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BACKGROUND: Eruptive syringomas are uncommon eccrine sweat gland tumours. Only 64 cases have been reported in the literature. OBJECTIVE: Clinical findings of 27 patients with eruptive syringomas were reviewed over a 47-year period. RESULTS: The tumours appeared as multiple yellow-brown-coloured papules localized on the neck, anterior trunk, axillae, shoulders, abdomen or pubic area. This disorder occurs more frequently among women, and is frequent in the prepubertal as well as in the postpubertal age. The diagnosis was not clinically suspected in most cases. CONCLUSIONS: Eruptive syringomas have to be considered in differential diagnosis of papular dermatosis at any age. | Syringoma |
Desmosomes are not formed in epithelial cell cultures growing in media with low (less than or equal to 0.1 mM) concentrations of Ca2+ (LCM) but appear rapidly upon shift to media of normal calcium concentrations (NCM). Previous authors using immunolocalization of desmoplakin, a marker protein for the desmosomal plaque, in LCM-grown cells have interpreted positively stained, dense, cytoplasmic aggregates on intermediate filaments (IF) bundles as preformed plaque units which upon NCM shift would move to the plasma membrane and contribute to desmosome formation. Studying various cell cultures, including primary mouse keratinocytes and human A-431 cells, we show that most, probably all, desmoplakin-positive aggregates in LCM-grown cells are associated with membranous structures, mostly vesicles, and also contain other desmosomal markers, including desmoglein, a transmembrane glycoprotein. We interpret such vesicles as residual desmosome-derived domains endocytosed upon cell dissociation. Only keratinocytes grown for long times (2-4 wk) in LCM are practically free from such vesicles. In addition, we demonstrate that certain cells such as A-431 cells, when passaged in LCM and in the absence of stable junctions, are able to continually assemble half-desmosomes" on the plasma membrane which in turn can be endocytosed as plaque-bearing vesicles. We also show that in LCM the synthesis of several desmosomal proteins (desmoplakins I and II, plakoglobin, desmoglein, "band 6 protein") continues and that most of the plaque protein, desmoplakin, is diffusely spread over the cytoplasm, apparently in a soluble monodisperse form of approximately 9S. From our results we propose that the plaque proteins occur in small, discrete, diffusible entities in the cytoplasm, in concentrations that are relatively high in LCM and low in NCM, from which they assemble directly, i.e., without intermediate precursor aggregates on IFs in the cytoplasm, on certain plasma membrane domains in a Ca2+ dependent process." | Desmosomes |
The DAZ family genes, including boule, dazl, and daz, play pivotal roles in germ cell development and differentiation during gametogenesis in organisms, which have been widely studied in mammals, reptiles, or fishes. Dazl was bisexual expressed in both mitotic and meiotic germ cells, daz was male premeiotic expressed, whereas boule exhibits largely in unisexual meiotic germ cells but bisexual expression in several fishes, however, there is lack of report on boule gene and the evolutionary conservation and divergence of dazl and boule in reptile. Here, both boule and dazl genes were characterized in Pelodiscus sinensis. The quantitative real-time polymerase chain reaction analysis showed that boule and dazl were abundantly expressed in adult ovary and testis but barely in somatic tissues, such as heart, brain, liver, spleen, and kidney. Moreover, through fluorescent in situ hybridization, bisexual and germline-specific expression profiles of boule and dazl messenger RNAs (mRNAs) were demonstrated. Boule mRNA exhibited a maximal meiotic expression in spermatocytes, and a relatively low, but distinct expression in oocytes at meiotic stages in P. sinensis, similar to the expression profile of human boule in ovary. However, dazl mRNA was richly distributed in male germ cells at almost all stages during spermatogenesis, and predominantly expressed in most of stages of oocytes including premeiotic and meiotic stages. These findings imply that boule and dazl would play distinct roles in the sexual differentiation of germ cells during turtle gametogenesis, and the major functions of daz family members involved in germ cell differentiation would be conserved across species including P. sinensis. | Spermatocytes |
We report a case of survival following prolonged immersion and hypothermia. The patient survived for over 9 h in open water, after his vessel capsized and sank in the Pacific Ocean off the coast of Northern California. Water temperature on the day of the sinking was 14.4 degrees C (58.0 degrees F). Although he did have adequate flotation, the patient did not wear a survival suit. On initial physical examination in the Emergency Department (ED), the patient's rectal temperature was 30.0 degrees C (86.0 degrees F). With active rewarming, his temperature returned to normal (37.0 degrees C (98.6 degrees F)) within 5 h. Body fat of the patient was 19.6%, near the 50th percentile for his age (19.0%). Surface/volume ratio of the patient (.0228 m(2)/L) was 19% smaller than a predicted average (.0282 m(2)/L). We believe that the patient's large body habitus contributed to survival and that surface/volume ratio was likely the biophysical variable most closely associated with decreased cooling. | Immersion |
Quantum mechanics/molecular mechanics (QM/MM) methods have become widely used for computational modeling of enzyme structure and mechanism. In these approaches, a portion of the enzyme of great interest (e.g., where a chemical reaction is occurring) is treated with QM, whereas the surrounding region is treated with MM. A critical challenge with these methods is the choice of the region to partition into QM and which to treat with MM along with numerous practical choices that must be made at each step of the modeling procedure. Here, we attempt to simplify this process by describing the steps involved in preparing protein structures, choosing the appropriate QM region size and electronic structure methods, preparing all necessary input files, and troubleshooting common errors for QM/MM simulations of enzymes. | Molecular Dynamics Simulation |
Dental repulsion techniques reported in the past decades have a high incidence of complications. Although the practice of surgical extractions in horses is limited because of the training, instrumentation, and experience required to perform these techniques, veterinarians should be aware these procedures are available, general anesthesia is not required, and when performed by skilled veterinary dentists they have low complication rates. Surgical techniques are often used after failure of other extraction techniques to remove retained tooth root and fragments or to debride chronically contaminated orofacial lesions. However, surgical extractions should be considered during initial treatment planning of all complicated cases. | Tooth Extraction |
Nationwide surveillance of Rh hemolytic disease of the newborn showed that associated infant mortality decreased from 941 deaths in 1968 to 269 deaths in 1975, or from 2.7 to 0.9 per 10,000 live births. The incidence of Rh hemolytic disease declined from 45 per 10,000 total births in 1970 to 21 per 10,000 in 1975. In 1970, an estimated 16,000 infants were affected, whereas in 1975, the number was 6,000. Several state-based Rh disease surveillance programs reported declining mortality and incidence and increasing use of Rh immune globulin. Rh immune globulin was administered to an estimated 80% of eligible Rh-negative women in 1974, eighty-one percent in 1975, and 82% in 1976. More concerted efforts are needed to determine the frequency of maternal sensitization and to identify and correct gaps in postpartum and postabortion use of Rh immune globulin. | Erythroblastosis, Fetal |
As the current COVID-19 pandemic is evolving, skin lesions are being reported more, the most common skin manifestation being morbilliform rashes. We describe a patient of severe COVID-19 infection, 48-year-old who initially presented with fever, cough and constitutional symptoms who developed morbilliform macular rashes during his illness. The rash appeared on 6th day of illness in the trunk, arms with sparing of palms and soles, associated with itching. He later developed features of the cytokine-storm syndrome. The exact mechanism for the rashes is yet to be elaborated, however, it is postulated that it is either due to immune-mediated vasodilation or micro thrombosis secondary to low-grade-coagulopathy associated with COVID-19. Recognition of rashes as a feature of this disease is particularly significant to clinicians as it aids in early diagnosis, particularly in resource-poor countries. There is no evident association, however, between the severity and the rashes in COVID-19 infection. | Exanthema |
Membrane-enclosed organelle compartmentalization is not the only way by which cell processes are spatially organized. Phase separation is emerging as a new driver in the organization of membrane-less compartments and biological processes. Liquid-liquid phase separation has been indicated as a new way to control the kinetics of molecular reactions and is based on weak multivalent interactions affecting the stoichiometry of the molecules involved. In the nucleus, liquid-liquid phase separation may represent an ancestral means of controlling genomic activity by forming discrete chromatin regions, regulating transcriptional activity, contributing to the assembly of DNA damage response foci, and controlling the organization of chromosomes. Liquid-liquid phase separation also contributes to chromatin function through its role in the reorganization of the nuclear periphery in the post-mitotic phase. Herein, we describe the basic principles regulating liquid-liquid phase separation, analyze examples of phase separation occurring in the nucleus, and dedicate attention to the implication of liquid-liquid phase separation in the reorganization of the nuclear periphery by the endosomal sorting complexes required for transport (ESCRT) machinery. Although some caution is warranted, current scientific knowledge allows for the hypothesis that many factors and processes in the cell are yet to be discovered which are functionally associated with phase separation. | Cell Nucleus Structures |
Anaplasma centrale (Rickettsiales: Anaplasmataceae) is used as a live vaccine for cattle against the pathogenic Anaplasma marginale in tropical and subtropical areas. Herein we report a clinical case of bovine anaplasmosis associated with A. centrale infection in Italy, together with the first molecular identification and phylogenetic analysis of this Anaplasma species or subspecies in Europe. | Anaplasma centrale |
Defibrillation energy requirements may be altered by antiarrhythmic agents. We investigated the effects of moricizine on the defibrillation threshold (DFT) in 18 pentobarbital-anesthetized pigs. The animals were randomized, in a blinded fashion, to moricizine or control (0.9% saline) treatment groups. Each group underwent three treatment phases: baseline, drug infusion (moricizine or saline), and drug infusion combined with lidocaine. Moricizine (2 mg/kg loading dose, 1.5 mg/kg/h infusion) and lidocaine (5 mg/kg loading dose, 4 mg/kg/h infusion) were dosed to achieve therapeutic concentrations. After 5 s of induced ventricular fibrillation, defibrillation was performed using a cardiac defibrillator interfaced with two epicardial electrode patches. DFTs were determined at baseline, during the drug phase, and during the combination of lidocaine with moricizine or saline. DFT values in the animals randomized to the control group were 15.2 +/- 4.2, 14.0 +/- 3.3, and 17.8 +/- 8.7 J at baseline, saline infusion, and saline combined with lidocaine, respectively. No significant differences were observed among the treatment phases. DFT values in the animals randomized to moricizine group were 12.1 +/- 2.8, 13.8 +/- 5.2, and 22.9 +/- 7.1 J at baseline, moricizine infusion, and moricizine combined with lidocaine, respectively. The DFT values during the lidocaine-moricizine combination treatment phase were significantly greater than baseline and moricizine alone (p < 0.002). The mean change in the DFT from baseline to moricizine (14% increase) was significantly different than the mean change in the DFT from baseline to saline (8% decrease) (p = 0.03). Lidocaine added to moricizine increased the DFT by 84%, which was significantly different from the 27% increase in the DFT when lidocaine was added to saline (p = 0.02). We conclude that moricizine minimally increases the DFT, but the combination of moricizine with lidocaine results in a synergistic rise in the DFT that may have detrimental clinical implications. | Moricizine |
OBJECTIVES: Nerve growth factor (NGF) is a protein important for growth and survival, but also for modulation of sensitivity of nociceptors and sympathetic neurons. The purpose of the present study was to investigate the effects of reduced NGF signaling in patients with hereditary sensory and autonomic neuropathies type V, congenital insensitivity to pain, caused by a mutation of the NGFbeta gene, including a characterization of single nociceptive fibers using microneurography (MNG). MATERIALS AND METHODS: One homozygote and 2 heterozygote patients with this mutation were examined with electromyography/neurography, thermal testing, quantitative sudomotor axon reflex test, and electrically induced axon reflex erythema in addition to MNG. RESULTS: Low quantitative sudomotor axon reflex test measurements of 0.02 (left foot) and 0.03 (right foot) muL/cm and elevated thermal thresholds for warmth and cold detection testing showed clear impairment of small nerve fibers, both sudomotor efferent and somatic afferent fibers, in the patient homozygote for the mutation. MNG from one of the heterozygote patients revealed changes in the small nociceptive fibers in skin, including abnormally low conduction velocity, spontaneous activity in A-delta fibers and C-nociceptors and abnormal or lacking response to heat. DISCUSSION: The findings of grossly intact pain thresholds compared with anamnestic insensitivity of pain in deep somatic tissue such as bone suggest a gradient of impairment dependent on different NGF availability in various tissues. Even though these patients in some aspects report insensitivity to pain, they also report chronic spontaneous pain as their main symptom, strikingly highlighting differential mechanisms of insensitivity to evoked pain versus spontaneous pain." | Pain Insensitivity, Congenital |
We redescribe and illustrate the type specimens of ten taxa of sea snakes of the genera Hydrophis Latreille in Sonnini Latreille, 1801 and Laticauda Laurenti, 1768 in the collections of the Zoological Survey of India. The specimens comprise holotypes and syntypes of ten synonymous nominal taxa that represent seven valid nominal taxa. We here clarify that one specimen ZSI 8278 is a syntype of Hydrophis dayanus Stoliczka, 1872, not holotype as previously stated. In one case, four holotypes of four nominal taxa are synonyms of the same taxonHydrophis cyanocinctus Daudin, 1803. Many of these type specimens are herein first depicted in photographs in a publication. | Alethinophidia |
The effects of 5-hydroxytryptamine and iproniazid on pregnancy in mice and rabbits were investigated. 5-Hydroxytryptamine can interrupt pregnancy at all stages in mice but is particularly effective early and late in pregnancy. Iproniazid exerts its action essentially in the first half of pregnancy. 5-Hydroxytryptamine produces striking hemorrhage in the placenta. | Iproniazid |
Recently, Missouri has followed an overall upward trend in opioid overdose deaths. In 2018, Missouri was the state with the largest absolute and percentage increase in opioid-related overdose fatality rates per capita over the previous year (18.3% and 3.1/100,000). This increase occurred despite an overall decrease in U.S. opioid-related death rates in the same period. This report identifies illicitly manufactured fentanyl (IMF) (and analogues) as the drug most responsible for this rise in opioid deaths in Missouri, with stimulant overdoses (primarily from methamphetamine) in second place. Within Missouri, we find the areas where opioid deaths are highest: St. Louis and the city's fringe areas, following the national trend for high rates in fringe areas. Based on reports from CDC Wonder data, county medical examiners, law enforcement agencies, and drug addiction prevention agencies, we conclude that IMF and related synthetic opioids arriving from China are primarily responsible for fatal narcotic overdoses in Missouri. Despite the COVID-19 disruption of fentanyl manufacturing and distribution centers in and around Wuhan, China early in the pandemic, preliminary 2020 data from medical examiners' offices show an upswing in opioid deaths, an indicator that Chinese fentanyl producers have restored the supply chain. | Opioid Epidemic |
Following the identification of cyclin-dependent kinases in the 1980s, kinases were hailed as the directors of mitosis. Although the action of kinases must necessarily be reversible, only recently has the involvement of specific phosphatases in mitosis become appreciated. Studies are now revealing how the timely execution of mitotic events depends on the delicate interplay between kinases and phosphatases. To date, the best-characterized mitotic phosphatases are Cdc25, that is required for entry into mitosis and Cdc14, that controls exit from mitosis in budding yeast. Recent work has now exposed the conserved serine-threonine phosphatases PP1 and PP2A as key regulators of various mitotic processes. | cdc25 Phosphatases |
Essential oils from aromatic plants are currently mentioned as suitable tools for excellent protection of stored grains from insect pest attacks. The present work aimed to study the processes of the synthesis insecticidal formulation with clay. The active terpenic compounds of essential oil of Eucalyptus globulus (Eg) were fixed in the palygorskite by adsorption process. Two sample types of palygorskites were used: raw and organo-palygorskite. The palygorskite clays were characterized by different physicochemical techniques including X-ray diffraction (XRD), Fourier transform infrared (FTIR) analyses, thermogravimetric analysis (TG), differential thermal analysis (DTA), Brunauer-Emmet-Teller (BET), and scanning electron microscope (SEM). Results reveal that the raw clay has a fibrous structure with impurities essential calcite. These structures and physicochemical properties of raw palygorskite and organo-palygorskite give it the potential of material adsorbent. Results show that the adsorption capacity strongly depends on affinity between terpenic compounds and organic cations rather than on interlayer distance of organo-palygorskite. The highest adsorption capacity of terpenic compounds is acquired with palygorskite interlaced by didodecyldimethylammonium bromide (DDDMA). These results validated the potential utility of the Paly-DDDMA as adsorbent fibrous clay for the retention of terpenic compounds in application of environmental preservation. | Magnesium Compounds |
Traditionally, information technology in health care has helped practitioners to collect, store, and present information and also to add a degree of automation to simple tasks (instrument interfaces supporting result entry, for example). Thus commercially available information systems do little to support the need to model, execute, monitor, coordinate, and revise the various complex clinical processes required to support health-care delivery. Workflow computing, which is already implemented and improving the efficiency of operations in several nonmedical industries, can address the need to manage complex clinical processes. Workflow computing not only provides a means to define and manage the events, roles, and information integral to health-care delivery but also supports the explicit implementation of policy or rules appropriate to the process. This article explains how workflow computing may be applied to health-care and the inherent advantages of the technology, and it defines workflow system requirements for use in health-care delivery with special reference to diagnostic pathology." | Clinical Laboratory Information Systems |
Betacyanins and phenolic compounds from acetonitrile:acidified water extracts of Alternanthera brasiliana and Alternanthera tenella were characterized and quantified using a high-performance liquid chromatography system coupled with diode array and electrospray mass spectrometry detection. Four betacyanins (amaranthine, isoamaranthine, betanin and isobetanin) were tentatively identified and quantified. Twenty eight phenolic compounds of four different families (hydroxybenzoic and hydroxycinnamic acids, flavones and flavonols) were separated and characterized on the basis of their accurate MS and MS/MS information out of which ten compounds were confirmed by authentic standards. These plant species could be considered as an especially rich source of natural bioactive compounds and potential food colorants. A. brasiliana showed the highest betacyanin and polyphenols content (89mug/g and 35,243mug/g, respectively). Among polyphenols, flavonols were the more abundant (kaempferol-glucoside, kaempferol-rutinoside and kaempferol-rhamnosyl-rhamnosyl-glycoside). Meanwhile, A. tenella showed a different polyphenols profile with flavones as major compounds (glucopyranosil-vitexin and vitexin). As a novelty, pentosyl-vitexin and pentosyl-isovitexin were detected for the first time in Alternanthera plants. Both A. brasiliana and A. tenella leaves showed high total polyphenol content and in vitro antioxidant activity (FRAP). These results provide an analytical base concerning the phenolic and betalains composition and the antioxidant properties of two members of the promising Alternanthera gender, for subsequent applications, such as functional food ingredients. | Betalains |
Since Smith's time, the essential role of collecting duct intercalated cells in controlling net acid excretion has been recognized. Rather than employing an H(+)-exchange mechanism, intercalated cells have V-ATPase on the plasma membrane and in plasmalemma-associated tubulovesicles, which functions in the bicarbonate reabsorption, regeneration, and bicarbonate secretion required for acid-base homeostasis. Several distinct mechanisms participate in regulating V-ATPase-driven H+ secretion in different cell types: (1) Renal epithelial cells have the capacity to express different structural forms of V-ATPase that have intrinsic differences in their enzymatic properties. 2) The kidney produces cytosolic regulatory proteins, capable of interacting directly with the V-ATPase, that may modify its activity. V-ATPases in different cell types may differ in the degree to which their activity is affected by regulatory factors, as a result of variations in V-ATPase structure. (3) In the alpha intercalated cell, the number of active V-ATPases on the luminal membrane is controlled in vivo by membrane vesicle-mediated traffic that may require unidentified mediators. In the beta intercalated cell, the number of active V-ATPases on the basolateral membrane may be controlled by regulated assembly and disassembly, responding directly to extracellular pH. | Kidney Tubules, Distal |
MOTIVATION: Previously constructed classifiers in predicting eukaryotic essential genes integrated a variety of features including experimental ones. If we can obtain satisfactory prediction using only nucleotide (sequence) information, it would be more promising. Three groups recently identified essential genes in human cancer cell lines using wet experiments and it provided wonderful opportunity to accomplish our idea. Here we improved the Z curve method into the lambda-interval form to denote nucleotide composition and association information and used it to construct the SVM classifying model. RESULTS: Our model accurately predicted human gene essentiality with an AUC higher than 0.88 both for 5-fold cross-validation and jackknife tests. These results demonstrated that the essentiality of human genes could be reliably reflected by only sequence information. We re-predicted the negative dataset by our Pheg server and 118 genes were additionally predicted as essential. Among them, 20 were found to be homologues in mouse essential genes, indicating that some of the 118 genes were indeed essential, however previous experiments overlooked them. As the first available server, Pheg could predict essentiality for anonymous gene sequences of human. It is also hoped the lambda-interval Z curve method could be effectively extended to classification issues of other DNA elements. AVAILABILITY AND IMPLEMENTATION: http://cefg.uestc.edu.cn/Pheg. CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. | Genes, Essential |
To investigate the sex differences in disability-adjusted life years (DALYs) due to ischemic stroke (IS) by year, location and age. We extracted sex-specific data on DALYs number, age-standardized DALYs rate (ASDR) and all-age DALYs rate of IS by year, location and age from the Global Burden of Diseases study 2019. The estimated annual percentage changes (EAPC) were calculated to evaluate the temporal trend of ASDR. For both sexes, although the ASDR of IS slightly decreased from 1990 to 2019, there has been an 60.3% increase in DALYs number worldwide. Sex difference in DALYs number (men minus women) decreased from - 2.83 million in 1990 to 0.14 million in 2019, while the men to women's ASDR ratio slightly increased from 1.10 in 1990 to 1.21 in 2019. The sex differences in IS DALYs showed remarkable regional variation. The largest sex differences in DALYs number and ASDR were in China and Vietnam. Middle-aged men had a higher IS DALYs than their age-matched counterparts. High systolic blood pressure accounted for the highest DALYs number in 2019, but the top three attributable risk factors that had the greatest sex differences were tobacco, dietary risk, and alcohol use. Sex differences in IS DALYs varied by year, location and age, mostly attributed to the disproportion of cardiovascular risk factors between sexes. Considering the population growth and aging, it is necessary to monitor the sex difference in IS DALYs in different populations and thus provide evidence for local administration to improve current preventive and management strategies of IS." | Disability-Adjusted Life Years |
Plasma aldosterone concentration (PAC), plasma renin concentration (PRC), plasma potassium, plasma sodium and blood pressure (BP) have been measured in 22 patients with essential hypertension before and after treatment for one month with alprenolol. PAC, PRC and BP decreased and plasma potassium increased significantly during treatment. Plasma sodium, however, was unchanged. Changes in PAC were inversely correlated to changes in plasma potassium. No relationship could be demonstrated between PAC and plasma sodium. Mean BP was inversely correlated to PAC during alprenolol treatment, but bot before treatment. No relationship was found between changes in BP and changes in PRC. The results suggest that plasma potassium is an important regulatory factor for aldosterone secretion during alprenolol treatment. Other factors, however, must have a modulating influence and since the renin- angiotensin system is not suppressed to very low values, this system is possibly the most important of these factors. It is suggested that aldosterone secretion is not of primary importance in BP regulation during alprenolol treatment. | Alprenolol |
Mosquito vectors are responsible for transmitting diseases such as malaria, dengue, chikungunya, Japanese encephalitis, dengue, and lymphatic filariasis. The use of synthetic insecticides to control mosquito vectors has caused physiological resistance and adverse environmental effects, in addition to high operational cost. Biosynthesis of silver nanoparticles has been proposed as an alternative to traditional control tools. In the present study, green synthesis of silver nanoparticles (AgNPs) using aqueous leaf extract of Bauhinia variegata by reduction of Ag(+) ions from silver nitrate solution has been investigated. The bioreduced silver nanoparticles were characterized by UV-visible spectrophotometry, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray analysis (EDX), and X-ray diffraction analysis (XRD). Leaf extract and synthesized AgNPs were evaluated against the larvae of Anopheles subpictus, Aedes albopictus, and Culex tritaeniorhynchus. Compared to aqueous extract, synthesized AgNPs showed higher toxicity against An. subpictus, Ae. albopictus, and Cx. tritaeniorhynchus with LC50 and LC90 values of 41.96, 46.16, and 51.92 mug/mL and 82.93, 89.42, and 97.12 mug/mL, respectively. Overall, this study proves that B. variegata is a potential bioresource for stable, reproducible nanoparticle synthesis and may be proposed as an efficient mosquito control agent. | Bauhinia |
Osteogenic Protein-1 (OP-1), a member of the bone morphogenetic protein (BMP) family that belongs to the TGF-beta superfamily, induces bone formation in vivo and stimulates the synthesis of biochemical markers characteristic of osteoblast phenotypes in vitro. In the present study, effects of OP-1 on the expression of the plasminogen activator inhibitor-1 (PAI-1) in fetal rat calvaria (FRC) cells were examined. The PAI-1 protein levels in conditioned media of FRC cells treated with OP-1 or solvent control were determined by quantitative 2-dimensional polyacrylamide gel electrophoresis. The identity of PAI-1 was confirmed by mass spectroscopy. OP-1 increased the PAI-1 protein level by about 5-fold after 48 h. Northern blot analysis showed that the PAI-1 mRNA level was elevated by OP-1 by about 25% compared to the control. The observed increase in the PAI-1 mRNA and protein level was regulated post-transcriptionally as supported by the following observations: (a) OP-1 did not stimulate the cloned PAI-1 promoter-reporter gene activity in transient transfection studies, (b) inhibition of transcription by actinomycin D did not change the PAI-1 mRNA level in the OP-1-treated FRC cells, and (c) the stability of the PAI-1 mRNA in FRC cells treated with OP-1 was increased by about 28% compared to that in the control cells. Hence, the present study shows that primary cultures of rat osteoblastic cells synthesize and secrete PAI-1 protein and that OP-1 elevates the PAI-1 protein level. At least, one of the regulatory mechanism is by stabilizing the PAI-1 mRNA. J. Cell. Biochem. Suppl. 36: 46-54, 2001." | Plasminogen Activator Inhibitor 1 |
The C3 receptor CR3 is expressed on phagocytic cells, minor subsets of B and T cells, and natural killer (NK) cells. It has important functions both as an adhesion molecule and a membrane receptor mediating recognition of diverse ligands such as intercellular adhesion molecule-1 (ICAM-1) and fixed iC3b. The receptor is capable of undergoing an activation event that regulates both its specificity for various ligands and its ability to mediate phagocytosis or extracellular cytotoxicity. Certain bacteria express carbohydrates or lipopolysaccharides (LPS) that can bind to and activate CR3, allowing the receptor to assume its activated state. Soluble beta-glucan derived from the yeast Saccharomyces cerevisiae is a particularly potent stimulator of CR3, and produces an activated state of the receptor that permits neutrophil phagocytosis of iC3b-coated erythrocytes or NK, cell cytotoxicity of iC3b-coated tumour cells, that are normally resistant to NK cells. | Receptors, Fibrinogen |
Despite testing since the mid-1900s, only in the past three years have some monoclonal antibodies provided sufficient efficacy and safety data to support regulatory approval as cancer therapy. Adjuvant-edrecolomab monoclonal antibody was approved in Germany after demonstration of a statistically significant 32% improvement over observation alone in the seven-year mortality rate for patients with colorectal cancer. Similarly, trastuzumab monoclonal antibody combined with chemotherapy prolonged the median time to the progression of breast cancer compared to chemotherapy alone. Unconjugated monoclonal antibodies investigated for the treatment of hematologic malignancies include anti-idiotype, CAMPATH-1, and rituximab. Rituximab was the first such therapy approved in the United States for relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma after demonstration of an overall response rate of 48% and a duration of response of 11.7 months. The radioisotope-conjugated monoclonal antibodies tested as therapy include anti-B1, LYM-1, LL2, anti-CD33, and ibritumomab tiuxetan. Clearly, the full potential of immunotherapy still lies ahead. | Antibodies, Monoclonal |
Codon usage bias (CUB)-preferential use of one of the synonymous codons, has been described in a wide range of organisms from bacteria to mammals, but it has not yet been studied in marine phytoplankton. CUB is thought to be caused by weak selection for translational accuracy and efficiency. Weak selection can overpower genetic drift only in species with large effective population sizes, such as Drosophila that has relatively strong CUB, while organisms with smaller population sizes (e.g., mammals) have weak CUB. Marine plankton species tend to have extremely large populations, suggesting that CUB should be very strong. Here we test this prediction and describe the patterns of codon usage in a wide range of diatom species belonging to 35 genera from 4 classes. We report that most of the diatom species studied have surprisingly modest CUB (mean Effective Number of Codons, ENC = 56), with some exceptions showing stronger codon bias (ENC = 44). Modest codon bias in most studied diatom species may reflect extreme disparity between astronomically large census and modest effective population size (N(e)), with fluctuations in population size and linked selection limiting long-term N(e) and rendering selection for optimal codons less efficient. For example, genetic diversity (pi ~0.02 at silent sites) in Skeletonema marinoi corresponds to N(e) of about 10 million individuals, which is likely many orders of magnitude lower than its census size. Still, N(e) ~10(7) should be large enough to make selection for optimal codons efficient. Thus, we propose that an alternative process-frequent changes of preferred codons, may be a more plausible reason for low CUB despite highly efficient selection for preferred codons in diatom populations. The shifts in the set of optimal codons should result in the changes of the direction of selection for codon usage, so the actual codon usage never catches up with the moving target of the optimal set of codons and the species never develop strong CUB. Indeed, we detected strong shifts in preferential codon usage within some diatom genera, with switches between preferentially GC-rich and AT-rich 3(rd) codon positions (GC3). For example, GC3 ranges from 0.6 to 1 in most Chaetoceros species, while for Chaetoceros dichaeta GC3 = 0.1. Both variation in selection intensity and mutation spectrum may drive such shifts in codon usage and limit the observed CUB. Our study represents the first genome-wide analysis of CUB in diatoms and the first such analysis for a major phytoplankton group. | Codon |
During ischemia, numerous effective endogenous extracellular mediators have been identified, particularly, nucleosides such as adenosine as well as purinergic and pyrimidinergic nucleotides. They may play important regulatory roles within the cardiovascular system and notably as cardio-protectants. Indeed, the distribution of the P2Y receptors in mammalian heart includes several cellular constituents relevant for the pathophysiology of myocardial ischemia. Beside the well-known cardioprotective effect of adenosine, the additional protective role of P2Y receptors has emerged. However, interpretation of experimental results may be sometimes perplexing. This is due to the variability of: the experimental models, the endpoints criteria, the chemical structure of agonist and antagonist ligands and their concentrations, the sequences of drug administration with respect to the model used (before and/or during and/or after ischemia). The net effect may be in the opposite direction after a transient or a prolonged stimulation. Nevertheless, the overall reading of published data highlights the beneficial role of the P2Y(2/4) receptor stimulation, the useful and synergistic role of P2Y(6/11) receptor activation and even of the P2Y(11) receptor alone in cardioprotection. More, the P2Y(11) receptor could be involved in counter-regulation of profibrotic processes. Paradoxically, transient P2X(7) receptor stimulation could contribute to the net cardioprotective effect of ATP. Recently, experimental data have shown that blocking the P2Y(12) receptor after ischemia confers cardioprotection independently of platelet antiaggregatory effect. This suggests for P2Y receptors an important role in primary prevention and as a therapeutic target in myocardial protection during ischemia and reperfusion. | Uridine Triphosphate |
AIM: The aim of this study was to assess the opinions and practices of different dentists about the cervical margin relocation (CMR) concept. MATERIALS AND METHODS: A total of 432 general dentists, advanced general dentists (AGDs), periodontists, restorative dentists, and prosthodontists practicing in Saudi Arabia were approached in person or asked to complete an electronic survey (Google Forms) assessing demographic data and their opinions and practice of CMR. Differences between groups were assessed using the Chi-squared test, and binary regression models were constructed to identify predictors of opinions and practice of CMR. RESULTS: About half of the surveyed dentists practiced CMR when indicated, but many felt that it represents an invasion of the biological width and might affect crown survival. Participants had several, often concurrent concerns about CMR. The opinions and practices of CMR were influenced by several factors including educational degree, work setting, country of clinical training, years of experience, and specialty. CONCLUSION: The relatively conservative attitude of dentists towards CMR is justifiable, as it is a relatively new concept with little long-term clinical data. Clinical trials with sufficient follow-up periods are now needed to evaluate outcomes from CMR to provide further confidence to dentists to implement the procedure. CLINICAL SIGNIFICANCE: Deep proximal carious lesions extending subgingivally is a common clinical scenario. Assessing the opinion and practice of dentists towards conservative treatment with CMR provides the basis for encouraging practitioners to use the procedure both clinically and in clinical trials. | Crown Lengthening |
Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. Patients with the most aggressive histological variant have an unfavorable prognosis due to a high metastasis incidence. Lysyl oxidase-like 2 (LOXL2) is a lysyl oxidase, member of a family of extracellular matrix (ECM) crosslinking enzymes that recently have emerged as important regulators of tumor progression and metastasis. We report that LOXL2 is overexpressed in RMS, suggesting a potential role for LOXL2 in RMS oncogenic progression. Consistently, transient and stable LOXL2 knockdown decreased cell migratory and invasive capabilities in two ARMS cell lines. Furthermore, introduction of LOXL2 in RMS non-expressing cells using wild type or mutated (catalytically inactive) constructs resulted in increased cell migration, cell invasion and number and incidence of spontaneous lung metastasis in vivo, independently of its catalytic activity. To further study the molecular mechanism associated with LOXL2 expression, a pull-down assay on LOXL2-transfected cells was performed and analyzed by mass spectrometry. The intermediated filament protein vimentin was validated as a LOXL2-interactor. Thus, our results suggest an oncogenic role of LOXL2 in RMS by regulating cytoskeleton dynamics and cell motility capabilities. | Rhabdomyosarcoma, Alveolar |
Estivation (aerobic dormancy) is characterized by sustained metabolic rate depression, which is crucial to survival in the face of unfavorable environmental conditions and enables the preservation of endogenous fuel reserves. Ion pumping is one of the most energetically taxing physiological processes in cells, and ion motive ATPases are likely loci to be differentially regulated in models of metabolic arrest. We proposed that the sarcoendoplasmic reticulum (SER) calcium-ATPase (SERCA) would be deactivated in the estivating desert snail Otala lactea, potentially contributing to the overall suppression of metabolism. SERCA kinetic parameters [decreased maximal velocities, increased substrate K (m) values, increased Arrhenius activation energy (E (a))] were indicative of a less active enzyme in the estivated state. Interestingly, the less active SERCA population in dormant snails featured greater kinetic (K (m) Mg.ATP versus temperature) and conformational (resistance to urea denaturation) stability than that in active snails. Western blotting confirmed that SERCA protein content did not change during estivation. In light of this observation, we proposed that estivation-dependent changes in SERCA activity was due to changes in SERCA phosphorylation state. In vitro studies promoting specific kinase or phosphatase action indicated that decreased SERCA activity in estivation was linked with endogenous kinase activity whereas reactivation of SERCA was facilitated by endogenous protein phosphatases (PP). | Estivation |
The popularity of international travel continues to increase among Americans, even though they often experience subsequent illness on return from their journey. The pathogens responsible are not necessarily endemic to the destination itself but are often the result of poor sanitary conditions or activities engaged in while away. Skin disease ranks third among all medical concerns in returning travelers. This review addresses the pathogenesis, epidemiology, clinical presentation, and treatment of the most common skin diseases in returning travelers: insect bites and bedbugs, cutaneous larva migrans, scabies, tungiasis, myiasis, leishmaniasis, viral exanthems, and marine envenomation. Primary care physicians and dermatologists should be familiar with these illnesses and a general approach to their evaluation and management. | Insect Bites and Stings |
Infectious disease outbreaks often exhibit superspreader dynamics, where most infected people generate no, or few secondary cases, and only a small fraction of individuals are responsible for a large proportion of transmission. Although capturing this heterogeneity is critical for estimating outbreak risk and the effectiveness of group-specific interventions, it is typically neglected in compartmental models of infectious disease transmission-which constitute the most common transmission dynamic modeling framework. In this study we propose different classes of compartmental epidemic models that incorporate transmission heterogeneity, fit them to a number of real outbreak datasets, and benchmark their performance against the canonical superspreader model (i.e., the negative binomial branching process model). We find that properly constructed compartmental models can capably reproduce observed superspreader dynamics and we provide the pathogen-specific parameter settings required to do so. As a consequence, we also show that compartmental models parameterized according to a binary clinical classification have limited support. | Epidemiological Models |
BACKGROUND: In the USA, inpatient phlebotomy services are under constant operational pressure to optimise workflow, improve timeliness of blood draws, and decrease error in the context of increasing patient volume and complexity of work. To date, the principles of Lean continuous process improvement have been rarely applied to inpatient phlebotomy. AIMS: To optimise supply replenishment and cart standardisation, communication and workload management, blood draw process standardisation, and rounding schedules and assignments using Lean principles in inpatient phlebotomy services. METHODS: We conducted four Lean process improvement events and implemented a number of interventions in inpatient phlebotomy over a 9-month period. We then assessed their impact using three primary metrics: (1) percentage of phlebotomists drawing their first patient by 05:30 for 05:00 rounds, (2) percentage of phlebotomists completing 08:00 rounds by 09:30, and (3) number of errors per 1000 draws. RESULTS: We saw marked increases in the percentage of phlebotomists drawing their first patient by 05:30, and the percentage of phlebotomists completing rounds by 09:30 postprocess improvement. A decrease in the number of errors per 1000 draws was also observed. CONCLUSIONS: This study illustrates how continuous process improvement through Lean can optimise workflow, improve timeliness, and decrease error in inpatient phlebotomy. We believe this manuscript adds to the field of clinical pathology as it can be used as a guide for other laboratories with similar goals of optimising workflow, improving timeliness, and decreasing error, providing examples of interventions and metrics that can be tailored to specific laboratories with particular services and resources. | Phlebotomy |
BACKGROUND AND OBJECTIVES: Heterotopic interstitial pregnancy (HIP) is a rare but potentially life-threatening condition that occurs more commonly in the setting of assisted reproductive technology (ART). It is significant to introduce a safe and effective laparoscopic strategy to manage HIP following the use of ART. METHODS: This study included 9 cases of patients with HIP who underwent laparoscopic management in our department. Our approach involves placement of a purse-string suture around the cornua of the uterus followed by removal of the interstitial pregnancy using a flushing technique. This is followed by repair of the uterine cornua, leaving the intrauterine pregnancy (IUP) undisturbed. The outcomes were reported regarding surgical complications during the procedure as well as outcomes for the remaining IUP including gestational age at delivery and any neonatal adverse events. RESULTS: Five of the 9 cases were asymptomatic at presentation. All cases underwent laparoscopic management with successful removal of the interstitial gestational product and preservation of the IUP. With the exception of one case that was lost to followup, all cases resulted in full-term delivery. The average intraoperative blood loss was 24.44 +/- 14.23 mL and the average operation time was 70.44 +/- 22.48 minutes. There were no postoperative complications, including persistent ectopic pregnancy, rupture of the uterus, spontaneous abortion, or preterm delivery. All newborns for whom data was available were healthy. CONCLUSION: This laparoscopic strategy is a safe, relatively simple, effective, and minimally invasive approach to address the challenging case of HIP after ART in the first trimester. | Pregnancy, Interstitial |
Increased investments and development of new technologies in drug discovery have barely improved the outcome of medicinal entities in the drug discovery market from a long time. Minimal success rates of drug approvals, poor safety profiles, and long development processes are some of many hurdles encountered in the drug discovery field. Therefore, drug repurposing can provide an alternative approach to meet the demands of the new, potent and safe anti-cancer agents in terms of both economic cost and time efficiency. The common molecular pathways of different diseases and secondary indications of most of the approved drugs, and advances in genomics, informatics and biology, as well as the availability of approved or safe drug libraries can certainly provide an improved and efficient way of screening safer drugs for new indications. Promising results of drug repurposing in different therapeutic areas have encouraged the scientific community to discover new drugs for different diseases using this methodology. Herein, we provide a general overview of structurally and functionally diverse approved drugs that have been repurposed as anti-cancer drugs. | Nelfinavir |
In December 2016, a low-pathogenic avian influenza (LPAI) A(H7N2) virus was identified to be the causative source of an outbreak in a cat shelter in New York City, which subsequently spread to multiple shelters in the states of New York and Pennsylvania. One person with occupational exposure to infected cats became infected with the virus, representing the first LPAI H7N2 virus infection in a human in North America since 2003. Considering the close contact that frequently occurs between companion animals and humans, it was critical to assess the relative risk of this novel virus to public health. The virus isolated from the human case, A/New York/108/2016 (NY/108), caused mild and transient illness in ferrets and mice but did not transmit to naive cohoused ferrets following traditional or aerosol-based inoculation methods. The environmental persistence of NY/108 virus was generally comparable to that of other LPAI H7N2 viruses. However, NY/108 virus replicated in human bronchial epithelial cells with an increased efficiency compared with that of previously isolated H7N2 viruses. Furthermore, the novel H7N2 virus was found to utilize a relatively lower pH for hemagglutinin activation, similar to human influenza viruses. Our data suggest that the LPAI H7N2 virus requires further adaptation before representing a substantial threat to public health. However, the reemergence of an LPAI H7N2 virus in the northeastern United States underscores the need for continuous surveillance of emerging zoonotic influenza viruses inclusive of mammalian species, such as domestic felines, that are not commonly considered intermediate hosts for avian influenza viruses.IMPORTANCE Avian influenza viruses are capable of crossing the species barrier to infect mammals, an event of public health concern due to the potential acquisition of a pandemic phenotype. In December 2016, an H7N2 virus caused an outbreak in cats in multiple animal shelters in New York State. This was the first detection of this virus in the northeastern United States in over a decade and the first documented infection of a felid with an H7N2 virus. A veterinarian became infected following occupational exposure to H7N2 virus-infected cats, necessitating the evaluation of this virus for its capacity to cause disease in mammals. While the H7N2 virus was associated with mild illness in mice and ferrets and did not spread well between ferrets, it nonetheless possessed several markers of virulence for mammals. These data highlight the promiscuity of influenza viruses and the need for diligent surveillance across multiple species to quickly identify an emerging strain with pandemic potential." | Influenza A Virus, H7N2 Subtype |
This study evaluated the therapeutic efficacy of Schisandrin A on systemic colibacillosis of chickens. One hundred and eighty, 1-day-old Hailan Brown chickens were divided into 6 groups of 30 chickens each and assigned to the following treatments: 1) uninfected/untreated control; 2) infected Escherichia coli; 3) infected-plus low dose of Schisandrin A therapy (50 mg/kg); 4) infected-plus medium dose of Schisandrin A therapy (100 mg/kg); 5) infected-plus high dose of Schisandrin A therapy (200 mg/kg) and 6) infected-plus antimicrobial therapy (florfenicol). Each group of chickens was placed in cages with a photoperiod of 12 h of light and 12 h of dark. Feed and water for all groups were provided ad libitum for the duration of the study. On d 14, all the chickens except the uninfected control group were intraperitoneally inoculated with a fresh culture of E. coli containing 1 x 10(8) CFU/mL. The parameters measured included: average daily weight gain (ADG), percent survivability, liver index, serum activity of enzymes (ALT and AST), hepatic and intestinal concentrations of TNF-alpha, IL-1beta, IL-6, IL-8, and LPS, expression of tight junction proteins (occludin, ZO-1, and claudin-1), relative abundance of bacterial species and histopathological changes in hepatic and intestinal tissue. The results showed that the medium and high doses of Schisandrin A ameliorated the detrimental effects of colibacillosis on weight gain. Regarding organ indexes, E. coli infection induced a significant increase in liver index, all the doses of Schisandrin A produced a significant reduction of liver index in comparison to the E. coli infected control. Serum activity of ALT and AST enzymes significantly increased due to E. coli infection, with the exception of the low dose of Schisandrin A for AST enzyme activity, all the Schisandrin A treatments significantly lowered enzyme activity in comparison to the E. coli infected control. Regarding concentrations of inflammatory markers in hepatic and intestinal, E. coli infection caused a significant increase in TNF-alpha, IL-1beta, IL-6, and IL-8, except the lowest dose of Schisandrin A for IL-1beta, the rest of the doses tested were able to significantly reduced the concentrations of inflammatory markers. Concentrations of LPS in hepatic and intestinal tissues were significantly increased by E. coli infection, all doses of Schisandrin A significantly reduced the concentration of LPS in hepatic and intestinal tissue. E. coli infection significantly reduced the expression of 2 tight junction proteins (ZO-1 and Claudin-1), the higher doses of Schisandrin A were effective in significantly increasing the expression of these tight junction proteins when compared with the E. coli infected control. Taken together, these results show that Schisandrin A has potential as an alternative therapy for the treatment of colibacillosis in chickens. | Escherichia coli Infections |
Cytochrome c(3) of Desulfovibrio desulfuricans strain G20 is an electron carrier for uranium (VI) reduction. When D. desulfuricans G20 was grown in medium containing a non-lethal concentration of uranyl acetate (1 mM), the rate at which the cells reduced U(VI) was decreased compared to cells grown in the absence of uranium. Western analysis did not detect cytochrome c(3) in periplasmic extracts from cells grown in the presence of uranium. The expression of this predominant tetraheme cytochrome was not detectably altered by uranium during growth of the cells as monitored through a translational fusion of the gene encoding cytochrome c(3) ( cycA) to lacZ. Instead, cytochrome c(3) protein was found tightly associated with insoluble U(IV), uraninite, after the periplasmic contents of cells were harvested by a pH shift. The association of cytochrome c(3) with U(IV) was interpreted to be non-specific, since pure cytochrome c(3) adsorbed to other insoluble metal oxides, including cupric oxide (CuO), ferric oxide (Fe(2)O(3)), and commercially available U(IV) oxide. | Desulfovibrio desulfuricans |
Change in ecosystem disturbance regimes from human land-use poses a worldwide problem for management of rare species. Two important types of disturbance influencing the persistence of species in Australian ecosystems are habitat fragmentation and fire. In this study, seed dispersal and the germination ecology of Pomaderris vacciniifolia-a critically endangered, rare endemic Australian shrub-were examined to identify likely influences of fire and fragmentation on the decline of populations. The response of seed germination to simulated effects of wildfire and canopy openings was investigated, as was the unaided dispersal capability of seeds from parent plants. A significant increase in germination rate was observed following 100 degrees C heat treatment to seeds, while smoke and light exposure had little influence. Seed imbibition was strongly influenced by heat treatment. The findings indicate a likely positive post-fire germination response, with implications for recruitment success determined by moisture availability following fire. Unaided seed dispersal was limited, which partly explains the apparent decline of populations. Understanding disturbance requirements for threatened species, and subsequent management of landscapes for disturbance, will aid conservation of rare species throughout the world. | Rhamnaceae |
The possibility of the registration of the interaction of the cells Azospirillum lipoferum Sp59b with the specific antibodies directly in the conducting suspensions by using an acoustic sensor was shown. The main element of the sensor is a piezoelectric resonator with a lateral electric field. The analysis is based on a comparison of the resonator's electrical impedance before and after the specific biological interaction between the cells and antibodies. By using this sensor one can detect and identify the bacterial cells directly in the buffer solution with the conductivity between 2.4 and 20â¯muS/cm. The minimum detectable concentration of the bacterial cells turned out to be approximately 10(3)â¯cells/ml and for a short time (less than 10â¯min). Also the possibility of the detection of the cells in the presence of the extraneous microflora was shown. The results provide the opportunities for the development of a new class of the methods for the analysis of the microbial cells in real-time directly in the buffer solution. | Azospirillum lipoferum |
Critical limb ischaemia is a severe manifestation of peripheral arterial disease characterised by intractable pain and tissue gangrene. Conventional treatments include percutaneous angioplasty and surgical bypass but up to one third of patients are not amenable to these interventions and will ultimately require amputation. Therapeutic neovascularisation has been proposed as an alternative treatment in these 'no option' patients and both cytokines and cells have shown impressive efficacy in the laboratory. Clinical trials in man, however, have had modest results. This discrepancy has put into question the relevance of the pre-clinical assays that are used to test potential agents. One of the most widely used of these assays is the hind limb ischaemia model that is often performed in young, healthy animals. This review critiques the techniques used to induce and assess ischaemia in this model and outlines the reasons why healthy rodents cannot fully recapitulate critical limb ischaemia in aged patients. Strategies that may produce a hind limb model that better simulates the human condition are proposed. | Hindlimb |
Clinicians often perform dental procedures and dentoalveolar surgery on patients who take prescribed anticoagulant medications. Such medications can present clinical challenges with regard to modifying or temporarily discontinuing a patient's anticoagulant regimen, which may not be medically indicated. In many instances discontinuation or altering of anticoagulation can be avoided through use of local hemostatic factors while patients are therapeutically continued on their prescribed warfarin doses. This article discusses a useful adjunct to dental treatment for the warfarin-anticoagulated patient- tranexamic acid (TA). The purpose of TA in these dental patients is to promote safe surgical site hemostasis for improved intraoperative visibility and postoperative hemostasis. | Tranexamic Acid |
Drug interaction studies are imperative to gain insights into the beneficial or harmful effects of therapeutic and dietary agents. This study investigated the mechanism of modulatory roles of glycyrrhizin (GLH) and myricetin (MYC) on the human CYP3A4 isoform using in silico and in vitro methods. While MYC had concentration-dependent inhibitory effect on CYP3A4 (IC(50) : 10.5 +/- 0.55 muM) with characteristic K(m) and V(max) values of 1.13 muM and 1.54 nM/min, respectively, GLH exhibited no inhibitory effect on CYP3A4 activity in vitro. These observations are consistent with the results of in silico evaluations where the effect of MYC compared well with that of ketoconazole (a known CYP3A4 inhibitor) against CYP3A4. Overall, the established interactions between the study compounds and CYP3A4 could potentiate clinically vital drug-drug interactions and has lent credence to the mechanism of modulatory effect of MYC and GLH on CYP3A4 that could guide their safe use as therapeutic agents. PRACTICAL IMPLICATIONS: Myricetin (MYR) and glycyrrhizin (GLH) occur freely in commonly ingested foods and their supplements are recommended for the treatment of several debilitating diseases such as diabetes, cancer, and cardiovascular complications. This study provided an insight on the possible interactions that could be established between these compounds (MYR and GLH) and CYP3A4 when ingested and metabolized by the liver. The results suggested possibilities of potential clinical drug-drug interactions and advocates for their cautious use within the therapeutic dose in food supplements or medications to avoid probable liver damage. | Cytochrome P-450 CYP3A |
Victor Horsley was intrigued by newly discovered, ancient trepanned skulls, especially those that revealed that the operation was performed on living patients. He examined the man-made openings as an expert on the locus of the primate motor cortex and as a surgeon who had successfully removed parts of the motor cortex to treat Jacksonian epilepsy. He postulated that trepanation originated as a way to treat pain and epilepsy caused by depressed cranial fractures over the motor cortex. Like Broca before him, Horsley helped create the exciting Zeitgeist that led others in the late-1 800s to explore, ponder, and write about ancient trepanned skulls. | Skull Fracture, Depressed |
Neisseria meningitidis is hosted only by humans and colonizes the nasopharynx; it survives in the human body by reaching an equilibrium with its exclusive host. Indeed, while cases of invasive disease are rare, the number of asymptomatic Neisseria meningitides carriers is far higher. The aim of this paper is to summarize the current knowledge of survival strategies of Neisseria meningitides against the human immune defences. Neisseria meningitidis possesses a variety of adaptive characteristics which enable it to avoid being killed by the immune system, such as the capsule, the lipopolysaccharide, groups of proteins that block the action of the antimicrobial proteins (AMP), proteins that inhibit the complement system, and components that prevent both the maturation and the perfect functioning of phagocytes. The main means of adhesion of Neisseria meningitides to the host cells are Pili, constituted by several proteins of whom the most important is Pilin E. Opacity-associated proteins (Opa) and (Opc) are two proteins that make an important contribution to the process of adhesion to the cell. Porins A and B contribute to neisserial adhesion and penetration into the cells, and also inhibit the complement system. Factor H binding protein (fhbp) binds factor H, allowing the bacteria to survive in the blood. Neisserial adhesin A (NadA) is a minor adhesin that is expressed by 50% of the pathogenic strains. NadA is known to be involved in cell adhesion and invasion and in the induction of proinflammatory cytokines. Neisserial heparin binding antigen (NHBA) binds heparin, thus increasing the resistance of the bacterium in the serum. | Neisseriaceae Infections |
Selective estrogen receptor modulators (SERMs) are a class of compounds that bind to estrogen receptors (ERs) and possess estrogen agonist or antagonist actions in different tissues. As such, they are widely used drugs. For instance, tamoxifen, the most prescribed SERM, is used to treat ERalpha-positive breast cancer. Aside from their therapeutic targets, SERMs have the capacity to broadly affect cellular cholesterol metabolism and handling, mainly through ER-independent mechanisms. Cholesterol metabolism reprogramming is crucial to meet the needs of cancer cells, and different key processes involved in cholesterol homeostasis have been associated with cancer progression. Therefore, the effects of SERMs on cholesterol homeostasis may be relevant to carcinogenesis, either by contributing to the anticancer efficacy of these compounds or, conversely, by promoting resistance to treatment. Understanding these aspects of SERMs actions could help to design more efficacious therapies. Herein we review the effects of SERMs on cellular cholesterol metabolism and handling and discuss their potential in anticancer pharmacology. | Lipid Metabolism |
Streptococcus salivarius DB-B5 was previously isolated from the supragingival plaque of a healthy female adult and selected for development as a probiotic candidate for oral health. Probiotics are an important emerging therapeutic method for preventing, treating, and maintaining oral health. Although S. salivarius is a predominant member of the commensal oral microbiota and generally regarded as a safe species, it is recognized that each strain needs to be comprehensively assessed for safety. This study describes the in silico, in vitro, and clinical testing that were conducted to evaluate the safety of S. salivarius DB-B5. Both 16S rRNA and multi-gene phylogenetic reconstruction was used to confirm the taxonomic identity of this strain. Bioinformatic analysis of the genome demonstrated the absence of transmissible antibiotic resistance genes or virulence factors. Phenotypic testing further showed S. salivarius DB-B5 to be susceptible to clinically relevant antibiotics. S. salivarius DB-B5 displayed weak alpha-hemolysis, and does not produce biogenic amines. In a randomized, double-blind, placebo-controlled clinical study, consumption of S. salivarius DB-B5 at 10 billion CFU/day for 4 weeks by healthy adults was safe and well-tolerated (ClinicalTrials.gov registry number NCT04492631). This work has indicated that S. salivarius DB-B5 is a safe probiotic candidate. | Streptococcus salivarius |
The venous vascular anatomy of the endolymphatic sac in human embryos was examined. The endolymphatic sac was found to be covered by sinusoid-like blood vessels arising from the sigmoid sinus. A rich and extensive capillary network was present on the epithelial surface of the endolymphatic sac. Connections between this capillary bed and the vein in the paravestibular canaliculus were seen. The blood of the endolymphatic sac can therefore drain either into the vein of the vestibular aqueduct in the paravestibular canaliculus or directly into the sigmoid sinus. The vessels lying on the endolymphatic sac are thin-walled and irregular. The endothelial cells lies in direct contact with the epithelial cells of the endolymphatic sac. The reduction of the dense capillary bed in the young embryo to only a few vessels in the order embryo is described. | Endolymphatic Duct |
Apoptosis, a morphologically defined form of physiological cell death, is implemented by a death machinery whose executionary arm is a family of cysteine proteases called caspases. These death proteases are part of a proteolytic caspase cascade that is activated by diverse apoptotic stimuli from outside and inside of the cell. The cell death machinery is evolutionarily conserved and composed of caspases and their regulatory components that include activators and repressors. These key components of the death machinery are linked to signaling pathways that are activated by either ligation of death receptors expressed at the cell surface or intracellular death signals. Caspases are normally present in the cell as proenzymes that require limited proteolysis for activation of enzymatic activity. Recent studies suggest that the basic mechanism of caspase activation is conserved in evolution. Binding of initiator caspase precursors to activator molecules appears to promote procaspase oligomerization and autoactivation. Enzymatic activation of initiator caspases leads to proteolytic activation of downstream (effector) caspases and cleavage of a number of vital proteins, resulting in the orderly demise and removal of the cell. | Enzyme Activation |
To understand the posttranslational conversion of the cellular prion protein (PrPC) to its pathologic conformation, it is important to define the intracellular trafficking pathway of PrPC within the endomembrane system. We studied the localization and internalization of PrPC in CHO cells using cryoimmunogold electron microscopy. At steady state, PrPC was enriched in caveolae both at the TGN and plasma membrane and in interconnecting chains of endocytic caveolae. Protein A-gold particles bound specifically to PrPC on live cells. These complexes were delivered via caveolae to the pericentriolar region and via nonclassical, caveolae-containing early endocytic structures to late endosomes/lysosomes, thereby bypassing the internalization pathway mediated by clathrin-coated vesicles. Endocytosed PrPC-containing caveolae were not directed to the ER and Golgi complex. Uptake of caveolae and degradation of PrPC was slow and sensitive to filipin. This caveolae-dependent endocytic pathway was not observed for several other glycosylphosphatidyl inositol (GPI)-anchored proteins. We propose that this nonclassical endocytic pathway is likely to determine the subcellular location of PrPC conversion. | Caveolins |
Polystyrene, despite its high flammability, is widely used as a thermal insulation material for buildings, for food packaging, in electrical and automotive industries, etc. A number of modification routes have been explored to improve the fire retardance and boost the thermal stability of commercially important styrene-based polymeric products. The earlier strategies mostly involved the use of halogenated fire retardants. Nowadays, these compounds are considered to be persistent pollutants that are hazardous to public and environmental health. Many well-known halogen-based fire retardants, regardless of their chemical structures and modes of action, have been withdrawn from built environments in the European Union, USA, and Canada. This had triggered a growing research interest in, and an industrial demand for, halogen-free alternatives, which not only will reduce the flammability but also address toxicity and bioaccumulation issues. Among the possible options, phosphorus-containing compounds have received greater attention due to their excellent fire-retarding efficiencies and environmentally friendly attributes. Numerous reports were also published on reactive and additive modifications of polystyrene in different forms, particularly in the last decade; hence, the current article aims to provide a critical review of these publications. The authors mainly intend to focus on the chemistries of phosphorous compounds, with the P atom being in different chemical environments, used either as reactive, or additive, fire retardants in styrene-based materials. The chemical pathways and possible mechanisms behind the fire retardance are discussed in this review. | Phosphorus Compounds |
An ethyl acetate extract of the roots of Rumex dentatus L. was investigated. Three compounds were identified by their spectroscopic data as chrysophanol (1), 6-methyl-7-acetyl-1, 8-dihydroxy-3-methoxy naphthalene-1-O-beta-D(L)-glucoside (2) and 6-methyl-7-acetyl-1, 8-dihydroxy naphthalene-1-O-beta-D(L)-glucoside (3) were found in the plant for the first time. Compounds 2 and 3 are novel compounds. Their antiproliferation activities were tested by the MTT assay in four cell lines (breast cancer MCF-7, gastric cancer 7901, melanoma A375 and oophoroma SKOV-3). | Rumex |
IMPORTANCE: The prognostic significance of clonal T-cell receptor (TCR) rearrangement or low-level blood involvement as assessed by flow cytometry for patients with early-stage cutaneous T-cell lymphoma (CTCL) is not clear. OBJECTIVE: To assess the association of low-level blood involvement by TCR clonality and flow cytometry with outcomes for patients with early-stage CTCL. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort analysis was conducted from September 1, 2019, to February 29, 2020, of 322 patients with early-stage (I-IIA) CTCL seen at the Winship Cancer Institute of Emory University and Grady Memorial Hospital. T-cell receptor gene rearrangement and flow cytometry records from the peripheral blood were documented at initial assessment. EXPOSURES: T-cell receptor clonality and peripheral blood flow cytometry. MAIN OUTCOMES AND MEASURES: Univariate and multivariable models and Kaplan-Meier assessments were analyzed for overall survival (OS) and time to next treatment. The primary outcome was OS from diagnosis and time to next treatment, and the hypotheses were formulated prior to data collection. RESULTS: A total of 322 patients (166 female patients [51.6%]; median age at diagnosis, 53.8 years [range, 8.6-87.4 years]) with early-stage CTCL diagnosed from 1990 to 2018 were identified; of these, 258 had data available for both flow cytometry and TCR. Positive results for both TCR clonality and flow cytometry were associated with inferior OS in early-stage CTCL compared with both having negative results (hazard ratio [HR], 2.86; 95% CI, 1.02-8.06; P = .046). Positive results for only TCR clonality or only flow cytometry were not associated with OS (TCR clonality: HR, 1.31; 95% CI, 0.70-2.47; P = .40; flow cytometry: HR, 1.21; 95% CI, 0.58-2.52; P = .61) or time to next treatment (TCR clonality: HR, 1.05; 95% CI, 0.77-1.43; P = .76; flow cytometry: HR, 0.74; 95% CI, 0.47-1.16; P = .12). However, positive flow cytometry results were associated with reduced OS in the stage IIA subgroup (n = 94; HR, 1.17; 95% CI, 1.18-8.74; P = .02). Covariates associated with reduced survival included advanced age at diagnosis, male sex, and higher disease stage. CONCLUSIONS AND RELEVANCE: This cohort study of patients with early-stage CTCL suggests that low-level blood involvement as indicated by positive results for both TCR gene rearrangement and flow cytometry was associated with inferior OS, whereas positive results for either flow cytometry or TCR clonality was not. More precise measurements of blood involvement in CTCL and larger multi-institutional cohorts are needed to validate the prognostic significance of low-level blood involvement in early-stage CTCL. | Genes, T-Cell Receptor |
BACKGROUND: Meige's syndrome is a rare form of segmental dystonia characterized by blepharospasm and oromandibular dystonia. Medical treatment including botulinum toxin injections usually present disappointing results. The experience on Deep Brain Stimulation (DBS) in the treatment of Meige's syndrome and other segmental dystonias is still limited. At the moment, only a few cases of pallidal DBS have been reported to improve this rare form of dystonia. CASE DESCRIPTION: We report on a case of a woman with a 7-year history of Meige's syndrome, which rendered her functionally blind. The treatment with botulinum toxin injections failed to improve her symptoms, whereas stereotactic bilateral DBS of the pallidum led to a dramatic clinical improvement. Clinical assessment using the Burke-Fahn-Mardsen Dystonia Rating Scale (BFMDRS) in a double-blind manner, showed an improvement of 70% in the Movement score and 93.33% in the Disability score (84% reduction of the total score) on the 3 and 6 month follow-up. CONCLUSIONS: Stereotactic pallidal DBS might be considered as a potential treatment in the management of Meige's syndrome. | Meige Syndrome |
Androgens are involved in the development of several tissues, including prostate, skeletal muscle, bone marrow, hair follicles, and brain. Most of the biological effects of the androgens are mediated through an intracellular transcription factor, the androgen receptor (AR) at the level of gene regulation. Several types of mutations in the AR gene have been linked to endocrine dysfunctions. The expansion of CAG codon repeat, coding for a polyglutamine (PolyQ) tract in the N-terminal domain is one such mutation. The polyQ chain length impacts AR's ability to interact with critical coregulators, which in turn modulates its transcriptional efficacy. Pathologic manifestations of variations in polyQ chain length have been associated with prostate cancer susceptibility, and the Spinal and Bulbar Muscular Atrophy (SBMA), a neurodegenerative disease. In this review article, we discuss multiple aspects of the role of polyQ chain length in the actions of the AR, their importance in prostate cancer development and progression, and SBMA with an aim to understand the underlying mechanisms involved in these diseases, which can be targeted for future therapeutic approaches." | Bulbo-Spinal Atrophy, X-Linked |
Critical thinking and clinical decision making are essential components of the knowledge and skills acquired in the perioperative education process. Although traditional didactic teaching methods remain predominant teaching strategies in perioperative nursing education, programs should include a variety of methods and tools to enhance learning of a considerable amount of complex material. Concept mapping is an active teaching strategy that can be used in nursing education to facilitate the development of critical thinking and decision-making skills. A concept map is a tool consisting of a main idea, subconcepts, and cross-links that organizes knowledge by showing relationships between concepts. Different types of maps can be used to present different types of learning material, depending on the focus of the lesson. Complex knowledge (eg, perioperative technology) can be better learned and retained when the brain works to organize information in a hierarchical framework and the information is built up with interacting concepts. | Perioperative Nursing |
To obtain information on the concentration and spectrum of bile acids in human cecal content, samples were obtained from 19 persons who had died an unnatural death from causes such as trauma, homicide, suicide, or drug overdose. Bile acid concentration was measured via an enzymatic assay for 3alpha-hydroxy bile acids; bile acid classes were determined by electrospray ionization mass spectrometry and individual bile acids by gas chromatography mass spectrometry and liquid chromatography mass spectrometry. The 3alpha-hydroxy bile acid concentration (mumol bile acid/ml cecal content) was 0.4 +/- 0.2 mM (mean +/- SD); the total 3-hydroxy bile acid concentration was 0.6 +/- 0.3 mM. The aqueous concentration of bile acids (supernatant after centrifugation) was identical, indicating that most bile acids were in solution. By liquid chromatography mass spectrometry, bile acids were mostly in unconjugated form (90 +/- 9%, mean +/- SD); sulfated, nonamidated bile acids were 7 +/- 5%, and nonsulfated amidated bile acids (glycine or taurine conjugates) were 3 +/- 7%. By gas chromatography mass spectrometry, 10 bile acids were identified: deoxycholic (34 +/- 16%), lithocholic (26 +/- 10%), and ursodeoxycholic (6 +/- 9), as well as their primary bile acid precursors cholic (6 +/- 9%) and chenodeoxycholic acid (7 +/- 8%). In addition, 3beta-hydroxy derivatives of some or all of these bile acids were present and averaged 27 +/- 18% of total bile acids, indicating that 3beta-hydroxy bile acids are normal constituents of cecal content. In the human cecum, deconjugation and dehydroxylation of bile acids are nearly complete, resulting in most bile acids being in unconjugated form at submicellar and subsecretory concentrations. | Deoxycholic Acid |
beta-Defensins play an important role in both innate and adaptive immunity, displaying a direct anti-microbial activity against a wide variety of micro-organisms as well as interesting immuno-modulatory effects on host cells. Interaction with biological membranes appears to be a central theme in modulating these activities, leading to different consequences such as membrane lysis, translocation into the cytoplasm or transfer to a receptor. We have investigated the structuring of human beta-defensins (hBD2 and hBD3) and rationally designed variants, in relation to their interactions with real and model membranes. Biophysical methods, such as circular dichroism (CD), transmission or reflection IR and dye release were used to probe their structure/activity in the presence of model membranes, while fluorimetric and flow cytometric assays were used to investigate the effects on prokaryotic cells. Our results indicate that structural features, such as the helical N-terminal domains and oligomerisation at the membrane surface, may modulate the efficiency of membrane insertion and selectivity for microbial or host-cell membranes. We propose that both peptides interact with membranes as extended beta-sheet platforms that present amphipathic helices for insertion into the lipid bilayer. | beta-Defensins |
Horizontal cells mediate inhibitory feedforward and feedback lateral interactions in the outer retina at photoreceptor terminals and bipolar cell dendrites; however, the mechanisms that underlie synaptic transmission from mammalian horizontal cells are poorly understood. The localization of a vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) to horizontal cell processes in primate and rodent retinae suggested that mammalian horizontal cells release transmitter in a vesicular manner. Toward determining whether the molecular machinery for vesicular transmitter release is present in horizontal cells, we investigated the expression of SNAP25 (synaptosomal-associated protein of 25 kDa), a key SNARE protein, by immunocytochemistry with cell type-specific markers in the retinae of mouse, rat, rabbit, and monkey. Different commercial antibodies to SNAP25 were tested on vertical sections of retina. We report the robust expression of SNAP25 in both plexiform layers. Double labeling with SNAP25 and calbindin antibodies demonstrated that horizontal cell processes and their endings in photoreceptor triad synapses were strongly labeled for both proteins in mouse, rat, rabbit, and monkey retinae. Double labeling with parvalbumin antibodies in monkey retina verified SNAP25 immunoreactivity in all horizontal cells. Pre-embedding immunoelectron microscopy in rabbit retina confirmed expression of SNAP25 in lateral elements within photoreceptor triad synapses. The SNAP25 immunoreactivity in the plexiform layers and outer nuclear layer fell into at least three patterns depending on the antibody, suggesting a differential distribution of SNAP25 isoforms. The presence of SNAP25a and SNAP25b isoforms in mouse retina was established by reverse transcriptase-polymerase chain reaction. SNAP25 expression in mammalian horizontal cells along with other SNARE proteins is consistent with vesicular exocytosis. | Retinal Horizontal Cells |
It is usually assumed that upper airway pressure receptors mediate the reflexes involved in sleep apneas, but many other receptors may be involved, including those responding to chemical stimuli. The reflexes to upper airway negative pressure have been further studied, and the timing of their inputs shown to be important. Their effects on the cardiovascular system, including cerebral blood flow, have been emphasized. The central nervous pathways for the upper airway reflexes and their relationship to the neuronal circuits of the respiratory rhythm generator are being analyzed, but no clear pattern has emerged. Many neurotransmitters have been identified, usually on the motor pathways, which points to possible therapeutic approaches. The central nervous pharmacology and the neuronal pattern for the cough reflex have been described, and a similar approach to other upper airway reflexes, especially those involved in sleep apneas, would be valuable. | Pharyngeal Muscles |
OBJECTIVE: The aim of this study was to assess pulmonary venous anatomy and to determine the frequency of each drainage pattern in a large cohort using multidetector computed tomography (MDCT) and three-dimensional (3D) imaging. MATERIAL AND METHODS: The chest CT images of 550 patients were retrospectively reviewed for pulmonary venous anatomy and variant patterns. All CT scans were performed using a 128 detectors row CT scanner after intravenous contrast administration. Pulmonary venous drainage pattern was documented for each patient and frequency of each drainage type was calculated. A useful classification system was used to simplify complex pulmonary venous anatomy. RESULTS: The expected typical anatomy was observed in 239 (43.5%) patients. The remaining 311 (56.5%) patients had anatomic variations on the right, left, or both sides. The most common variation was left common vein, seen in 177 (32.2%) patients, followed by accessory right middle lobe vein(s), seen in 112 (20.4%) patients. In the present study the frequency of variant anatomy on the right (34%) and left (33.3%) sides were similar. CONCLUSION: The use of MDCT with 3D imaging is a preferable imaging tool for demonstrating pulmonary venous anatomy in detail, which shows significant variability. Considering the high prevalence of variations in the population, performing preprocedural MDCT may facilitate higher success rates in radiofrequency catheter ablation (RFCA) and help to perform safe and accurate surgery especially in video-assisted thoracic surgery (VATS)." | Multidetector Computed Tomography |
PURPOSE: To determine the influence of curing mode on the surface hardness of seven resin cements used to lute indirect composite restorations. MATERIALS AND METHODS: Seven commercial dual-curing resin cements were tested: two were total-etch (RelyX ARC [3M ESPE, St. Paul, MN, USA] and Variolink II [Ivoclar Vivadent, Schaan, Liechtenstein]); one was self-etch (Multilink Automix [Ivoclar Vivadent]), and four were self-adhesive (RelyX Unicem [3M ESPE], Maxcem Elite [Kerr Corp., Orange, CA, USA], SmartCem2 [Dentsply, Detrey, GmbH, Konstanz, Germany], and G-Cem [GC CORPORATION, Itabashi-Ku, Tokyo, Japan]). Three specimens (0.5 x 6.5mm) of each material were prepared for each of three experimental groups: Group 1 (cements allowed to self cure); Group 2 (cements light-cured for 40 seconds); and Group 3 (cements light-cured for 80 seconds). All specimens were cured through a 4-mm-thick composite cylinder (Filtek Z250-A3). Surface microhardness numbers were determined at 20 min after preparation. Results were analyzed by two-way analysis of variance and Student-Newman-Keuls tests (p<0.05). RESULTS: Superficial hardness was significantly influenced by the resin cement tested (p<0.0001), the curing mode (p<0.0001), and their interaction (p<0.0001). RelyX ARC exhibited the highest mean microhardness values regardless of the curing mode. Light-curing significantly increased the microhardness of all resin cements studied, and these values increased even further with a doubling of irradiation time. Self-adhesive cements exhibited different behavior according to the curing mode. RelyX Unicem was highly sensitive to light irradiation, showing the lowest mean values in the self-curing mode. After light irradiation for 40 or 80 seconds, Maxcem Elite exhibited the lowest mean hardness values of all the resin cements tested. CONCLUSION: The microhardness of resin cements is highly dependent on the brand. Dual-curing resin cements should always be light irradiated for longer periods than that recommended by manufacturers. CLINICAL SIGNIFICANCE: Dual-curing resin cements should always be light-cured for longer irradiation times, as light irradiation for 80 seconds yields the highest microhardness values in comparison with self-curing or light irradiation for 40 seconds. However, some self-adhesive resin cements exhibit low microhardness values when used to cement 4-mm-thick indirect composite restorations regardless of the curing mode applied. | Self-Curing of Dental Resins |
Interim monitoring is routinely conducted in phase II clinical trials to terminate the trial early if the experimental treatment is futile. Interim monitoring requires that patients' responses be ascertained shortly after the initiation of treatment so that the outcomes are known by the time the interim decision must be made. However, in some cases, response outcomes require a long time to be assessed, which causes difficulties for interim monitoring. To address this issue, we propose a Bayesian trial design to allow for continuously monitoring phase II clinical trials in the presence of delayed responses. We treat the delayed responses as missing data and handle them using a multiple imputation approach. Extensive simulations show that the proposed design yields desirable operating characteristics under various settings and dramatically reduces the trial duration." | Clinical Trials, Phase II as Topic |
Luminescent quantum dots (QDs)-semiconductor nanocrystals were promising alternative to organic dyes for fluorescence-based applications. In this paper, we developed procedures to use mercaptoacetic acid (MAA) to modify ZnSe nanoparticles and made the nanoparticles to be soluble for the quantitative and selective determination of bovine serum albumin (BSA). Maximum fluorescence intensity was produced at pH 7.0, with excitation and emission wavelengths at 242 and 348 nm, respectively. Under optimal conditions, the straight line equation: Delta(F) = 0.38 + 0.34 C (microg/ml) was found between the relative fluorescence intensity and the concentration of BSA in the range of 9.6-124.8 microg/ml, and the limit of detection was 2 microg/ml. | Selenium Compounds |
CTNNB1-related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1-related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1-related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations." | Familial Exudative Vitreoretinopathies |
INTRODUCTION: Autologus augmentation of wound remodeling with platelet concentrate is a burgeoning field with promising results. We hypothesized that the addition of filtered platelet concentrate (fPC) to an acellular biologic graft would improve crural healing and tissue integrity in hiatal hernia repair. METHODS: Sixteen healthy Yorkshire female pigs were divided into three groups: hiatus repair (HR) (n = 7), HR with biologic graft (HRM; n = 8, and HR with biologic graft and fPC (fPC; n = 9). Surgeries were performed by a single surgeon. Animals were euthanized at 8 weeks, and the distal esophagus with hiatus was harvested en-block. Tissue was graded by a histopathologist on collagen deposition, vascularization, and inflammation at the graft-hiatal interface. Tensile strength testing was performed using the Teststar IIs (MTS), coupled with a strain extensometer (Epsilon). Samples of equal dimensions were preloaded to 1 N and deformed at a constant rate of 0.2 mm/s. Statistical analysis was performed via Kruskal-Wallis one-way analysis of variance. RESULTS: Aspirate analysis revealed a mean platelet count of 3 million platelets/1 mL of aspirate. Animals in the fPC group had significantly increased mean chronic inflammation (3.1 +/- 1.1 vs. 1.8 +/- 1.6, 1.2 +/- 1.2, p = 0.04) compared to HR alone and HR + biologic graft. Vascular deposition did not differ between groups (p = 0.8). A trend toward increased collagen deposition was demonstrated for the fPC group (1.4 +/- 1.1 vs. 2.0 +/- 0.6 in HR group and 3.0 +/- 1.2 in HRM group, p = 0.06). There was a statistically significant increase in tensile strength, yield force, and Young's modulus in the fPC group compared with HR and HR + biologic mesh (p < 0.01). CONCLUSION: A trend toward increased collagen deposition and vascularity of the fPC group was demonstrated. In addition, there was an increase in tensile strength and yield force in the fPC group. Use of autologous fPC appears a safe and promising adjunct to wound remodeling and healing in a swine model. | Hernia, Hiatal |
In this issue of Blood, Lorenz et al elucidate the mechanisms by which antibody-mediated targeting of platelet C-type lectinlike receptor 2 (CLEC-2) induces receptor downregulation and thrombocytopenia. This information is important because antibody-mediated targeting of CLEC-2 may have therapeutic utility as antithrombotic therapy, especially if thrombocytopenia can be avoided. | Lectins, C-Type |
This study developed an air-liquid interface (ALI) corneal model using explants bovine eyes for ocular toxicity assessment of ten chemicals and seven hair straightening mixtures. It was successfully maintained physiologically viable and normal for six days. Both eye damage (GHS cat. 1) and irritating (GHS cat. 2) chemicals induced corneal injury in our model. However, cat. 2 irritants triggered moderate damage when compared to cat. 1 agents, which induced a marked cytotoxicity profile. The mixtures were also able to trigger viability reduction associated with histopathological changes in the corneal tissues, especially when the exposure was via aerosol particles. Thus, the chemical exposure microenvironment simulation seemed to provide more reliable toxicological data. Moreover, mixture-induced corneal damage correlated with increased ROS levels, suggesting a close correlation between tissue death and oxidative stress. Besides mixtures showing the potential to induce moderate/mild ocular toxicity, we could verify that the corneal tissue damage showed reversibility due to the recovery from the injury after exposure to some of the mixtures. Hence, our ex vivo corneal model seems to be a simple and cost-effective approach for future studies related to further investigating the reversibility of damage in the cornea triggered by chemicals and their mixtures. | Toxic Optic Neuropathy |
The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the maintenance of basal and stress-related homeostasis. The hypothalamus controls the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which in turn stimulates the secretion of glucocorticoids from the adrenal cortex. Glucocorticoids, the final effectors of the HPA axis, regulate a broad spectrum of physiologic functions essential for life and exert their effects through their ubiquitously distributed intracellular receptors. Alterations in the activity of the HPA axis may present with symptoms and signs of glucocorticoid deficiency or excess. Detailed endocrinologic evaluation is of primary importance in determining the diagnosis and/or etiology of the underlying condition. We review the most common endocrinologic investigations used in the evaluation of the HPA axis integrity and function." | Pituitary-Adrenal Function Tests |
The incidence rate of chest wall invasion in operated bronchogenic carcinoma is about 3%. From 1973 to 1984, 12 patients in our hospital underwent en bloc lung and partial chest wall resection for bronchogenic carcinoma with local invasion of the thoracic wall. All were male, between 49 and 74 years of age. Chest wall or back pain was the most prominent complaint. The duration of symptoms varied from 2 to 20 months. In 10 the tumour was peripherally and in 2 centrally located. Mediastinoscopies, selectively performed were negative. In 11 patients there was a squamous cell and in 1 an adenocarcinoma. 10 lobectomies and 2 pneumonectomies were performed. Macroscopic size of the tumour ranged from 3 to 17 cm, the number of partially resected ribs ranged from 1 to 4. There was 1 operative death (8%). 3 patients died within 5 months and 3 other patients within 14 months. 5 patients are still alive, 2 more than 5 years (17%). The survival is unfavourably influenced by lymph node involvement. The majority of patients became free of pain one month after surgery. | Carcinoma, Bronchogenic |
The role of sino-aortic reflexes in the control of circulation during normal behavior was investigated by comparing cardiovascular reactions during various but reproducible types of behavior before and after bilateral sino-aortic deafferentation. Chronic deafferentation caused little change in baseline blood pressure, but a subtler, important role of sino-aortic reflexes was revealed by examining the integrated cardiovascular responses to behavioral stimuli. During desynchronized sleep, the buffering action of sino-aortic reflexes prevented a marked and diffuse vasodilation, with an action that was particularly evident on muscle blood vessels. During emotional behavior, especially when emotion was accompanied by movement, sino-aortic reflexes opposed the consequences of muscle vasodilation by inducing tachycardia and vasoconstriction in the viscera and in noncontracting muscles. A reciprocal type of interaction between behavior and sino-aortic reflexes was shown by testing the amplitude of the carotid occlusion response before and during desynchronized sleep; the latter condition was consistently associated with decreased effectiveness of the reflex response. The possibility is considered that this might indicate central suppression of the carotid sinus reflex during desynchronized sleep and that a similar inhibitory interference might occur during emotional behavior. Alternatively, reduction of the reflex response might result from a shift of the stimulus-response curve on either side of its steep portion. | Carotid Sinus |
Variants of human pancreatic carboxypeptidase B (HCPB), with specificity for hydrolysis of C-terminal glutamic acid and aspartic acid, were prepared by site-directed mutagenesis of the human gene and expressed in the periplasm of Escherichia coli. By changing residues in the lining of the S1' pocket of the enzyme, it was possible to reverse the substrate specificity to give variants able to hydrolyse prior to C-terminal acidic amino acid residues instead of the normal C-terminal basic residues. This was achieved by mutating Asp253 at the base of the S1' specificity pocket, which normally interacts with the basic side-chain of the substrate, to either Lys or Arg. The resulting enzymes had the desired reversed polarity and enzyme activity was improved significantly with further mutations at residue 251. The [G251T,D253K]HCPB double mutant was 100 times more active against hippuryl-L-glutamic acid (hipp-Glu) as substrate than was the single mutant, [D253K]HCPB. Triple mutants, containing additional changes at Ala248, had improved activity against hipp-Glu substrate when position 251 was Asn. These reversed-polarity mutants of a human enzyme have the potential to be used in antibody-directed enzyme prodrug therapy of cancer. | Carboxypeptidases |
This study provides transcriptomic characterization of the cells of the crista ampullaris, sensory structures at the base of the semicircular canals that are critical for vestibular function. We performed single-cell RNA-seq on ampullae microdissected from E16, E18, P3, and P7 mice. Cluster analysis identified the hair cells, support cells and glia of the crista as well as dark cells and other nonsensory epithelial cells of the ampulla, mesenchymal cells, vascular cells, macrophages, and melanocytes. Cluster-specific expression of genes predicted their spatially restricted domains of gene expression in the crista and ampulla. Analysis of cellular proportions across developmental time showed dynamics in cellular composition. The new cell types revealed by single-cell RNA-seq could be important for understanding crista function and the markers identified in this study will enable the examination of their dynamics during development and disease. | Semicircular Ducts |
Even though medical devices have improved a lot over the past decades, there are still issues regarding their anti-biofouling properties and tribological performance, and both aspects contribute to the short- and long-term failure of these devices. Coating these devices with a biocompatible layer that reduces friction, wear, and biofouling at the same time would be a promising strategy to address these issues. Inspired by the adhesion mechanism employed by mussels, here, dopamine is made use of to immobilize lubricious mucin macromolecules onto both manufactured commercial materials and real medical devices. It is shown that purified mucins successfully adsorb onto a dopamine pre-coated substrate, and that this double-layer is stable toward mechanical challenges and storage in aqueous solutions. Moreover, the results indicate that the dopamine/mucin double-layer decreases friction (especially in the boundary lubrication regime), reduces wear damage, and provides anti-biofouling properties. The results obtained in this study show that such dopamine/mucin double-layer coatings can be powerful candidates for improving the surface properties of medical devices such as catheters, stents, and blood vessel substitutes. | Friction |
PURPOSE: Congenital tracheal stenosis (CTS) is rare and challenging. Complete tracheal rings cause a wide spectrum of airway-obstructing lesions and varying degrees of respiratory distress. Although surgical reconstruction is the primary option for symptomatic CTS, sometimes an appropriate management strategy may be difficult due to other anomalies. We aimed to identify pitfalls in the management of CTS. METHODS: We retrospectively reviewed the records of patients with CTS during the last 10 years in our institution. RESULTS: Sixteen pediatric patients were diagnosed with CTS. Of the 16 patients, 12 (75.0%) had cardiovascular anomalies including seven left pulmonary artery sling. Six patients with dyspnoea caused by CTS and three patients with difficult intubations due to CTS underwent tracheoplasty. Four patients underwent only cardiovascular surgery without tracheoplasty. Three asymptomatic patients were followed up without undergoing any surgical procedure. We repeatedly discussed management of four patients with especially complex pathophysiology at multidisciplinary meetings. Right ventricular outflow tract obstruction, tracheobronchial malacia, increased pulmonary blood flow, and pulmonary aspiration due to gastroesophageal reflux presumably accounted for their severe respiratory distress, and we forewent their tracheal reconstruction. CONCLUSION: The management of CTS should be individualized, and conservative management is a feasible option in selected cases. | Tracheal Stenosis |
BACKGROUND: Liver cirrhosis and ascites are risk factors for intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS); however, data is scarce. We aimed to determine the prevalence of IAH/ACS in a population of critically ill cirrhotic patients with acute medical illness in intensive care and to assess for risk factors and clinical outcomes. METHODS: This was a multicentric retrospective cohort study including two general ICUs and pooled data from a multicentric study between January 2009 and October 2019. RESULTS: A total of 9,345 patients were screened, and 95 were included in the analysis. Mean age was 56.7+/-1.3 years, and 79% were male. Liver cirrhosis etiology included alcohol in 45.3% and alcohol plus hepatitis C virus in 9.5%. Precipitating events included infection in 26% and bleeding in 21% of cases. Mean severity score MELD and SAPS II were 26.2+/-9.9 and 48.5+/-15.3, respectively, at ICU admission. The prevalence of IAH and ACS was respectively 82.1% and 23.2% with a mean value of maximum IAP of 16.0+/-5.7 mmHg and IAH grades: absent 17.9%, I 26.3%, II 33.7%, III 17.9%, and IV 4.2%. Independent risk factors for IAH were alcoholic cirrhosis (p = 0.01), West-Haven score (p = 0.01), and PaO2/FiO2 ratio (p = 0.02); as well as infection (p = 0.048) for ACS. Overall, 28-day mortality was 52.6% associated with higher IAP and ACS, and independent risk factors were MELD (p = 0.001), white blood cell count (p = 0.03), PaO2/FiO2 ratio (p = 0.03), and lactate concentration (p = 0.04) at ICU admission. CONCLUSIONS: This study demonstrates a very high prevalence of IAH/ACS in the critically ill cirrhotic patient in intensive care. Increased IAP and ACS were associated with severity of disease and adverse outcomes and independent risk factors for IAH were alcoholic cirrhosis, hepatic encephalopathy and PO2/FiO2 ratio, as well as infection for ACS. Early diagnosis, prevention, and treatment of IAH/ACS might improve outcome in critically ill cirrhotic patients. | Intra-Abdominal Hypertension |
Screening of halophiles with antimicrobial activity in saltpan soil samples from Nagapattinam district, Tamil Nadu, revealed isolate VE-2 as the most potent, identified as Bacillus firmus strain VE-2 through 16s rRNA gene sequencing. It had an optimum growth condition (OD 3.1) and antimicrobial protein (AMP) production (450 mug/mL) at 37 degrees C, pH 8, 25% NaCl, and 36 h incubation. SDS-PAGE analysis of the purified AMP showed the molecular weight of 36 kDa. HPLC analysis of the purified AMP showed different amino acids, such as asparagines, alanine, lysine, proline, threonine, glycine, cysteine, serine, aspartic acid leucine, and valine. Further characterization and identification using FT-IR, 2D-PAGE, MALDI-TOF, and in-silico analysis showed that the isolated AMP had the highest similarity to Subtilisin-A. It showed antibacterial activity against clinical bacterial pathogens like S. aureus, S. pyogenes, C. diphtheria, E. coli, and P. aeruginosa with the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration of 2.5 mug/mL and 20 mug/mL and also against various fungal pathogens such as A. niger, A. flavus, C. albicans, C. tropicalis and C. parapsilosis with the MIC and minimum fungicidal concentrations of 1.25-80 mug/mL. The purified AMP had excellent antioxidant potential, showed a scavenging effect against DPPH and Nitric oxide radicals, and displayed anticancer activity against HeLa cell lines with the IC(50) values 53 mug/mL. Hence, the purified bioactive antimicrobial peptides (AMP) could also be used in anticancer therapies. | Bacillus firmus |
PURPOSE: The economic cost linked to the increasing number of proximal femur fracture and their postoperative care is immense. Mortality rates are high. As early surgery is propagated to lower mortality and reduce complication rates, a 24-h target for surgery is requested. It was our aim to determine the cut-off for the time to surgery from admission and therefore establish a threshold at which the in-house mortality rate changes. METHODS: A retrospective single-center cohort study was conducted including 1796 patients with an average age of 82.03 years treated operatively for a proximal femoral fracture between January 2016 and June 2020. A single treatment protocol was performed based on the type of anticoagulant, surgery, and renal function. Patient data, surgical procedure, time to surgery, complications, and mortality were assessed. RESULTS: In-house mortality rate was 3.95%, and the overall complication rate was 22.7%. A prolonged length of hospital stay was linked to patient age and occurrence of complications. Mortality is influenced by age, number of comorbidities BMI, and postoperative complications of which the most relevant is pneumonia. The mean time to surgery for the entire cohort was 26.4 h. The investigation showed no significant difference in mortality rate among the two groups treated within 24 h and 24 to 48 h while comparing all patients treated within 48 h and after 48 h revealed a significant difference in mortality. CONCLUSIONS: Age and number of comorbidities significantly influence mortality rates. Time to surgery is not the main factor influencing outcome after proximal femur fractures, and mortality rates do not differ for surgery up to 48 h after admission. Our data suggest that a 24-h target is not necessary, and the first 48 h may be used for optimizing preoperative patient status if necessary. | Proximal Femoral Fractures |
For the first time inflorescences of a plant species from the genus Plantago (Pantaginaceae)-Plantago lanceolata L. (Ribwort Plantain), a known medicinal plant, were subjected to studies of phenolic compounds, which resulted in an isolation of two new compounds: a flavonoid-isorhamnetin 3-O-alpha-L-(4)C(1)-arabinopyranosyl-(1-->2)-beta-D-(4)C(1)-glucopyranoside) (1) and a phenylethanoid glycoside-2-(3,4-dihydroxyphenyl)ethyl O-alpha-L-arabinofuranosyl-(1-->2)-[alpha-L-(1)C(4)-rhamnopyranosyl-(1-->3)][E-caffeoyl-1-->4]-beta-D-(4)C(1)-glucopyranoside (14), along with fourteen known compounds-eight flavonoids (2-9) and six phenylethanoid glycosides (10-13, 15-16). The chemical structures were established by 1 D and 2 D NMR and HRESIMS spectral methods. The known phenylethanoids were the same as reported for leaves or aerial parts of P. lanceolata or other Plantago species. The flavonoids appeared to be only flavonols, mainly isorhamnetin 3-O- and 3,4'-O- glycosides, and thus completely different from flavones, mainly luteolin and apigenin glucuronides, previously reported in the leaves. The possible medicinal and chemotaxonomic relevance of the phenolics found in P. lanceolata inflorescences were taken into consideration. | Plantago |
Trichomonas vaginalis is a protozoan with an extracellular obligatory parasitic lifestyle exclusively adapted to the human urogenital tract and responsible for nearly a quarter billion sexually transmitted infections worldwide each year. This review focuses on symbiotic Trichomonasvirus and mycoplasmas carried by the protozoan, their molecular features and their role in altering the human vaginal microbiome and the immunopathogenicity of the parasite. Improved diagnostics and larger clinical interventional studies are needed to confirm the causative role of protozoan symbionts in the variable clinical presentation of trichomoniasis and its morbid sequelae, including adverse reproductive outcome, susceptibility to viral infections and cancer. | Totiviridae |
The culinary and medicinal mushroom Hericium erinaceus is widely consumed in Asian countries, but apparently not in the United States, for its nutritional and health benefits. To stimulate broader interest in the reported beneficial properties, this overview surveys and consolidates the widely scattered literature on the chemistry (isolation and structural characterization) of polysaccharides and secondary metabolites such as erinacines, hericerins, hericenones, resorcinols, steroids, mono- and diterpenes, and volatile aroma compounds, nutritional composition, food and industrial uses, and exceptional nutritional and health-promoting aspects of H. erinaceus. The reported health-promoting properties of the mushroom fruit bodies, mycelia, and bioactive pure compounds include antibiotic, anticarcinogenic, antidiabetic, antifatigue, antihypertensive, antihyperlipodemic, antisenescence, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties and improvement of anxiety, cognitive function, and depression. The described anti-inflammatory, antioxidative, and immunostimulating properties in cells, animals, and humans seem to be responsible for the multiple health-promoting properties. A wide range of research advances and techniques are described and evaluated. The collated information and suggestion for further research might facilitate and guide further studies to optimize the use of the whole mushrooms and about 70 characterized actual and potential bioactive secondary metabolites to help prevent or treat human chronic, cognitive, and neurological diseases. | Fruiting Bodies, Fungal |
A Lactobacillus-dominated vaginal microbiota (VMB) has been associated with health and considered an important host defense mechanism against urogenital infections. Conversely, depletion of lactobacilli and increased microbial diversity, amplifies the risk of adverse gynecologic and obstetric outcomes. A common clinical condition that exemplifies dysbiosis is bacterial vaginosis (BV). BV is currently treated with antibiotics, but frequently recurs, due in part to persistent dysbiosis and failure of lactobacilli to repopulate the vagina. New treatment options are needed to address BV. The VMB is relatively simple and optimally dominated by one or several species of Lactobacillus. Lactobacillus crispatus is strongly associated with vaginal health and depleted in dysbiosis. Replenishing the dysbiotic VMB with protective L. crispatus CTV-05 is a promising approach to prevent recurrent infections and improve women's health. Here we discuss confirmation of this approach with the microbiome-based biologic drug, LACTIN-V (L. crispatus CTV-05), focusing on prevention of BV recurrence. | Lactobacillus crispatus |
Ever since Hirata's report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. Despite extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine-type Daphniphyllum alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol coupling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Our approach paves the way for the synthesis of other yuzurimine-type alkaloids and related natural products. | Daphniphyllaceae |
AIM: To investigate the skeletal, dental, and soft tissue changes in girls with class II division 1 malocclusion after growth spurt peak under the effect of activator appliance. MATERIALS AND METHODS: In this clinical trial study, 15 female patients, with skeletal class II and mandibular growth deficiency and at least 5 mm overjet, were randomly selected 6 months after their menarche. The mean of their ages at the beginning was 12.33 +/- 0.81 years, and in the end it was 13.73 +/- 0.79 years; the mean duration of treatment was 12.2 +/- 3.18 months. Lateral, cephalometric radiographs were taken from all the patients before and after the treatment. Data were analyzed with Statistical Package for the Social Sciences (SPSS) 20 using paired t-test. RESULTS: On an average, the ANB angle, the angle of the upper incisors with the S-N, facial convexity, and overjet decreased by 2.6 degrees +/- 0.9, 5.4 degrees +/- 0.8, 3.8 degrees +/- 3.4, and 5.6 +/- 1.8 mm respectively. The SNB angle, the angle of the lower incisors with the N-B, the labiomental angle, the total length of the mandible, the lower anterior facial height, the lower lip distance, the first molar of the mandible, and the soft tissue pogonion to the vertical line from the S point increased by 2.8 degrees +/- 1.8, 3.4 degrees +/- 3, 14.7 +/- 15, 3.7 +/- 2.6, 2.1 +/- 1.6, 6.3 +/- 2.5, 4.4 +/- 2.4, and 6 +/- 3.3 mm respectively. All these figures were statistically significant (p = 0.000). CONCLUSION: The functional appliance improved the dental-skeletal relations and the soft tissue profile of patients after the growth spurt peak of puberty in a group of Iranian girls, whereas dental changes were more than skeletal ones. CLINICAL SIGNIFICANCE: Functional appliances can be used for correction of skeletal class II malocclusion 6 months after menarche in girls. | Activator Appliances |
Photosynthetic organisms have a variety of accessory pigments, on which their classification has been based. Despite this variation, it is generally accepted that all chloroplasts are derived from a single cyanobacterial ancestor. How the pigment diversity has arisen is the key to revealing their evolutionary history. Prochlorophytes are prokaryotes which perform oxygenic photosynthesis using chlorophyll b, like land plants and green algae (Chlorophyta), and were proposed to be the ancestors of chlorophyte chloroplasts. However, three known prochlorophytes (Prochloron didemni, Prochlorothrix hollandica and Prochlorococcus marinus) have been shown to be not the specific ancestors of chloroplasts, but only diverged members of the cyanobacteria, which contain phycobilins but lack chlorophyll b. Consequently it has been proposed that the ability to synthesize chlorophyll b developed independently several times in prochlorophytes and in the ancestor of chlorophytes. Here we have isolated the chlorophyll b synthesis genes (chlorophyll a oxygenase) from two prochlorophytes and from major groups of chlorophytes. Phylogenetic analyses show that these genes share a common evolutionary origin. This indicates that the progenitors of oxygenic photosynthetic bacteria, including the ancestor of chloroplasts, had both chlorophyll b and phycobilins. | Prochloron |
BACKGROUND: Perforating keratoplasty (PKP) for the treatment of keratoconus is a temporary procedure that sacrifices the healthy recipient endothelium. As an alternative to PKP we perform live-epikeratophakia (L-EPI) in keratoconus I-II and deep lamellar keratoplasty (DLKP) in keratoconus II-III. PATIENTS AND METHODS: 20 patients with keratoconus were operated on either with L-EPI for keratoconus I-II (n = 10) or DLKP for keratoconus II-III (n = 10) respectively. In all cases, corneal tissue eligible for corneal transplantation was used. L-EPI: The corneal lenticule was prepared by means of the Barraquer-Krumeich-Swinger (BKS) set. The recipient cornea was trephined to a depth of 0.3 mm with the Guided-Trephine-System (GTS). The incision was extended manually (inner diameter 7.0 mm, outer diameter 9.0 mm). No keratectomy was performed. The lenticule was fixed with a 10 x 0 nylon double-running anti-torque suture (DRA). DLKP: The recipient cornea was trephined with the 8.0 mm GTS to a depth of 0.68 mm. A lamellar removal of the upper layers was performed by hand. After mechanical removal of the graft endothelium, the remaining full thickness donor cornea was sutured into the bed with a 10 x 0 nylon DRA suture. RESULTS: L-EPI: Within this series, there was no disturbance of the healing process. Spherical equivalent and corneal astigmatism remained stable from the first month on. Visual acuity of 20/40 or better was obtained in 40% of the cases at 1 month, 53% at 6 months, and 100% at 1 year and 2 years. We did not observe any late decline of VA. Two patients with kerato-conus borderline stage II did not reach useful VA due to insufficiently reduced pre-existing irregular corneal astigmatism. These patients successfully underwent DLKP at 8 and 10 months respectively. DLKP: Except for 1 case (neurodermatitis), all lenticules remained stable with respect to refraction and radii up to the longest follow-up of 2 years. Starting from the first month on, refraction was stable. Visual acuity of 20/40 or better was reached in 33% of the cases at 1 month, in 56% at 6 months, and in 89% at 1 and 2 years. We did not administer systemic cyclosporine-A in either group. In the lamellar techniques presented, we did not observe any graft rejection. According to corneal topography, corneal astigmatism, spherical equivalent, and keratometry we did not observe any late re-onset of a progression of the cone. CONCLUSION: In patients with keratoconus stage I to III, L-EPI or DLKP appeared to be very useful therapies. Both procedures seem to end progression of the disease and allow to preserve the healthy recipient endothelium. If unsuccessful, either procedure may be repeated. Neither procedure precludes possibly later needed PKP. | Epikeratophakia |
OBJECTIVE: Aceruloplasminemia is an iron metabolic disorder caused by mutations in the ceruloplasmin gene. It is characterized by progressive neurodegeneration in association with iron accumulation. Excess iron functions as a potent catalyst of biologic oxidation. Previously we showed that an increased iron concentration is associated with the products of lipid peroxidation in the serum, cerebrospinal fluid, and brain tissues. To clarify the free radical-mediated tissue injury caused by intracellular iron accumulation through mitochondrial dysfunction. PATIENTS AND METHODS: We have measure brain oxygen and glucose metabolisms using positron emission tomography (PET) and examined brains at autopsy for iron contents and activities of the mitochondrial respiratory chain in two affected patients who had different truncation mutations of the ceruloplasmin gene. RESULTS: PET showed a marked decrease in glucose and oxygen consumption in the entire brain of aceruloplasminemia patients, with a preponderance of metabolic reduction in basal ganglia. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to approximately 45% and 42% respectively for complexes I and IV. An inverse relationship was shown between the amounts of iron accumulated and the levels of mitochondrial enzyme activities in all the brain regions examined. CONCLUSION: Iron-mediated free radicals may contribute to the impairment of mitochondrial energy metabolism in aceruloplasminemia. | Iron Metabolism Disorders |
Recent developments in nanotechnology have paved the way for using quantum dots (QDs) in nanodiagnostics and nanotherapeutics. Careful design and preparation of QDs are guided by these application-specific requirements. QDs will probably be one of the first nanomaterial to reach clinical applications, however many challenges in this field have yet to be overcome. In this article, we present an extensive review of the pharmacokinetic properties of QDs. The representative studies responsible for observing quantitative determination of QDs biodistribution in vivo are presented. The effects of size, surface chemistry, and target moiety on their pharmacokinetics are discussed. Finally, future directions for improving the pharmacokinetics of QDs and perspectives in the field are discussed. The understanding of its absorption, distribution, metabolism, and excretion from the body will provide important guidelines for the successful clinical use of QDs. | Quantum Dots |
The key role of gp120 in the cellular entry of HIV makes this glycoprotein an attractive target for new drugs. Various polyanions bind to the positively charged V3 loop of gp120. Here, we consider a series of anionic porphyrins bearing two sulfonate groups and two carboxylic chains with various degree of esterification. These molecules carry an overall negative charge between 4 and 2. Upon activation by light, these compounds, known as photosensitizers, produce highly reactive oxygen species able to damage amino acid chains. The interactions of these molecules with the V3 loop and a positively charged area in the C5 region were investigated in the dark by using specific antibodies and ELISA protocols. Competitive inhibition of the anti-V3 antibody was observed with an increased efficiency for the esterified compounds. No evidence for binding to the C5 region was found. In contrast, when gp120 was irradiated with light in presence of the porphyrin prior to the addition of the antibody, strong inhibition of the anti-C5 antibody was observed revealing irreversible photo-damages in this region. No effect on the V3 loop was observed. Irradiations at two wavelengths made it possible to identify porphyrin monomers as the photoactive forms despite the presence of large excess of dimers in the incubation solution. It is suggested that porphyrins bound to the V3 loop could produce photo-damages at some distance, in particular within the C5 region that contains several photosensitive amino acids. | HIV Envelope Protein gp120 |
The NADH-dependent nitrite reductase of Escherichia coli, which contains sirohaem, flavin, non-haem iron and labile sulphide, was examined by low-temperature e.s.r. spectroscopy. The enzyme, stored in the presence of nitrite and ascorbate, gave the spectrum of a nitrosyl derivative, with hyperfine splitting due to the nitrosyl nitrogen. On removal of these reagents, a series of signals centred around g = 6 was observed, typical of high-spin ferric haem. Cyanide converted this into a low-spin form. On reduction of the enzyme with NADH, an axial spectrum at g = 1.92, 2.01 was observed. The temperature-dependence of this signal is indicative of a [2Fe-2S] iron-sulphur cluster. The midpoint potential of this cluster was estimated to be -230 +/- 15 mV by two independent methods. Reduction of the enzyme with dithionite yielded further signals, which are at present unidentified, at g = 2.1-2.28. No signals were observed that could be assigned to a [4Fe-4S] cluster, such as is found in other sulphite reductases and nitrite reductases that contain sirohaem. | Nitrite Reductase (NAD(P)H) |
BACKGROUND: Rickets is a common disease worldwide. In the developed world, its prevalence dramatically decreased but still diagnosed in at-risk populations. The skin plays a critical role in vitamin D synthesis. Therefore, several skin diseases, especially keratinization disorders, could lead to impaired vitamin D metabolism and vitamin D deficient rickets. OBJECTIVE: The article aimed to summarize the current knowledge of skin diseases and conditions associated with rickets. METHODS: To examine the association between rickets and skin diseases, we performed a systematic review of the literature using PubMed database. The search included studies published from the database inception to August 2019. RESULTS: A total number of 75 articles were included. Identified conditions associated with rickets were ichthyosis being a more common skin diseases, alopecia, epidermal and melanocytic nevi, xeroderma pigmentosum, mastocytosis, psoriasis, and atopic dermatitis. Three types of rickets were identified: vitamin D-dependent rickets, hypocalcemic vitamin D-dependent rickets type 2, and hypophosphatemic rickets. Cutaneous skeletal hypophosphatemia syndrome is a newly described and under-recognized condition. It is defined by the association of epidermal or melanocytic nevi, hypophosphatemic rickets, and elevated levels of fibroblast growth factor 23. Rickets in patients with ichthyosis was mainly due to impaired ability of ichthyotic skin to synthesize vitamin D, poor UV penetration of the skin caused by keratinocyte proliferation, and dark phototype. The latter may be considered a risk factor for rickets in patients with ichthyosis. CONCLUSION: Despite its rarity, these associations should be properly recognized by dermatologists. Early diagnosis of rickets is important to prevent growth retardation and skeletal deformities. | Rickets |
Forensic methods to independently trace timber origin are essential to combat illegal timber trade. Tracing product origin by analysing their multi-element composition has been successfully applied in several commodities, but its potential for timber is not yet known. To evaluate this potential the drivers of wood multi-elemental composition need to be studied. Here we report on the first study relating wood multi-elemental composition of forest trees to soil chemical and physical properties. We studied the reactive soil element pools and the multi-elemental composition in sapwood and heartwood for 37 Azobe (Lophira alata) trees at two forest sites in Cameroon. A total of 46 elements were measured using ICP-MS. We also measured three potential drivers of soil and wood elemental composition: clay content, soil organic matter and pH. We tested associations between soil and wood using multiple regressions and multivariate analyses (Mantel test, db-RDA). Finally, we performed a Random Forest analysis of heartwood elemental composition to check site assignment accuracy. We found elemental compositions of soil, sapwood and heartwood to be significantly associated. Soil clay content and organic matter positively influenced individual element concentrations (for 13 and 9 elements out of 46 respectively) as well as the multi-elemental composition in wood. However, associations between wood and topsoil elemental concentrations were only significant for one element. We found close associations between element concentrations and composition in sapwood and heartwood. Lastly, the Random Forest assignment success was 97.3 %. Our findings indicate that wood elemental composition is associated with that in the topsoil and its variation is related to soil clay and organic matter content. These associations suggests that the multi-elemental composition of wood can yield chemical fingerprints obtained from sites that differ in soil properties. This finding in addition to the high assignment accuracy shows potential of multi-element analysis for tracing wood origin. | Soil |
Agarwood, the resinous heartwood produced by some Aquilaria species such as Aquilaria crassna, Aquilaria malaccensis and Aquilaria sinensis, has been traditionally and widely used in medicine, incenses and especially perfumes. However, up to now, the authentication of agarwood has been largely based on morphological characteristics, a method which is prone to errors and lacks reproducibility. Hence, in this study, we applied metabolomics and a genetic approach to the authentication of two common agarwood chips, those produced by Aquilaria crassna and Aquilaria malaccensis. Primary metabolites, secondary metabolites and DNA markers of agarwood were authenticated by (1)H NMR metabolomics, GC-MS metabolomics and DNA-based techniques, respectively. The results indicated that agarwood chips could be classified accurately by all the methods illustrated in this study. Additionally, the pros and cons of each method are also discussed. To the best of our knowledge, our research is the first study detailing all the differences in the primary and secondary metabolites, as well as the DNA markers between the agarwood produced by these two species. | Thymelaeaceae |
BACKGROUND: The aetiology of transient monocular vision loss is not necessarily thromboembolic, and careful history-taking is crucial in making the correct diagnosis. CASE PRESENTATION: A previously healthy woman in her thirties was referred to our outpatient stroke clinic on suspicion of recurring amaurosis fugax in her right eye. The ophthalmic and neurologic examinations were normal. A review of the medical history revealed that her symptoms occurred in connection with using her smartphone in bed, typically while lying on her left side with the left eye covered by the pillow. When standing up from the bed again with the lights turned off in the bedroom, she noticed vision loss in her right eye. INTERPRETATION: We concluded that the patient had experienced transient smartphone blindness. This phenomenon can occur when monocularly using a smartphone under scotopic lighting conditions; only the occluded eye adapts to darkness, and the other eye is perceived to be blind if looking away from the bright smartphone screen. | Sensation Disorders |
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)(1-3). Targeted therapies are approved for patients with 'classical' mutations and a small number of other mutations(4-6). However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown(1,3,7-10). Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations. | Afatinib |
Functional alterations in brain connectivity have previously been described in Parkinson's disease, but it is not clear whether individual differences in connectivity profiles might be also linked to severity of motor-symptom manifestation. Here we investigated the relevance of individual functional connectivity patterns measured with resting-state fMRI with respect to motor-symptom severity in Parkinson's disease, through a whole-brain, data-driven approach (connectome-based predictive modeling). Neuroimaging and clinical data of Parkinson's disease patients from the Parkinson's Progression Markers Initiative were derived at baseline (session 1, n = 81) and at follow-up (session 2, n = 53). Connectome-based predictive modeling protocol was implemented to predict levels of motor impairment from individual connectivity profiles. The resulting predictive model comprised a network mainly involving functional connections between regions located in the cerebellum, and in the motor and frontoparietal networks. The predictive power of the model was stable along disease progression, as the connectivity within the same network could predict levels of motor impairment, even at a later stage of the disease. Finally, connectivity profiles within this network could be identified at the individual level, suggesting the presence of individual fingerprints within resting-state fMRI connectivity associated with motor manifestations in Parkinson's disease. | Motor Disorders |
Newly synthesized polypeptides entering the endoplasmic reticulum (ER) encounter a large array of molecular chaperones and folding factors that facilitate proper folding as well as assess folding status, retaining non-native proteins within the ER. Calnexin (CNX), an ER membrane protein, and its soluble homologue, calreticulin (CRT), are two important molecular chaperones that contribute to both processes. They are highly unusual chaperones in that they act as lectins, binding the Asn-linked oligosaccharides of newly synthesized glycoproteins, as well as recognizing the polypeptide segments of glycoproteins. Furthermore, they associate with ERp57, a thiol oxidoreductase, that is thought to enhance the oxidative folding of glycoproteins bound to CNX/CRT. These characteristics of CNX and CRT as well as their mode of action have been elucidated though the use of multiple in vitro and in vivo approaches. This chapter will focus on the description of a number of in vitro assays that have been used to characterize the lectin and ERp57-binding functions of CNX/CRT and also their abilities to act as molecular chaperones to suppress protein aggregation. In addition, we will describe insect and mammalian expression systems in which major histocompatibility complex class I molecules are used as model glycoprotein substrates for CNX and CRT. These systems have been valuable in assessing folding and quality control events in vivo that are influenced by CNX or CRT as well as in characterizing the spectrum of substrates that are recognized by these chaperones." | Intracellular Calcium-Sensing Proteins |
Bipolar disorder is a complex condition that is difficult to diagnose and treat, and many patients with this illness are not receiving adequate care, particularly in the early stages of the disorder when effective treatment is most critical. Self-Assessment CME is an educational activity in which clinicians answer a series of multiple-choice questions to ascertain their current knowledge and practice in treating CNS disorders. After completing the self-assessment, clinicians have the opportunity to review correct answers, see how their colleagues responded, and receive recommendations for further reading. This Self-Assessment CME activity focuses on recognizing and bridging gaps in knowledge pertaining to bipolar disorder recognition and treatment. | Bipolar Disorder |
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