that the spin trap agent, N-tert-butyl-alpha-phenylnitrone (PBN) can function not only as an antioxidant but also as a nitric oxide (NO) donor. To characterize the pharmacological activities of PBN against oxidative damage, we examined the effect of PBN on NO generation under hyperoxic conditions. The formation of NO in mice exposed to 95% oxygen was determined using a NOx analyzer and electron spin resonance (ESR). Levels of NOx, an oxidative product of NO, increased in the blood of mice under these conditions. However, the increase was returned to a normal level by the NOS (nitric oxide synthase) inhibitor, L-NMMA, indicating that the NO was formed via a biosynthetic pathway. In addition, ESR spectra of the liver and brain of control and experimental mice that were measured using Fe(DETC)2 as an NO trap reagent showed strong ESR signals from NO complexes in the livers of mice exposed to 95% oxygen. When examining the effect of PBN in mice, PBN reduced the NOx formation in the blood under the same hyperoxic conditions. In addition, the ESR intensity of the NO complex was weaker in the PBN-treated mice than in the non-treated mice, showing that PBN possess anti-inflammatory properties. However, under a normal atmosphere, NOx and ESR analyses showed that NO levels increased in PBN-treated mice but not in control mice. These findings suggested that PBN functions as an NO donor under specific physiological conditions. PBN appears to protect against hyperoxia-induced NO toxicity by anti-inflammatory action rather than by serving as an NO donor.


Assessing the Potential Effectiveness of Pictorial Messages to Deter Young Women from Indoor Tanning: An Experimental Study.
The recent Surgeon General's call-to-action to prevent skin cancer indicates an urgent need for research on messages to deter young women from tanning indoors. Answering this call, the current study assessed differences in the potential effectiveness of pictorial indoor tanning messages. We randomly assigned undergraduate female participants (N = 568) to one of three message conditions visually depicting health effects, appearance damage, or immediate risks, or to a text-only control. All participants viewed three messages within their condition and answered questions after message exposure. Factorial ANOVAs indicated that compared to the text-only condition, pictorial messages produced greater negative emotional reactions and were perceived as more effective than text-only messages. Text-only messages, however, were significantly more believable than pictorial messages. We observed several differences among the pictorial conditions and among the messages within the pictorial conditions. We conclude that messages discouraging indoor tanning should use pictorial messages illustrating the negative health and appearance damaging effects of indoor tanning, focusing on particular health and appearance consequences. Additional research is needed to guide the selection of images that are believable and will most discourage indoor tanning behavior.


The in vitro production and characterization of neutrophils from embryonic stem cells.
An embryonic stem (ES) cell/OP9 coculture system for the effective production of functional neutrophils is described. A 3-step differentiation strategy was developed that uses liquid culture, enabling reliable and abundant production of neutrophils at high purity without the need of sorting for isolation of mature neutrophils. Use of the OP9 stromal cell line significantly enhances the number, percentage, and duration of differentiated neutrophils produced from embryonic stem cells. Effective and sustained differentiation of ES cells into neutrophils provides a useful model system for studying neutrophil differentiation and function and the factors that regulate them. Morphologic and functional evaluation of these ES-derived neutrophils indicates that large numbers of mature neutrophils can be produced from pluripotent ES cells in vitro. Specifically, their morphology, ability to produce superoxides, flux calcium, undergo chemotaxis in response to macrophage inflammatory protein 2 (MIP-2), stain for the granulocyte-specific marker-specific chloroacetate esterase, and contain the neutrophil-specific markers Gr-1 and the mouse neutrophil-specific antigen indicates that they are comparable with purified mouse bone marrow neutrophils. They also express gelatinase and lactoferrin granule proteins. During the differentiation of these ES-derived neutrophils, regional areas of neutrophil production can be identified that have been designated as neutrophil generating regions (NGRs).


Agents combining thromboxane receptor antagonism with thromboxane synthase inhibition: [[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]alkanoic acids.
A new class of compounds combining thromboxane-A2 (TxA2) receptor antagonism and thromboxane synthase inhibition is described. A first series of (E)- and (Z)-[[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]pentanoic acids showed relevant thromboxane synthase inhibition associated with weak TxA2 receptor antagonism, while a series of (+/-)-(E)-[[[2-(1H-imidazol-1-yl)-3-phenylpropylidene]amino]oxy] pentanoic acids, structurally derived from the former, showed potent and well-balanced dual activity. Structural requirements for significant single and dual activity are discussed. Two close congeners of the latter series, (+/-)-(E)-5-[[[1-cyclohexyl-2-(1H-imidazol-1-yl)-3- phenylpropylidene]amino]oxy]pentanoic acid 23c and its p-fluorophenyl analog 23m, inhibited TxB2 production in vitro, in rat whole blood during clotting, with IC50 of 0.06 and 0.37 microM and antagonized the binding of [3H]SQ 29548 to washed human platelets, with IC50 of 0.08 and 0.02 microM, respectively. These two compounds were selected for further pharmacological evaluation and were shown to antagonize U46619-induced platelet aggregation in human platelet rich plasma with IC50 of 0.30 and 0.44 microM, respectively. They were both orally available, and in particular 23m caused a long lasting ex vivo TxA2 synthase inhibition in the fed rat. The levorotatory enantiomer of 23c, stereospecifically synthesized as a model compound, was found to be more potent than racemic 23c with regard to TxA2 receptor antagonism (IC50 = 0.04 microM) and equivalent to the latter with regard to TxA2 synthase inhibition. A molecular modeling study concerning the levorotatory enantiomer of 23c (S), TxA2, and representative TxA2 antagonists of different classes led to the definition of a putative pharmacophoric model for the TxA2 receptor ligands.


Cost and predictors of lost productive time in chronic migraine and episodic migraine: results from the American Migraine Prevalence and Prevention (AMPP) Study.
To quantify the cost differences and predictors of lost productive time (LPT) in persons with chronic migraine (CM) and episodic migraine (EM). The American Migraine Prevalence and Prevention (AMPP) study is a US national longitudinal survey of severe headache. Cost estimates were obtained via U.S. Census income data. To elucidate the unique predictors of LPT, the optimal distribution for modeling was determined. Zero inflation models for LPT were predicted from sociodemographics, headache features, characteristics and disability, medication use, and depression. The interaction between headache status and age was the primary effect of interest. The eligible sample included 6329 persons with EM and 374 persons with CM. Men with CM aged 45 to 54 years cost employers nearly $200 per week more than do their EM counterparts. Likewise, for women, costs were higher for CM, with the cost differential between EM and CM being $90 per week. After comprehensive adjustment, increases in LPT with age were significantly higher in CM than in EM (rate ratio 1.03; 95% confidence interval 1.01-1.05). When age was recoded to a decade, metric rates of LPT increased 25% more per decade for CM than for EM (rate ratio 1.25; 95% confidence interval 1.004-1.5). LPT is more costly and increases more rapidly for those with CM than for those with EM as age increases.


Insights into the structure and Ion transport of pectin-[BMIM][PF6] electrolytes.
We investigate the effect of pectin on the structure and ion transport properties of the room-temperature ionic liquid electrolyte 1-n-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) using molecular dynamics simulations. We find that pectin induces intriguing structural changes in the electrolyte that disrupt large ionic aggregates and promote the formation of smaller ionic clusters, which is a promising finding for ionic conductivity. Due to pectin in [BMIM][PF6] electrolytes, the diffusion coefficient of cations and anions is observed to decrease by a factor of four for a loading of 25 wt. % of pectin in [BMIM][PF6] electrolyte. A strong correlation between the ionic diffusivities (D) and ion-pair relaxation timescales (τc) is observed such that D ∼ τc-0.75 for cations and D ∼ τc-0.82 for anions. The relaxation timescale exponents indicate that the ion transport mechanisms in pectin-[BMIM][PF6] electrolytes are slightly distinct from those found in neat [BMIM][PF6] electrolytes (D∼τc-1). Since pectin marginally affects ionic diffusivities at the gain of smaller ionic aggregates and viscosity, our results suggest that pectin-ionic liquid electrolytes offer improved properties for battery applications, including ionic conductivity, mechanical stability, and biodegradability.


Gender-specific automatic valence recognition of affective olfactory stimulation through the analysis of the electrodermal activity.
This study reports on the development of a gender-specific classification system able to discern between two valence levels of smell, through information gathered from electrodermal activity (EDA) dynamics. Specifically, two odorants were administered to 32 healthy volunteers (16 males) while monitoring EDA. CvxEDA model was used to process the EDA signal and extract features from both tonic and phasic components. The feature set was used as input to a K-NN classifier implementing a leave-one-subject-out procedure. Results show strong differences in the accuracy of valence recognition between men (62.5%) and women (78%). We can conclude that affective olfactory stimulation significantly affect EDA dynamics with a highly specific gender dependency.


Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis of Polysubstituted Butadienes and Macrocyclic P-glycoprotein Inhibitors.
The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes, represents a great challenge in organic synthesis. Herein, we wish to report a distinctive Pd(0) carbene-initiated decarboxylative olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate to high yields and with excellent stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability. Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein and dramatically reversed multidrug resistance in cancer cells by 190-fold.


Human hepatic cytochrome P450 2D6-like activity in nonhuman primates: catalytic characterization in vitro.
Previous studies have identified the monkey as an animal model for the genetic polymorphism affecting human hepatic cytochrome P450 2D6 enzyme. However, contrary to an earlier in vivo observation, the present study failed to find evidence of polymorphism of this enzyme activity in liver preparations of 84 African green (Cercopithecus aethiops) monkeys. The kinetics of dextromethorphan O-demethylation were similar in liver microsomes from African green (n = 21) and Crab eater (Macaca fascicularis, n = 7) monkeys (Km = 1.1 +/- 0.07 and 1.7 +/- 0.27 microM; Vmax = 215 +/- 71.7 and 152 +/- 21.1 nmol/mg/h, respectively). These Km values were lower and less variable than those in liver microsomes from 10 human extensive metabolizers (5.3 +/- 2.43 microM). Furthermore, the Vmax of the reaction in human liver microsomes was significantly lower (32 +/- 15.7 nmol/mg/h; P < .001). Inhibitor constants (Ki values) determined in monkey and human liver microsomes were highly correlated (r = 0.97), but two high-affinity inhibitors of the human enzyme (quinidine and lobeline) were approximately 40-fold less potent in monkey livers than in human livers. These data show that the monkey enzyme is functionally homologous, but is not identical to human hepatic cytochrome P450 2D6. Failure to observe poor metabolizer monkeys does not preclude their potential usefulness in evaluating the role of human hepatic cytochrome P450 2D6 activity in drug addiction and neurotoxicity because of the possibility of producing poor metabolizer phenocopies by potent hepatic cytochrome P450 2D6-like enzyme inhibitors in monkeys.


Use of milbemycin oxime in the treatment of dogs with nasal mite (Pneumonyssoides caninum) infection.
Clinical diagnosis of canine nasal mite (Pneumonyssoides caninum) infection is difficult due to the mite's location in the caudal nasal cavity and frontal sinuses. The current study was performed to evaluate the efficacy of milbemycin oxime in treating dogs with nasal mite infection. A prospective open uncontrolled study included 20 dogs with case histories indicating possible nasal mite infection. Inclusion criteria consisted of either nasal mites being demonstrated (group 1, four dogs), or suspicious clinical signs with no other apparent causes, combined with eosinophilia (group 2, 16 dogs). Milbemycin oxime 1 mg/kg was given orally three times at 10-day intervals. In 17 (85 per cent) dogs, clinical signs resolved completely following milbemycin therapy; within 10 days of the first treatment in 13 cases (group 1, four dogs; group 2, nine dogs) and within 14 days in four cases. In the remaining three dogs clinical signs persisted but were diminished.


[Proliferative activity of stromal cells--bone marrow precursors possessing clonogenic properties].
Proliferative activity of bone marrow clonogenic stromal precursor cells was studied by using the thymidine "suicide" method in vitro. Crude bone marrow stromal clonogenic cells failed to proliferate in vivo. But 24 hours after the explantation they entered the S-period and formed colonies of fibroblasts in monolayer cultures. 39+/-4% of these clonogenic cells were subject to thymidine "suicide". It follows that, in difference from cells-precursors in the crude bone marrow, clonogenic stromal cells were actively proliferating in monolayer cultures.


Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease.
Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss-of-function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase-inactive laforin rescues the laforin-deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin- or malin-deficient mouse lines expressing phosphatase-inactive laforin. We find that: (i) in laforin-deficient mice, phosphatase-inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin-deficient mice, phosphatase-inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD We conclude that laforin's principle function is to control glycogen chain lengths, in a malin-dependent fashion, and that loss of this control underlies LD.


The molecular origins of nonlinear response in solute energy relaxation: the example of high-energy rotational relaxation.
A key step in solution-phase chemical reactions is often the removal of excess internal energy from the product. Yet, the way one typically studies this process is to follow the relaxation of a solute that has been excited into some distribution of excited states quite different from that produced by any reaction of interest. That the effects of these different excitations can frequently be ignored is a consequence of the near universality of linear-response behavior, the idea that relaxation dynamics is determined by the solvent fluctuations (which may not be all that different for different kinds of solute excitation). Nonetheless, there are some clear examples of linear-response breakdowns seen in solute relaxation, including a recent theoretical and experimental study of rapidly rotating diatomics in liquids. In this paper we use this rotational relaxation example to carry out a theoretical exploration of the conditions that lead to linear-response failure. Some features common to all of the linear-response breakdowns studied to date, including our example, are that the initial solute preparation is far from equilibrium, that the subsequent relaxation promotes a significant rearrangement of the liquid structure, and that the nonequilibrium response is nonstationary. However, we show that none of these phenomena is enough to guarantee a nonlinear response. One also needs a sufficient separation between the solute time scale and that of the solvent geometry evolution. We illustrate these points by demonstrating precisely how our relaxation rate is tied to our liquid-structural evolution, how we can quantitatively account for the initial nonstationarity of our effective rotational friction, and how one can tune our rotational relaxation into and out of linear response.


How beneficial is bacterial prophylaxis to periodontal health?
The term "probiotics" has become common among general practitioners. There has been an explosion in the interest regarding this topic, which is reflected in the number of scientific publications. The World Health Organization defined probiotics as: "Living microorganisms which when administered in adequate amount confirms a health benefit on the host". Probiotics have been studied extensively in the gastrointestinal tract for their health-promoting effects and have shown promising results. However, in recent times, probiotics have also been used in periodontal health and have shown promising results in controlling gastrointestinal tract infections. Probiotics have potential, but as with many other clinical situations, multicenter or randomized, controlled studies on humans are still required before they can be recommended as prophylaxis for caries or periodontal disease. In the present study, we review the effects of probiotics on maintaining periodontal health. Relevant studies were identified from 1970 to February 2010 using Old Medline, Cochrane Library, and Google Scholar.


Ciclesonide, a novel inhaled steroid, does not affect hypothalamic-pituitary-adrenal axis function in patients with moderate-to-severe persistent asthma.
Inhaled corticosteroids (ICSs) reduce local airway inflammation, which is an underlying cause of asthma symptoms. However, potential systemic side effects associated with ICS use are a major concern for asthmatic patients. Adult patients (n = 60; > or = 18 years of age) with moderate-to-severe asthma were randomized to receive 4 weeks of treatment with ciclesonide (CIC), 320 microg bid (CIC 640), CIC, 640 microg bid (CIC 1280), fluticasone propionate (FP), 440 microg bid (FP 880), FP 880 microg bid (FP 1760), or placebo (PBO) [all doses expressed as ex-actuator; comparable to ex-valve doses of 800 and 1,600 microg/d for CIC and 1,000 and 2,000 microg/d for FP, respectively]. After 29 days of treatment, CIC 640, CIC 1280, and FP 880 had no significant effect on the mean serum cortisol area under the curve for 0 to 24 h (AUC0-24h). FP 1760 produced a statistically significant suppression in mean serum cortisol AUC0-24h compared to PBO (p = 0.0009; 95% confidence interval [CI] -117.5 [corrected] to -32.1). Results obtained with cosyntropin stimulation revealed no statistically significant differences among the groups. The CIC 640 group demonstrated a significant increase compared to the PBO group in 24-h urinary cortisol levels from baseline at week 4 (p = 0.0224; 95% CI, 0.0023 to 0.0283), while the other treatment groups revealed no change in this parameter. The incidence of treatment-emergent adverse events was similar in all groups, and all adverse events were mild or moderate in severity. Treatment with moderate and high doses of CIC does not result in hypothalamic-pituitary-adrenal-axis suppression as compared with PBO.


Age- and sex-related differences in masseter size and its role in oral functions.
The masseter muscle plays a key structural and functional role in the stomatognathic system. Researchers' cumulative evidence has suggested that the variation in the size of a person's masseter muscle may be a critical factor related to individual differences in oral functions. However, researchers have not yet investigated systematically the effect of a person's age and sex on masseter muscle size and the association of masseter muscle size with other clinical metrics, including masticatory performance (MP) and salivary flow rate (SFR). Using T1-weighted magnetic resonance imaging (MRI) data provides a noninvasive method for assessing masseter muscle volume (MMV). Using T1-weighted MRI data, the authors developed a voxel-based method to assess MMV and investigated the associations among MMV, MP, and SFR. The authors acquired T1-weighted MRI data from scans of the heads of 62 healthy adults and assessed MMV by means of using a voxel-based approach. The authors' assessment results had acceptable rates of inter-rater and intrarater reliability. MMV was significantly lower in the older subgroup and in the female subgroup. In addition, the correlation for MMV was significantly positive with MP and stimulated SFR. The study results revealed evidence that the authors' voxel-based approach, which they designed on the basis of T1-weighted MRI data, would be a reliable method for quantifying MMV. The findings suggest that the variation in masseter muscle size may be a critical factor to assess individual differences in oral functions.


Obesity in patients with major depression is related to bipolarity and mixed features: evidence from the BRIDGE-II-Mix study.
The Bipolar Disorders: Improving Diagnosis, Guidance and Education (BRIDGE)-II-Mix study aimed to estimate the frequency of mixed states in patients with a major depressive episode (MDE) according to different definitions. The present post-hoc analysis evaluated the association between obesity and the presence of mixed features and bipolarity. A total of 2811 MDE subjects were enrolled in a multicenter cross-sectional study. In 2744 patients, the body mass index (BMI) was evaluated. Psychiatric symptoms, and sociodemographic and clinical variables were collected, comparing the characteristics of MDE patients with (MDE-OB) and without (MDE-NOB) obesity. Obesity (BMI ≥30) was registered in 493 patients (18%). In the MDE-OB group, 90 patients (20%) fulfilled the DSM-IV-TR criteria for bipolar disease (BD), 225 patients (50%) fulfilled the bipolarity specifier criteria, 59 patients (13%) fulfilled DSM-5 criteria for MDEs with mixed features, and 226 patients (50%) fulfilled Research-Based Diagnostic Criteria for an MDE. Older age, history of (hypo)manic switches during antidepressant treatment, the occurrence of three or more MDEs, atypical depressive features, antipsychotic treatment, female gender, depressive mixed state according to DSM-5 criteria, comorbid eating disorders, and anxiety disorders were significantly associated with the MDE-OB group. Among (hypo)manic symptoms during the current MDE, psychomotor agitation, distractibility, increased energy, and risky behaviors were the variables most frequently associated with MDE-OB group. In our sample, the presence of obesity in patients with an MDE seemed to be associated with higher rates of bipolar spectrum disorders. These findings suggest that obesity in patients with an MDE could be considered as a possible marker of bipolarity.


The GMZ2 malaria vaccine: from concept to efficacy in humans.
GMZ2 is a recombinant protein consisting of conserved domains of GLURP and MSP3, two asexual blood-stage antigens of Plasmodium falciparum, and is designed with the aim of mimicking naturally acquired anti-malarial immunity. The rationale for combining these two antigens is based on a series of immune epidemiological studies from geographically diverse malaria endemic regions; functional in vitro studies; and pre-clinical studies in rodents and New World monkeys. GMZ2 adjuvanted with alhydrogel® (alum) was well tolerated and immunogenic in three phase 1 studies. The recently concluded phase 2 trial of GMZ2/alum, involving 1849 participants 12 to 60 month of age in four countries in West, Central and Eastern Africa, showed that GMZ2 is well tolerated and has some, albeit modest, efficacy in the target population. Areas covered: PubMed ( www.ncbi.nlm.nih.gov/pubmed ) was searched to review the progress and future prospects for clinical development of GMZ2 sub-unit vaccine. We will focus on discovery, naturally acquired immunity, functional activity of specific antibodies, sequence diversity, production, pre-clinical and clinical studies. Expert commentary: GMZ2 is well tolerated and has some, albeit modest, efficacy in the target population. More immunogenic formulations should be developed.


Roentgen diagnosis of traumatic rupture of the aorta.
Traumatic rupture of the aorta is a frequent (10-15%) cause of death in automobile accidents. 10-20% of patients with this rupture live some hours to days before dying, and yet can be saved if the diagnosis is made in time. As clinical signs may be slight or absent the diagnosis must be made by the radiologist, who has three main tasks, namely (1) to detect the signs of the rupture on the plain film; (2) to perform angiography to prove the suspicion or to make a differential diagnosis; (3) to make angiography easily accessible without loss of time.


Oxidative stress and anti-oxidant status in leprosy patients.
Severe oxidative stress has been reported in leprosy patients because of malnutrition and poor immunity. The purpose of this study was to investigate the serum lipid peroxidation products, serum LDH and important free radical scavenging enzymes, i.e. superoxide dismutase (SOD), and catalase and anti-oxidant glutathione levels and total anti-oxidant status, in different types of leprosy patients. The subjects for this study were normal human volunteers (NHVs, n=14), paucibacillary leprosy patients (PB, n=18), untreated MB patients (MB1, n=18), MB patients under treatment (MB2, n=19), and MB patients released from treatment (RFT) (MB3, n=28). The levels of lipid peroxidation product, malondialdehyde (MDA), and LDH increased significantly (p<0.001) in MB (MB1, MB2, MB3) patients, and both gradually decreased with clinical improvement following MDT. The levels of SOD, catalase and glutathione, and the total anti-oxidant status decreased significantly in MB (MB1, MB2, MB3) patients (p<0.001), in comparison with NHVs. They gradually increased with clinical improvement with MDT. There was no significant variation of these parameters in PB leprosy patients in comparison with healthy volunteers. High free radical activity and low anti-oxidant levels observed in MB (MB1, MB2, MB3) leprosy patients indicate that there is an oxidative stress in MB cases, irrespective of the treatment status and suggest a suitable anti-oxidant therapy to prevent possible tissue injury.


Atom probe tomography study of the nanoscale heterostructure around an Al20Mn3Cu2 dispersoid in aluminum alloy 2024.
Atom probe tomography (APT) has been used to investigate the surface and sub-surface microstructures of aluminum alloy 2024 (AA2024) in the T3 condition (solution heat treated, cold worked, and naturally aged to a substantially stable condition). This study revealed surface Cu enrichment on the alloy matrix, local chemical structure around a dispersoid Al20Mn3Cu2 particle including a Cu-rich particle and S-phase particle on its external surface. Moreover, there was a significant level of hydrogen within the dispersoid, indicating that it is a hydrogen sink. These observations of the nanoscale structure around the dispersoid particle have considerable implications for understanding both corrosion and hydrogen embrittlement in high-strength aluminum alloys.


Preparation, characterization, and pharmacodynamics of insulin-loaded fumaryl diketopiperazine microparticle dry powder inhalation.
Purpose: With the increase of population aging and the proportion of overweight and obese, a growing number of people are suffering from diabetes. Insulin (INS) as the most widely used hypoglycemic agent was always chosen as the most effective treatment method of diabetes. In this study, fumaryl diketopiperazine (FDKP) was used as a carrier for the pulmonary delivery of insulin. Patients and methods: The INS-loaded FDKP microspheres (INS@FDKP-MPs) were prepared by spray drying and physicochemical properties (drug loading, particle size, flowability, moisture content, morphology, and crystalline state) were further investigated. Pharmacodynamics was investigated on diabetic model rats administrated by intratracheal insufflation. Results: The INS-loaded FDKP microspheres show satisfied flowability and in vitro deposition with FPF 50.2% and MMAD 3.45 ± 0.13 μm, and the blood glucose level was significantly decreased. Moreover, no inflammatory reaction was observed during the safety study. Conclusion: To sum up, the aim was to develop a non-injection system for insulin, INS@FDKP-MPs powder inhalation with high dose, low toxicity, and good lung deposition inhalation could rapidly decrease the blood glucose level without immune stimulation, which shows remarkably potential on diabetes treatment by pulmonary delivery route.


Determination of sunitinib and its active metabolite, N-desethyl sunitinib in mouse plasma and tissues by UPLC-MS/MS: assay development and application to pharmacokinetic and tissue distribution studies.
A simple, sensitive and specific method using ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was developed to determine sunitinib and N-desethyl sunitinib in mouse plasma and tissues. The analytes were separated by an isocratic mobile phase consisting of acetonitrile and buffer solution (water with 0.1% formic acid and 5 m m ammonium acetate; 40: 60, v/v) running at a flow rate of 0.35 mL/min for 2 min. Quantification was performed using a mass spectrometer by multiple reaction monitoring in positive electrospray ionization mode. The transition was monitored at m/z 399 → 283, m/z 371 → 283 and m/z 327 → 270 for sunitinib, N-desethyl sunitinib and internal standard, respectively. Calibration curves were linear over concentration ranges of 2-500, 0.5-50 and 1-250 ng/mL for plasma, heart and other biosamples. The method was successfully applied to animal experiments. The pharmacokinetic study indicated that sunitinib was eliminated quickly in mice with a half-life of 1.2 h; tissue distribution data showed more sunitinib and its metabolite in liver, spleen and lung, which provided reference for further study.


Complete Genome Sequences of Three Representative Mycobacterium tuberculosis Beijing Family Strains Belonging to Distinct Genotype Clusters in Hanoi, Vietnam, during 2007 to 2009.
We present here three complete genome sequences of Mycobacterium tuberculosis Beijing family strains isolated in Hanoi, Vietnam. These three strains were selected from major genotypic clusters (15-MIRU-VNTR) identified in a previous population-based study. We emphasize their importance and potential as reference strains in this Asian region.


Chrysotile and rock wool fibers induce chromosome aberrations and DNA damage in V79 lung fibroblast cells.
According to global estimates, at least 107,000 people die each year from asbestos-related lung cancer, mesothelioma, and asbestosis resulting from occupational exposure. Chrysotile accounts for approximately 90% of asbestos used worldwide. Artificial substitutes can also be cytotoxic to the same degree as chrysotile. But only a few researchers focused on their genetic effects and mutagenicity information which is useful in evaluating the carcinogenicity of chemicals. In this study, chrysotile from Mangnai, Qinghai, China, and an artificial substitute, rock wool fiber were prepared as suspensions and were tested at concentrations of 50, 100, and 200 μg/ml in V79 lung fibroblasts. Chromosome aberrations were detected by micronucleus assay after exposure for 24 h, and DNA damage were estimated by single cell gel electrophoresis after exposure for 12, 24, or 48 h. According to the results, chrysotile and rock wool fibers caused micronuclei to form in a dose-dependent manner in V79 cells; olive tail moment values increased in a dose- and time-dependent manner. When V79 cells were exposed to a concentration of 200 μg/ml, the degree of DNA damage induced by chrysotile fibers was greater than rock wool fibers. Our study suggests that both chrysotile and rock wool fibers could induce chromosome aberrations and DNA damage. These materials are worthy of further study.


Comparison of four methods for determining nitrate utilization by cryptococci.
This study evaluated the following methods for determining nitrate utilization: Wickerham broth, a special nitrate broth, Delft plate, and nitrate strip. With 236 isolates of cryptococci as test organisms, the special nitrate broth method gave 99% correct results and the Wickerham broth method gave 98%. The nitrate strip and Delft plate methods gave correct results in 94 and 86% of tests, respectively. The special nitrate broth method is judged superior because it provides accurate results within 48 h, compared to 14 days with the Wickerham broth method.


Anticardiolipin antibodies in classic pediatric hemolytic-uremic syndrome: a possible pathogenic role.
Anticardiolipin (aCL) antibodies have been associated with thrombocytopenia, hemolytic anemia and an increased risk of thrombosis in different vascular locations, even in the absence of lupus. The classic hemolytic-uremic syndrome is a postinfectious acute renal failure characterized by hemolytic anemia, thrombocytopenia and the presence of widespread glomerular thrombosis in the kidney, with pathogenic mechanisms that remain to be identified. In order to establish the frequency of aCL antibodies in this syndrome and to identify a possible role in the pathogenesis and clinical manifestations, 17 patients were studied during the reactant phase of the disease looking for an association between the presence of aCL antibodies (isotypes IgG, IgA and IgM) and the main clinical variables of the syndrome. In 8 patients IgG aCL was present, 2 patients had IgM aCL, and 1 had IgA antibodies on the solid-phase ELISA aCL assays, but no association could be demonstrated with the clinical variables studied. Although it might correspond to an epiphenomenon related to the triggering intestinal infection, a pathogenic role cannot be discarded and additional studies should be performed.


[The effects of graphene quantum dots on hematopoietic system in rats].
To study the effects of graphene quantum dots (GQDs) on hematopoietic system in rats. Thirty male SD rats were randomly divided into three groups (n = 10): control group, high dose group (10 mg/kg · d), low dose group (5 mg/kg · d), The rats in experimental group were intravenous injected with GQDs for 28 days and those in control group were injected with normal saline at the same volume. Routine blood and the function of liver and kidney were detected by instrument analysis. The cycle and apoptosis of bone marrow mononuclear cells (BMCs) were detected by FCM. The other three only healthy male SD rat bone marrow mononuclear cells (BMCs) were cultured by joining GQDs for 24 h, 48 h,72 h in vitro, the proliferation was assayed by CCK-8, the content of granulocyte macrophage colony stimulating factor (GM-CSF) from cultural supernatants were detected by ELISA. The amount of red blood cell and concentration of hemoglobin from experimental group were increased significantly compared with those of control groups (P < 0.05), the concentration of triglyceride and high density lipoprotein were decreased. DNA synthesis period was prolonged (P < 0.01), there was no significant difference in apoptosis. BMCs were promoted proliferation clearly after using GQDs for 72 h (P < 0.05). The content of GM-CSF was increased (P < 0.01) . GQDs may promote hematopoietic function in rats.


[Acute neurorehabilitation in neurooncology: Swiss Pilot Project and review of the litterature].
New treatment modalities in oncology, radiation oncology and surgery have led to a significant improvement in life expectancy for cancer patients. Some will however develop severe neurologic deficits that will impact their quality of life. To limit this impact, it is essential to offer optimal neurorehabilitation. In this context, a pilot project of early and intensive neurorehabilitation for brain tumor patients has been set up. A collaboration between the teams of neurooncology, acute neurorehabilitation and neurosurgery from the CHUV and the Clinique La Lignière allows an intensive and direct neurorehabilitation following neurosurgery. This neuroreeducation has allowed 75% of the patients included in this program to return home.


[Therapeutic response of various histological osteosarcoma subtypes to high-dose methotrexate treatment].
The successful or unsuccessful chemotherapy of osteosarcoma has given rise to the division of these tumors into responders and non responders from the clinical point of view. In order to work out drug sensitive tumor components we studied 9 osteosarcomas by a histological subdivision of the osteosarcoma tissue into 6 subtypes. Seven of the 9 osteosarcoma patients had developed lung metastases under adjuvant high dosage methotrexate (HDMTX) therapy. The aim was to identify the components of the primary tumors which had endured HDMTX-therapy as lung metastases. As HDMTX-sensitive histologic differentiation form of osteosarcoma tissue we regarded the no matrix producing-subtype (III), because it did not occur in the lung metastases. The classical subtype (IV) seems to be only partially sensitive because the corresponding lung metastases showed a higher osteoblastic differentiation with increased osteoid production. No therapeutic effect could be observed in the chondromatous (I) and in the sarcomatous (II) subtypes as well as in the two subtypes with intensive osteoid production being termed trabecularly sclerosing (V) and massively osteoid producing subtypes (VI).


A novel method for continuous measurements of clinical practice guideline adherence.
Clinical practice guidelines (hereafter 'guidelines') are crucial in providing evidence-based recommendations for physicians and multidisciplinary teams to make informed decisions regarding diagnostics and treatment in various diseases, including cancer. While guideline implementation has been shown to reduce (unwanted) variability and improve outcome of care, monitoring of adherence to guidelines remains challenging. Real-world data collected from cancer registries can provide a continuous source for monitoring adherence levels. In this work, we describe a novel structured approach to guideline evaluation using real-world data that enables continuous monitoring. This method was applied to endometrial cancer patients in the Netherlands and implemented through a prototype web-based dashboard that enables interactive usage and supports various analyses. The guideline under study was parsed into clinical decision trees (CDTs) and an information standard was drawn up. A dataset from the Netherlands Cancer Registry (NCR) was used and data items from both instruments were mapped. By comparing guideline recommendations with real-world data an adherence classification was determined. The developed prototype can be used to identify and prioritize potential topics for guideline updates. CDTs revealed 68 data items for recording in an information standard. Thirty-two data items from the NCR were mapped onto information standard data items. Four CDTs could sufficiently be populated with NCR data. The developed methodology can evaluate a guideline to identify potential improvements in recommendations and the success of the implementation strategy. In addition, it is able to identify patient and disease characteristics that influence decision-making in clinical practice. The method supports a cyclical process of developing, implementing and evaluating guidelines and can be scaled to other diseases and settings. It contributes to a learning healthcare cycle that integrates real-world data with external knowledge.


Effects of Acute Partial Sleep Deprivation and High-Intensity Interval Exercise on Postprandial Network Interactions.
Introduction: High-intensity interval exercise (HIIE) is deemed effective for cardiovascular and autonomic nervous system (ANS) health-related benefits, while ANS disturbance increases the risk for cardiovascular disease (CVD). Postprandial lipemia and acute-partial sleep deprivation (APSD) are considered as CVD risk factors due to their respective changes in ANS. Exercising in the morning hours after APSD and have a high-fat breakfast afterwards may alter the interactions of the cardiovascular, autonomic regulation, and postprandial lipemic systems threatening individuals' health. This study examined postprandial network interactions between autonomic regulation through heart rate variability (HRV) and lipemia via low-density lipoprotein (LDL) cholesterol in response to APSD and HIIE. Methods: Fifteen apparently healthy and habitually good sleepers (age 31 ± 5.2 SD yrs) completed an acute bout of an isocaloric HIIE (in form of 3:2 work-to-rest ratio at 90 and 40% of VO2 reserve) after both a reference sleep (RSX) and 3-3.5 h of acute-partial sleep deprivation (SSX) conditions. HRV time and frequency domains and LDL were evaluated in six and seven time points surrounding sleep and exercise, respectively. To identify postprandial network interactions, we constructed one correlation analysis and one physiological network for each experimental condition. To quantify the interactions within the physiological networks, we also computed the number of links (i.e., number of significant correlations). Results: We observed an irruption of negative links (i.e., negative correlations) between HRV and LDL in the SSX physiological network compared to RSX. Discussion: We recognize that a correlation analysis does not constitute a true network analysis due to the absence of analysis of a time series of the original examined physiological variables. Nonetheless, the presence of negative links in SSX reflected the impact of sleep deprivation on the autonomic regulation and lipemia and, thus, revealed the inability of HIIE to remain cardioprotective under APSD. These findings underlie the need to further investigate the effects of APSD and HIIE on the interactions among physiological systems.


Extracellular matrix inflammation in vascular cognitive impairment and dementia.
Vascular cognitive impairment and dementia (VCID) include a wide spectrum of chronic manifestations of vascular disease related to large vessel strokes and small vessel disease (SVD). Lacunar strokes and white matter (WM) injury are consequences of SVD. The main vascular risk factor for SVD is brain hypoperfusion from cerebral blood vessel narrowing due to chronic hypertension. The hypoperfusion leads to activation and degeneration of astrocytes with the resulting fibrosis of the extracellular matrix (ECM). Elasticity is lost in fibrotic cerebral vessels, reducing the response of stiffened blood vessels in times of increased metabolic need. Intermittent hypoxia/ischaemia activates a molecular injury cascade, producing an incomplete infarction that is most damaging to the deep WM, which is a watershed region for cerebral blood flow. Neuroinflammation caused by hypoxia activates microglia/macrophages to release proteases and free radicals that perpetuate the damage over time to molecules in the ECM and the neurovascular unit (NVU). Matrix metalloproteinases (MMPs) secreted in an attempt to remodel the blood vessel wall have the undesired consequences of opening the blood-brain barrier (BBB) and attacking myelinated fibres. This dual effect of the MMPs causes vasogenic oedema in WM and vascular demyelination, which are the hallmarks of the subcortical ischaemic vascular disease (SIVD), which is the SVD form of VCID also called Binswanger's disease (BD). Unravelling the complex pathophysiology of the WM injury-related inflammation in the small vessel form of VCID could lead to novel therapeutic strategies to reduce damage to the ECM, preventing the progressive damage to the WM.


Destruction and resurgence of the quasiperiodic shearless attractor.
We consider a dissipative version of the standard nontwist map. It is known that nontwist systems may present a robust transport barrier, called shearless curve, that gives rise to an attractor that retains some of its properties when dissipation is introduced. This attractor is known as shearless attractor, and it may be quasiperiodic or chaotic depending on the control parameters. We describe a route for the destruction and resurgence of the quasiperiodic shearless attractor by analyzing the manifolds of the unstable periodic orbits (UPOs) which are fixed points of the map. We show that the shearless attractor is destroyed by a collision with the UPOs and it resurges after the reconnection of the unstable manifolds of different UPOs.


Transition path sampling study of flip-flop transitions in model lipid bilayer membranes.
The microscopic dynamics of lipids in biomembranes is of special relevance in the study of chemical reactions produced in cells. The mechanism of the exchange of a model lipid molecule between both sides of a flexible bilayer membrane or flip-flop in an aqueous environment has been studied by computer simulation using the recently developed transition path sampling technique, since flip-flop transitions are infrequent events of the lipid dynamics. In addition, structural changes in the membrane have been investigated at ambient conditions and for increasing temperature. Our results highlight the cooperative effort of the whole system in order to allow a lipid molecule to cross the bottleneck in configuration space associated with the transition state of the flip-flop event. Within the time interval of the transition, all molecules of the system significantly change the frequency of their molecular motions.


Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes: A genetic association study in Europeans.
Rare genetic variants in the CUBN gene encoding the main albumin-transporter in the proximal tubule of the kidneys have previously been associated with microalbuminuria and higher urine albumin levels, also in diabetes. Sequencing studies in isolated proteinuria suggest that these variants might not affect kidney function, despite proteinuria. However, the relation of these CUBN missense variants to the estimated glomerular filtration rate (eGFR) is largely unexplored. We hereby broadly examine the associations between four CUBN missense variants and eGFRcreatinine in Europeans with Type 1 (T1D) and Type 2 Diabetes (T2D). Furthermore, we sought to deepen our understanding of these variants in a range of single- and aggregate- variant analyses of other kidney-related traits in individuals with and without diabetes mellitus. We carried out a genetic association-based linear regression analysis between four CUBN missense variants (rs141640975, rs144360241, rs45551835, rs1801239) and eGFRcreatinine (ml/min/1.73 m2, CKD-EPIcreatinine(2012), natural log-transformed) in populations with T1D (n ~ 3,588) or T2D (n ~ 31,155) from multiple European studies and in individuals without diabetes from UK Biobank (UKBB, n ~ 370,061) with replication in deCODE (n = 127,090). Summary results of the diabetes-group were meta-analyzed using the fixed-effect inverse-variance method. Albeit we did not observe associations between eGFRcreatinine and CUBN in the diabetes-group, we found significant positive associations between the minor alleles of all four variants and eGFRcreatinine in the UKBB individuals without diabetes with rs141640975 being the strongest (Effect=0.02, PeGFR_creatinine=2.2 × 10-9). We replicated the findings for rs141640975 in the Icelandic non-diabetes population (Effect=0.026, PeGFR_creatinine=7.7 × 10-4). For rs141640975, the eGFRcreatinine-association showed significant interaction with albuminuria levels (normo-, micro-, and macroalbuminuria; p = 0.03). An aggregated genetic risk score (GRS) was associated with higher urine albumin levels and eGFRcreatinine. The rs141640975 variant was also associated with higher levels of eGFRcreatinine-cystatin C (ml/min/1.73 m2, CKD-EPI2021, natural log-transformed) and lower circulating cystatin C levels. The positive associations between the four CUBN missense variants and eGFR in a large population without diabetes suggests a pleiotropic role of CUBN as a novel eGFR-locus in addition to it being a known albuminuria-locus. Additional associations with diverse renal function measures (lower cystatin C and higher eGFRcreatinine-cystatin C levels) and a CUBN-focused GRS further suggests an important role of CUBN in the future personalization of chronic kidney disease management in people without diabetes.


Drug release from a multiparticulate pellet system.
Multiparticulate pellet systems are used as both immediate and modified release dosage forms. Previous work has classified uncoated pellet systems prepared from microcrystalline cellulose as an inert matrix. The Higuchi square root of time equation, derived to describe drug release from a single planar system, is the accepted method to evaluate drug release from both planar and spherical heterogeneous inert granular matrices. A second equation of interest, the Higuchi cubic equation, was derived to describe drug release from a spherical pellet. Both equations predict a linear relationship between drug release and the square root of time or time. The purpose of the present study was to evaluate drug release from a multiparticulate pellet system using both equations and to study any differences when both equations are used to describe the same drug release data. By evaluating dissolution data from various pellet mesh cuts representing different bead radii and surface areas, changes in the slopes of both plots would be expected. Pellets were manufactured using extrusion/spheronization technology and consisted of 90% microcrystalline cellulose and 10% acetaminophen. Statistical comparison indicates that the Higuchi cubic equation seems to be more sensitive to changes in pellet size. While the square root of time equation describes the drug release data from granular, inert, spherical pellets, it may be better to utilize the Higuchi cubic equation because it is more sensitive to changes in particle size.


Illuminating the Cell's Biochemical Activity Architecture.
All cellular behaviors arise through the coordinated actions of numerous intracellular biochemical pathways. Over the past 20 years, efforts to probe intracellular biochemical processes have undergone a fundamental transformation brought about by advances in fluorescence imaging, such as the development of genetically encoded fluorescent reporters and new imaging technologies; the impact of these approaches on our understanding of the molecular underpinnings of biological function cannot be understated. In particular, the ability to obtain information on the spatiotemporal regulation of biochemical processes unfolding in real time in the native context of a living cell has crystallized the view, long a matter of speculation, that cells achieve specific biological outcomes through the imposition of spatial control over the distribution of various biomolecules, and their associated biochemical activities, within the cellular environment. Indeed, the compartmentalization of biochemical activities by cells is now known to be pervasive and to span a multitude of spatial scales, from the length of a cell to just a few enzymes. In this Perspective, part of this special issue on "Seeing into cells", we highlight several recent imaging studies that provide detailed insights into not just where molecules are but where molecules are active within cells, offering a glimpse into the emerging view of biochemical activity architecture as a complement to the physical architecture of a cell.


Hyposensitization therapy with alum-precipitated pyridine extracts in animal dander sensitive patients.
Hyposensitization therapy with APP extracts was found to be effective in 80% of 185 patients allergic to animals (96 to cats, 84 to dogs and 5 to horses) with a minimum of reactions (2.5 local and 0.2% constitutional). Lower respiratory symptoms were the most common complaints, followed by nasal, ocular and respiratory, singly or in combination.


State-of-the-art usage of simulation in anesthesia: skills and teamwork.
This review describes the level of evidence for the use of medical simulation in anesthesia. It also discusses the topic of realism in simulation and its use for assessment. Medical simulation in anesthesia covers a variety of techniques used for training and assessment. The current level of evidence for the use of medical simulation strongly supports a shift from learning on patients to learning on simulators. Skill and multidisciplinary team training are effective modalities and improve (team) performance and patient outcome.Well defined learning objectives, not a high level of realism should be the main focus of a simulation activity. Simulation centers should focus on faculty development as emphasis on simulation facilities and simulator fidelity alone does not guarantee effective training.Formative and summative assessment can help identify the omissions in knowledge, skills, and the ability to work in a team for both residents and anesthesiologists. Not only does it help to obtain competence, it also helps to maintain it. Simulation for skill and team training should be a mandatory component for anesthesia residency programs and continuous medical education. The 'see one, do one, teach one' approach is obsolete and should be abandoned.