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Interprofessional education (IPE) is required in the advanced nursing practice curriculum to promote collaboration between health care professionals. Time constraints, accessibility, and geographical locations are common barriers to overcome when considering implementing IPE experiences. Utilizing virtual modalities to develop these experiences can increase IPE opportunities. An innovative approach was taken to incorporate a telehealth Objective Structured Clinical Examination involving family nurse practitioner and pharmacy students from different academic institutions for an IPE virtual simulation. Faculty evaluated student performance based on competencies. Faculty and student feedback regarding the IPE experience was positive. | Family Nurse Practitioners |
BACKGROUND: Data on angioedema risk among sacubitril-valsartan (SV) users in real-world settings are limited. OBJECTIVES: We sought to evaluate the risk of angioedema among SV new users compared with angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor-blocker (ARB) new users separately. METHODS: We conducted a propensity score-matched cohort study, comparing SV new users (no use of SV, ACE inhibitor, ARB 6 months before) and SV new users with prior use (within 183 or 14 days) of ACE inhibitor or ARB (ACE inhibitor-SV and ARB-SV users; recent ACE inhibitor-SV and recent ARB-SV users, respectively) vs ACE inhibitor and ARB new users separately. RESULTS: Compared with ACE inhibitor, SV new (HR: 0.18; 95% CI: 0.11-0.29) and ACE inhibitor-SV users (HR: 0.31; 95% CI: 0.23-0.43) showed lower risk of angioedema. On the other hand, there was no difference in angioedema risk when SV new users (HR: 0.59; 95% CI: 0.35-1.01) or ARB-SV users (HR: 0.85; 95% CI: 0.58-1.26) were compared with ARB new users. Compared with SV new users, ACE inhibitor-SV users (HR: 1.62; 95% CI: 0.91-2.89) trended toward higher angioedema risk, which intensified when the ACE inhibitor to SV switch occurred within 14 days (recent ACE inhibitor-SV) (HR: 1.98; 95% CI: 1.11-3.53). Similarly, ARB-SV users (HR: 2.03; 95% CI: 1.16-3.54) experienced an increased risk compared with SV new users, which intensified for the more recent switchers (recent ARB-SV) (HR: 2.45; 95% CI: 1.36-4.43). CONCLUSIONS: We did not observe an increased risk of angioedema among SV new users compared with ACE inhibitor or ARB users. However, there was an increased risk of angioedema among SV users who recently switched from ACE inhibitor or ARB compared with SV new users. | Renin Inhibitors |
PURPOSE: Cardiovascular diseases remain the number one death cause worldwide. Preclinical 4D flow phase contrast magnetic resonance imaging can provide substantial insights in the analysis of aortic pathophysiologies in various animal models. These insights may allow a better understanding of pathophysiologies, therapy monitoring, and can possibly be translated to humans. This study provides a framework to acquire the velocity field within the aortic arch. It analyses important flow values at different locations within the aortic arch. Imaging parameters with high temporal and spatial resolution are provided, that still allow combining this time-consuming method with other necessary imaging-protocols. METHODS: A new setup was established where a prospectively gated 4D phase contrast sequence is combined with a highly sensitive cryogenic coil on a preclinical magnetic resonance scanner. The sequence was redesigned to maintain a close to steady state condition of the longitudinal magnetization and hence to overcome steady state artifacts. Imaging parameters were optimized to provide high spatial and temporal resolution. Pathline visualizations were generated from the acquired velocity data in order to display complex flow patterns. RESULTS: Our setup allows data acquisition with at least two times the rate than that of previous publications based on Cartesian encoding, at an improved image quality. The steady state" sequence reduces observed artifacts and provides uniform image intensity over the heart cycle. This made possible quantification of blood speed and wall shear stress (WSS) within the aorta and its branches. The highest velocities were observed in the ascending aorta with 137.5 +/- 8 cm/s. Peak velocity values in the Brachiocephalic trunk were 57 +/- 12 cm/s. Quantification showed that the peak flow occurs around 20 ms post R-wave in the ascending aorta. The highest mean axial wall shear stress was observed in the analysis plane between the left common carotid artery (LCCA) and the left subclavian artery. A stable image quality allows visualizing complex flow patterns by means of streamlines and for the first time, to the best of our knowledge, pathline visualizations from 4D flow MRI in mice. CONCLUSION: The described setup allows analyzing pathophysiologies in mouse models of cardiovascular diseases in the aorta and its branches with better image quality and higher spatial and temporal resolution than previous Cartesian publications. Pathlines provide an advanced analysis of complex flow patterns in the murine aorta. An imaging protocol is provided that offers the possibility to acquire the aortic arch at sufficiently high resolution in less than one hour. This allows the combination of the flow assessment with other multifunctional imaging protocols." | Microscopy, Phase-Contrast |
A bis-ligation reaction of S-nitrosothiols using triaryl substituted phosphine-thioester substrates has been developed. This reaction converts unstable primary S-nitrosothiols to stable disulfide-iminophosphorane products in high yields under mild conditions. It can potentially be applied for the detection of S-nitrosation in protein systems. | Phosphoranes |
RESEARCH QUESTION: There is no widely accepted grading system for IPF disease severity, although physiologic impairment based on pulmonary function testing is frequently employed. We sought to describe clinical and functional characteristics as well as outcomes of patients with severe physiologic impairment. PATIENTS AND METHODS: IPF patients with severe physiologic impairment defined by FVC </= 50% and/or DLco </= 30% predicted evaluated in the Inova Advanced Lung Disease Program between 2011 and 2019 were included. Demographic, physiologic, functional treatment and outcome data were collated. RESULTS: There were 531 patients with IPF evaluated of whom 242 (46%) had severe physiologic impairment. Mean age was 72 +/- 8 years; baseline FVC was 53 +/- 17% and DL(CO) 28 +/- 9% of predicted. The mean 6 min walks test (6MWT) distance was 304 +/- 121 m with 59% of the patients requiring supplemental oxygen ([Formula: see text] group). There was a poor correlation between the 6MWT distance and both FVC% and DLco%. Patients in the 6MWT(RA) group had a better transplant-free survival than the [Formula: see text] group (p = 0.002). Patients managed before October 2014 and not receiving antifibrotic therapy had worse outcomes with reduced transplant-free survival compared with patients presenting after this date who did receive antifibrotic therapy (n = 113) (log rank p < 0.0001). CONCLUSION: IPF patients often present with severe physiologic impairment which may be poorly correlated with their functional status. Assessment of IPF disease severity should not be based on physiologic impairment alone, but should also encompass functional status as well as need for supplemental oxygen. Antifibrotic therapy in patients with severe physiologic impairment is associated with improved outcomes. | Walk Test |
To mimic the levels of spatiotemporal control that exist in nature, tools for chemically induced dimerization (CID) are employed to manipulate protein-protein interactions. Although linker composition is known to influence speed and efficiency of heterobifunctional compounds, modeling or in vitro experiments are often insufficient to predict optimal linker structure. This can be attributed to the complexity of ternary complex formation and the overlapping factors that impact the effective concentration of probe within the cell, such as efflux and passive permeability. Herein, we synthesize a library of modular chemical tools with varying linker structures and perform quantitative microscopy in live cells to visualize dimerization in real-time. We use our optimized probe to demonstrate our ability to recruit a protein of interest (POI) to the mitochondria, cell membrane, and nucleus. Finally, we induce and monitor local and global phase separation. We highlight the importance of quantitative approaches to linker optimization for dynamic systems and introduce new, synthetically accessible tools for the rapid control of protein localization. | Dimerization |
Kobuviruses have been detected in humans and several animal species, including cattle, swine, sheep, canines, mice, and probably bats. While investigating the possibility of Kobuviruses infecting additional animal host species, we detected kobuvirus in three fecal samples from domestic Korean black goats. In a maximum parsimony tree and a Bayesian tree, the 08KG680 strain fell within the bovine kobuvirus lineage, but the 09KG172 and 10KG056 strains did not fall within any of the known animal kobuvirus lineages. Comparative analysis of the partial nucleotide sequences of the RNA-dependent RNA polymerase (RdRp) gene of the 08KG680 strain also revealed high amino acid sequence identity and a close genetic relationship with bovine kobuvirus, but the amino acid sequences of the other two strains had low similarity to those of known kobuvirus isolates from any animal species. The similarity of the sequence of the 08KG680 strains with the bovine kobuvirus indicate that the infectious may have originated from cattle, but the possible source for remaining strains could not be classified. | Kobuvirus |
Population health is changing the focus of nursing practice as nurses are challenged to focus on health promotion and education for communities rather than limiting their practice to restorative care for individual acute care patients. This new focus is necessary to improve knowledge of maternal and infant health among vulnerable populations. One particularly vulnerable population is members of Old Order Mennonite communities, who frequently rely on self-trained local midwives in the community for home births and home remedies when caring for their infants. Providing evidence-based education to members of this isolated population can be a challenge because they do not typically access information outside of the community. The purpose of this article is to share the process of developing, publishing, and disseminating a culturally sensitive infant care manual for an Old Order Mennonite community using a community-based participatory model and to highlight the impact nursing outreach can have on improving health knowledge. | Infant Health |
Motile bacteria often use sophisticated chemotaxis signaling systems to direct their movements. In general, bacterial chemotactic signal transduction pathways have three basic elements: (1) signal reception by bacterial chemoreceptors located on the membrane; (2) signal transduction to relay the signals from membrane receptors to the motor; and (3) signal adaptation to desensitize the initial signal input. The chemotaxis proteins involved in these signal transduction pathways have been identified and extensively studied, especially in the enterobacteria Escherichia coli and Salmonella enterica serovar typhimurium. Chemotaxis-guided bacterial movements enable bacteria to adapt better to their natural habitats via moving toward favorable conditions and away from hostile surroundings. A variety of oral microbes exhibits motility and chemotaxis, behaviors that may play important roles in bacterial survival and pathogenesis in the oral cavity. | Selenomonas |
The aim of the study was the assessment of leisure time among third-year students from the Faculty of Pharmacy of the Medical University of Lublin. It analysed quantity of time devoted to school activity and ways of spending free time. The study involved 114 students (82 women and 32 men). The study revealed that women had less free time than men, who, most probably did not attend some lectures. The most popular activities among the questioned students were: sleeping (average 6.8 hours a day), studying (average 3.6 hours a day), listening to the radio (average 2.9 hours a day), talking with friends (average 1.9 hours a day), personal hygiene (average 1.1 hours a day), watching TV (average 1.1 hours a day), housework. Students devoted the least of their free time on active rest, for example walking (women did it more often than men) or practising sport (more popular among men). Cultural life of the students consisted only of meetings with friends and going to the cinema (women did it more often). The least popular way of spending free time was going to the theatre, opera, concerts and exhibitions. Few students spent their time working. Their number increased significantly during holidays. The way of spending free time by third-year students from the Faculty of Pharmacy (both men and women) during the day was similar, differences related only to the amount of time devoted to each activity. | Time Management |
Constrictive pericarditis and restrictive cardiomyopathy are 2 forms of diastolic dysfunction with similar presentation but different treatment options. Whereas constrictive pericarditis has the potential of being cured with pericardiectomy, restrictive cardiomyopathy is usually incurable. It is therefore crucial to differentiate between the 2 disorders. In the last few years, new diagnostic techniques have become available to differentiate these causes of diastolic dysfunction from each other. This review provides a complete, in-depth comparison of the 2 disorders with regard to their symptoms and clinical features, etiology, pathophysiology, hemodynamics, echocardiographic presentation, and finally the different available management options. | Cardiomyopathy, Restrictive |
BACKGROUND: Although inducible defences have been studied extensively, only little is known about how the presence of parasites might interfere with these anti-predator adaptations. Both parasites and predators are important factors shaping community structure and species composition of ecosystems. Here, we simultaneously exposed Daphnia magna to predator cues (released by the tadpole shrimp, Triops, or by a fish) and spores of the yeast parasite Metschnikowia sp. to determine how life history and morphological inducible defences against these two contrasting types of predators are affected by infection. RESULTS: The parasite suppressed some Triops-induced defences: Daphnia lost the ability to produce a greater number of larger offspring, a life-history adaptation to Triops predation. In contrast, the parasite did not suppress inducible defences against fish: induction (resulting in smaller body length of the mothers as well as of their offspring) and infection acted additively on the measured traits. Thus, fish-induced defences may be less costly than inducible defences against small invertebrate predators like Triops; the latter defences could no longer be expressed when the host had already invested in fighting off the parasite. CONCLUSIONS: In summary, our study suggests that as specific inducible defences differ in their costs, some might be suppressed if a target prey is additionally infected. Therefore, adding parasite pressure to predator-prey systems can help to elucidate the costs of inducible defences. | Metschnikowia |
An abundant human papillomavirus (HPV) protein E1/\E4 is expressed late in the virus life cycle in the terminally differentiated layers of epithelia. The expression of E1/\E4 usually coincides with the onset of viral DNA amplification. However, the function of E1/\E4 in viral life cycle is not completely understood. To examine the role of E1/\E4 in the virus life cycle, we introduced a single nucleotide change in the HPV-11 genome to result in a truncation of E1/\E4 protein without affecting the E2 amino acid sequence. This mutated HPV-11 genome was introduced into a human foreskin keratinocyte cell line immortalized by the catalytic subunit of human telomerase, deficient in p16(INK4a) expression, and previously shown to support the HPV-11 life cycle when grown in organotypic raft culture. We have demonstrated that E1/\E4 is dispensable for HPV-11 viral DNA amplification in the late stages of the viral life cycle. | Human papillomavirus 11 |
As part of a research program on neurotransmitters in a biological fluid, the fragmentations characterising catecholamines protonated under electrospray ionisation (ESI) conditions, under low collision energy in a triple-quadrupole mass spectrometer, were investigated. The decompositions of protonated noradrenaline (VH) and normetanephrine (VIH) were studied. Both precursor ions eliminate first H2O at very low collision energy, and the fragmentations of [MH-H2O]+ occur at higher collision energy. The breakdown graphs of [MH-H2O]+ ions, with collision energy varying from 0-40 eV in the laboratory frame, are presented. [VIH-H2O]+ ions lose competitively NH3 and CH3OH. For [VH-H2O]+ the loss of NH3 is dominant while H2O is eliminated at very low abundance at all collision energies. All of these secondary fragmentations are followed at higher collision energies by elimination of CO. These fragmentations are interpreted by means of ab initio calculations up to the B3LYP/6-311+G(2d,2p) level of theory. The elimination of H2O requires first the isomerisation of N-protonated forms, chosen as energy references, to O-protonated forms. The isomerisation barriers are calculated to be lower than 81 kJ/mol above the N-protonated forms. The elimination of NH3 from [MH-H2O]+ requires first the migration, via a cyclisation, of the amine function from the linear chain to the aromatic ring in order to prevent the formation of unstable disubstituted carbocations in the ring. The barriers associated with the loss of NH3 are located 220 and 233 kJ/mol above VH and 219 kJ/mol above VIH. The energy barrier for the loss of ROH is located 236 and 228 kJ/mol above VH and VIH, respectively. The absence of ions corresponding to [VH-2H2O]+ is due to a parasitic mechanism with an activation barrier lower than 236 kJ/mol that leads to a stable species unable to fragment, thus preventing the second loss of H2O. Losses of CO following the secondary fragmentations involve activation barriers higher than 330 kJ/mol. | Normetanephrine |
Myositis ossificans (MO) is a fairly common evolution in sports activity and can be due to direct trauma or to repeated micro-injuries. The traditional therapeutic approach relies on a variety of treatments, such as physical therapy but evidence of their proven clinical efficacy is lacking. The latest therapeutic option is surgical removal but this is a demolitive procedure and is frequently associated with a significant loss of functional integrity. There are few articles in literature about the treatment of post-traumatic MO, and none on extracorporeal shock wave therapy (ESWT). We illustrate a case series of 24 sportsmen treated with three sessions of electro-hydraulic shockwave therapy and an associated rehabilitation program. Only a partial reduction of the ossification was observed in the X-ray images but all the patients showed signs of functional improvement immediately after therapy. Two months after the therapy, a normal range of motion and no signs of weakness were observed. Three months after treatment, 87.5% of patients resumed regular sports activities. | Myositis Ossificans |
The composition of complexes containing C1 inactivator (C1 IA), C1r and C1s was investigated in normal serum after activation of C1 under various conditions. Analyses were performed with PAGE of eluates from Sepharose beads coated with F(ab')2 fragments of anti C1s followed by immunoblotting with anti C1 IA, anti C1s or anti C1r. Eluates obtained from serum treated with aggregated IgG (AGG) contained C1 IA in complex with C1r and C1s with both subcomponents in activated form. Eluates from serum incubated at 37 degrees C for 1, 2 or 3 days without activators showed C1 IA complexed with activated C1r and with C1s in proenzyme state associated to the complex. On analysis of serum, treated as mentioned above, by a variant of the electroimmunoassay using an intermediate gel containing anti-C1 IA and with anti-C1s in the anodal gel the two types of C1r--C1s--C1 IA complexes could be distinguished. Investigation of fresh sera and synovial fluids from patients with rheumatoid arthritis in this assay showed complexes containing C1 IA and C1r-C1s in activated form in the synovial fluids, while C1 IA-activated C1r-proenzyme C1s complexes were found in the corresponding sera. | Complement C1 |
PURPOSE: To devise a cost-effective imaging guide for the evaluation of third nerve palsies (TNP), based on an extensive review of the literature. METHODS: A review of the pertinent English language literature was performed to devise a guideline for the evaluation and neuroimaging of TNP. The authors also report a retrospective review of the cost of imaging studies performed on 91 patients with TNP. RESULTS: On the basis of the available literature, an imaging guide was developed and applied to a retrospective chart review of 91 patients from a single tertiary care center (Baylor College of Medicine). The cost effectiveness as well as the efficacy of the imaging guide was analyzed. CONCLUSIONS: The evaluation of TNP can be difficult; however, using such guides may allow for more appropriate and cost-effective evaluation of these patients. | Oculomotor Nerve Diseases |
Currently, there is an increasing focus on the implementation of pharmacokinetic-pharmacodynamic (PK-PD) studies and modelling as essential tools for drug development. Strategies involving specifically the population approach, which are based on relatively recent statistical methodology (e.g. nonlinear mixed effects modelling, NONMEM) have been advocated for investigating pharmacokinetic and pharmacodynamic variability as well as dose-concentration-effect relationships. The present article outlines this approach, and discusses how it can be implemented within the framework of the studies currently performed as part of the clinical phases of new drug development. It also considers study design and performance, based on real-life experiences. Population approaches, if designed carefully and early, as part of the planning of the drug development programme, are expected to play a significant role at every phase of the programme and to contribute to providing information that is valuable for registration purposes. Statistical methodology and software are now widely available. However, practical issues such as integration of the population approach within existing protocols, quality control of the data, timing of laboratory and statistical analyses, as well as resource allocation, remain legitimate concerns to be considered in prospective studies." | Epidemiologic Study Characteristics |
OBJECTIVE: To examine the efficacy of weight-adjusted D-cycloserine (DCS) (35 or 70 mg) relative to placebo augmentation of intensive exposure therapy for youth with obsessive-compulsive disorder (OCD) in a double-blind, randomised controlled trial, and examine whether antidepressant medication or patient age moderated outcomes. METHODS: Youth (n = 100, 7-17 years) with OCD were randomised in a 1:1 ratio to either DCS + exposure (n = 49) or placebo + exposure (n = 51). Assessments occurred posttreatment, 1 month later, and at 3 and 6 months. Pills were ingested immediately before sessions. RESULTS: Significant improvements on all outcomes were observed at posttreatment, and to 6-month follow-up. Treatment arms did not differ across time, with no significant time-by-medication interactions on symptom severity (T1 to T2 estimate: 9.3, 95% confidence interval [CI]: -11.2 to -7.4, and estimate -10.7, 95% CI: -12.6 to -8.7), diagnostic severity (T1 to T2 estimate: -2.0, 95% CI: -2.4 to -1.5 and estimate -2.5, 95% CI: -3.0 to -2.0) or global functioning (T1 to T2 estimate: 13.8, 95% CI: 10.6 to 17.0, and estimate 16.6, 95% CI: 13.2 to 19.9). Neither antidepressants at baseline nor age moderated primary outcomes. There were significantly fewer responders/remitters at 1- and 6-month follow-up among youth in the DCS condition stabilised on SSRIs, relative to youth not taking SSRIs. CONCLUSIONS: DCS augmented intensive exposure therapy did not result in overall additional benefits relative to placebo. Intensive exposure proved effective in reducing symptoms for the overall sample. | Cycloserine |
Trichlorfon (TCF) is a widely used pesticide, which according to some epidemiological and experimental data, is suspected of being aneugenic in human and mouse cells. In particular, in vitro studies in mouse oocytes showed the induction of aneuploidy and polyploidy at the first meiotic division and of severe morphological alterations of the second meiotic spindle. We have tested the hypothesis that an acute treatment of mice with TCF might similarly affect chromosome segregation in maturing oocytes. Superovulated MF-1 mice were intraperitoneally injected with 400mg/kg TCF or orally administered with 600mg/kg TCF either at the time of or 4h after human chorionic gonadotrophin (HCG) injection. Oocytes were harvested 17h after HCG and metaphase II chromosomes were cytogenetically analyzed. No significant increase of aneuploid or polyploid cells was detected at any treatment condition. A significant (p<0.001) decrease of metaphases showing premature chromatid separation or premature anaphase II in all TCF-treated groups with respect to controls suggested that TCF treatment may have delayed the first meiotic division. To evaluate possible effects of the pesticide upon the second meiotic division, a group of females orally treated with 600mg/kg TCF at resumption of meiosis was mated with untreated males and zygotes were collected for cytogenetic analysis. No evidence of aneuploidy induction was obtained, but the frequency of polyploid zygotes was increased fivefold over the control level (p<0.01). Such polyploid embryos might have arisen from fertilization of oocytes that were either meiotically delayed and still in metaphase I at fertilization or progressed through anaphase II without cytokinesis. These findings show that in vivo studies on aneuploidy induction in oocytes may yield results different from those obtained by in vitro experiments and that both kinds of data may be necessary for risk assessment of environmentally relevant exposures. | Trichlorfon |
Ezrin, Radixin, Moesin binding phosphoprotein 50 (EBP50) is a scaffold protein that possesses two PDZ interacting domains. We have shown that, in isolated artery stimulated with noradrenaline, EBP50 interacts with several elements of the cytoskeleton. However, the contribution of EBP50 to the organization of the cytoskeleton is unknown. We have used primary cultured vascular smooth muscle cells to investigate the involvement of EBP50 in the regulation of cell architecture, motility and cell cycle, and to identify its target proteins and subsequent action mechanism. The results showed that depletion of EBP50 by siRNA transfection induced changes in cell architecture and increased cell migration. The same phenotype was induced by inhibition of myosin IIa and this effect was not additive in cells depleted for EBP50. Moreover, a larger proportion of binucleated cells was observed after EBP50 depletion, indicating a defect in cytokinesis. The identification, after co-immunoprecipitation, of a direct interaction of EBP50 with both tubulin and myosin IIa suggested that EBP50 could regulate cell migration and cytokinesis by linking myosin IIa fibers and microtubule network. Indeed, depletion of EBP50 also dismantled myosin IIa fibers and induced the formation of stable microtubules in lamellae expansions and Rac1 activation. This signaling cascade leads to the formation of lamellipodia, trailing tails and decrease of focal adhesion formation, triggering cell migration. | Nonmuscle Myosin Type IIA |
Ankyrin-B (encoded by ANK2), originally identified as a key cytoskeletal-associated protein in the brain, is highly expressed in the heart and plays critical roles in cardiac physiology and cell biology. In the heart, ankyrin-B plays key roles in the targeting and localization of key ion channels and transporters, structural proteins, and signaling molecules. The role of ankyrin-B in normal cardiac function is illustrated in animal models lacking ankyrin-B expression, which display significant electrical and structural phenotypes and life-threatening arrhythmias. Further, ankyrin-B dysfunction has been associated with cardiac phenotypes in humans (now referred to as ankyrin-B syndrome") including sinus node dysfunction, heart rate variability, atrial fibrillation, conduction block, arrhythmogenic cardiomyopathy, structural remodeling, and sudden cardiac death. Here, we review the diverse roles of ankyrin-B in the vertebrate heart with a significant focus on ankyrin-B-linked cell- and molecular-pathways and disease." | Ankyrins |
Fibrous tremolite is a mineral species belonging to the amphibole group. It is present almost everywhere in the world as a natural contaminant of other minerals, like talc and vermiculite. It can be also found as a natural contaminant of the chrysotile form of asbestos. Tremolite asbestos exposures result in respiratory health consequences similar to the other forms of asbestos exposure, including lung cancer and mesothelioma. Although abundantly distributed on the earth's surface, tremolite is only rarely present in significant deposits and it has had little commercial use. Significant presence of amphibole asbestos fibers, characterized as tremolite, was identified in mineral powders coming from the milling of feldspar rocks extracted from a Sardinian mining site (Italy). This evidence raises several problems, in particular the prevention of carcinogenic risks for the workers. Feldspar is widespread all over the world and every year it is produced in large quantities and it is used for several productive processes in many manufacturing industries (over 21 million tons of feldspar mined and marketed every year). Until now the presence of tremolite asbestos in feldspar has not been described, nor has the possibility of such a health hazard for workers involved in mining, milling and handling of rocks from feldspar ores been appreciated. Therefore the need for a wider dissemination of knowledge of these problems among professionals, in particular mineralogists and industrial hygienists, must be emphasized. In fact both disciplines are necessary to plan appropriate environmental controls and adequate protections in order to achieve safe working conditions. | Asbestos, Amphibole |
The genetically encodable fluorescent tag miniSOG is expected to revolutionize correlative light- and electron microscopy due to its ability to produce singlet oxygen upon light irradiation. The quantum yield of this process was reported as PhiDelta = 0.47 +/- 0.05, as derived from miniSOG's ability to photooxidize the fluorescent probe anthracene dipropionic acid (ADPA). In this report, a significantly smaller value of PhiDelta = 0.03 +/- 0.01 is obtained by two methods: direct measurement of its phosphorescence at 1275 nm and chemical trapping using uric acid as an alternative probe. We present insight into the photochemistry of miniSOG and ascertain the reasons for the discrepancy in PhiDelta values. We find that miniSOG oxidizes ADPA by both singlet oxygen-dependent and -independent processes. We also find that cumulative irradiation of miniSOG increases its PhiDelta value ~10-fold due to a photoinduced transformation of the protein. This may be the reason why miniSOG outperforms other fluorescent proteins reported to date as singlet oxygen generators. | Singlet Oxygen |
PURPOSE: Foot pronation is not an isolated factor influencing lower limb functions. Exploring gait variability and impact loading associated with the foot posture are crucial for understanding foot pronation-related injury mechanisms. This study aimed to evaluate how foot posture affects impact loading and running variability during running. METHODS: Twenty-five male participants were recruited into this study. Pressure under the foot arch, acceleration and marker trajectory were recorded in the right limb for each runner after 1, 4, 7 and 10 km running, respectively. Linear mixed effects models were used to analyze the statistical difference of the data. RESULTS: FPI-6 has significantly increased after the 10 km running (p<0.01). For the tibial acceleration, peak resultant acceleration after 10 km running was significantly increased than after 4 km running (p=0.02). At the dorsum of the foot, the short-time largest Lyapunov exponent (LyE) after 10 km running decreased 0.28 bit/s compared with LyE after 7 km running ( p = 0.03). In the tibia, LyE after 4 km and 10 km running was decreased significantly ( p < 0.01 and p = 0.01). CONCLUSIONS: The foot was significantly pronated at the middle and at the end of running. Foot pronation during distance running increased the distal tibia peak impact acceleration but did not increase running instability. | Lye |
Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine tumors. Nevertheless, although somatostatin analogs effectively control hormonal hypersecretion by GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors, significant differences are observed among patients with respect to the efficacy of treatment. This may be related to a differential expression of somatostatin receptor subtypes among tumors. In addition, the property of somatostatin receptor subtypes to undergo agonist-induced internalization has important consequences for visualizing, as well as for therapy, of receptor-positive tumors using radioisotope- or chemotherapeutic-compound-coupled somatostatin analogs. This review covers the pathophysiological role of somatostatin receptor subtypes in determining the efficacy of treatment of patients with somatostatin receptor-positive tumors using somatostatin analogs, as well as the preclinical and clinical consequences of agonist-induced receptor internalization for somatostatin receptor-targeted radio- and chemotherapy. Herein, the development and potential role of novel somatostatin analogs is discussed." | Receptors, Pituitary Hormone-Regulating Hormone |
Conformational analyses have been performed on several phenothiazine and thioxanthene dopamine antagonists using the MM2-87 program and parameter set. The compounds that were examined are thioridazine (2), methotrimeprazine (3), cis- and trans-chlorprothixene, and a piperidylidene derivative of chlorprothixene. In addition, (+)-2 and (-)-3 were determined by X-ray crystallography to have the R absolute configuration. The above compounds were superimposed onto loxapine, which was used as a template for the previously proposed dopamine D2 receptor ligand model. The conformational properties and receptor affinities of these compounds were found to be entirely consistent with the ligand model. For example, a conformer of (+)-R-2 that is consistent with the ligand model is lower in energy than a consistent conformer for (-)-S-2, which agrees with the higher D2 receptor affinity of the former. Similarly, in agreement with the much higher affinity of (-)-R-3 relative to (+)-S-3, only the former contains a low energy conformer consistent with the ligand model. The ligand model is also consistent with the greater potency of cis-thioxanthenes over the trans isomers. These results emphasize the importance of the correct orientation of the ammonium hydrogen for high affinity at the D2 receptor. The pharmacophore for D2 receptor ligands is compared with a recently proposed pharmacophore for D1 ligands. | Thioxanthenes |
Discs large MAGUK scaffold protein 5 (DLG5) is a multi-domain member of membrane-associated guanylate kinase (MAGUK) family, which plays a major role in the maintenance of cell epithelial polarity being part of the SCRIB-LGL-DLG complex. Although polarity proteins have been generally considered tumor suppressors, recent discoveries led to reconsidering their role in cancer. This is also true for DLG5 in different cancer types, including hepatocellular carcinoma (HCC). In this cancer, DLG5 was negatively associated with malignant characteristics, however recent findings associated DLG5 expression with advanced stages of HCC. In vitro studies evidenced its possible role in sustaining cell growth and migration by the interaction with several intracellular pathways, such as Hippo, Hedgehog, and PI3K/AKT signaling pathways. In this review, we summarize the recent finding on the dual role of DLG5 and other polarity proteins in cancers. What emerges is a still undefined role of those proteins in cancers, especially in HCC, one of the most frequent cancers worldwide, where the function of DLG5 and other polarity proteins is still largely unexplored. | Guanylate Kinases |
The lateral organization of receptors on cell surfaces is critically important to their function; many receptors transmit transmembrane signals when redistributed into clusters, while the response of others is potentiated by their aggregation. Cell-cell contact can play a crucial role in receptor aggregation, even when the bonds between receptors on one cell and ligands on the other are monovalent. Monte Carlo simulations on a two-membrane model were carried out to determine whether weak enthalpic interactions among receptors in one membrane, and among ligands in another, can work synergistically to give large-scale clustering when the two membranes are brought into contact. The simulations give support to such a clustering mechanism. In addition, because clustering is a cooperative process akin to a phase separation, individual receptors and ligands may undergo repeated binding and unbinding while in a clustered phase," and a single ligand could interact with multiple different receptor partners. The results suggest a resolution of the dichotomy between serial triggering and aggregation models of T cell activation." | Receptor Aggregation |
Dysregulation of cellular ribose uptake can be indicative of metabolic abnormalities or tumorigenesis. However, analytical methods are currently limited for quantifying ribose concentration in complex biological samples. Here, we utilize the highly specific recognition of ribose by ribose-binding protein (RBP) to develop a single-protein ribose sensor detectable via a sensitive NMR technique known as hyperpolarized (129)Xe chemical exchange saturation transfer (hyper-CEST). We demonstrate that RBP, with a tunable ribose-binding site and further engineered to bind xenon, enables the quantitation of ribose over a wide concentration range (nM to mM). Ribose binding induces the RBP closed" conformation, which slows Xe exchange to a rate detectable by hyper-CEST. Such detection is remarkably specific for ribose, with the minimal background signal from endogenous sugars of similar size and structure, for example, glucose or ribose-6-phosphate. Ribose concentration was measured for mammalian cell lysate and serum, which led to estimates of low-mM ribose in a HeLa cell line. This highlights the potential for using genetically encoded periplasmic binding proteins such as RBP to measure metabolites in different biological fluids, tissues, and physiologic states." | Periplasmic Binding Proteins |
BACKGROUND: Laryngeal palpation is a common clinical method for the assessment of neck and laryngeal muscles in muscle tension dysphonia (MTD). OBJECTIVE: To review the available laryngeal palpation methods used in patients with MTD for the assessment, diagnosis, or document of treatment outcomes. STUDY DESIGN (METHOD): A systematic review of the literature concerning palpatory methods in MTD was conducted using the databases MEDLINE (PubMed), ScienceDirect, Scopus, Web of science, Web of knowledge and Cochrane Library between July and October 2013. Relevant studies were identified by one reviewer based on screened titles/abstracts and full texts. Manual searching was also used to track the source literature. RESULTS: There were five main as well as miscellaneous palpation methods that were different according to target anatomical structures, judgment or grading system, and using tasks. There were only a few scales available, and the majority of the palpatory methods were qualitative. Most of the palpatory methods evaluate the tension at both static and dynamic tasks. There was little information about the validity and reliability of the available methods. CONCLUSION: The literature on the scientific evidence of muscle tension indicators perceived by laryngeal palpation in MTD is scarce. Future studies should be conducted to investigate the validity and reliability of palpation methods. | Dysphonia |
Ten adult men who underwent two successive pancreatic function tests in tandem received hyoscine-N-butylbromide intravenously before the second test. The drug inhibited secretin-stimulated protein, trypsin and amylase secretion and increased the bicarbonate concentration in the pancreatic juice. It is important to take these findings into account when interpreting the results of pure pancreatic juice collections taken during retrograde endoscopic pancreatography if the drug has been used as a duodenal relaxant. | Pancreatic Juice |
As landscapes have become increasingly dominated by intensive agricultural production, plant diversity has declined steeply along with communities of pollinating insects including bees. Semi-natural habitats, such as field edge meadows and hedgerows, can be maintained to provide a diversity of flowering plants that can increase floral resources required by bees. An additional habitat enhancement practice is that of sowing strips of native prairie vegetation within row-cropped fields. In this study, conducted in Iowa, USA, we found that increases in both the abundance and diversity of floral resources in strips of native prairie vegetation within agricultural production fields greatly and positively influenced the bee community. The benefits to the bee community were important for both common and uncommon species and the effect may be strongest early in the season. Using networks of co-occurrence between plant and bee species, we were able to identify two native prairie plants, Ratibida pinnata and Zizia aurea, as potentially keystone resources that can be used to support native bees. When we evaluated the effect of reconstructed prairie strips on bees in the context of the surrounding landscape, we found that these conservation practices had positive effects on bees in agriculturally-dominated areas and that these effects were detectable in low to high complexity landscapes with 8-69% natural habitat. In landscapes dominated by crops with few pollen and nectar resources the inclusion of native prairie strips can buffer the decline of bees and effectively increase bee abundance and diversity. | Ratibida |
Section 8(g) of the National Labor Relations Act, added in the 1974 amendments to the Act, requires a labor organization to give an employer in the health-care field ten days' notice of an intended strike or picketing. The purpose is to allow the health-care employer time to make arrangements to ensure the continuation of health-care services to critically ill patients. Failure of a union to give this notice constitutes a violation of the Act, and individuals who engaged in the activity may, as a result, lose their status as employees under the Act. In the following article, the authors examine the requirements of section 8(g) and the case law interpreting this statute. They suggest likely future interpretations of this law and make practical suggestions for responding to strikes in the health-care setting. | Labor Unions |
Legumes are an excellent source of nutrients and phytochemicals. They have been recognized for their contributions to health, sustainability, and the economy. Although legumes comprise several species and varieties, little is known about the differences in their phytochemical composition and the magnitude of these. Therefore, the aim of this review is to describe and compare the qualitative profile of phytochemicals contained in legumes and identified through LC-MS and GC-MS methods. Among the 478 phytochemicals reported in 52 varieties of legumes, phenolic compounds were by far the most frequently described (n = 405, 85%). Metabolomics data analysis tools were used to visualize the qualitative differences, showing beans to be the most widely analyzed legumes and those with the highest number of discriminant phytochemicals (n = 180, 38%). A Venn diagram showed that lentils, beans, soybeans, and chickpeas shared only 7% of their compounds. This work highlighted the huge chemical diversity among legumes and identified the need for further research in this field and the use of metabolomics as a promising tool to achieve it. | Fabaceae |
Aquatic ecosystems are fuelled by biogeochemical inputs from surrounding lands and within-lake primary production. Disturbances that change these inputs may affect how aquatic ecosystems function and deliver services vital to humans. Here we test, using a forest cover gradient across eight separate catchments, whether disturbances that remove terrestrial biomass lower organic matter inputs into freshwater lakes, thereby reducing food web productivity. We focus on deltas formed at the stream-lake interface where terrestrial-derived particulate material is deposited. We find that organic matter export increases from more forested catchments, enhancing bacterial biomass. This transfers energy upwards through communities of heavier zooplankton, leading to a fourfold increase in weights of planktivorous young-of-the-year fish. At least 34% of fish biomass is supported by terrestrial primary production, increasing to 66% with greater forest cover. Habitat tracers confirm fish were closely associated with individual catchments, demonstrating that watershed protection and restoration increase biomass in critical life-stages of fish. | Fresh Water |
Hereditary spherocytosis is a common and very heterogeneous hemolytic anemia caused by defects of the red cell membrane proteins. In recent years, major advances in our understanding of the red cell membrane skeleton and a better characterization of its individual components have allowed a brighter insight into the pathogenesis of the disease. In this article, we present an overview of the erythrocyte skeleton and its individual constituents. We also review the clinical aspects of the disease and describe the currently known molecular defects involving the membrane proteins which have been shown to play an essential role in the underlying mechanism of hereditary spherocytosis. Finally we examine several models that have been proposed in an attempt to clarify the mechanism leading from the initial molecular insult to the clinical phenotype. | Spherocytosis, Hereditary |
In the present study, we have investigated, by binding and functional experiments, the pharmacological profile of a new human tachykinin NK(2) receptor splice variant named beta isoform. Neurokinin A, nepadutant, SR48968 [(S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl) butyl]benzamide] and substance P have been tested for binding on the receptor expressed in whole CHO transfected cells. Only SR48968 binds, but with an affinity about sixfold lower in respect to the alpha isoform. Moreover, neurokinin A was unable to inhibit the [(3)H]SR48968 binding to the beta isoform up to microM concentrations. In cells expressing the human tachykinin NK(2) receptor beta isoform, contrary to those expressing the alpha isoform, natural or selective tachykinin receptor agonists (1 microM) were unable to produce a significant activation of inositol phosphate (IP) production or increase of intracellular calcium concentration [Ca(2+)](i). The recently discovered tachykinins, endokinins C and D, did not activate IP production or [Ca(2+)](i) increase in cells expressing the alpha or beta isoform of the human tachykinin NK(2) receptor. The present data indicate that the human tachykinin NK(2) receptor beta isoform is poorly or not expressed on the cell membrane surface and that it may possibly act as a regulator of tachykinin NK(2) receptor function. We cannot exclude the possibility that this receptor could interact with other presently unknown ligands. | Receptors, Neurokinin-2 |
A total of 66 Thai children with uncomplicated falciparum malaria were treated orally with regimens of either quinine or quinidine. Radical cures were observed in 85% (28 of 33) of the children who received quinine and in 88% (29 out of 33) of those who received quinidine. Treatment failures in both groups were RI responses.The mean trough level of quinidine (10 mumol/l) was about 2.5-times less than that of quinine (25 mumol/l). The electrocardiograms of the two treatment groups differed significantly in that there was an acute prolongation of the QT(c) interval in 56% of those who received quinidine compared with 21.0% of those given quinine. In vitro assays of the pretreatment drug susceptibilities of the isolates of Plasmodium falciparum indicated that the mean minimum inhibitory concentration (MIC) for quinidine (1.44 mumol/l) was about half that for quinine (3.02 mumol/l). Although both drugs are equally effective, quinine is recommended for treatment of multidrug-resistant malaria in paediatric patients, primarily because of the cardiac effects produced by quinidine. | Quinuclidines |
Precise history-taking and a complete clinical examination including all the components of the perineum guide diagnosis in anorectal disorders and most often indicate treatment. Ancillary investigations are sometimes needed for more precise diagnosis or to complete pretreatment workup. Such additional investigations should always be discussed, indicated and interpreted in view of the clinical examination. | Anus Diseases |
Of the many multidrug resistance (MDR) mechanisms, the ATP binding cassette (ABC) transporters expelling drug molecules out of cells is a major culprit in limiting the efficacy of present-day anticancer drugs. The present review offers an updated information on structure, function, and regulatory mechanisms of major MDR related ABC transporters such as P-glycoprotein, MRP1, BCRP and effect of modulators on their functions. An attempt has been made to provide a focused information on different modulators of ABC transporters so as utilize them in clinical practice for amelioration of emerging MDR crisis in cancer treatment. Finally, the importance ABC transporters as therapeutic targets has been discussed in the light of future strategic planning for translating the ABC transporter inhibitors in clinical practice." | Multidrug Resistance-Associated Proteins |
Wnt signalling is prevented by the proteosomal degradation of beta-catenin, which occurs in a destruction complex containing adenomatous polyposis coli (APC), APC-like (APCL), Axin and Axin2. Truncating mutations of the APC gene result in the constitutive stabilisation of beta-catenin and the initiation of colon cancer, although tumour cells tolerate the expression of wild-type APCL. Using the colocalisation of overexpressed Axin, APC and APCL constructs as a readout of interaction, we found that Axin interacted with the second twenty amino acid repeat (20R2) of APC and APCL. This interaction involved a domain adjacent to the C-terminal DIX domain of Axin. We identified serine residues within the 20R2 of APCL that were involved in Axin colocalisation, the phosphorylation of truncated APCL and the down-regulation of beta-catenin. Our results indicated that Axin, but not Axin2, displaced APC, but not APCL, from the cytoskeleton and stimulated its incorporation into bright cytoplasmic dots that others have recognised as beta-catenin destruction complexes. The SAMP repeats in APC interact with the N-terminal RGS domain of Axin. Our data showed that a short domain containing the first SAMP repeat in truncated APC was required to stimulate Axin oligomerisation. This was independent of Axin colocalisation with 20R2. Our data also suggested that the RGS domain exerted an internal inhibitory constraint on Axin oligomerisation. Considering our data and those from others, we discuss a working model whereby beta-catenin phosphorylation involves Axin and the 20R2 of APC or APCL and further processing of phospho-beta-catenin occurs upon the oligomerisation of Axin that is induced by binding the SAMP repeats in APC. | Axin Protein |
BACKGROUND AND OBJECTIVES: Currently, enhanced external counterpulsation (EECP) devices mainly produce one counterpulsation per cardiac cycle. However, the effect of other frequencies of EECP on the hemodynamics of coronary and cerebral arteries is still unclear. It should be investigated whether one counterpulsation per cardiac cycle leads to the optimal therapeutic effect in patients with different clinical indications. Therefore, we measured the effects of different frequencies of EECP on the hemodynamics of coronary and cerebral arteries to determine the optimal counterpulsation frequency for the treatment of coronary heart disease and cerebral ischemic stroke. METHODS: We established 0D/3D geometric multi-scale hemodynamics model of coronary and cerebral arteries in two healthy individuals, and performed clinical trials of EECP to verify the accuracy of the multi-scale hemodynamics model. The pressure amplitude (35 kPa) and pressurization duration (0.6 s) were fixed. The global and local hemodynamics of coronary and cerebral arteries were studied by changing counterpulsation frequency. Three frequency modes, including one counterpulsation in one, two and three cardiac cycles, were applied. Global hemodynamic indicators included diastolic / systolic blood pressure (D/S), mean arterial pressure (MAP), coronary artery flow (CAF), and cerebral blood flow (CBF), whereas local hemodynamic effects included area-time-averaged wall shear stress (ATAWSS) and oscillatory shear index (OSI). The optimal counterpulsation frequency was verified by analyzing the hemodynamic effects of different frequency modes of counterpulsation cycles and full cycles. RESULTS: In the full cycle, CAF, CBF and ATAWSS of coronary and cerebral arteries were the highest when one counterpulsation per cardiac cycle was applied. However, in the counterpulsation cycle, the global and local hemodynamic indicators of coronary and cerebral artery reached the highest when one counterpulsation in one cardiac cycle or two cardiac cycles was applied. CONCLUSIONS: For clinical application, the results of global hemodynamic indicators in the full cycle have more clinical practical significance. Combined with the comprehensive analysis of local hemodynamic indicators, it can be concluded that for coronary heart disease and cerebral ischemic stroke, applying one counterpulsation per cardiac cycle may provide the optimal benefit. | Counterpulsation |
Among bone morphogenetic proteins (BMPs), the decapentaplegic (Dpp; BMP2, BMP4) and glass bottom boat (Gbb/60A; BMP5, BMP6, BMP7) subgroups have well-described functions guiding autonomic and sensory neuronal development, fiber formation and neurophenotypic identities. Evaluation of rat superior cervical ganglia (SCG) post-ganglionic sympathetic neuron developmental regulators identified that selected BMPs of the transforming growth factor beta superfamily have reciprocal effects on neuronal pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) expression. Dpp and Gbb/60A BMPs rapidly down-regulated PACAP expression, while up-regulating other sympathetic neuropeptides, including PACAP-related VIP. The suppressive effects of BMP on PACAP mRNA and peptide expression were potent, efficacious and phosphorylated mothers against decapentaplegic homolog (Smad) signaling-dependent. Axotomy of SCG dramatically increases PACAP expression, and the possibility that abrogation of inhibitory retrograde target tissue BMP signaling may contribute to this up-regulation of sympathetic neuron PACAP was investigated. Replacement of BMP6 to SCG explant preparations significantly blunted the injury-induced elevated PACAP expression, with a concomitant decrease in sympathetic PACAP-immunoreactive neuron numbers. These studies suggested that BMPs modulate neuropeptide identity and diversity by stimulating or restricting the expression of specific peptidergic systems. Furthermore, the liberation of SCG neurons from target-derived BMP inhibition following axotomy may be one participating mechanism associated with injury-induced neuropeptidergic plasticity. | Bone Morphogenetic Protein 5 |
The world health organization reports that 80% of the population living within the developing countries depends basically on traditional medicine for his or her primary health care. Quite half the entire world's population still depends entirely on plants for medicines, and plants provides the active ingredients to the most traditional medical products. Hamelia patens that belong to the family Rubiaceae, is mainly found in tropical and sub-tropical areas. It is used in folk medicine against a wide range of diseases such as athlete's foot, skin problems, insect sting, psychiatric disorder, rheumatism, headache, asthma, dysentery, menses, ovarian and uterine disorders. Hamelia consists of an important bioactive constituent such as oxindole alkaloids, flavonoids, and phenolic content. Due to the presence of chlorogenic acid and epicatechin constituent in the methanolic extract of Hamelia patens, there is a noticeable anti-hyperglycemic activity as well as it possesses antioxidant activity. Acute and sub-acute toxicity study has been performed on Hamelia patens which shows that it is safe and can be used for humans. Against fungi and bacteria, the ethanol leaf extract of Hamelia has a maximum inhibitory effect. The plant has various therapeutic effects like anti-inflammatory, analgesic, anti-diarrheal, anthelmintic, antidepressant, hepatoprotective, antiurolithiatic, diuretic, wound healing, and many others. In this article, we have discussed chemical constituent, pharmacological activity and traditional use of Hamelia patens. | Hamelia |
La terapia de resincronizacion cardiaca mediante estimulacion hisiana ha demostrado ser efectiva en pacientes con bloqueo de rama izquierda del haz de His e insuficiencia cardiaca. Paciente masculino, con 47 anos de edad, con insuficiencia cardiaca, fraccion de expulsion del 17% y miocardio dilatada idiopatica, electrocardiograma en ritmo sinusal, bloqueo auriculoventricular de 1.(er) grado, intervalo PR 400 ms, bloqueo completo de rama derecha del haz de His, bloqueo del fasciculo anterior de la rama izquierda del haz de His, duracion del QRS 200 ms. Se decidio realizar estimulacion selectiva del haz de His. La resincronizacion cardiaca biventricular convencional en pacientes con presencia de bloqueo completo de la rama derecha del haz de His no esta indicada debido a la pobre respuesta al tratamiento. La estimulacion hisiana permite reclutar la rama bloqueada y reestablecer la conduccion a traves de ella, de tal forma que, en ausencia de necrosis, se logre sincronia biventricular. En el caso presentado el reclutamiento de la rama derecha mediante estimulacion hisiana se reflejo en el restablecimiento de la sincronia biventricular, medida por rastreo de marcas (speckle tracking) e incremento significativo de la fraccion de expulsion del ventriculo izquierdo del 17 al 36.6%, con un incremento absoluto del 19.6%. Cardiac resynchronization therapy has proven to be an effective therapy in patients with left bundle branch block and heart failure. Male, 47 years old, heart failure with a left ventricle ejection fraction of 17%, idiopathic heart failure. ECG with sinus rhythm, 1(st) degree AV block, PR 400 ms, complete right bundle branch block, anterior hemi-fascicle of the left bundle of His, and QRS duration 200 ms. We decided to perform a selective His bundle pacing. In patients with right bundle branch block the biventricular cardiac resynchronization is not indicated due to low treatment response. His bundle pacing allows recruiting the blocked branch and restoring conduction throughout it, therefore, in the absence of necrosis the biventricular synchrony is achieved. We presented a case of His bundle pacing with recruitment of the right bundle branch, which reestablish biventricular synchrony measured by speckle tracking, and with a significant increase of the left ventricle ejection fraction from 17 to 36.6%, with an absolute increase of 19.6%. | Bundle-Branch Block |
Theranostics, a new term consisting of the words therapy" and "diagnostics," represents the concept of selecting specific patients for appropriate drug administration using diagnostics. For the development of a molecular targeting drug, the theranostics approach is effective. Therefore, the market for molecular diagnostics is likely to grow at an extraordinary rate over the next 10 years. In this review, we focus on aptamer-based electrochemical biosensors for theranostics. Aptamers are molecular recognition elements that can bind to various target molecules from small compounds to proteins with affinities and specificities comparable to those of antibodies. Inasmuch as various molecules would be targeted for analysis using theranostics, aptamer-based biosensors would be an attractive format because they can be developed for various molecules using the same sensing format. Although a diverse sensing system can be constructed, we focus on electrochemical biosensors in this review because they can measure biomarkers rapidly in a miniaturized sensing system with low cost, such as blood glucose sensors. We summarize the sensing systems of aptamer-based electrochemical biosensors and discuss their advantages for theranostics." | Conductometry |
BACKGROUNDS: Survival and aortic-related adverse events after thoracic endovascular aortic repair (TEVAR) for aortic intramural hematoma (IMH) and aortic dissection (AD) are controversial. We aimed to assess the preoperative characteristics and to evaluate TEVAR outcomes of acute type B IMH and AD. METHODS: Between June 2002 and May 2021, 83 patients with acute type B IMH and 755 patients with acute type B AD underwent TEVAR at the General Hospital of Northern Theater Command. We retrospectively analyzed data from these patients, including clinical characteristics and follow-up outcomes. RESULTS: The patients with IMH were significantly older than the ones with AD (P < 0.001). Diabetes mellitus (P = 0.035) and ischemic cerebrovascular disease (P = 0.017) were more common in the IMH group than in the AD group. The results demonstrated a less long-term aortic-related death-free survival rate in the IMH group than the AD group for all the patients (P = 0.014) and the matched patients (P = 0.027). It also presents a lower long-term overall survival rate (P = 0.047) and aortic-related event-free rate (P = 0.048) in the IMH group than in the matched patients. CONCLUSIONS: Compared with AD patients, patients with IMH who underwent TEVAR had a worse long-term outcome of aortic-related survival in all and matched patients. | Aortic Intramural Hematoma |
Statistical methods for molecular dating of viral origins have been used extensively to infer the time of most common recent ancestor for many rapidly evolving pathogens. However, there are a number of cases, in which epidemiological, historical, or genomic evidence suggests much older viral origins than those obtained via molecular dating. We demonstrate how pervasive purifying selection can mask the ancient origins of recently sampled pathogens, in part due to the inability of nucleotide-based substitution models to properly account for complex patterns of spatial and temporal variability in selective pressures. We use codon-based substitution models to infer the length of branches in viral phylogenies; these models produce estimates that are often considerably longer than those obtained with traditional nucleotide-based substitution models. Correcting the apparent underestimation of branch lengths suggests substantially older origins for measles, Ebola, and avian influenza viruses. This work helps to reconcile some of the inconsistencies between molecular dating and other types of evidence concerning the age of viral lineages. | Rinderpest virus |
PURPOSE: The aim of this study was to compare the efficacy of the topical regimens of iodine/steroids vs. antibiotics/steroids in acute to subacute adenoviral keratoconjunctivitis. STUDY DESIGN: A prospective open-label study. PATIENTS AND METHODS: Nineteen patients diagnosed with unilateral or bilateral adenoviral conjunctivitis at less than 1 week from onset were enrolled in this study. Patients were divided randomly into two groups; group 1 was treated with 1.5% levofloxacin with 0.1% fluorometholone administered four times a day and group 2 was treated with a sixfold dilution of polyvinyl alcohol iodine (PAI) solution with 0.1% fluorometholone four times a day. Conjunctival samples from all affected eyes were obtained for real-time PCR. The total scores of acute signs (i.e., eyelid edema, conjunctival injecton, conjunctival discharge, follicules, pseudomembranes, subconjunctival hemorrhage) and symptoms, HAdV DNA copy number, and the presence of multiple subepithelial corneal infiltrates (MSI) were evaluated every 5 visits up to Day 30 after diagnosis. RESULTS: Comparing the total scores of acute signs and symptoms and viral load, we observed no significant differences between the two groups. At day 15 after diagnosis the proportion of patients with MSI in group 2 (35.7%) was significantly lower than in group 1 (0%). CONCLUSIONS: The impact of topical iodine/steroid therapy on acute signs and symptoms associated with adenoviral conjunctivitis is limited and not substantially different in the responses to antibiotics/steroids. However, this regimen results in a significant decrease in the incidence of MSI during the subacute phase of infection. | Fluorometholone |
Methylxanthines have been used in clinical practice for over 100 years, and although understanding of their mechanisms of action is growing their effects are not fully understood. Nevertheless the knowledge to date has brought about a general upsurge of interest in methylxanthines and the development of novel derivatives. Methylxanthines are poised to escape the confines of their traditional role as these agents are applied in novel ways to surgical illnesses such as septic shock, the adult respiratory distress syndrome, cancer cachexia and functional neutrophil disorders. Methylxanthines, alone or in combination with other compounds, may well become part of the surgeon's future stock-in-trade. | Pentoxifylline |
Major depressive disorder is the greatest burden of developed countries in the context of morbidity caused by mental disorders. Until recent, ketamine has been mostly used for anesthesia, analgesia, sedation and treatment of chronic pain syndromes. However, unique pharmacodynamic properties of ketamine have increased interests in it's use for treatment of depression. It is assumed that ketamine reverses synaptic chronic stress pathology within one day of administration by postsynaptic glutamate activation, providing synaptic connectivity restoration that last for days or weeks. Potential glutamatergic agents, in context of treatment of major depressive disorder are not entirely novel phenomenon. Considering the aforementioned, current neurobiological view of depression as a solely monoaminergic phenomenon should be reassessed in order to prompt discovery of putative antidepressant drugs of novel generation. Acute side effects, such as increased salivation, increase in heart rate, systemic arterial pressure and intracranial pressure necessitate careful monitoring during intravenous administration of ketamine, even in subanesthetic doses. However, major burden of ketamine administration lies in it's ability to produce psychotomimetic side effects and emergence delirium. Esketamine nasal spray has now been widely approved and is considered safe in terms of acute side effects, tolerability and consistent therapeutic benefit. | Ketamine |
Propofol, an intravenous general anaesthetic, exerts anaesthetic actions through interaction with gamma-aminobutyric acid type A (GABA(A)) receptors in the supraspinal nervous system. However, whether propofol has any significant effects on synaptic transmission at the spinal level and whether it exhibits antinociceptive action is still not fully clarified. Spontaneous activity and stimulus-evoked responses of substantia gelatinosa (SG) neurones to noxious pinch stimuli were recorded using spontaneously breathing rats under propofol anaesthesia using in vivo whole-cell patch-clamp techniques. Precise actions of propofol on GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) as well as excitatory postsynaptic currents (EPSCs) in SG neurones were also analyzed in spinal cord slice preparations. At clinical doses (5 mg/kg), propofol reversibly depressed action potentials elicited by noxious mechanical stimuli applied to the skin in the majority (6/8) of SG neurons recorded under in vivo conditions. This depression may have been caused by interactions of propofol with GABA(A) receptors, as decay time of GABAergic sIPSCs was prolonged after propofol injection (128 +/- 11% of control, n = 5) with minimal effect on EPSCs. Although prolongation of IPSCs in vivo was reversible, IPSCs were progressively prolonged even after washout of propofol when the effect was tested using spinal cord slices. Propofol had a mild depressant effect on Adelta- and C-afferent-mediated EPSCs. We conclude that systemic bolus injection of propofol reversibly depressed nociceptive transmission, at least in part, by enhancing postsynaptic GABA(A) receptor-mediated responses in the SG. | Substantia Gelatinosa |
This study investigated effects of dietary fumonisins (FBs) on gut and faecal microbiota of weaned pigs. In total, 18 7-week-old male pigs were fed either 0, 15 or 30 mg FBs (FB(1) + FB(2) + FB(3))/kg diet for 21 days. The microbiota was analysed with amplicon sequencing of the 16S rRNA gene V3-V4 regions (Illumina MiSeq). Results showed no treatment effect (p > 0.05) on growth performance, serum reduced glutathione, glutathione peroxidase and malondialdehyde. FBs increased serum aspartate transaminase, gamma glutamyl-transferase and alkaline phosphatase activities. A 30 mg/kg FBs treatment shifted microbial population in the duodenum and ileum to lower levels (compared to control (p < 0.05)) of the families Campylobacteraceae and Clostridiaceae, respectively, as well as the genera Alloprevotella, Campylobacter and Lachnospiraceae Incertae Sedis (duodenum), Turicibacter (jejunum), and Clostridium sensu stricto 1 (ileum). Faecal microbiota had higher levels of the Erysipelotrichaceae and Ruminococcaceae families and Solobacterium, Faecalibacterium, Anaerofilum, Ruminococcus, Subdoligranulum, Pseudobutyrivibrio, Coprococcus and Roseburia genera in the 30 mg/kg FBs compared to control and/or to the 15 mg/kg FBs diets. Lactobacillus was more abundant in the duodenum compared to faeces in all treatment groups (p < 0.01). Overall, the 30 mg/kg FBs diet altered the pig gut microbiota without suppressing animal growth performance. | Fumonisins |
It has been widely accepted that ergot is a fungal disease caused by infection with the parasitic Claviceps purpurea leading to the development of typical black kernels n the plant. Ingestion of infected rye grains containing ergot alkaloids-usually in the form of contaminated rye bread-causes poisoning, also known as ergotism. The negative impacts of ergot contamination of grain on the health of humans and animals were first documented in ancient times. The history of ergotism shows the influence of food on human health. Although ergot has been known for ages, until the 18th century, its nature was not recognized. It was a part of the rye plant and it was used in traditional medicine. The diet was based was mostly on rye that led to neurologic disorders and gangrene. In the Middle Ages, in regions where rye was a dietary staple, many cases of a peculiar epidemic were recorded. Two names are usually used to describe it: Saint Anthony's fire" and "holy fire," although there are many more appellations. The history of ergotism is a very important part of history of dermatology. The saint who people prayed to for protection against the disease was Anthony the Great (251-356). Monks of the Order of Saint Anthony played a particular role in treating ergotism by natural methods and specialized in treating skin diseases. Ergot alkaloids still pose a risk to human and animal safety if they appear in food." | Claviceps |
Fourteen patients with malignant gliomas were entered on a phase II study of 5-fluorouracil 300-370 mg/m2 plus folinic acid 200 mg/m2 x 5 days q4 weeks. To be eligible, patients could not have received more than 1 prior chemotherapy regimen. A single patient with a recurrent oligodendroglioma responded. Toxicity (predominantly stomatitis, diarrhea, and granulocytopenia) was tolerable and was similar to that seen in studies of 5-fluorouracil plus folinic acid in other tumor types. This regimen has minimal activity in recurrent malignant gliomas. | Formyltetrahydrofolates |
OBJECTIVE: Most chronic disease self-management interventions emphasise the integral role of self-efficacy in achieving behaviour change. We explored the applicability of this model in a low-income setting, from the perspective of both patients and clinicians. METHODS: Interviews with multimorbid patients and their health providers at two rural community health centres in Victoria, Australia. We used a phenomenological methodology, exploring themes of confidence to manage health, outcome expectations and goals. RESULTS: Many assumptions in which the self-efficacy model is grounded did not apply to this population. Past experiences and resource constraints, especially poverty and healthcare access, influenced confidence, expectations and the ability to achieve desired outcomes. DISCUSSION: The focus of traditional self-management support on individual behaviour change disadvantages rural low-income patients, who face barriers related to life experience and resource constraints. For this group, self-management support needs to return to its roots, moving away from a narrow conception of behaviour change and reinstating the role of 'support' into 'self-management support' interventions. Health providers working in rural low-income settings should recognise the limits inherent in self-efficacy focussed interventions and think broadly about engaging with their clients in whatever way supports them to find a life with meaning and purpose. | Self Efficacy |
Generation and maintenance of a cancer complexity and robustness are impossible without hydrogen element. It is essential element for the cancer signaling through the AKT locus. Hyperactivated AKT locus by a positive feedback loops from the cancer hypoxic microenvironment generates a hydrogen bond network. Such network initiates protein-protein interaction at the AKT active site and at the same time stabilizes signal propagation. A hydrogen bond network conforms an entropy/enthalpy energetic process used for the interconversion of the AKT protein in metastasis formation and maintenance. Targeting the AKT locus by the redox balance change or hydrogen balance change or proton beam radiation disrupts a hydrogen bond network leading to the disappearance of a cancer complexity and robustness causing failure of the complex energy system in solid cancers and hematological malignancy. J. Cell. Biochem. 119: 130-133, 2018. (c) 2017 Wiley Periodicals, Inc. | Proto-Oncogene Proteins c-akt |
The present study was aimed at enhancing phytase (Phy-Ck) production from Citrobacter koseri PM-7 using response surface methodology (RSM) and improving the bioaccessibility of minerals (Fe and Zn) and protein digestibility in high-phytate food using Phy-Ck. A five-variable and three-level central composite design of RSM using wheat bran (6.681%, w/v), inoculum level (2.5%, v/v), and triton X-100 (0.2%, v/v) resulted in up to 5.57-fold (1.047 U/ml) improvement in Phy-Ck yield from C. koseri PM-7 when compared with fermentation media I and II. The model was successfully validated in the design space by taking a random set of variable combinations. Treatment of high-phytate food with partially purified Phy-Ck showed improvement in mineral bioaccessibility maximally for defatted sesame flour (DSF) (Fe 45.5%; Zn 50.7%) followed by wheat flour (WF) (Fe 13.5%; Zn 14.4%), green gram flour (GGF) (Fe 0.7%; Zn 3.8%) and defatted groundnut flour (DGF) (Zn 5.6%). The in vitro protein digestibility (IVPD) of WF increased from 48.83 to 65.04%, GGF from 45.04 to 57.12%, and DSF from 47.34 to 55.7% after Phy-Ck treatment. | Citrobacter koseri |
The observation by Todd (1964) of a diffuse fibrinolytic activity related to the human endometrium in its secretory stage initiated a reinvestigation of the development of fibrinolytic activity in the uterus and vagina of the rat using the histochemical fibrin slide technique. In addition to the plasminogen activator known to be related to uterine vessels, in the rat in particular to myometrial arteries, diffuse fibrinolytic activity appeared fleetingly at the endometrial surface epithelium in relation to the oestrous cycle. Endometrial glandular epithelium remained inactive. The fibrinolytic activity of the endometrial epithelium is presumably released during cellular degeneration in the secretory phase. The vaginal epithelium produced fibrinolytic activity at an earlier phase of the ovarian cycle than did the endometrial epithelium. | Uterus |
Verticillium wilt, caused by the fungal pathogen Verticillium dahliae, is the major cause of disease-related yield losses in cotton (Gossypium hirsutum). Despite these losses, the major cultivars of G. hirsutum remain highly susceptible to Verticillium wilt. The lack of understanding on the genetic basis for Verticillium wilt resistance may further hinder progress in deploying elite cultivars with proven resistance, such as the wilt resistant G. hirsutum cultivar Zhongzhimian No. 2. To help remedy this knowledge gap, we sequenced the whole genome of Zhongzhimian No. 2 and assembled it from a combination of PacBio long reads, Illumina short reads, and high-throughput chromosome conformation capture technologies. The final assembly of the genome was 2.33 Gb, encoding 95,327 predicted coding sequences. The GC content was 34.39% with 99.2% of the bases anchored to 26 pseudo-chromosomes that ranged from 53.8 to 127.7 Mb. This resource will help gain a detailed understanding of the genomic features governing high yield and Verticillium wilt resistance in this cultivar. Comparative genomics will be particularly helpful, since there are several published genomes of other Gossypium species. [Formula: see text] Copyright (c) 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license. | Verticillium |
The Mr = 160,000 epidermal growth factor (EGF) receptor in A431 cells is partially cleaved during membrane isolation to a Mr = 145,000 polypeptide containing both EGF binding and phosphate acceptor sites. We show that the proteolytic degradation of the EGF receptor depends upon the presence of Ca2+ in the medium used to scrape the cells from the substratum. Only the high molecular weight form of the receptor is detected in membranes prepared in the absence of Ca2+. Ca2+-dependent proteolysis occurs rapidly (t1/2 approximately 5 min) following cell scraping. Proteolysis results in a decrease in EGF-dependent phosphorylation of the receptor while retaining EGF binding capacity. In addition, membranes containing the uncleaved form of the receptor reveal a substantial increase in EGF-dependent phosphorylation of proteins with Mr approximately 80, 89, and 185 X 10(3). In the presence of Ca2+, addition of iodoacetic acid to the scraping medium strongly inhibits receptor fragmentation, whereas other inhibitors (phenylmethylsulfonyl fluoride, leupeptin, and pepstatin) have no effect. The results implicate a role for a Ca2+-dependent, SH-sensitive protease in EGF receptor degradation. Prevention of proteolysis yields membrane preparations with highly active EGF-dependent kinase system. | Iodoacetates |
Nitric oxide (NO) was first detected in mammals and has since been found in plants and in micro-organisms such as bacteria. NO is an important signalling molecule involved in a number of critical signal transduction pathways. To date, NO has not been directly detected in fungi, and little research on NO and fungi has been completed. Here, the role of NO in the germination of Colletotrichum coccodes conidia was investigated. Conidia were germinated on microscope slides, treated with chemicals to block NO, to add NO, and/or to detect NO, and assessed for their stage of development over 24 h. NO was detected in germinating conidia at all stages of development. Exogenous NO delayed germination, while treatment with NO inhibitors accelerated germination, suggesting NO may have a regulatory effect in germination. The differential effect of the various inhibitors suggests the fungal isoform of nitric oxide synthase (NOS) may be biochemically similar to mammalian constitutive NOS. | Colletotrichum |
Three new insecticide smear preparations for the control of Chrysomya bezziana larvae infesting wounds of cattle have been tested under field and laboratory conditions and compared with an established preparation EQ 335 which is based on 3% lindane. Two preparations based on 3% coumaphos proved comparable to EQ 335 in the field trials and exhibited more prolonged residual effectiveness in laboratory tests. A smear preparation based on 2.5% methoxychlor was only effective in controlling 1 and 2 day-old larvae in wounds and was generally inferior to other smears tested in the laboratory. | Coumaphos |
Noncoding sequences constitute the major part of the human genome and also of pre-mRNAs. Single nucleotide variants in these regions are often overlooked, but may be responsible for much of the variation of phenotypes observed. Mutations in the noncoding part of pre-mRNAs often reveal new and meaningful insights into the regulation of cellular gene expression. Thus, the mechanistic analysis of the pathological mechanism of such mutations will both foster a deeper understanding of the disease and the underlying cellular pathways. Even synonymous mutations can cause diseases, since the primary mRNA sequence not only encodes amino acids, but also encrypts information on RNA-binding proteins and secondary structure. In fact, the RNA sequence directs assembly of a specific mRNP complex, which in turn dictates the fate of the mRNA or regulates its biogenesis. The accumulation of genomic sequence information is increasing at a rapid pace. However, much of the diversity uncovered may not explain the phenotype of a certain syndrome or disease. For this reason, we also emphasize the value of mechanistic studies on pathological mechanisms being complementary to genome-wide studies and bioinformatic approaches. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > 3' End Processing RNA in Disease and Development > RNA in Disease. | Gene Expression Regulation |
London's Guy's and St Thomas' NHS Foundation Trust has installed a complete barrier laundry system from Electrolux Professional at its St Thomas' Hospital location for specialist washing of an estimated 7,000 microfibre cloths and 5,000 microfibre mops each day from both the St Thomas' and Guy's Hospital sites. Since the installation, as Electrolux Professional national account manager Kurt Fryer reports, the cost-effective" equipment's high performance has seen laundry staff achieve a significant increase in productivity." | Laundry Service, Hospital |
High temperature requirement protein A1 (HtrA1), a secreted serine protease of the HtrA family, is associated with a multitude of human diseases. However, the exact functions of HtrA1 in these diseases remain poorly understood. We seek to unravel the mechanisms of HtrA1 by elucidating its interactions with chemical or biological modulators. To this end, we screened a small molecule library of 500 bioactive compounds to identify those that alter the formation of extracellular HtrA1 complexes in the cell culture medium. An initial characterization of two novel hits from this screen showed that protoporphyrin IX (PPP-IX), a precursor in the heme biosynthetic pathway, and its metalloporphyrin (MPP) derivatives fostered the oligomerization of HtrA1 by binding to the protease domain. As a result of the interaction with MPPs, the proteolytic activity of HtrA1 against Fibulin-5, a specific HtrA1 substrate in age-related macular degeneration (AMD), was increased. This physical interaction could be abolished by the missense mutations of HtrA1 found in patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Furthermore, knockdown of HtrA1 attenuated apoptosis induced by PPP-IX. These results suggest that PPP-IX, or its derivatives, and HtrA1 may function as co-factors whereby porphyrins enhance oligomerization and the protease activity of HtrA1, while active HtrA1 elevates the pro-apoptotic actions of porphyrin derivatives. Further analysis of this interplay may shed insights into the pathogenesis of diseases such as AMD, CARASIL and protoporphyria, as well as effective therapeutic development. | Protoporphyrins |
PURPOSE: Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. DESIGN: Meta-analysis of prevalence data. PARTICIPANTS: A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. METHODS: AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). MAIN OUTCOME MEASURES: Prevalence of early and late AMD, BCVA, and number of AMD cases. RESULTS: Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%-5.0%) in those aged 55-59 years to 17.6% (95% CI 13.6%-21.5%) in those aged >/=85 years; for late AMD these figures were 0.1% (95% CI 0.04%-0.3%) and 9.8% (95% CI 6.3%-13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer >/=80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million. CONCLUSION: We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti-vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans. | Geographic Atrophy |
Zika virus (ZIKV) is emerging as a significant pathogen worldwide and may cause severe neurological disorders such as fetal microcephaly and Guillain-Barre syndrome. No drug or listed vaccines are currently available for preventing ZIKV infection. As a major target of neutralizing, ZIKV envelop (E) protein usually used for vaccine development. Nevertheless, the immunogenicity of ZIKV envelop (E) protein expressed by baculovirus display system has never been assessed. In this study, we reported a new strategy for surface display of ZIKV E protein by a recombinant baculovirus vector derived from Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) and assessed its immunogenicity in mice. We produced recombinant fusion ZIKV E protein linked with signal peptide (SP) and transmembrane domain (TM) of AcMNPV GP64. The results showed that the recombinant protein was easy to produce by baculovirus display system. BALB/c mice immunized with this recombinant E protein developed ZIKV specific serum antibodies. The anti-E protein sera from the mice were able to effectively neutralize ZIKV in vitro. More importantly, AG6 (IFN-alpha/beta and IFN-gamma receptor deficient) mice immunized with recombinant E protein were protected against lethal ZIKV challenge. Together, these findings demonstrated that the recombinant E protein displayed by baculovirus can be conveniently prepared and displayed good immunogenicity in immunized mice. It is a promising practical approach for prompting the development of vaccine and related immunology research. | Viral Envelope |
1. (R)-(+)-Pulegone is a monoterpene that is oxidized by cytochromes P-450 to reactive metabolites that initiate events in the pathogenesis of hepatotoxicity in mice, rats and humans. 2. Selective labelling of (R)-(+)-pulegone with deuterium revealed that menthofuran was a proximate hepatotoxic metabolite formed by oxidation of the allylic methyl groups of pulegone. Incubations of pulegone with mouse liver microsomes in an atmosphere of 18O2 resulted in the formation of menthofuran that contained only oxygen-18 in the furan moiety. These results are consistent with oxidation of pulegone to an allylic alcohol that reacts intramolecularly with the ketone moiety to form a hemiketal that subsequently dehydrates to generate menthofuran. 3. Studies on the metabolism of menthofuran revealed that it is oxidized by cytochromes P-450 to an electrophilic gamma-ketoenal that reacts with nucleophilic groups on proteins to form covalent adducts. In addition, diastereomeric mintlactones are formed. Investigations with H2(18)O and 18O2 are indicative of a furan epoxide intermediate, or a precursor, in the formation of the gamma-ketoenal and mintlactones. | Cyclohexane Monoterpenes |
Worldwide, stranded marine mammals and the network personnel who respond to marine mammal mortality have provided much of the information regarding marine morbillivirus infections. An assay to determine the amount of virus present in tissue samples would be useful to assist in routine surveying of animal health and for monitoring large-scale die-off events. False negatives from poor-quality samples prevent determination of the true extent of infection, while only small amounts of tissue samples or archived RNA may be available at the time of collection for future retrospective analysis. We developed a one-step duplex real-time reverse transcriptase-quantitative-PCR assay (RT-qPCR) based on Taqman probe technology to quantify phocine distemper virus (PDV) isolated from an outbreak in harbor (Phoca vitulina concolor) and gray seals (Halichoerus grypus) along the northeast US coast in 2006. The glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) gene was selected to assess RNA quality. This duplex assay is specific for PDV and sensitive through a range of 10(0) to 10(9) copies ds-plasmid DNA. For the GAPDH target, the reaction in duplex amplified 10(0) to 10(9) copies of ds-plasmid DNA and was detectable in multiple seal species. This assay reduced the likelihood of false negative results due to degradation of tissues and well-to-well variability while providing sensitive and specific detection of PDV, which would be applicable in molecular epidemiologic studies and pathogen detection in field and laboratory investigations involving a variety of seal species. | Distemper Virus, Phocine |
IMPORTANCE: Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. OBJECTIVE: To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017. MAIN OUTCOMES AND MEASURES: Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. RESULTS: Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01). CONCLUSIONS AND RELEVANCE: Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance. | Acrylamides |
The treatment of anaplastic large cell lymphoma (ALCL) has largely relied on anthracycline-based chemotherapy. Targeted lymphoma therapy, using an anti-CD30 antibody, provides an innovative treatment modality for specific lymphomas, particularly ALCL. Brentuximab vedotin (BV; SGN-35) uses a CD30 monoclonal antibody to generate apoptosis of targeted lymphoma cells. We present a pediatric patient with ALCL who experienced second relapse after standard chemotherapy and autologous and allogeneic hematopoietic stem cell transplantation. This patient has been treated with BV as a single agent and has sustained remission for several months. BV offers a targeted treatment for relapsed ALCL, even after multiple relapses. | Brentuximab Vedotin |
The effects of intraventricular cycloheximide (CHX) pretreatment were examined on the ability of rats to recall a light position discrimination task. The CHX pretreatment used inhibited brain protein synthesis at the time of training by 71%. Following treatment with CHX the animals demonstrated no retention of the task 18 hr later. Free feeding for 24 hr prior to treatment with cerebro-spinal-like fluid (CSF) produced similar effects as CHX. It is proposed that the amnesic effect of CHX in this behavioral paradigm may be a nonspecific action resulting from decreased motivation. Both the CHX-treated and satiated animals exhibited low responding levels during training, despite comparable behavioral activity levels for the CHX- and CSF-treated groups. | Cycloheximide |
The 2019-novel coronavirus (nCoV) is a major source of disaster in the 21(th) century. However, the lack of specific drugs to prevent/treat an attack is a major need at this current point of time. In this regard, we conducted a systematic review to identify major druggable targets in coronavirus (CoV). We searched PubMed and RCSB database with keywords HCoV, NCoV, corona virus, SERS-CoV, MERS-CoV, 2019-nCoV, crystal structure, X-ray crystallography structure, NMR structure, target, and drug target till Feb 3, 2020. The search identified seven major targets (spike protein, envelop protein, membrane protein, protease, nucleocapsid protein, hemagglutinin esterase, and helicase) for which drug design can be considered. There are other 16 nonstructural proteins (NSPs), which can also be considered from the drug design perspective. The major structural proteins and NSPs may serve an important role from drug design perspectives. However, the occurrence of frequent recombination events is a major deterrent factor toward the development of CoV-specific vaccines/drugs. | Coronaviridae |
BACKGROUND: The perinatal management of congenital complete heart block (CCHB) remains controversial. The purpose of this study was to present a therapeutic modality for CCHB. METHODS: We collected retrospective cases of all pregnant women admitted to our hospital between January 1992 and June 1999 whose babies developed CCHB antenatally. After a series of examinations, maternal, fetal and neonatal data were analyzed. RESULTS: Nine fetuses from six mothers (cases 1-6) in nine different pregnancies were studied. In case 1, both consecutive fetuses had CCHB and in case 2, all three consecutive fetuses had CCHB. The other mothers (cases 3-6) had only one fetus each with CCHB. Of the seven fetuses with isolated CCHB, four underwent observation only due to late-onset, or nonimmunologic CCHB, two received dexamethasone and/or intravenous immunoglobulin therapy because of the presence of hydropic signs, and one received dexamethasone at 23 weeks' gestation due to early-onset CCHB. Shortening fractions of the right ventricle had good compensation in four fetuses, without any treatment, and improving compensation in two of three fetuses receiving dexamethasone therapy. All seven fetuses were delivered smoothly and pacemakers were implanted shortly after birth. Two other fetuses had a poor outcome due to associated ventricular septal defect or hemoglobin Bart's disease. Furthermore, we gave dexamethasone (2 mg/day) instead of prednisolone (10 mg/day) for the next pregnancies of patients 3 to 5, beginning at 12 weeks of gestation. No fetal CCHB developed again. CONCLUSIONS: For pregnant women with previous fetal immunologic CCHB, early initiation of dexamethasone instead of prednisolone might be effective to cross the placenta and avoid recurrences. Dexamethasone is also effective for fetal CCHB of early onset, fetal hydrops or heart failure. Observation only is suggested for nonimmunologic CCHB and remote or late-onset immunologic CCHB. Other modalities were tried for very sick fetuses, but their effectiveness was not predictable. | Heart Block |
Here we report the novel bacteriostatic function of a five-domain Kunitz-type serine protease inhibitor (KPI) from the tick Dermacentor variabilis. As ticks feed, they release anticoagulants, anti-inflammatory and immunosuppressive molecules that mediate the formation of the feeding lesion on the mammalian host. A number of KPIs have been isolated and characterized from tick salivary gland extracts. Interestingly, we observe little D. variabilis KPI gene expression in the salivary gland and abundant expression in the midgut. However, our demonstration of D. variabilis KPI's anticoagulant properties indicates that D. variabilis KPI may be important for blood meal digestion in the midgut. In addition to facilitating long-term attachment and blood meal acquisition, gene expression studies of Drosophila, legumes, and ticks suggest that KPIs play some role in the response to microbial infection. Similarly, in this study, we show that challenge of D. variabilis with the spotted fever group rickettsia, Rickettsia montanensis, results in sustained D. variabilis KPI gene expression in the midgut. Furthermore, our in vitro studies show that D. variabilis KPI limits rickettsial colonization of L929 cells (mouse fibroblasts), implicating D. variabilis KPI as a bacteriostatic protein, a property that may be related to D. variabilis KPI's trypsin inhibitory capability. This work suggests that anticoagulants play some role in the midgut during feeding and that D. variabilis KPI may be involved as part of the tick's defense response to rickettsiae." | Trypsin Inhibitor, Kunitz Soybean |
In humans, the prenatal transfer of IgG from mother to foetus is facilitated by a receptor for IgG on the placenta. However, amniotic fluid contains IgG of maternal origin, and transfer of swallowed IgG into the circulation from the foetal intestine represents another potential pathway of passive immunization. In this study we assayed for a foetal intestinal IgG receptor to support the hypothesis of this alternate pathway of antibody transfer. Microvillous membrane (MVM) from small bowel of aborted foetuses (18 weeks gestation) were probed with [125I]IgG to detect specific IgG binding sites. Binding was pH dependent and was maximal at pH 6. Competitive inhibition of the binding of [125I]IgG was noted with the addition of increasing amounts of unlabelled IgG. Scatchard analysis showed one binding site with a dissociation constant of 1.58 x 10(-7), similar to that of the IgG receptor described on the suckling rat intestine. The binding of labelled IgG to the human MVM receptor was Fc mediated. These observations provide evidence for an Fc receptor on the human foetal intestine. | Immunity, Maternally-Acquired |
OBJECTIVE: To review the literature on various endometrial factors assumed to be of importance to implantation and to evaluate their potential clinical value in the assessment of endometrial function at the time of implantation in infertile women in natural and stimulated cycles. DESIGN: Literature review. RESULT(S): Cytokines such as leukemia inhibitory factor, colony-stimulating factor-1, and interleukin-1 have all been shown to play important roles in the cascade of events that leads to implantation. They participate in a synchronized cooperation between the endometrium and the preimplanting embryo under the influence of steroid hormones. The same applies to the integrin alpha(v)beta(3), glycodelin, and the polymorphic mucin 1. The usefulness of these factors to assess endometrial receptivity and to estimate the prognosis for pregnancy in natural and artificial cycles remains to be proven. CONCLUSION(S): The studies performed to date have mostly included only small groups of patients with a lack of fertile controls, and only a few prospective, controlled trials have been carried out. Therefore, definite conclusions about the clinical value of these factors in the assessment of endometrial function and prognosis for pregnancy after artificial reproductive therapy cannot be drawn at present. Further evaluation of their importance for and function during implantation is needed. | Glycodelin |
First derivative and dual-wavelength spectrophotometric methods were used in the quantum yield determination of the photochemical decomposition reactions of three thiazide diuretics (chlorothiazide, hydrochlorothiazide and trichloromethiazide) in ethanolic solution. The radiation absorbed by the compounds was measured using iron(III) oxalate actinometry based on absorption spectrophotometry. An apparatus is described in which the drugs were irradiated in quartz cuvettes cooled by water in a stand built on a magnetic stirrer. The wavelength region available to the reaction cuvette was restricted to 313 nm with chemical potassium chromate filter solutions and a Corning filter plate. Chlorothiazide proved to be more photostable than hydrochlorothiazide and trichloromethiazide in ethanol. | Thiazides |
The discovery of biogenic magnetic nanoparticles (BMNPs) in the human brain gives a strong impulse to study and understand their origin. Although knowledge of the subject is increasing continuously, much remains to be done for further development to help our society fight a number of pathologies related to BMNPs. This review provides an insight into the puzzle of the physiological origin of BMNPs in organisms of all three domains of life: prokaryotes, archaea, and eukaryotes, including humans. Predictions based on comparative genomic studies are presented along with experimental data obtained by physical methods. State-of-the-art understanding of the genetic control of biomineralization of BMNPs and their properties are discussed in detail. We present data on the differences in BMNP levels in health and disease (cancer, neurodegenerative disorders, and atherosclerosis), and discuss the existing hypotheses on the biological functions of BMNPs, with special attention paid to the role of the ferritin core and apoferritin. | Apoferritins |
Eukaryotic translation initiation factor 2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. Mutations in any of its five subunits lead to leucoencephalopathy with vanishing white matter, an inherited chronic-progressive fatal brain disease with unknown aetiology, which is among the most prevalent childhood white matter disorders. We generated the first animal model for the disease by introducing a point mutation into the mouse Eif2b5 gene locus, leading to R132H replacement corresponding to the clinically significant human R136H mutation in the catalytic subunit. In contrast to human patients, mice homozygous for the mutant Eif2b5 allele (Eif2b5(R132H/R132H) mice) enable multiple analyses under a defined genetic background during the pre-symptomatic stages and during recovery from a defined brain insult. Time-course magnetic resonance imaging revealed for the first time the delayed development of the brain white matter due to the mutation. Electron microscopy demonstrated a higher proportion of small-calibre nerve fibres. Immunohistochemistry detected an abnormal abundance of oligodendrocytes and astrocytes in the brain of younger animals, as well as an abnormal level of major myelin proteins. Most importantly, mutant mice failed to recover from cuprizone-induced demyelination, reflecting an increased sensitivity to brain insults. The anomalous development of white matter in Eif2b5(R132H/R132H) mice underscores the importance of tight translational control to normal myelin formation and maintenance." | Eukaryotic Initiation Factor-2B |
Natural dihydrocoumarin, which is of great interest in the flavor industry, was biotechnologically produced from pure coumarin or tonka bean meal with Pseudomonas orientalis, Bacillus cereus, and various Saccharomyces cerevisiae strains. Coumarin was shown to be converted to melilotic acid, which yielded dihydrocoumarin upon distillation during purification. About 1.0 g/L product was obtained from 25 g/L tonka beans with S. cerevisiae within 147 h. This dihydrocoumarin thus fulfills all of the criteria of a natural raw material and can be used as a natural flavoring in accordance with U.S. and European Union regulations. | Dipteryx |
The use of genetic genealogy techniques to identify Joseph James DeAngelo as the prime suspect in the Golden State Killer case in 2018 has opened up a new approach to investigation of cold cases. Since that breakthrough, genetic genealogy methods have been reported to be applied to around 100 cases. To date, all of these reports relate to investigations in the US, where the high uptake of "direct-to-consumer" (DTC) genetic testing by individuals conducting private ancestral research has provided the necessary publicly available data for successful forensic investigations. We have conducted a study to assess the likely effectiveness of genetic genealogy techniques if applied to investigations in the UK. Ten volunteers provided their own SNP array data, downloaded from a DTC provider of their choice. These data sets were anonymised and uploaded to the GEDmatch Genesis genealogy website, mimicking data sets from unsourced crime samples or unidentified human remains. A team of experienced genealogists then attempted to identify the donors of the anonymised data sets by working with matches on the database and identifying points where the matches' trees intersect to determine their shared family lineages which were further investigated using traditional resources (such as birth, marriage, death and census records, social media and online family trees). Through these methods, four of the ten donors were identified, at least to the level of one of a set of siblings. This confirms that, despite the over-representation of US citizens on publicly accessible genealogy databases, there is still potential for effective use in investigations outside the US where legislation permits. One of our four identified individuals was of Indian heritage (via St Vincent and the Grenadines) highlighting that in the right circumstances individuals of non-European origin can be identified." | Direct-To-Consumer Screening and Testing |
This is the first study based on a planned and intensive sampling effort that describes the community composition and structure of the ground-dwelling arthropod assemblage of Peninsula Valdes (Patagonia). It was carried out using pitfall traps, opened for two weeks during the summers of 2005, 2006 and 2007. A total of 28,111 individuals were caught. Ants(Hymenoptera: Formicidae) dominated this community, followed by beetles (Coleoptera) and spiders (Araneae). The most abundant species were Pheidole bergi Mayr (Hymenoptera:Formicidae) and Blapstinus punctulatus Solier (Coleoptera: Tenebrionidae). Two new species were very recently described as new based on specimens collected during this study: Valdesianacuriosa Carpintero, Dellape & Cheli (Hemiptera, Miridae) and Anomaloptera patagonica Dellape& Cheli (Hemiptera, Oxycarenidae). The order Coleoptera was the most diverse taxa. The distribution of abundance data was best described by the logarithmic series model both at the family and species levels, suggesting that ecological relationships in this community could be controlled by a few factors. The community was dominated by predators from a trophic perspective. This suggests that predation acts as an important factor driving the distribution and abundances of surface-dwelling arthropods in this habitat and as such serves as a key element in understanding desert, above-ground community structure. These findings may also be useful for management and conservation purposes in arid Patagonia. | Arthropods |
Retroviruses must selectively recognize their unspliced RNA genome (gRNA) among abundant cellular and spliced viral RNAs to assemble into newly formed viral particles. Retroviral gRNA packaging is governed by Gag precursors that also orchestrate all the aspects of viral assembly. Retroviral life cycles, and especially the HIV-1 one, have been previously extensively analyzed by several methods, most of them based on molecular biology and biochemistry approaches. Despite these efforts, the spatio-temporal mechanisms leading to gRNA packaging and viral assembly are only partially understood. Nevertheless, in these last decades, progress in novel bioimaging microscopic approaches (as FFS, FRAP, TIRF, and wide-field microscopy) have allowed for the tracking of retroviral Gag and gRNA in living cells, thus providing important insights at high spatial and temporal resolution of the events regulating the late phases of the retroviral life cycle. Here, the implementation of these recent bioimaging tools based on highly performing strategies to label fluorescent macromolecules is described. This report also summarizes recent gains in the current understanding of the mechanisms employed by retroviral Gag polyproteins to regulate molecular mechanisms enabling gRNA packaging and the formation of retroviral particles, highlighting variations and similarities among the different retroviruses. | Gene Products, gag |
Vascular calcification (VC) is one of the most dramatic consequences of chronic kidney disease (CKD). It has been considered a passive process, resulting essentially from mineral metabolism disorders and alterations in calcium and phosphate balance. But during the last decade, it has been elucidated how VC is not only a passive but more properly an active process, in which different factors are deeply involved. The progression of vessel wall mineralization is commonly associated with factors that promote VC, such as age, dialysis vintage and mineral metabolism abnormalities. Furthermore, many substances seem to be dynamically implicated in the regulation of the molecular mechanisms of VC. Between them, the matrix Gla protein and fetuin-A have recently been investigated in CKD. In this review, along with the most promising possible treatments, the new molecular mechanisms involved in the VC process will be elucidated. | Fetuins |
Losartan binds selectively to the angiotensin II subtype 1 receptor, blocking the activity of angiotensin II. Losartan 50-100 mg/day was compared with atenolol 50-100 mg/day in patients with essential hypertension and left ventricular hypertrophy (LVH) [n = 9,193] in the randomized, double-blind Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Two substudies compared these drugs in patients with diabetes mellitus (n = 1,195) or isolated systolic hypertension (ISH) [n = 1326]. The target BP (<140/90 mm Hg) was achieved in approximate, equals 45% of losartan and atenolol recipients in the LIFE study. Significant regression of LVH occurred with losartan versus atenolol in the LIFE study, as well as in the diabetes mellitus and ISH substudies. In the LIFE study, although BP reduction was similar for the two treatments, the risk of a cardiovascular event (the composite of cardiovascular death, stroke, and myocardial infarction; primary endpoint), stroke, or new-onset diabetes mellitus was significantly lower with losartan than with atenolol. Losartan was generally well tolerated in patients with hypertension and LVH in the LIFE study. Significantly fewer losartan than atenolol recipients discontinued treatment because of adverse events, drug-related adverse events, or serious, drug-related adverse events. | Losartan |
Purpose: To assess the efficacy of interferon (IFN) alpha-2a in the treatment of post-uveitic refractory macular edema (ME).Methods: Retrospective cohort of patients with post-uveitic refractory ME, who received subcutaneous IFN alpha-2a injections for at least 3 months. Baseline central macular thickness (CMT) and best-corrected visual acuity (BCVA) were compared with those at follow-up visits up to 12 months.Results: Thirty-seven patients were included. Treatment duration (median [interquartile range]) was 14[8-24] months with a follow-up of 17[10-38] months. CMT (mean [standard deviation]) decreased from 438[140] to 335[119] mum after 1 month (p < 0.0001) and remained significantly lower up to 12 months (286[98] mum, p = 0.001). BCVA (0.48[0.33] logMAR at baseline) improved by 0.26[0.33] logMAR (p = 0.001) at 12 months. There were 14 recurrences. Seven patients had treatment side effects, without serious adverse events.Conclusions: IFN alpha-2a was effective, safe, and well tolerated in treating post-uveitic refractory ME. | Interferon alpha-2 |
The term 'chronicity' is still widely used in psychiatric discourse and practice. A category employed in political, administrative and therapeutic contexts, it guides practitioners' beliefs and actions. This paper attempts a review of the attitudes and procedures that result as a consequence of identifying 'chronically' disturbed identities in clinical practice. An essentially social, relational and materialist understanding of mental illness is used to highlight the kind of thinking underlying the notion of 'chronic' identities in day-to-day psychiatric routines. Problematising the notions of singularity and expressiveness, as well as mind/body- and self/other-distinctions, it claims the category itself is responsible for creating a 'chronic' kind of being. A spatial metaphor is presented in the conclusion, illustrating a mental strategy by which we can re-shape our thinking about 'chronic' identities. It attempts to describe how the shift from an epistemological to a praxeographic approach could build a more complete understanding of mental illness. | Anthropology, Medical |
In this study, we sought to validate the importance of p63, CK5/CK6, CK7, and surfactant-A (SP-A) to classify 42 non-small cell lung cancers in autopsy and surgical resection specimens and to study the usefulness of these markers in distinguishing between squamous cell carcinomas and adenocarcinomas because of their different implications regarding treatment and prognosis. All adenocarcinoma cases were negative for p63; 9 (56.2%) of 16 were CK5/CK6 positive, 16 (94.1%) of 17 were CK7 positive, and 4 (26.6%) of 15 were SP-A positive. In squamous cell carcinoma, 1 case was CK7 and SP-A positive and 14 (77.8%) of 18 were p63 positive. The latter appears to be useful in differentiating squamous cell carcinoma from adenocarcinoma of the lung in small biopsies without keratinization or glandular differentiation; thus, for advanced-stage cases, where there is no possibility of surgical resection and the treatment of choice is radiotherapy plus chemotherapy, we would be able to differentiate between the two histological types, establishing then a different therapy. | Keratin-6 |
In the present study, Marteilia sp. was detected by histological examination and in situ hybridisation in Ostrea edulis and Ostrea stentina collected in southern Iberian Peninsula. Marteilia refringens DNA was detected by PCR in O. edulis (collected in southern Portugal) and O. stentina (collected in southern Spain and Portugal). Sequencing analysis revealed the presence of M. refringens type O in O. edulis, and type O and M in O. stentina. This is the first confirmed detection of M. refringens in Portugal and the first report on the occurrence of M. refringens infecting O. stentina in Europe. | Cercozoa |
The results of long experience with psychotropic drugs in the treatment of chronic and severe pain resistant to ordinary therapy are reported. In 103 in-patients with chronic and severe pain caused by neurological conditions and treated with a combination of thymoleptics and neuroleptics, 82% showed a marked improvement. These encouraging results are compared with the results of other studies published in this field. The pharmacological basis of this good action is briefly discussed, together with the advantages of the use of psychotropic drugs and especially the combination of thymoleptics and neuroleptics. A clearcut dosage schedule for in- and out-patients using imipramine (Tofranil) or chlorimipramine (Anafranil) and haloperidol (Haldol) is established. | Methotrimeprazine |
B and T lymphocytes of the adaptive immune system undergo proliferative bursts to generate pools of antigen-specific cells for effective immunity. Here we show that in contrast to the canonical view that G1 progression signals are essential after mitosis to reenter S phase, B lymphocytes sustain several rounds of mitogen-independent cell division following the first mitosis. Such division appears to be driven by unique characteristics of the postmitotic G1 phase that has features of S and G2/M phases. Birc5 (survivin), a protein associated with chromosome segregation in G2/M, is expressed in the G1 phase of divided B cells and is necessary for mitogen-independent divisions. The partially active G1 phase and propensity for apoptosis inherited after each division may underlie rapid proliferation and cell death, which are hallmarks of B cell proliferative responses. | Survivin |
Reconstruction strategies for aortic valve insufficiency in the presence of aortic annulus dilatation are usually surgically challenging. We demonstrate a simple, modified Taylor technique of downsizing and stabilization of the aortic annulus using a single internal base suture. Since April 2011, 22 consecutive patients have undergone safe aortic valve annuloplasty. No reoperations for aortic valve insufficiency and no deaths occurred. | Cardiac Valve Annuloplasty |
Mouse mammary tumor virus, a type-B retrovirus, was shown to mediate fusion of cultured cells following low-pH treatment. Fusion could be demonstrated both with virus-infected cells or with uninfected cells carrying freshly absorbed virus. Although the fusion response was variable between different cell lines, one line of MMTV-infected mink lung cells, designated MGR4, was particularly susceptible to fusion at reduced pH. Since expression of MMTV in these cells is strongly regulated by glucocorticoids, it was possible to demonstrate that cell fusion was dependent on MMTV-encoded functions. With MGR4 cells, a pH threshold for membrane fusion was observed, centered on pH 5.5, at which 50% of the cells were fused. At lower pHs virtually all of the cells in the monolayer fused. These results are similar to those described for other virus groups and are consistent with the idea that most enveloped animal viruses infect cells by a common mechanism involving membrane fusion triggered by low pH. | Cell Fusion |
1. The distribution of fusimotor axons to bag1, bag2 and chain muscle fibres in cat tenuissimus spindles has been studied using a modification of the glycogen-depletion technique of Edstrrom & Kugelberg (1968). Single fusimotor axons were stimulated intermittently at 40-100/sec for long periods (30-90 sec) during blood occlusion. Portions of muscle containing the activated spindles were quick-frozen, fixed in absolute ethanol during freeze-substitution, and then embedded in paraffin wax. Serial transverse sections were stained for glycogen using the periodic acid-Schiff method, and examined for depletion. 2. Dynamic gamma axons (i.e. those that increase the dynamic index of primary-ending responses to ramp stretches of large amplitude) depleted bag1 fibres almost exclusively. 3. Static gamma axons (i.e. those that reduce or abolish the dynamic index) depleted both bag and chain fibres. Bag1 and bag2 fibres were depleted about equally. 4. A single static gamma axon may activate both bag and chain fibres in one spindle (the most common pattern), chain fibres only in another, and bag fibres only in a third spindle. 5. Static gamma axons with conduction velocities less than 25 m/sec also had a non-selective distribution, but no depletion was observed in bag2 fibres. 6. The zones of depletion produced by dynamic gamma axons were distributed more or less equally in the intra- and extracapsular parts of spindle poles, whereas those produced by static gamma axons were mainly intracapsular. 7. The results are compared with the glycogen-depletion studies of Brown & Butler (1973, 1975) and our own study of the distribution of static gamma axons to spindles in which all other motor axons had degenerated (Barker, Emonet-Denand, Laporte, Proske & Stacey, 1973). The implications of the finding that both static gamma and dynamic gamma axons activate bag1 fibres are discussed. | Muscle Spindles |
The application of bone morphogenetic protein 2 (BMP-2) has been extensively investigated to improve diabetes-impaired bone healing; however, the delivery of BMP-2 by gene therapy for bone regeneration has rarely been investigated in diabetic animals. In this study, we aimed to evaluate which cells induce more new bone formation in diabetic animals when cell-based BMP2 gene therapy is applied. For this purpose, we harvested bone marrow stromal cells (BMSCs) twice in the same animal before (non-diabetic BMSCs; nBMSCs) and after diabetes induction (diabetic BMSCs; dBMSCs) using modified bone marrow ablation methods. And then, cells were transduced by adenoviral vectors carrying the BMP2 gene (AdBMP2). In in vitro, AdBMP2-transfected dBMSCs (B2/dBMSCs) produced higher BMP-2 mRNA levels over 48 h, whereas AdBMP2-transfected nBMSCs (B2/nBMSCs) exhibited a transient increase in BMP-2 mRNA followed by a decrease to the baseline level within 48 h. Both B2/dBMSCs and B2/nBMSCs induced secretion of BMP-2 for 3 weeks. However, B2/dBMSC BMP-2 secretion peaked from day 3 to 10, whereas B2/nBMSC BMP-2 secretion peaked from day 1 to 7. The analysis of osteogenic activity revealed that mineralization nodule formation and the expression levels of osteogenic genes were significantly higher in B2/dBMSCs than B2/nBMSCs and were accompanied by upregulation of canonical Wnt/beta-catenin and Smad signaling. AdBMP2-transfected autologous cells were implanted into critical-sized calvarial defects in diabetic animals and induced significantly more bone regeneration than non-AdBMP2-transfected cells. In addition, B2/dBMSCs led to significantly more new bone formation than B2/nBMSCs. Thus, BMP2 gene therapy using diabetic cells effectively supported diabetic bone healing and it was related to the enhanced responses to AdBMP2 of dBMSCs. | Bone Regeneration |
The current adenosine diphosphate inhibitors, ticlopidine and clopidogrel, are thienopyridine compounds that inhibit adenosine diphosphate mediated platelet aggregation. They interfere with platelet activation by selectively and irreversibly blocking P2Y12 sub-unit of the adenosine diphosphate receptor on the surface of platelets. This provides an antiplatelet effect that is additive to the inhibition of the thromboxane A2 pathway by aspirin. Dual antiplatelet therapy is extensively used in cardiovascular medicine. Randomized controlled trials have substantiated the fact that thrombotic complications after percutaneous coronary intervention procedures can be decreased by using dual antiplatelet therapy. However, there is a concern of bleeding due to enhanced and irreversible platelet inhibition in patients who will require any operation including coronary artery bypass grafting while on adenosine diphosphate inhibitors. This applies to a large population of patients requiring either coronary artery bypass grafting after angiographic definition of their coronary anatomy, or patients requiring semi-elective or urgent operation while under dual antiplatelet therapy. This concern is more present in era of drug-eluting stents, where long-term use of dual antiplatelet therapy is encouraged, and the incidence of late thrombosis after late cessation of adenosine diphosphate inhibitors is increasingly surfacing in the literature. The goal this review is to provide the medical chemistry of most commonly used adenosine diphosphate inhibitors, examine the literature on the effect of adenosine diphosphate inhibitors in hemorrhagic-related complications after surgical intervention, and provide the ramifications and alternatives in modern clinical practice. | Adenosine Diphosphate |
In inflammatory cells, the low K(m) cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) 4 subtype is predominant in terms of expression and function, although more recently it has been suggested that PDE 7 may also play a role in regulating inflammatory cell activity. In the present study, PDE 4 and PDE 7 subtype messenger ribonucleic acid (mRNA) transcripts in CD4 and CD8 lymphocytes from healthy (n=10) and asthmatic (n=10) subjects and polymorphonuclear neutrophils (PMNs) and CD8 lymphocytes obtained from healthy (n=10) and chronic obstructive pulmonary disease (COPD) (n=7) subjects were identified and quantified. PDE 4A, PDE 4B, PDE 4D and PDE 7A mRNA were present in similar quantities in both CD4 and CD8 lymphocytes obtained from healthy and asthmatic subjects and in CD8 lymphocytes obtained from healthy and COPD subjects. Expression of PDE 4C and PDE 7B mRNA was also observed, although transcript levels were low and variable between individuals. In addition, the effects of selective PDE 7 inhibition on both phytohaemagluttinin (PHA)-induced human peripheral blood mixed mononuclear cell (HPBMNC) proliferation and fMLP-induced neutrophil elastase (NE) release were studied. HPBMNC and human neutrophils, isolated from the venous blood of healthy volunteers (n=6) were treated with either a novel selective PDE 7 inhibitor PF 0332040 alone or in combination with rolipram. Proliferation of HPBMNC was stimulated by PHA (2microgml(-1)) and assessed by [(3)H]-thymidine incorporation, while fMLP-induced (100nM) NE release was determined using a chromogenic substrate. Both rolipram (0.003-10microM) and PF 0332040 (0.003-10microM) significantly inhibited PHA-stimulated proliferation of HPBMNC ((**)P<0.01). Co-administration of rolipram (0.3-10microM) and PF 0332040 (0.003-10microM) significantly increased the degree of inhibition observed, compared to when either drug was administered alone ((**)P<0.01). PF 0332040 (0.003-10microM) had no inhibitory effect on NE release from human peripheral blood neutrophils stimulated with fMLP (100nM), while rolipram (0.003-10microM) significantly inhibited neutrophil degranulation ((**)P<0.01). These findings suggest no evidence of altered PDE 4 or PDE 7 mRNA transcript levels in inflammatory cells isolated from the peripheral venous blood of mild asymptomatic asthmatic subjects or stable COPD subjects, however, inhibition of PDE 7 may influence mononuclear cell function." | Cyclic Nucleotide Phosphodiesterases, Type 7 |
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