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Today the vast majority of children and adolescents diagnosed with cancer achieve relatively high rates of remission and long-term survival, due to significant advances in oncological treatment. Oncological surgery, radiotherapy and chemotherapy however, are often detrimental to fertility, thus substantially impacting a patient's quality of life. Concerns about fertility are similar for men and women; however, their opportunities for intervention differ considerably. This article reviews the literature, discusses the etiology and effects of cancer treatment on fertility, and presents the current and emerging options for the preservation of fertility in patients with cancer. The various diagnostic methods of assessing the fertility potential at the time of diagnosis and the efficacy of the different fertility preserving methods after cancer treatment are also presented. | Ovulation Inhibition |
Different strategies for HPLC separation, including molecular sieving, ion-exchange, and hydrophobic interaction as well as reversed phase chromatography, were used to study molecular components in human cerebrospinal fluid (CSF). The separations were followed by photodiode-array UV detection, which is a recently developed technique allowing a direct and rapid discrimination between peptides and proteins differing in their content of aromatic amino acids. By the various HPLC techniques in conjunction with diode-array detection it was possible to identify and characterize several protein and peptide components present in CSF. The procedure also allowed quantitative analysis of CSF proteins using minute amounts of the fluid. | Cerebrospinal Fluid Proteins |
BACKGROUND/AIMS: Ectropion correction is a challenge in plastic surgery. Correction of the lower lid area, including restoration of the shape and position of lid margin, is the surgical goal. In this study, we describe a new surgical technique, the tarsal belt, for the correction of ectropion and evaluation of the effective outcome and complications of this procedure. METHODS: Between January 2008 and January 2012, a total of 42 patients aged between 48 and 75 years (average age 61.5 years) were treated with this technique. This procedure consists in a trans-tarsal mattress non-absorbable suture anchored to the periosteum of the lateral orbital rim, combined with a small wedge excision of a lateral portion of the tarsus close to the lateral canthal tendon. During the same period, 66 patients were treated with the standard lateral tarsal strip technique. Preoperative and postoperative Ectropion Grading Scale (EGS) was recorded to evaluate anatomical improvement. The average follow-up period was 24 months. RESULTS: Rate of success was 100% for involutional and cicatricial ectropions, 90% for lid retraction and 87.5% for paralytic ectropions. Anatomical success according to EGS scale was obtained in 41 patients. Recurrence of ectropion occurred in only one patient 6 months after the first surgery and required a further operation with a larger posterior lamella resection and new tarsal belt suture. CONCLUSIONS: The tarsal belt seems to be effective to correct the horizontal and vertical instability of the lid. The suture supports the lower eyelid along the entire tarsal plate length and corrects the outward buckling of the tarsal plate. | Ectropion |
This essay focuses on the role of plectin and its various isoforms in mediating intermediate filament (IF) network functions. It is based on previous studies that provided comprehensive evidence for a concept where plectin acts as an IF recruiter, and plectin-mediated IF networking and anchoring are key elements in IF function execution. Here, plectin's global role as modulator of IF functionality is viewed from different perspectives, including the mechanical stabilization of IF networks and their docking platforms, contribution to cellular viscoelasticity and mechanotransduction, compartmentalization and control of the actomyosin machinery, connections to the microtubule system, and mechanisms and specificity of isoform targeting. Arguments for IF networks and plectin acting as mutually dependent partners are also given. Lastly, a working model is presented that describes a unifying mechanism underlying how plectin-IF networks mechanically control and propagate actomyosin-generated forces, affect microtubule dynamics, and contribute to mechanotransduction. | Plakins |
Neurotropic strains of mouse hepatitis viruses (MHV) such as MHV-A59 (A59) and MHV-4 (JHMV) cause acute and chronic encephalomyelitis and demyelination in susceptible strains of mice and rats. They are widely used as models of human demyelinating diseases such as multiple sclerosis (MS), in which immune mechanisms are thought to participate in the development of lesions in the central nervous system (CNS). The effects of MHV infection on target cell functions in the CNS are not well understood, but A59 has been shown to induce the expression of MHC class I molecules in glial cells after in vivo and in vitro infection. Changes in class I expression in infected cells may contribute to the immunopathogenesis of MHV infection in the CNS. In this communication, a large panel of MHV strains was tested for their ability to stimulate class I expression in primary astrocytes in vitro. The data show that the more hepatotropic strains, such as MHV-A59, MHV-1, MHV-2, MHV-3, MHV-D, MHV-K, and MHV-NuU, were potent inducers of class I expression in astrocytes during acute infection, measured by radioimmunoassay. The Kb molecule was preferentially expressed over Db. By contrast, JHMV and several viral strains derived from it did not stimulate the expression of class I molecules. Assays of virus infectivity indicated that the class I-inducing activity did not correlate with the ability of the individual viral strain to replicate in astrocytes. However, exposure of the viruses or the supernatants from infected astrocytes to ultraviolet light abolished the class I-inducing activity, indicating that infectious virus is required for class I expression. These data also suggest that class I expression was induced directly by virus infection, and not by the secretion of a soluble substance into the medium by infected astrocytes. Finally, analyses of A59/JHMV recombinant viral strains suggest that class I-inducing activity resides in one of the A59 structural genes. | Murine hepatitis virus |
Phytochemical investigation of Adiantum flabellulatum L. led to the isolation of four natural compounds, including a novel unsaturated fatty acid with a cyclopropane moiety, i.e. (S,E)-7-(2-octylcyclopropylidene)heptanoic acid (1), together with three known compounds, isoadiantol B (2), stigmast-4-en-6beta-ol-3-one (3), beta-sitosterol (4). Compound 3 was isolated from the A. flabellulatum L. for the first time. The structure of 1 was elucidated following a comprehensive analysis of spectroscopic analyses including MS, 1 D and 2 D NMR, and by a mass spectrometry experiment of the dimethyl disulfide (DMDS) adduct, while the known compounds were identified by comparisons with those reported in the literature. Enzyme evaluation of 1 indicated this compound possesses anti- protein tyrosine phosphatase (PTP1B) activity with an IC(50) value of 6.99 +/- 0.41 muM in vitro." | Protein Tyrosine Phosphatases, Non-Receptor |
Cysts of the bone are a common pathology that, although benign, are frequently treated because of their tendency to compromise the integrity of affected bone. Two common entities are unicameral bone cysts and aneurysmal bone cysts. Although these are two distinct pathologies, they are treated similarly and thus will be discussed in tandem. The optimal treatment of calcaneal bone cysts in pediatric patients has long been debated among orthopaedic surgeons because of the relatively small number of cases and varied results within the literature. Currently, there are three lines of thought regarding treatment: observation, injection, and surgical intervention. When considering which course of treatment is best for an individual patient, the surgeon must consider the fracture risk without treatment, the risk of complications with treatment, and the recurrence rate with each treatment approach. There are limited data on pediatric calcaneal cysts specifically. Still, there are much data concerning simple bone cysts of long bones in the pediatric population and calcaneal cysts in the adult population. Because of the lack of literature on the subject, there is a need for a review of the available literature and a consensus on the approach to treating calcaneal cysts in the pediatric population. | Bone Cysts |
The negative influence of alcohol (ethanol) and its metabolites on innate and adaptive immunity is well-recognized. Much attention has recently been focused on the impact of acute and chronic alcohol exposure on antigen-presenting cells (APC). In particular, insights have been gained into how the properties of human blood monocytes and rodent macrophages are influenced by alcohol in vitro and in vivo. Here, we review the impact of alcohol on various aspects of APC function and the underlying mechanisms, including its effects on intracellular signaling events. We also discuss new information regarding the influence of alcohol on various APC populations in the liver, a primary site of alcohol metabolism. | Antigen-Presenting Cells |
Bioactive compounds such as karrikinolide (KAR(1) from smoke) and eckol (from the seaweed Ecklonia maxima) show promising effects on several important crop plants. These plant growth-stimulating organic biomolecules, along with crude extracts (smoke-water and Kelpak((R)) product prepared from Ecklonia maxima), were tested on spinach plants. Eckol sprayed at 10(-6) M significantly increased all the growth and biochemical parameters examined compared to control spinach plants. All tested plant growth biostimulants significantly increased total chlorophyll, carotenoids and protein content of spinach leaves. The cytokinin profile of spinach plants was also determined. Cis-zeatin, dihydrozeatin and isopentenyladenine types of cytokinins were promoted by both smoke- and seaweed-based biostimulants. In comparison to the control plants, the level of free sinapic acid was greater in all spinach plants treated with these biostimulants. The application of these biostimulants can help spinach crop by improving growth, yield and nutritional quality; moreover, they are organic and cost-effective. | Spinacia oleracea |
This work presents the development of a simple and efficient analytical protocol for the direct enantioselective resolution of sugars. A racemic mixture of the C3 sugar d,l-glyceraldehyde and the C5 monosaccharides d,l-arabinose, d,l-ribose, d,l-xylose, and d,l-lyxose was subjected to derivatization with trifluoroacetic anhydride, and corresponding derivatives were separated on a beta-cyclodextrin column with excellent resolution factors. Even though each aldopentose shows beside the linear form four predominant cyclic hemiacetals being the alpha- and beta-furanose along with the alpha- and beta-pyranose, we show that the overall enantiomeric excess of each compound can be precisely determined. Moreover, the measured detection limit for derivatized aldopentoses ranges from 0.015 to 0.019pmol on the column, while the quantification limit varies from 0.5 to 0.64pmol on the column. | Monosaccharides |
Recent findings about the effects of biorhythms on cardiovascular disorders are reviewed, and their implications for drug therapy are discussed. The chronobiological approach to physiology evaluates time-dependent changes in biological functions and considers those changes to be multifactorial. Characterization of disease states with this approach allows more accurate determination of the times when patients are at highest risk and therefore in greatest need of preventive measures; it also provides a mechanism for designing optimal drug regimens. There is evidence of circadian variations in the occurrence of myocardial ischemia, acute myocardial infarction, ventricular tachycardia, and sudden cardiac death. Many cardiovascular disorders occur with greatest frequency between 0600 and 1200 in the general population. Blood pressure, too, follows a distinct circadian pattern. Factors affecting circadian variations in cardiovascular disorders include physiological determinants, such as heart rate, catecholamine release, and platelet aggregation--which themselves vary cyclically--and exogenous factors, such as mental stress, anxiety, and physical activity. In chronotherapy, circadian variations in disease states and in the pharmacodynamic properties of drugs are exploited to improve prevention and treatment. Conditions in which research suggests a chronotherapeutic approach may be advantageous include thromboembolism, hypertension, stable exertional angina, variant angina, sustained ventricular tachycardia, and acute myocardial infarction. Information on circadian patterns in the occurrence of many cardiovascular disorders is enabling clinicians to tailor treatment in ways that may lead to improved patient outcomes. | Chronobiology Phenomena |
OBJECTIVE: To study gastric rupture, a progressive, rapid and high mortality condition, caused by acute gastric distention (GRAGD) and its appropriate diagnosis and treatment. METHODS: The etiology, pathology, clinical manifestations and experiences in 3 children with GRAGD were reviewed. RESULTS: Case 1: After diagnosing GRAGD and stabilizing her shock with massive fluid replacement, gastrostomy was performed. Her postoperative course was uneventful because of fasting, suction, fluid infusion, correction of acidosis and supporting nutrition. Case 2: After diagnosing gastric distention which subsided with conservative therapy for 9 days, she suddenly had gastric rupture when she had not eaten for 6 days. She died of shock and had no chance for surgery. Case 3: The patient had sudden abdominal pain, distention and vomiting with severe shock for 4 days. Emergency surgery found gastric rupture and the method was the same as Case 1. The patient survived but has brain impairment. Case 1 and 3 showed multifocal transmural necrosis. CONCLUSIONS: Symptoms like overeating, bulimia, changes in kind of food, X-ray showing large distended stomach and massive pneumoperitoneum were seen after gastric rupture and can help to diagnose this condition. Clinical course of gastric distention with toxic shock progresses rapidly, however subsequent gastric rupture exacerbates the shock and makes the treatment difficult treatment. It is extremely important that a laparotomy be performed at once after stabilizing shock with massive fluid replacement. Postoperative nutritional support and fluid replacement will increase survival. It is very important that when gastric distention disappears after conservative therapy, the doctor should assess carefully whether the gastric wall recovery is under way by using effective methods of examination. | Stomach Rupture |
Total flavonoid content (TFC) and cyanidin-3-glucoside (Cyd-3-glu) of seed and seed coat extract of 16 genotypes from five species of Carthamus were studied, and their major polyphenolic compounds and antioxidant activity of the seed coat extracts were determined using HPLC analysis and DPPH assay, respectively. Additionally, fatty acids composition of the seed oil was analyzed by GC. In general, TFC and Cyd-3-glu content of seed coat extracts were higher than those of seed extracts. A novel breeding line with black seed coat (named A82) depicted lower TFC (3.79 mg QUE/g DW) but higher Cyd-3-glu (24.64 mg/g DW) compared to the white and other seed-pigmented genotypes. DPPH radical scavenging activity showed a strong association with Cyd-3-glu content (r = 0.84), but no correlation with TFC (r = -0.32). HPLC analysis of seed coat extracts revealed that four compounds were dominant constituents including rutin (7.23 - 117.95 mg/100 g DW), apigenin (4.37 - 64.88 mg/100 g DW), quercetin (3.09 - 14.10 mg/100 g DW), and ferulic acid (4.49 - 30.41 mg/100 g DW). Interestingly, the genotype A82 with an appropriate polyunsaturated/saturated fatty acids index (5.46%) and a moderate linoleic fatty acid content (64.70%) had higher nutritional and pharmaceutical value than all the other genotypes. | Carthamus |
Given the high risk of HIV infection among university students in sub-Saharan Africa, there is a need for culturally appropriate risk-reduction interventions specifically targeting this population. Efforts to reduce the risk require an understanding of the modifiable antecedents of sexual-risk behaviors. We report the results of a semi-structured elicitation survey based on the reasoned action approach to identify behavioral, normative, and control beliefs regarding abstinence, condom use, and limiting sexual partners. Two coders classified into 64 belief categories the written responses of 96 sub-Saharan African university students. Most students believed each behavior could reduce risk of HIV infection. The students reported that peer pressure and being in a risky environment made it harder to practice abstinence. Good communication made it easier to use condoms and to limit partners; however, unstable relationships made practicing these protective behaviors harder. The identified beliefs help to inform the development of theory-based HIV risk-reduction interventions. | Condoms |
Herbal medicine use in the United States has increased substantially. Despite this upward trend, patients often fail to disclose use of these medicines to their healthcare provider. Currently, the US Food and Drug Administration (FDA) does not require preclinical animal studies, controlled clinical trials, or postmarket surveillance of herbal supplements. Lack of FDA oversight leads to product variation in quality, purity, efficacy, harvesting, and storage. Intentional or unintentional addition of contaminants to these products remains substantial. Because herbal medicines have the potential to adversely react with medications used in the perioperative period, anesthesia providers should be aware of the purported uses of common herbal supplements, potential drug interactions with these medicines or possible contaminants, and the anesthetic implications for patients who use these medicines. | Gnetophyta |
Prostaglandin (PG) analogues are a new class of ocular hypotensive drugs that have been developed for the treatment of open angle glaucoma. Two of these drugs, latanoprost and unoprostone, are presently commercially available. Latanoprost was introduced in 1996 in the US and Europe. Presently it enjoys the most widespread use and is the most well documented drug of this group. It reduces the intraocular pressure (IOP) by a mechanism of action different from other drugs; namely by increasing the uveoscleral outflow. The aqueous inflow is not affected. The optimal dose regimen is one drop of 50 microg/ml once daily, which reduces the IOP by approximately 30% in patients with glaucoma. A more pronounced ocular hypotensive effect is demonstrated when latanoprost is combined with other glaucoma therapies, including beta-blockers, adrenergic and cholinergic agonists or carbonic anhydrase inhibitors. Latanoprost is well tolerated. The drug reaches a plasma concentration below that needed for stimulation of the FP-receptor, which may explain its favourable systemic tolerability profile. The major ocular adverse effect is increased iris pigmentation, which is due to increased synthesis of melanin in the melanocytes of the iris stroma. It is most frequently seen in green-brown eyes and it is probably permanent. A low frequency of cystoid macular oedema has also been reported, predominantly in predisposed eyes. Unoprostone was launched in Japan in 1994, but there is little experience with this drug outside the Japanese market and the documentation is more limited. Its main mechanism of action is on outflow, but this is not yet fully elucidated. The recommended dosage regimen is 1 drop of 1.2 mg/ml twice daily. No comparative studies in humans between the 2 drugs have yet been published. | Autacoids |
Suspension arrays present a promising tool for multiplexed assays in large-scale screening applications. A simple and robust platform for quantitative multiprotein immunoanalysis has been developed with the use of magnetic Co:Nd:Fe(2)O(3)/luminescent Eu:Gd(2)O(3) core/shell nanoparticles (MLNPs) as a carrier. The magnetic properties of the MLNPs allow their manipulation by an external magnetic field in the separation and washing steps in the immunoassay. Their optical properties enable the internal calibration of the detection system. The multiplexed sandwich immunoassay involves dual binding events on the surface of the MLNPs functionalized with the capture antibodies. Secondary antibodies labeled with conventional organic dyes (Alexa Fluor) are used as reporters. The amount of the bound secondary antibody is directly proportional to the concentration of the analyte in the sample. In our approach, the fluorescence intensity of the reporter dye is related to the luminescence signal of the MLNPs. In this way, the intrinsic luminescence of the MLNPs serves as an internal standard in the quantitative immunoassay. The concept is demonstrated for a simultaneous immunoassay for three model proteins (human, rabbit, and mouse IgGs). The method uses a standard bench plate reader. It can be applied to disease diagnostics and to the detection of biological threats. | Fluoroimmunoassay |
Neuronal nitric oxide synthase (nNOS) catalyses the production of the neurotransmitter nitric oxide. nNOS is expressed in the dorsal raphe nucleus (DRN), a source of ascending serotonergic projections. In this study, we examined the distribution nNOS and the function of nitric oxide in the DRN and adjacent median raphe nucleus (MRN) of the rat. We hypothesized that nNOS is differentially expressed across the raphe nuclei and that nitric oxide influences the firing activity of a subgroup of 5-HT neurons. Immunohistochemistry revealed that, nNOS is present in around 40% of 5-HT neurons, throughout the DRN and MRN, as well as in some non-5-HT neurons immediately adjacent to the DRN and MRN. The nitric oxide receptor, soluble guanylyl cyclase, was present in all 5-HT neurons examined in the DRN and MRN. In vitro extracellular electrophysiology revealed that application of the nitric oxide donor, diethylamine NONOate (30-300 microM) inhibited 60%-70% of putative 5-HT neurons, excited approximately 10% of putative 5-HT neurons and had no effect on the rest. The inhibitory response to nitric oxide was blocked by [1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ, 30 or 100 microM), indicating mediation by soluble guanylyl cyclase. Juxtacellular labelling revealed that nitric oxide inhibits firing in both putative 5-HT neurons which express nNOS and those which do not express nNOS. Our data are consistent with the notion that nitric oxide acts as both a trans-synaptic and autocrine signaller in 5-HT neurons in the DRN and MRN and that its effects are widespread and primarily inhibitory. | Raphe Nuclei |
Many prokaryotes lack a tRNA synthetase to attach asparagine to its cognate tRNA(Asn), and instead synthesize asparagine from tRNA(Asn)-bound aspartate. This conversion involves two enzymes: a nondiscriminating aspartyl-tRNA synthetase (ND-AspRS) that forms Asp-tRNA(Asn), and a heterotrimeric amidotransferase GatCAB that amidates Asp-tRNA(Asn) to form Asn-tRNA(Asn) for use in protein synthesis. ND-AspRS, GatCAB, and tRNA(Asn) may assemble in an approximately 400-kDa complex, known as the Asn-transamidosome, which couples the two steps of asparagine biosynthesis in space and time to yield Asn-tRNA(Asn). We report the 3.7-A resolution crystal structure of the Pseudomonas aeruginosa Asn-transamidosome, which represents the most common machinery for asparagine biosynthesis in bacteria. We show that, in contrast to a previously described archaeal-type transamidosome, a bacteria-specific GAD domain of ND-AspRS provokes a principally new architecture of the complex. Both tRNA(Asn) molecules in the transamidosome simultaneously serve as substrates and scaffolds for the complex assembly. This architecture rationalizes an elevated dynamic and a greater turnover of ND-AspRS within bacterial-type transamidosomes, and possibly may explain a different evolutionary pathway of GatCAB in organisms with bacterial-type vs. archaeal-type Asn-transamidosomes. Importantly, because the two-step pathway for Asn-tRNA(Asn) formation evolutionarily preceded the direct attachment of Asn to tRNA(Asn), our structure also may reflect the mechanism by which asparagine was initially added to the genetic code. | RNA, Transfer, Asn |
Under Medicare, swing beds are beds that can be used by small rural hospitals to furnish both acute and post-acute care. The swing-bed program was instituted under the provisions of the Omnibus Reconciliation Act of 1980 (Public Law 96-499). Under Medicare, post-acute care in the hospital would be covered as services equivalent to skilled nursing facility level of care. Data show that the program has had a rapid rate of growth. By 1987, swing beds accounted for 9.7 percent of the admissions to skilled nursing facility services, 6.0 percent of the covered days of care, and 6.2 percent of the reimbursements. Over one-half of the swing-bed services are furnished in the North Central States. | Health Facility Planning |
Grid cells in medial entorhinal cortex are notoriously variable in their responses, despite the striking hexagonal arrangement of their spatial firing fields. Indeed, when the animal moves through a firing field, grid cells often fire much more vigorously than predicted or do not fire at all. The source of this trial-to-trial variability is not completely understood. By analyzing grid-cell spike trains from mice running in open arenas and on linear tracks, we characterize the phenomenon of missed" firing fields using the statistical theory of zero inflation. We find that one major cause of grid-cell variability lies in the spatial representation itself: firing fields are not as strongly anchored to spatial location as the averaged grid suggests. In addition, grid fields from different cells drift together from trial to trial, regardless of whether the environment is real or virtual, or whether the animal moves in light or darkness. Spatial realignment across trials sharpens the grid representation, yielding firing fields that are more pronounced and significantly narrower. These findings indicate that ensembles of grid cells encode relative position more reliably than absolute position." | Limbic Lobe |
During the past 12 months an apparently new disease of cats has occurred with increasing frequency throughout the United Kingdom causing high morbidity and mortality and arousing considerable interest both within and outside the profession. The purpose of this paper is to report what is known about the disease and to indicate lines of current research. As there is an urgent need to communicate information it will be appreciated that this paper is incomplete in certain areas such as pathology and epidemiology where studies are still in progress. | Syndrome |
In the face of global food security crises, it is necessary to boost agricultural production. One factor hampering the attempts to increase food production is elevated soil salinity, which can be due to salt that is naturally present in the soil or a consequence of excessive or prolonged irrigation or application of fertiliser. In response to environmental stresses, plants activate multiple molecular mechanisms, including the timely activation of stress-responsive transcriptional networks. However, in the case of salt stress, the combined effects of the initial osmotic shock and the subsequent ion-specific stress increase the complexity in the selective regulation of gene expressions involved in restoring or maintaining osmotic balance, ion homeostasis and reactive oxygen species scavenging. Histone modifications and chromatin remodelling are important epigenetic processes that regulate gene expressions by modifying the chromatin status and recruiting transcription regulators. In this review, we have specifically summarised the currently available knowledge on histone modifications and chromatin remodelling in relation to plant responses to salt stress. Current findings have revealed the functional importance of chromatin modifiers in regulating salt tolerance and identified the effector genes affected by epigenetic modifications, although counteraction between modifiers within the same family may occur. Emerging evidence has also illustrated the crosstalk between epigenetic modifications and hormone signalling pathways which involves formation of protein complexes. With an improved understanding of these processes, plant breeders will be able to develop alternative strategies using genome editing technologies for crop improvement. | Salt Stress |
Fractures of the calcaneus and talus are severe injuries that usually result from high-energy trauma. The calcaneus and talus are essential for the transmission of body weight, so an optimal reduction and/or fixation of fractures is required to prevent disabling consequences. These fractures almost always have an articular involvement, and an anatomical reduction is required; any residual step-off would lead to joint incongruity and secondary arthrosis.The aims of imaging are first, to guide management by describing the fracture characteristics (e.g., location, displacement, fragments, articular involvement, soft tissue compromise), and second, to detect early and late surgical complications (e.g., infection, malunion, nonunion, arthrosis, hardware issues). Although radiographs remain the first-line imaging modality for the screening of ankle and foot trauma, computed tomography is almost always required for the initial management and follow-up of the patient. | Foot Bones |
Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness(1,2). They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Na(v)1.4 or the calcium channel Ca(v)1.1(1,2). Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis(1,2) by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state(3,4). Mutations of the third gating charge (R3) cause normokalaemic periodic paralysis (5) owing to cation leak in both activated and inactivated states (6) . Here we present high-resolution structures of the model bacterial sodium channel Na(v)Ab with the analogous gating-charge mutations(7,8), which have similar functional effects as in the human channels. The R2G and R3G mutations have no effect on the backbone structures of the voltage sensor, but they create an aqueous cavity near the hydrophobic constriction site that controls gating charge movement through the voltage sensor. The R3G mutation extends the extracellular aqueous cleft through the entire length of the activated voltage sensor, creating an aqueous path through the membrane. Conversely, molecular modelling shows that the R2G mutation creates a continuous aqueous path through the membrane only in the resting state. Crystal structures of Na(v)Ab(R2G) in complex with guanidinium define a potential drug target site. Molecular dynamics simulations illustrate the mechanism of Na(+) permeation through the mutant gating pore in concert with conformational fluctuations of the gating charge R4. Our results reveal pathogenic mechanisms of periodic paralysis at the atomic level and suggest designs of drugs that may prevent ionic leak and provide symptomatic relief from hypokalaemic and normokalaemic periodic paralysis." | NAV1.4 Voltage-Gated Sodium Channel |
There is a relevant gap between the medicine learned on books and the clinical practice made of suffering humans facing us. Guidelines recommendations don't usually cover this aspect. The Slow Medicine movement, born in 2011, stands as a model a sober respectful and right healthcare. Everyone is entitled to express himself freely: a respectful medicine receives worths, choices and tendencies of the patient in every moment of his life. The keystone of slow decisions is to respect patient's freedom and autonomy, and to recognize his ability to make decisions even if he is elderly and frail. Listening to a patient's biography and welcoming his personal needs and expectations allows the physician to spread comfort, trust and gratification. | Personal Autonomy |
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection." | ATP Binding Cassette Transporter, Subfamily B, Member 11 |
PURPOSE: To identify gender differences in leadership and academic rank within academic reproductive endocrinology (REI) programs with fellowships in the USA. METHODS: Official institutional websites of the 2017-2018 American Board of Obstetrics and Gynecology (ABOG)-accredited reproductive endocrinology fellowship programs were reviewed, and gender representation at each leadership position and academic rank (Division and Fellowship Director and Full, Associate, and Assistant Professor) was recorded. Univariate comparisons were performed using Chi-square tests, with significance at p < 0.05. RESULTS: Among 49 ABOG-accredited reproductive endocrinology programs, 263 faculty were identified, 129 (49.0%) male and 134 (51.0%) female. Division directors were 69.3% male and 30.7% female (p = 0.006). Similarly, fellowship directors were 65.3% male and 34.6% female (p = 0.03). Full professors (n = 101) were more frequently male (70.3% vs. 29.7%, p < 0.001). There was no difference in gender among associate professors (n = 60, 51.7% male vs. 48.3% female, p = 0.79), while significantly more assistant professors were female than male (n = 102, 73.6% vs. 26.4%, p < 0.001). CONCLUSION: While a majority of residents in obstetrics and gynecology and half of reproductive endocrinology academic faculty are female, women are still underrepresented among leadership positions and full professors in academic reproductive endocrinology programs with fellowship programs. | Endocrinology |
In this work, the external and internal airflow analysis in an urban bus is carried out through computational fluid dynamics. The research addresses the study of the internal flow to estimate the air change rate caused by the opening of windows. Two cases are considered: fully opening and partially opening the windows, and three bus speeds of 20, 40, and 60 km/h are assessed. The quantification of the air flow rate through the windows clearly displays that air enters through the rear windows and exits the bus through the front windows. This effect is explained by the pressure distribution in the outer of the bus, which causes the suction of the indoor air. At low bus speeds, the incoming air flow rate increases linearly with the speed, but the improvement is lower for high speeds. The theoretical air change time at 20 km/h is around 25.7 s, which is 9 times lower than expected by using HVAC systems. On the other hand, the estimation of the real air renewal time by solving a concentration shows that 40 s are needed to exchange 85% of the internal air of the bus. The research also assesses the effect of different levels of occupation inside the bus. Results are conclusive to recommend the circulation with full or partial window opening configurations in order to reduce the risk of airborne disease transmission. | Air Movements |
Previously proposed models of intake regulation focus on specific variables thought to influence overall intake, and include factors involved in negative feedback loops with intake as well as genetic influences on intake. Recent evidence, however, suggests that these models although informative, are incomplete. They cannot account for the observations of prolonged and increasing deviations from defended levels, weakness and transitoriness of compensatory responses, the presence of powerful factors that are not compensated, and behavioral genetic data suggesting that there are a wide variety of independent genetic influences on numerous factors that influence intake. As a result we propose a new general model of intake regulation in which intake is influenced by both a set of uncompensated factors that are not influenced by intake and by a set of compensated factors that are. The preferred levels of intake and both sets of factors are specified as influenced by heredity. Further, the model includes impact factors, weights, which specify the magnitude of the effect each factor has on intake. The weights are assumed to be different for different individuals and their values are determined by heredity. A computer simulation of the new model demonstrated that it maintains different levels depending upon the external and internal environments, that changes in these environments result in new levels, and that inherited individual differences in responsiveness to these factors can markedly influence the levels obtained. The proposed general model appears to fit existing knowledge and is parsimonious and widely applicable. Future work should be directed to testing the general model and further developing specific models within the conceptual framework employing known physiological systems and uncompensated stimuli. | Appetite Regulation |
Corneal transplantation, the most common transplantation procedure done in the United States, requires access to a sufficient number of donor eyes. We examined how laws governing tissue donation affect availability of corneal tissue by reviewing records of the Lions Eye Bank of Texas, Houston, from 1961 through 1990 (43,696 eyes from 21,898 donors). Relevant Texas statutes included the Uniform Anatomical Gift Act of 1970, the Justice of the Peace/Medical Examiner Law of 1977, and the Routine Inquiry Law of 1988. Before 1970, the mean (+/- SD) number of donated corneas was 72 +/- 38 per year; enactment of each statute above was associated with increased mean annual donations of 215 +/- 87, 1329 +/- 562, and 1958 +/- 33 corneas, respectively. The Justice of the Peace/Medical Examiner Law yielded significantly younger donors (who died of trauma), and the Routine Inquiry Law increased the number of hospitalized donors. Data from this eye bank were compared with current state laws nationwide. Effective legislation is a means to meet national ophthalmic surgical needs. | Eye Banks |
Previous work has suggested that many stem cells can be found in microanatomic niches, where adjacent somatic cells of the niche control the differentiation and proliferation states of their resident stem cells. Recently published work examining intestinal stem cells (ISCs) in the adult Drosophila midgut suggests a new paradigm where some stem cells actively control the cell fate decisions of their daughters. Here, we review recent literature((1)) demonstrating that, in the absence of a detectable stem cell niche, multipotent Drosophila ISCs modulate the Notch signaling pathway in their adjacent daughter cells in order to specify the differentiated lineages of their descendants. These observations made in Drosophila are challenging and advancing our understanding of stem cell biology. | Multipotent Stem Cells |
Asymptomatic carriers of Plasmodium parasites hamper malaria control and eradication. Achieving malaria eradication requires ultrasensitive diagnostics for low parasite density infections (<100 parasites per microliter blood) that work in resource-limited settings (RLS). Sensitive point-of-care diagnostics are also lacking for nonfalciparum malaria, which is characterized by lower density infections and may require additional therapy for radical cure. Molecular methods, such as PCR, have high sensitivity and specificity, but remain high-complexity technologies impractical for RLS. Here we describe a CRISPR-based diagnostic for ultrasensitive detection and differentiation of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae, using the nucleic acid detection platform SHERLOCK (specific high-sensitivity enzymatic reporter unlocking). We present a streamlined, field-applicable, diagnostic comprised of a 10-min SHERLOCK parasite rapid extraction protocol, followed by SHERLOCK for 60 min for Plasmodium species-specific detection via fluorescent or lateral flow strip readout. We optimized one-pot, lyophilized, isothermal assays with a simplified sample preparation method independent of nucleic acid extraction, and showed that these assays are capable of detection below two parasites per microliter blood, a limit of detection suggested by the World Health Organization. Our P. falciparum and P. vivax assays exhibited 100% sensitivity and specificity on clinical samples (5 P. falciparum and 10 P. vivax samples). This work establishes a field-applicable diagnostic for ultrasensitive detection of asymptomatic carriers as well as a rapid point-of-care clinical diagnostic for nonfalciparum malaria species and low parasite density P. falciparum infections. | Plasmodium |
BACKGROUND/AIMS: Anti-thymocyte globulin (ATG) treatment for acute T-cell mediated rejection (TCMR) can increase the risk of cytomegalovirus (CMV) infection. We aimed to evaluate the effect of valacyclovir prophylaxis against CMV infection after ATG administration as anti-rejection therapy. METHODS: We retrospectively analyzed 55 kidney transplant recipients (KTRs) receiving ATG for steroid resistant TCMR. In all KTRs, we used intravenous ganciclovir during ATG injection. In 34 KTRs treated before July 2013, we performed preemptive therapy for CMV infection after ATG therapy. They were regarded as the historic control group (CONT). After July 2013, we used valacyclovir maintenance for 1 month after ATG therapy in 21 patients (VAL). The primary outcome was the incidence of CMV infection, and the secondary outcomes were subsequent acute rejection, and graft and patient outcome. RESULTS: Valacyclovir prophylaxis significantly reduced the incidence of CMV infection (VAL, 9.6% vs. CONT, 67.6%; p < 0.001), and CMV-free survival rate was higher in the VAL group compared to the CONT group (p = 0.009). In the VAL group, two cases of CMV infection were limited to CMV viremia, but CMV disease or syndrome (n = 3) was detected in the CONT group. There was no difference in graft failure (CONT, 70.5% vs. VAL, 47.6%; p = 0.152), incidence of subsequent rejection after ATG treatment (CONT, 41.1% vs. VAL, 33.3%; p = 0.776), and graft or patient survival between the two groups. There were no major adverse events associated with valacyclovir prophylaxis. CONCLUSION: In conclusion, valacyclovir prophylaxis is effective in the prevention of CMV infection after ATG treatment for steroid resistant TCMR. | Valacyclovir |
Hydrogen sulfide can signal through 3 distinct mechanisms: 1) reduction and/or direct binding of metalloprotein heme centers, 2) serving as a potent antioxidant through reactive oxygen species/reactive nitrogen species scavenging, or 3) post-translational modification of proteins by addition of a thiol (-SH) group onto reactive cysteine residues: a process known as persulfidation. Below toxic levels, hydrogen sulfide promotes mitochondrial biogenesis and function, thereby conferring protection against cellular stress. For these reasons, increases in hydrogen sulfide and hydrogen sulfide-producing enzymes have been implicated in several human disease states. This review will first summarize our current understanding of hydrogen sulfide production and metabolism, as well as its signaling mechanisms; second, this work will detail the known mechanisms of hydrogen sulfide in the mitochondria and the implications of its mitochondrial-specific impacts in several pathologic conditions.-Murphy, B., Bhattacharya, R., Mukherjee, P. Hydrogen sulfide signaling in mitochondria and disease. | Cystathionine gamma-Lyase |
The hip grows by a complex process involving several growth cartilages, each one playing a specific role. Dysfunction of any of these cartilages, whatever its cause, may result in architectural defects of the hip. These defects must be perfectly known in order to foresee the consequences of some hip diseases in children and sometimes to prevent these diseases by orthopaedic measures. The copious blood supply of the acetabulum protects it against all traumas, in contrast with the poor blood supply of the upper end of the femur which exposes to the risk of femoral head necrosis. | Hip |
This project was planned to study the production of cholesterol lowering drug mevastatin by Aspergillus terreus GCBL-03 on pretreated substrate bagasse in solid state fermentation. Bagasse was pretreated by potassium hydroxide to delignify the substrate to readily become available to microorganism. It was noticed that pretreated bagasse exhibited 13.69+/-0.64 mg/100mL yield of mevastatin and 6.63+/-0.48 g dry cell mass as compared to nontreated substrate that showed 7.04+/-0.81 mg/100 mL and 6.04+/-0.24 g dry cell mass. The fermentation profile like pH (5.5), temperature (30 degrees C), moisture contents (60%) inoculum size (2 mL), and incubation time (72 h) showed the optimum production (30.63+/-1.24 mg/100 mL) of mevastatin. Furthermore, fermented drug showed noteworthy antifungal activity against battery of selected fungal strains assessed by disc diffusion and measurement of minimum inhibitory concentration by micro dilution method. It was concluded from the study that fermented mevastatin was effective against fungal strains. | Lovastatin |
Dismemberment of a corpse has always been viewed by society to be a more hideous crime than the homicide itself. In this study, we present a case of a 57-year-old woman who was decapitated and her right arm and both hands were dismembered. It was determined that the victim was murdered and dismembered by her 33-year-old daughter, who had been receiving treatment for schizophrenia for 15 years. On the victim's head and back there were 71 incised and stab wounds in total. They were superficial, except the five stab wounds which were connected to the right chest cavity and which incapacitated the victim. Although there is not a regulation for the act of dismembering the corpse in the Turkish Penal Code, since this type of case is rare, the crime scene and the autopsy findings were evaluated together with other pertinent data available in the literature. | Corpse Dismemberment |
The term Medical devices" includes technology-based devices or articles, both basic and complex. Due to these types of variations, a strict, robust, transparent, and sustainable regulatory framework is required. In recent clinical practice, incidents including the breast implant and the hip replacement crisis have made it necessary to improve the regulatory and compliance approaches for the industry to ensure the manufacturing and distribution of safe and innovative MDs within the EU. In response to this, the EU revised the laws governing medical devices and in vitro diagnostics to align with the developments of the sector, address critical safety issues and support innovation. The new regulation (EU) 2017/745 on Medical Devices (MDR) is now applicable from May 26 2021 and the In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 will take effect from May 2022.In this review, we aim to provide an update on the new Medical Device Regulations in the context of the current medical needs of the world, and also to give a glimpse at the non-EU regulatory landscape. Finally, we take a look at the closed-system transfer devices (CSTD) and COVID facilitated changes promoting demand for continuous improvement and trends in the pharmaceutical and medical industry related areas." | Medical Device Legislation |
BACKGROUND: Baseline imbalances, skewed costs, the correlation between costs and effects, and missing data are statistical challenges that are often not adequately accounted for in the analysis of cost-effectiveness data. This study aims to illustrate the impact of accounting for these statistical challenges in trial-based economic evaluations. METHODS: Data from two trial-based economic evaluations, the REALISE and HypoAware studies, were used. In total, 14 full cost-effectiveness analyses were performed per study, in which the four statistical challenges in trial-based economic evaluations were taken into account step-by-step. Statistical approaches were compared in terms of the resulting cost and effect differences, ICERs, and probabilities of cost-effectiveness. RESULTS: In the REALISE study and HypoAware study, the ICER ranged from 636,744euro/QALY and 90,989euro/QALY when ignoring all statistical challenges to - 7502euro/QALY and 46,592euro/QALY when accounting for all statistical challenges, respectively. The probabilities of the intervention being cost-effective at 0euro/ QALY gained were 0.67 and 0.59 when ignoring all statistical challenges, and 0.54 and 0.27 when all of the statistical challenges were taken into account for the REALISE study and HypoAware study, respectively. CONCLUSIONS: Not accounting for baseline imbalances, skewed costs, correlated costs and effects, and missing data in trial-based economic evaluations may notably impact results. Therefore, when conducting trial-based economic evaluations, it is important to align the statistical approach with the identified statistical challenges in cost-effectiveness data. To facilitate researchers in handling statistical challenges in trial-based economic evaluations, software code is provided. | Actuarial Analysis |
Rectal bioavailability of Ara-C (serum AUC 4 h: 65 micrograms h-1 ml-1) administered in a suppository formulation containing tetrahydrouridine (a deamination inhibitor) and sodium salicylate (an adjuvant) to dogs was better than that from a suppository formulation without tetrahydrouridine (serum AUC 4 h: 18 micrograms h-1 ml-1). | Tetrahydrouridine |
Several studies have reported that active compounds isolated from Piper nigrum possess anticancer properties. However, there are no data on anticancer activity of (-)-kusunokinin and piperlonguminine. The purposes of this study were to isolate active compounds from P. nigrum and identify the molecular mechanisms underlying growth and apoptosis pathway in breast cancer cells. Two bioactive compounds, (-)-kusunokinin and piperlonguminine, were isolated from P. nigrum. Cytotoxicity and the molecular mechanism were measured by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry and Western blot analysis. We found that the active compounds, which effect cancer cell lines were (-)-kusunokinin and piperlonguminine. These compounds have potent cytotoxic effects on breast cancer cells (MCF-7 and MDA-MB-468) and colorectal cells (SW-620). (-)-Kusunokinin demonstrated a cytotoxic effect on MCF-7 and MDA-MB-468 with IC(50) values of 1.18 and 1.62mug/mL, respectively. Piperlonguminine had a cytotoxic effect on MCF-7 and MDA-MB-468 with IC(50) values of 1.63 and 2.19mug/mL, respectively. Both compounds demonstrated lower cytotoxicity against normal breast cell lines with IC(50) values higher than 11mug/mL. Cell cycle and apoptotic analysis using flow cytometry, showed that the (-)-kusunokinin and piperlonguminine induced cell undergoing apoptosis and drove cells towards the G2/M phase. Moreover, both compounds decreased topoisomerase II and bcl-2. The increasing of p53 levels further increased p21, bax, cytochrome c, caspase-8, -7 and -3 activities, except caspase-9. These results suggest that the (-)-kusunokinin and piperlonguminine have been shown to have potent anticancer activities through extrinsic pathway and G2/M phase arrest. | Piper nigrum |
Assays utilizing fluorophores are common throughout life science research and diagnostics, although detection limits are generally limited by weak emission intensity, thus requiring many labeled target molecules to combine their output to achieve higher signal-to-noise. We describe how the synergistic coupling of plasmonic and photonic modes can significantly boost the emission from fluorophores. By optimally matching the resonant modes of a plasmonic fluor (PF) nanoparticle and a photonic crystal (PC) with the absorption and emission spectrum of the fluorescent dye, a 52-fold improvement in signal intensity is observed, enabling individual PFs to be observed and digitally counted, where one PF tag represents one detected target molecule. The amplification can be attributed to the strong near-field enhancement due to the cavity-induced activation of the PF, PC band structure-mediated improvement in collection efficiency, and increased rate of spontaneous emission. The applicability of the method by dose-response characterization of a sandwich immunoassay for human interleukin-6, a biomarker used to assist diagnosis of cancer, inflammation, sepsis, and autoimmune disease is demonstrated. A limit of detection of 10 fg mL(-1) and 100 fg mL(-1) in buffer and human plasma respectively, is achieved, representing a capability nearly three orders of magnitude lower than standard immunoassays. | Fluorescence |
Subscribing to a long-term care (LTC) insurance plan for future health care and services is one of the most difficult decisions aging Americans need to make today. Although it may be difficult to predict who will need an LTC plan and for how long, various factors play an important role in determining whether to purchase LTC insurance. This article provides general information about LTC plans including private insurance, their coverage, and implications for gerontologic nurses. | Insurance, Long-Term Care |
Biocatalyzed synthesis of nucleoside analogues was carried out using two thermostable nucleoside phosphorylases from the hyperthermophilic aerobic crenarchaeon Aeropyrum pernix K1. The synthesis of the 2,6-diaminopurine nucleoside and 5-methyluridine was used as a reaction model to test the process. Both the purine nucleoside phosphorylase (apPNP) and uridine phosphorylase (apUP) were functionally expressed in Escherichia coli. The recombinant enzymes were characterized after purification, and both enzymes showed high thermostability and broad substrate specificity. Both enzymes retained 100 % of their activity after 60 min at high temperature, and the optimum temperature for the enzymes was 90-100 degrees C. The nucleoside phosphorylases obtained from A. pernix are valuable industrial biocatalysts for high-temperature reactions that produce nucleoside drugs in high yields. | Pentosyltransferases |
OBJECTIVE: To identify the prevalence and risk factors of diabetes and prediabetes in the community residents above 18 years old in the suburbs of Guangzhou. METHODS: Between April and May in 2008, the residents above 18 years living in 6 communities of Guangzhou for 5 or more years were sampled with multistage clustering sampling. The sampled residents were surveyed by questionnaires, and physical examination and glucose determination were carried out. RESULTS: A total of 1532 residents were sampled. The incidence of diabetes mellitus in these community residents was 8.46%, and that of impaired glucose regulation was 6.59%. Age, body mass index, family history of diabetes mellitus, case history of hypertension, hyperlipidemia, hypertension and smoking were all the independent risk factors for impaired glucose regulation and diabetes mellitus. CONCLUSION: Diabetes and prediabetes are prevalent in the community residents in Guangzhou. Controlling the risk factors such as obesity, hypertension, lipid metabolism disorder among the residents above 40 years with a family history of diabetes mellitus and hypertension is key to prevention of impaired glucose regulation and diabetes mellitus. | Suburban Health |
A 52-year-old male underwent living-related renal transplantation. He received prednisolone, azathioprine, and cyclosporine as immunosuppression protocol. Eleven years after transplantation, he developed pyrexia with multiple nodular lesions on his limbs, trunk, and face. Skin biopsy and smears showed the presence of numerous acid-fast bacilli with 5% sulfuric acid indicative of Mycobacterium leprae. He was initiated on multidrug therapy (MDT) including dapsone, clofazimine, and rifampicin. After 2 years of MDT, he developed new multiple erythematous, tender subcutaneous nodules in crops over his face and upper limbs. Skin biopsies and histopathological examination confirmed the diagnosis of type 2 lepra reaction or erythema nodosa leprosum. He was managed with an increase in the dose of prednisolone and thalidomide. He was continued on MDT. | Leprosy, Multibacillary |
Factor VIIIa is a non-covalent heterotrimer of A1, A2, and A3-C1-C2 subunits. Previously, we speculated that the central portion of the A2 subunit, in and around the activated protein C-sensitive bond at Arg562-Gly (Fay, P. J., Smudzin, T.M., and Walker, F.J. (1991) J. Biol. Chem. 266, 20139-20145), is important for macromolecular interactions within the factor Xase enzyme complex. A peptide corresponding to factor VIII residues 558-565, SVDQRGNQ and designated FVIII558-565, was chemically synthesized and inhibited factor Xa generation in a purified system with an apparent KI of 105 microM. Tryptic cleavage of FVIII558-565 eliminated its inhibitory activity, whereas a scrambled sequence version of the peptide possessed < 30% the inhibitory activity of the native version. Overlapping peptides FVIII556-564 and FVIII561-569 were also inhibitory and confirmed the importance of residues in and around the scissile bond for functional factor Xase. Kinetic analysis revealed that peptide-mediated inhibition was non-competitive with respect to factor X. However, increasing factor IXa concentration overcame the observed inhibition. Furthermore, the peptide inhibited the factor IXa-dependent enhancement of factor VIIIa reconstituted from isolated A1/A3-C1-C2 dimer plus A2 subunit. Isolated factor VIII heavy chain (contiguous A1-A2 domains) was cleaved at Arg336 by an equimolar concentration of factor IXa in a reaction that was phospholipid-independent. No proteolysis of the isolated A1 subunit was observed in a similar reaction. These results indicate that the A2 subunit sequence delineated by residues 558-565 contributes to the interaction of cofactor with protease and that this interaction is essential for intrinsic factor Xase activity. Furthermore, that this peptide blocks both factor Xase activity and the capacity of factor IXa to stabilize the labile factor VIIIa heterotrimer suggest that this latter property is of physiologic significance. | Factor IXa |
To assess whether Smad signaling affects skin development, we generated transgenic mice in which a Smad antagonist, Smad7, was induced in keratinocytes, including epidermal stem cells. Smad7 transgene induction perturbed hair follicle morphogenesis and differentiation, but accelerated sebaceous gland morphogenesis. Further analysis revealed that independent of its role in anti-Smad signaling, Smad7 bound beta-catenin and induced beta-catenin degradation by recruiting an E3 ligase, Smurf2, to the Smad7/beta-catenin complex. Consequently, Wnt/beta-catenin signaling was suppressed in Smad7 transgenic hair follicles. Coexpression of the Smurf2 and Smad7 transgenes exacerbated Smad7-induced abnormalities in hair follicles and sebaceous glands. Conversely, when endogenous Smad7 was knocked down, keratinocytes exhibited increased beta-catenin protein and enhanced Wnt signaling. Our data reveal a mechanism for Smad7 in antagonizing Wnt/beta-catenin signaling, thereby shifting the skin differentiation program from forming hair follicles to sebaceous glands. | Smad7 Protein |
Slow transit constipation is a clinical syndrome predominantly affecting young women, characterized by constipation and delayed colonic transit, occasionally associated with pelvic floor dysfunction. The disorder spans a spectrum of variable severity, ranging from patients who have relatively mild delays in transit but who are otherwise indistinguishable from irritable bowel syndrome patients at one extreme, to patients with colonic inertia or chronic megacolon at the other extreme. Potential mechanisms for impaired colonic propulsion include fewer colonic HAPCs or a reduced colonic contractile response to a meal. The cause of the syndrome is unclear. The treatment is primarily medical; surgery is reserved for patients with severe disease or colonic inertia. Recognition and treatment of pelvic floor dysfunction is crucial for patients treated medically or surgically. Collaborative studies are necessary to determine the pathophysiology of this disorder and to ascertain the efficacy of novel prokinetic agents. | Gastrointestinal Transit |
OBJECTIVES: Severe acute pancreatitis (SAP) has high morbidity and mortality but there are no widely accepted predictive biomarkers in clinical use. Matrix metalloproteinases (MMPs) are active in tissue destruction and inflammatory responses. We studied whether serum levels of activated MMP-8 (aMMP-8), MMP-9 and their regulators tissue inhibitor of matrix metalloproteinases (TIMP)-1, myeloperoxidase (MPO) and human neutrophil elastase (HNE) could predict the development of SAP. METHODS: The study comprised 214 AP patients (revised Atlanta classification: 142 mild, MAP; 54 moderately severe, MSAP; 18 SAP) referred to Helsinki University Hospital. A venous blood sample was taken within 72 h from the onset of symptoms. Serum levels of aMMP-8 were determined using immunofluorometric assay, and those of MMP-9, TIMP-1, MPO and HNE using enzyme-linked immunosorbent assay. AP groups were compared using Jonckheere-Terpstra test and predictive value for SAP was analyzed using receiver operating characteristics (ROC) analysis. RESULTS: Serum aMMP-8 levels were higher in SAP (median 657 ng/ml, interquartile range 542-738 ng/ml) compared to MSAP (358 ng/ml, 175-564 ng/ml; p < 0.001) and MAP (231 ng/ml, 128-507 ng/ml; p < 0.001). Similar trend was seen with TIMP-1 and MPO. In ROC analysis aMMP-8, MPO and TIMP-1 emerged as potential markers for the development of SAP (areas under ROC curves 0.83, 0.71 and 0.69, respectively). CONCLUSIONS: Serum aMMP-8 measured early in the course of AP (within 72 h of symptom onset) predicted the development of SAP. | Matrix Metalloproteinase 8 |
OBJECTIVE: To study the relationship between blood lead levels and cognitive abilities of children exposed to this metal. METHOD: This is a cross-sectional study that included 134 children aged 6 to 8.5 years old from 3 schools with different risks of lead exposure located in El Callao (Peru). Cognitive assessments were made by means of the Graphic Test of Reasoning (GTR) and the Kohs Block Design Test (KBDT). Blood lead levels and other laboratory tests were performed. RESULTS: Children with lead > 10 ug/dl presented greater prevalence of low scores in the Graphic Test of Reasoning (18.9% vs. 7.1%, p = 0.049) and in the Kohs Block Design Test (KBDT) (39.6% vs. 18.6%, p = 0.01) compared with those with lower lead blood levels. A deficit of 1 category in the Graphic Test of Reasoning was associated with an increase in lead blood level of 16.78 ug/dl (assuming a linear relationship) and from 1 to 5.19 ug/dl (logarithmic model). For each 10 ug/dl of increase in lead levels, the Kohs Block Design Test decreases in 6.24 units (12.91 in males and 0.216 in females) (linear model), and an increase from 1 to 10 ug/dl corresponds to a drop of 16.44 points in the Kohs Block Design Test (31.19 in males and 3.98 in females) (logarithmic model). Considering the Graphic Test of Reasoning subscales, lead levels correlated negatively with the areas of numerical problems (rho = -0.445, p < 0.001), numerical relationships (rho = -0.365, p < 0.001), inferences (rho = -0.281, p = 0.002) and similarities (rho = -0.250, p = 0.005). CONCLUSIONS: Lead levels were non-linearly associated with lower cognitive abilities, especially in males, being the numerical reasoning the most affected area." | Lead Poisoning, Nervous System, Childhood |
Using the Bekesy tracking method, tone-on-tone masking patterns were measured with eight subjects at eight masker frequencies between 250 Hz and 6.03 kHz. Masking patterns were obtained for five masker levels between 20 and 60 dB SPL. Test-tone frequencies were chosen within two critical bands above and below the masker frequency. A level-dependent frequency asymmetry of masking was observed at all masker frequencies except at 250 Hz. At low levels there was a greater spread of masking towards the lower frequencies than toward the higher frequencies, but at high levels there was a greater spread of masking towards the higher frequencies than toward the lower frequencies. Only at masker levels of 40 dB SPL were the masking patterns approximately symmetrical. | Psychoacoustics |
The effects of exogenous and endogenous granulocyte colony-stimulating factor (G-CSF) on invasion by cancer cells were studied, using lung cancer cell lines that produce G-CSF (NCI-H157) and lines that do not (PC-9 and NCI-H23). The invasive capacity of NCI-H157 cells was 26- to 27-fold higher than that of PC-9 and NCI-H23 cells. The invasiveness of PC-9 cells was stimulated by exogenous G-CSF, while that of NCI-H157 cells was not. Antibodies against G-CSF blocked the stimulation of PC-9 cell invasiveness by exogenous G-CSF. Anti G-CSF antibodies also inhibited invasion by NCI-H157 cells in the absence of exogenous G-CSF. These results suggest that endogenous and exogenous G-CSF both stimulate invasion by lung cancer cells." | Granulocyte Colony-Stimulating Factor |
In 1964, Vincent Allfrey and colleagues reported the identification of histone acetylation and with deep insight proposed a regulatory role for this protein modification in transcription regulation. Subsequently, histone acetyltransferases (HATs), histone deacetylases (HDACs) and acetyl-Lys-binding proteins were identified as transcription regulators, thereby providing compelling evidence for his daring hypothesis. During the past 15 years, reversible protein acetylation and its modifying enzymes have been implicated in many cellular functions beyond transcription regulation. Here, we review the progress accomplished during the past 50 years and discuss the future of protein acetylation. | Acetylation |
Beginning with Turing's seminal work [1], decades of research have demonstrated the fundamental ability of biochemical networks to generate and sustain the formation of patterns. However, it is increasingly appreciated that biochemical networks also both shape and are shaped by physical and mechanical processes [2, 3, 4]. One such process is fluid flow. In many respects, the cytoplasm, membrane and actin cortex all function as fluids, and as they flow, they drive bulk transport of molecules throughout the cell. By coupling biochemical activity to long-range molecular transport, flows can shape the distributions of molecules in space. Here, we review the various types of flows that exist in cells, with the aim of highlighting recent advances in our understanding of how flows are generated and how they contribute to intracellular patterning processes, such as the establishment of cell polarity. | Actomyosin |
Aeromonas salmonicida causes furunculosis in salmonids and is a threat to Atlantic salmon aquaculture. The epithelial surfaces that the pathogen colonizes are covered by a mucus layer predominantly comprised of secreted mucins. By using mass spectrometry to identify mucin glycan structures with and without enzymatic removal of glycan residues, coupled to measurements of bacterial growth, we show here that the complex Atlantic salmon intestinal mucin glycans enhance A. salmonicida growth, whereas the more simple skin mucin glycans do not. Of the glycan residues present terminally on the salmon mucins, only N-acetylglucosamine (GlcNAc) enhances growth. Sialic acids, which have an abundance of 75% among terminal glycans from skin and of <50% among intestinal glycans, cannot be removed or used by A. salmonicida for growth-enhancing purposes, and they shield internal GlcNAc from utilization. A Ca(2+) concentration above 0.1 mM is needed for A. salmonicida to be able to utilize mucins for growth-promoting purposes, and 10 mM further enhances both A. salmonicida growth in response to mucins and binding of the bacterium to mucins. In conclusion, GlcNAc and sialic acids are important determinants of the A. salmonicida interaction with its host at the mucosal surface. Furthermore, since the mucin glycan repertoire affects pathogen growth, the glycan repertoire may be a factor to take into account during breeding and selection of strains for aquaculture. | Aeromonas salmonicida |
BACKGROUND: A new candidate vector vaccine against human brucellosis based on recombinant influenza viral vectors (rIVV) subtypes H5N1 expressing Brucella outer membrane protein (Omp) 16, L7/L12, Omp19 or Cu-Zn SOD proteins has been developed. This paper presents the results of the study of protection of the vaccine using on guinea pigs, including various options of administering, dose and frequency. Provided data of the novel vaccine candidate will contribute to its further movement into the preclinical stage study. METHODS: General states of guinea pigs was assessed based on behavior and dynamics of a guinea pig weight-gain test. The effectiveness of the new anti-brucellosis vector vaccine was determined by studying its protective effect after conjunctival, intranasal and sublingual administration in doses 10(5) EID(50), 10(6) EID(50) and 10(7) EID(50) during prime and boost vaccinations of animals, followed by challenge with a virulent strain of B. melitensis 16 M infection. For sake of comparison, the commercial B. melitensis Rev.1 vaccine was used as a control. The protective properties of vaccines were assessed by quantitation of Brucella colonization in organs and tissues of infected animals and compared to the control groups. RESULTS: It was observed a gradual increase in body weight of guinea pigs after prime and booster immunization with the vaccine using conjunctival, intranasal and sublingual routes of administration, as well as after using various doses of vaccine. The most optimal way of using the vaccine has been established: double intranasal immunization of guinea pigs at a dose of 10(6) EID(50), which provides 80% protection of guinea pigs from B. melitensis 16 M infection (P < 0.05), which is comparable to the results of the effectiveness of the commercial B. melitensis Rev.1 vaccine. CONCLUSIONS: We developed effective human vaccine candidate against brucellosis and developed its immunization protocol in guinea pig model. We believe that because of these studies, the proposed vaccine has achieved the best level of protection, which in turn provides a basis for its further promotion. | Brucella Vaccine |
Central environmental protection inspection (CEPI) is a major institutional innovation in China's environmental governance, but its effectiveness in improving air quality is still unclear. However, the effectiveness of CEPI is of great significance and can be regarded as an important reference for deepening the reform of environmental governance system in China. This article takes the CEPI as a quasi-natural experiment and uses the regression discontinuity design (RDD) and the difference-in-differences (DID) methods to examine the effectiveness of this policy. The study found that the first round of CEPI reduced the air pollution of cities in the inspected provinces in a short time. Moreover, this positive policy effect persisted in the aftermath of the inspection, but this long-term effect is mainly reflected in PM(10) and SO(2.) Heterogeneity analysis showed that CEPI was only effective in reducing air pollutants of industry-oriented cities, cities in Central and Eastern China, and cities with large or small population size. The moderating effect analysis indicated that a healthy relationship (close and clean) between the local governments and businesses was conducive to reducing air pollution. The research confirmed the presence of selective" reduction of air pollutants in the long run caused by CEPI, thereby providing new inspiration for the improvement of campaign-style environmental governance and the follow-up CEPI work." | Air Pollution |
Adult cockroaches were found to survive up to 22 weeks when provided with 1% Formalin (0.4% formaldehyde) in lieu of drinking water. Given 4% Formalin or 2% glutaraldehyde they survived up to 41 days. During the experiments eggs were laid and hatched and the offspring continued to grow. Combined with surface disinfection, this may hold out a simple method of rendering adult cockroaches gnotobiotic or even axenic. | Cockroaches |
Pharmacokinetic interactions between natural products and conventional drugs can adversely impact patient outcomes. These complex interactions present unique challenges that require clear communication to researchers. We are creating a public information portal to facilitate researchers' access to credible evidence about these interactions. As part of a user-centered design process, three types of intended researchers were surveyed: drug-drug interaction scientists, clinical pharmacists, and drug compendium editors. Of the 23 invited researchers, 17 completed the survey. The researchers suggested a number of specific requirements for a natural product-drug interaction information resource, including specific information about a given interaction, the potential to cause adverse effects, and the clinical importance. Results were used to develop user personas that provided the development team with a concise and memorable way to represent information needs of the three main researcher types and a common basis for communicating the design's rationale." | National Center for Complementary and Integrative Health (U.S.) |
The production and use of dibutyl phthalate (DBP) are increasing, and the resulting health and environmental problems are of concern. Therefore, the present study focused on the biodegradation of DBP in liquid fermentation using endophytic Penicillium species and evaluated the cytotoxic, ecotoxic, and phytotoxic effects of the fermented filtrate (by-product). Higher biomass yield was observed in fungal strains grown in DBP-containing media (DM) compared to DBP-free (control) media (CM). The highest esterase activity was observed at 240 h during fermentation with Penicillium radiatolobatum (PR) grown in DM (PR-DM). As per gas chromatography/mass spectrometry (GC/MS) results, the PR degraded 99.986 % of DBP after 288 h of fermentation. Furthermore, compared to DM treatment, the fermented filtrate of PR-DM demonstrated negligible toxicity in HEK-293 cells. Besides, the treatment of PR-DM in Artemia salina indicated >80 % viability and showed a trivial ecotoxic effect. However, compared to the control, the fermented filtrate of PR-DM treatment resulted in ~90 % of the roots and shoots growth of Zea mays seeds, indicating no phytotoxicity. Overall, the findings of this study suggested that PR can degrade DBP in liquid fermentation without generating toxic byproducts. | Dibutyl Phthalate |
A gram-negative, facultatively anaerobic, straight to slightly curved rod-shaped bacterium (RE35F/12T) sensitive to vibriostatic agent O/129 was previously isolated from sea water (Western Mediterranean Sea, Bay of Calvi, Corsica, France) by 0.2 microm-membrane filtration. Strain RE35/F12T (= CIP 107077T = DSM 14347T) was facultatively oligotrophic, halophilic, required Na+ for growth and produced acid but no gas from D-glucose under anaerobic conditions. Comparative 165 rRNA gene-sequence analyses demonstrated that the bacterium is most closely related (94.3%) to Vibrio scophthalmi. Similarities to the sequences of all other established Vibrio species ranged from 93.6% (with Vibrio aestuarianus) to 90.7% (with Vibrio rumoiensis). Strain RE35/F12T occupies a distinct phylogenetic position; this is similar to the case of Vibrio hollisae, because RE35F/12T represents a relatively long subline of descent sharing a branching point with the outskirts species V. hollisae. The G+C content of the DNA was 49.5 mol%. Ubiquinone Q-8 was the main respiratory lipoquinone, and 16:1omega9cis, 16:0 and 18:1trans9, cis11 were the major cellular fatty acids, 16:1omega9cis being predominant. The polyamine pattern was characterized by the presence of the triamine sym-norspermidine. On the basis of the polyphasic information summarized above, a new Vibrio species is described for which the name Vibrio calviensis sp. nov. is proposed. | Vibrio |
The Eighth Circuit Court of Appeals affirmed a lower court decision that had held Nebraska's statute banning partial-birth abortion to be unconstitutional under the Fourteenth Amendment to the U.S. Constitution. The lower court had permanently enjoined enforcement of the statute. Nebraska's Partial-Birth Abortion Act prohibited an abortion procedure in which the person performing the abortion partially delivers vaginally a living unborn child before killing the unborn child and completing the delivery." A physician who performs abortions had challenged this statute as being vague and overly broad. The lower court had ruled that the statute was unconstitutional under the Fourteenth Amendment since it banned the common dilation and evacuation (D&E) procedure thereby creating an undue burden for women seeking to terminate a pregnancy before the fetus becomes viable." | Social Control, Formal |
BACKGROUND: Basal nitric oxide (NO) activity has a pivotal role in the regulation of glomerular hemodynamics, and in animal experiments, its alteration has been associated with morphological changes characteristic of diabetic nephropathy. STUDY DESIGN: Prospective observational-study during a mean follow-up of 2.1 years. SETTING & PARTICIPANTS: 66 hypertensive patients (aged 30 to 80 years) with type 2 diabetes and estimated glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m(2) with normoalbuminuria or microalbuminuria. PREDICTOR: Mean arterial pressure during follow-up during treatment with telmisartan or ramipril for 9 weeks, followed by treatment according to the discretion of the individual primary care physician. OUTCOMES & MEASUREMENTS: Renal vascular resistance, renal plasma flow, GFR, and change in renal plasma flow in response to infusion of the NO synthase inhibitor N-monomethyl-L-arginine as an indicator of basal NO activity in the renal vasculature. RESULTS: 50 of 66 patients could be reexamined. At follow-up, mean arterial pressure decreased from 106 +/- 9.1 to 100 +/- 11 mm Hg (P < 0.001). Body mass index and hemoglobin A(1c) levels were unaltered. Renal vascular resistance decreased (from 128 +/- 44 to 103 +/- 30 mm Hg/mL/min/1.73 m(2); P < 0.001), renal plasma flow increased (from 490 +/- 133 to 589 +/- 154 mL/min/1.73 m(2); P < 0.001), and GFR did not change (113 +/- 22 versus 116 +/- 26 mL/min/1.73 m(2); P = 0.4) during follow-up. The decrease in renal plasma flow in response to N-monomethyl-l-arginine infusion was more pronounced at follow-up (-56.7 +/- 39 versus -73.4 +/- 48 mL/min/1.73 m(2); P = 0.02), indicating improved basal NO activity. After adjustment for possible confounders, patients with a marked decrease in mean arterial pressure showed more improved basal NO activity during follow-up than those with a less pronounced decrease in mean arterial pressure (P = 0.04). LIMITATIONS: Patients were treated according to the discretion of the individual primary care physician. CONCLUSIONS: During follow-up, renal vascular resistance, renal plasma flow, and renal endothelial function (indicated by basal NO activity) improved. Better blood pressure control was associated with improved endothelial function of the renal vasculature, thereby potentially mediating the changes in renal hemodynamics. | Renal Plasma Flow |
The GABAergic efferent pathway from the striatum exerts inhibitory control on the substantia nigra pars reticulata (SNR) neurones. We studied sequential changes in spontaneous single-unit activities in the ipsilateral SNR 1 h, 1 day, 7 days and 14 days after striatal infarction induced by middle cerebral artery occlusion (MCAO) in rats. Compared with a sham-operated group, there was no change in the firing rate 1 h after MCAO, and one day after MCAO the mean firing rate decreased. The firing rate of SNR neurones at 7 and 14 days after MCAO was significantly reduced compared with the sham-operated group. Only two neurones (sham-operated group and 1 h after MCAO group) fired with high frequency. Histological examination revealed degeneration of the ipsilateral SNR 7 and 14 days after MCAO. Our results indicated that SNR neuronal degeneration accompanied by striatal ischaemia does not simply depend on hyperexcitation due to the activation of a disinhibition mechanism. | Substantia Nigra |
Tramadol is an analgesic drug that is mainly excreted in the urine. The entry of Tramadol into water samples causes their biological contamination. Therefore, three catalysts such as bismuth ferrite, cobalt-doped bismuth ferrite, and a magnetized Keggin type of polyoxometalate (alpha-Fe(2)O(3)@phosphotungstic acid), were synthesized as photocatalysts to degrade Tramadol in water samples. The morphology and properties of the prepared photocatalysts were evaluated using several techniques. Effects of several factors, including tramadol concentration, pH, hydrogen peroxide concentration, and photocatalyst amount, were studied and optimized by a design experiment procedure based on Box-Behnken design for reducing the number of experiments and cost and investigating the interactions between factors in the photocatalytic degradation process of Tramadol. These factors were optimized for each prepared photocatalyst individually. Under the optimum conditions, the percentages of tramadol degradation and kinetics of the degradation process were evaluated in the presence of each photocatalyst. The tramadol degradation percentages using bismuth ferrite, cobalt-doped bismuth ferrite, and alpha-Fe(2)O(3) @phosphotungstic acid were 81.10% for 120 min, 90.63% for 80 min, and 91.32% for 80 min, respectively. The rate constants of tramadol degradation were 0.0145, 0.0329, and 0.0312 min(-1) for bismuth ferrite, cobalt-doped bismuth ferrite, and alpha-Fe(2)O(3) @phosphotungstic acid, respectively. The results indicated the highest percentage of tramadol degradation and rate of the degradation process were obtained using alpha-Fe(2)O(3) @phosphotungstic acid and cobalt-doped bismuth ferrite, respectively. | Phosphotungstic Acid |
Abnormal airway smooth muscle function can contribute to cystic fibrosis (CF) airway disease. We previously found that airway smooth muscle from newborn CF pigs had increased basal tone, an increased bronchodilator response, and abnormal calcium handling. Since CF pigs lack airway infection and inflammation at birth, these findings suggest intrinsic airway smooth muscle dysfunction in CF. In this study, we tested the hypothesis that CFTR loss in airway smooth muscle would produce a distinct set of changes in the airway smooth muscle transcriptome that we could use to develop novel therapeutic targets. Total RNA sequencing of newborn wild-type and CF airway smooth muscle revealed changes in muscle contraction-related genes, ontologies, and pathways. Using connectivity mapping, we identified several small molecules that elicit transcriptional signatures opposite of CF airway smooth muscle, including NVP-TAE684, an inhibitor of proline-rich tyrosine kinase 2 (PYK2). In CF airway smooth muscle tissue, PYK2 phosphorylation was increased and PYK2 inhibition decreased smooth muscle contraction. In vivo NVP-TAE684 treatment of wild-type mice reduced methacholine-induced airway smooth muscle contraction. These findings suggest that studies in the newborn CF pig may provide an important approach to enhance our understanding of airway smooth muscle biology and for discovery of novel airway smooth muscle therapeutics for CF and other diseases of airway hyperreactivity. | Focal Adhesion Kinase 2 |
Chikungunya virus (CHIKV) is an arthropod-borne alphavirus, transmitted by Aedes aegypti and Aedes albopictus mosquitoes. It is responsible for a febrile illness, typically accompanied by maculopapular rash and severe, incapacitating arthralgia. The disease, although generally self-limiting, frequently evolves into a long-lasting, debilitating rheumatic disorder, which shares many clinical features with rheumatoid arthritis (RA). The underlying mechanism by which CHIKV induces persistent arthritis remains under investigation, however, currently, attention is drawn to the fact, that chronic chikungunya (CHIK) and RA have many common cellular and cytokine pathways involved in their pathogenesis. Over the past decades, the virus has dispersed unexpectedly from tropical and subtropical regions of Africa and Asia, affecting millions of people worldwide. No licensed vaccine, nor antiviral drug against CHIKV is yet available. Treatment of acute CHIK is symptomatic, whereas in chronic stages, different disease-modifying anti-rheumatic drugs (DMARDs) have been used with variable success. Hence, chronic CHIK is an emerging rheumatic condition that rheumatologists have to deal with. This review provides brief insights into the epidemiology, pathogenesis, clinical features and management of Chikungunya disease, with special regard to post-chikungunya rheumatic disorder and its relationship with RA. | Chikungunya Fever |
As one of the effective control devices of air pollutants, the wet electrostatic precipitator (ESP) is an effective technique to eliminate acid mist and fine particles that are re-entrained in a collection electrode. However, its collection efficiency can deteriorate, as its operation is subject to water-induced corrosion of the collection electrode. To overcome this drawback, we modified the wet ESP system with the installation of a PVC dust precipitator wherein water is supplied as a replacement of the collection electrode. With this modification, we were able to construct a compact wet ESP with a small specific collection area (SCA, 0.83 m(2)/(m(3)/min)) that can acquire a high collection efficiency of fine particles (99.7%). | Electrowetting |
Precocious puberty in children is one of the common endocrine diseases in paediatrics. Epidemiological surveys have shown that the number of children with precocious puberty has significantly increased globally. Precocious puberty negatively affects the physical and mental health of children and may increase the risk of hypertension, diabetes, obesity and infertility in adulthood. Therefore, the initiating factors of adolescence have become core issues in the study of sexual development in children. Owing to developments in molecular genetics, many studies have been able to show that precocious puberty is mostly resulted in autosomal inheritance. For instance, makorin ring finger protein 3 gene (MKRN3) may be implicated in familial CPP. Gonadotropin-releasing hormone agonist (GnRHa) is the gold standard for treatment, but its safety still requires long-term evaluation and management. Traditional medicinal plants have been used in clinical treatments and in exploring novel treatment methods. From the collected datas, in Asia, traditional Chinese medicine treatment is based on the principles of nourishing Yin, lowering fire and draining fire from the liver to help precocious children and alleviate or delay the onset of precocious puberty by medicinal plants such as Anemarrhena asphodeloides Bge., Phellodendron amurense Rupr., Rehmannia glutinosa and Poria cocos Wolf. They play an important role in exploring the pharmacological mechanisms of precocious puberty treatment effects and drug development. Therefore, by elucidating the occurrence and development of precocious puberty, this review provides novel and valuable insights of paediatric endocrine therapy accessing the published researches on the effectiveness of traditional herbal medicine in the treatment of precocious puberty and its therapeutic mechanisms. | Puberty, Precocious |
The purpose of the present study is to examine whether the use of fins is identifiable based on swimmers' technique and to find out technique-related features that depict fins' influence. First, a number of features were extracted from kinematic data given by movement sensors attached to swimmers' bodies during butterfly swimming technique. Then, dimensionality reduction, feature selection and classification methods were applied to the extracted features. Two classification tasks were defined, one for the three classes of long, short and no fins, attaining accuracy up to 70, 62 and 70%, respectively, and the two-class simplified version (long fins, no fins) with accuracy up to 78%. These high accuracy levels were also found statistically significant and suggest that the use of fins influences swimming technique in a recognizable way and that the selected features that depict those differences are swimming type depended. | Swimming |
Assisted reproductive technology (ART) employs superovulation, in vitro culture and other micromanipulation to complete oocyte maturation, fertilization and early embryo development. Although these techniques have been successfully applied to solve infertility problems, the process may interfere in cell proliferation, differentiation and growth. The clinical and laboratory studies on the safety issue of ART are reviewed in this article. Studies found that the incidence of birth defects increased in ART offspring. Superovulation, in vitro culture and intracytoplasmic sperm injection may induce epigenetic aberrations during embryo development, which would influence the development of ART conceived children. The epigenetic susceptibility related to ART might be transmitted to subsequent generations, and the potential impact on ART offspring still need further investigation. In addition, ART treatments may also increase the risk of genetic diseases." | Reproductive Techniques, Assisted |
Chloroperoxidase (CPO) is thought to be the most versatile heme-containing enzyme with enormous applications in organic synthesis, biotransformation, pharmaceutical production, and detoxification of environmental pollutants. Any improvement in the stability of this enzyme will greatly enhance its application in the mentioned areas. In the present study, the effects of three polysaccharides (soluble starch, beta-cyclodextrin, and dextrin) on the stability of CPO at elevated temperatures (20, 30, 35, 40, and 50 degrees C) or in aqueous-organic solvents media (methanol, dioxane, DMSO, and DMF) were investigated. An improved catalytic performance of CPO was observed in the presence of a small amount of the three polysaccharides, where dextrin provided the most effective promotion. The changes of enzyme structure and microenvironment around heme in the presence of additives were studied by fluorescence, circular dichroism, and UV-vis spectra analyses, as well as kinetic parameters measurement. A catalytically favorable structure of CPO was induced, including the strengthening of the alpha-helix structure and more exposure of heme for easy access of the substrate, resulting in an increase of catalytic turnover frequency (k (cat)) and the improvement of affinity and selectivity of CPO to substrate. The results revealed that the introduction of trace soluble starch, beta-cyclodextrin, and dextrin (<10 mumol/L) in reaction media was an effective strategy for the enhancement of the thermodynamic and the operational stability of the enzyme, which are promising in view of the industrial applications of this versatile biological catalyst. | Chloride Peroxidase |
Abiotic stresses often disrupt protein folding and induce endoplasmic reticulum (ER) stress. There is a sophisticated ER quality control (ERQC) system to mitigate the effects of malfunctioning proteins and maintain ER homeostasis. The accumulation of misfolded proteins in the ER activates the unfolded protein response (UPR) to enhance ER protein folding and the degradation of misfolded proteins mediate by ER-associated degradation (ERAD). That ERQC reduces abiotic stress damage has been well studied in mammals and yeast. However, in plants, both ERAD and UPR have been studied separately and found to be critical for plant abiotic stress tolerance. In this study, we discovered that UPR-associated transcription factors AtbZIP17, AtbZIP28 and AtbZIP60 responded to tunicamycin (TM) and NaCl induced ER stress and subsequently enhanced Arabidopsis thaliana abiotic stress tolerance. They regulated the expression level of ER chaperones and the HRD1-complex components. Moreover, overexpression of AtbZIP17, AtbZIP28 and AtbZIP60 could restore stress tolerance via ERAD in the HRD1-complex mutant hrd3a-2, which suggested that UPR and ERAD have an interactive mechanism in Arabidopsis. | Unfolded Protein Response |
Pet ownership provides a unique relationship that is beneficial to many aspects of the pet owner's life, including mental health and companionship. Mental health and social isolation are negatively impacted by homelessness, increasing the importance of the owner-pet bond during this time. However, this relationship is complicated by the need for pet owners to urgently find accommodation for themselves while still caring for their pets. This paper explores two firsthand narratives of the relationship between a person and their pets during a period of homelessness and subsequent search for accommodation. Both narratives highlight important aspects of the emotional bond between owner and pet: the concept of choosing pet over place; improved mental health and changed behaviours; and stressors or negative emotions of parental concern, separation anxiety and grief. These narratives emphasise the importance of supporting, expanding and creating new pet-friendly crisis and permanent accommodation options for pet owners experiencing homelessness. | Human-Animal Bond |
Morgellons disease" has been a controversial topic in the history of psychodermatology. The most consensual scientific opinion is that it is a primary psychiatric disorder, particularly, a delusional disorder, although others were also pointed out. Some authors have suggested that it may correspond to a common dermatosis with secondary psychopathology. The Morgellons Research Foundation has advocated that it is "an emerging infectious" entity. This paper intends to critically review the main ideas and controversies, since its first description." | Morgellons Disease |
Multiple association studies found that the human 9p21.3 chromosome locus is a risk factor for atherosclerosis. The purpose of this study was to investigate the association of the severity and early-onset of coronary artery disease with variant rs1333049 on chromosome 9p21.3 polymorphism and the impact of this variant on cardiovascular risk factors in type 2 diabetic patients. The study population consisted of a control CAD group (101 patients) and 273 consecutive type 2 diabetic patients. Severity and extent of coronary atherosclerosis were scored numerically using the Gensini scoring system. The diabetic population was divided into three groups according to Gensini score: Group 1: no stenosis; Group 2: moderate CAD; Group 3, severe CAD. The homozygous CC genotype of rs1333049 was significantly associated with CAD in Group 2 (OR: 1.36; p = 0.02) and Group 3 (OR: 5.77, p < 0.001) compared to Group 1 (OR: 0.18; p = 0.2) and control group (OR: 0.22; p = 0.21). Among diabetic patients with early-onset CAD, CC genotype carriers had significantly higher Gensini scores than non-CC genotype carriers (49 +/- 21.3 versus 14.87 +/- 25.22; p < 0.001). The homozygous CC genotype of rs1333049 confers a magnified risk of early-onset and severe CAD in type 2 diabetic Tunisian population. | Chromosomes, Human, Pair 9 |
We describe a method for high-pressure freezing and rapid freeze-substitution of cells in tissue culture which provides excellent preservation of membrane detail with negligible ice segregation artefacts. Cells grown on sapphire discs were placed 'face to face' without removal of tissue culture medium and frozen without the protection of aluminium planchettes. This reduction in thermal load of the sample/holder combination resulted in freezing of cells without visible ice-crystal artefact. Freeze-substitution at -90 degrees C for 60 min in acetone containing 2% uranyl acetate, followed by warming to -50 degrees C and embedding in Lowicryl HM20 gave consistent and clear membrane detail even when imaged without section contrasting. Preliminary data indicates that the high intrinsic contrast of samples prepared in this way will be valuable for tomographic studies. Immunolabelling sensitivity of sections of samples prepared by this rapid substitution technique was poor; however, reducing the uranyl acetate concentration in the substitution medium to 0.2% resulted in improved labelling. Samples substituted in this lower concentration of uranyl acetate also gave good membrane detail when imaged after section contrasting. | Freeze Substitution |
Myeloproliferative neoplasms are characterized by transduction pathway recognized as mutually exclusive molecular abnormalities such as BCR-ABL translocation, JAK2V617F or JAK2 exon 12 mutations, MPL w515, and CALR mutations. However, in some rare cases, associations of such mutations are found in 1 patient. This can be related to 2 pathologies (at least 2 different clones harboring 2 mutations) or associated mutations in 1 clone. We describe here such an association of CALR and MPL mutations in a patient harboring the second mutation in a subclone during the phenotypic evolution of the myeloproliferative neoplasms. | Thrombocythemia, Essential |
Buffering agents have not been comprehensively profiled in terms of their capacity to influence water retention prior to exercise. The purpose of this investigation was to profile the fluid retention characteristics of sodium bicarbonate (BIC) and sodium citrate (CIT) to determine the efficacy of these buffering mediums as hyperhydrating agents. Nineteen volunteers (13 males and six females; age = 28.3 +/- 4.9 years) completed three trials (randomized and cross-over design). For each trial, a baseline measurement of body mass, capillary blood, and urine was collected prior to ingestion of their respective condition (control condition [CON] = 25 ml/kg artificially sweetened water; BIC condition = CON + 7.5 g/L of sodium in the form of BIC; CIT condition = CON + 7.5 g/L of sodium in the form of CIT). The fluid loads were consumed in four equal aliquots (0, 20, 40 and 60 min; fluid intake was 1.972 +/- 361 ml [CON]; 1.977 +/- 360 ml [BIC]; 1.953 +/- 352 ml [CIT]). Samples were recorded at 20 (body mass and urine) and 60 min (blood) intervals for 180 min. Blood buffering capacity (HCO3-) was elevated (p < .001) in both BIC (32.1 +/- 2.2 mmol/L) and CIT (28.9 +/- 3.8 mmol/L) at 180 min compared with CON (25.1 +/- 1.8 mmol/L). Plasma volume expansion was greater (p < .001) in both BIC (8.1 +/- 1.3%) and CIT (5.9 +/- 1.8%) compared with CON (-1.1 +/- 1.4%); whereas, total urine production was lower in BIC and CIT at 180 min (BIC vs. CON, mean difference of 370 +/- 85 ml; p < .001; CIT vs. CON, mean difference of 239 +/- 102 ml; p = .05). There were no increases observed in body mass (p = .9). Under resting conditions, these data suggest BIC and CIT induce a greater plasma hypervolemic response as compared with water alone. | Sodium Citrate |
Beliefs in mind-body dualism--that is, perceiving one's mind and body as two distinct entities--are evident in virtually all human cultures. Despite their prevalence, surprisingly little is known about the psychological implications of holding such beliefs. In the research reported here, we investigated the relationship between dualistic beliefs and health behaviors. We theorized that holding dualistic beliefs leads people to perceive their body as a mere "shell" and, thus, to neglect it. Supporting this hypothesis, our results showed that participants who were primed with dualism reported less engagement in healthy behaviors and less positive attitudes toward such behaviors than did participants primed with physicalism. Additionally, we investigated the bidirectionality of this link. Activating health-related concepts affected participants' subsequently reported metaphysical beliefs in mind-body dualism. A final set of studies demonstrated that participants primed with dualism make real-life decisions that may ultimately compromise their physical health (e.g., consuming unhealthy food). These findings have potential implications for health interventions." | Mind-Body Relations, Metaphysical |
Nine new compounds, together with 16 known analogs, were isolated from the whole plants of Rehmannia chingii. The structures of compounds 1-9 were elucidated on the basis of their spectroscopic data and chemical evidence. In addition, the new compounds were tested for their hepatoprotective activities against APAP-induced HepG2 cell damage and their ability to inhibit LPS-induced nitric oxide production in the murine microglia BV2 cell line. Compounds 2 and 5 exhibited pronounced hepatoprotective activities against APAP-induced HepG2 cell damage at a concentration of 10 muM, and compounds 4 and 9 showed moderate inhibitory activity against microglial inflammation factor with IC50 values of 3.51 and 7.11 muM, respectively. | Rehmannia |
Facioscapulohumeral muscular dystrophy (FSHD) is a disabling inherited muscular disorder characterized by asymmetric, progressive muscle weakness and degeneration. Patients display widely variable disease onset and severity, and sometimes present with extra-muscular symptoms. There is a consensus that FSHD is caused by the aberrant production of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. DUX4 is normally expressed during early embryonic development, and is then effectively silenced in all tissues except the testis and thymus. Its reactivation in skeletal muscle disrupts numerous signalling pathways that mostly converge on cell death. Here, we review studies on DUX4-affected pathways in skeletal muscle and provide insights into how understanding these could help explain the unique pathogenesis of FSHD." | Muscular Dystrophy, Facioscapulohumeral |
Isolated stigmata of light grown cells of Euglena gracilis strain Z were solubilized by a zwitterionic surfactant. The resulting extract was fractionated by gel filtration, and two fractions were obtained. These were then examined for the presence of carotenoproteins and nucleic acids using the techniques of UV/visible spectroscopy, thin layer chromatography and isoelectrofocusing. DNA but not RNA was shown to be present in the high molecular weight fraction, while carotenoid pigments were present in the low molecular weight fraction but they were shown not to be in stoichiometric combination with protein. | Euglenida |
Objective: Data are lacking from empirically supported therapies implemented in residential programs for eating disorders (EDs). Common elements treatments may be well-suited to address the complex implementation and treatment challenges that characterize these settings. This study assessed the preliminary effect of implementing a common elements therapy on clinician treatment delivery and patient (N = 616) symptom outcomes in two residential ED programs. Method: The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders was adapted to address ED and co-occurring psychopathology and implemented across sites. Therapists' treatment fidelity was rated independently to assess implementation success. Additionally, longitudinal (pre-post) design compared treatment outcomes among patients treated before and after implementation. Patient outcomes included ED and depressive symptoms, experiential avoidance, anxiety sensitivity, and mindfulness. Results: Following training and implementation, clinicians demonstrated adequate to good fidelity. Relative to pre-implementation, post-implementation patients showed significantly greater improvements in experiential avoidance, anxiety sensitivity, and mindfulness at discharge (ps </= .04) Relative to patients who were treated during the pre-implementation phase, patients in the post-implementation phase experienced more favorable outcomes on ED symptom severity, depression, mindfulness, and anxiety sensitivity at 6-month-follow-up (ps </= .001). A similar result was observed for experiential avoidance, yet this interaction effect was no longer statistically significant (p = .10) when the time x length of stay effect/covariate was added to the model. Conclusions: Preliminary pilot data support the feasibility of implementing transdiagnostic common elements therapy in residential ED treatment, and suggest that implementation may benefit transdiagnostic outcomes for patients. Clinical or methodological significance of this article: Limited data are available to guide evidence-based residential treatment for eating disorders. This study represents a unique effort to adapt, implement, and test an evidence-based therapy protocol across a large private network of intensive eating disorder treatment programs. | Residential Treatment |
Concentration gradients inside cells are involved in key processes such as cell division and morphogenesis. Here we show that a model of the enzymatic step catalized by phosphofructokinase (PFK), a step which is responsible for the appearance of homogeneous oscillations in the glycolytic pathway, displays Turing patterns with an intrinsic length-scale that is smaller than a typical cell size. All the parameter values are fully consistent with classic experiments on glycolytic oscillations and equal diffusion coefficients are assumed for ATP and ADP. We identify the enzyme concentration and the glycolytic flux as the possible regulators of the pattern. To the best of our knowledge, this is the first closed example of Turing pattern formation in a model of a vital step of the cell metabolism, with a built-in mechanism for changing the diffusion length of the reactants, and with parameter values that are compatible with experiments. Turing patterns inside cells could provide a check-point that combines mechanical and biochemical information to trigger events during the cell division process. | Phosphofructokinases |
Combining optical tweezers with single molecule fluorescence offers a powerful technique to study the biophysical properties of single proteins and molecules. However, such integration into a combined, coincident arrangement has been severely limited by the dramatic reduction in fluorescence longevity of common dyes under simultaneous exposure to trapping and fluorescence excitation beams. We present a novel approach to overcome this problem by alternately modulating the optical trap and excitation beams to prevent simultaneous exposure of the fluorescent dye. We demonstrate the dramatic reduction of trap-induced photobleaching effects on the common single molecule fluorescence dye Cy3, which is highly susceptible to this destructive pathway. The extension in characteristic fluorophore longevity, a 20-fold improvement when compared to simultaneous exposure to both beams, prolongs the fluorescence emission to several tens of seconds in a combined, coincident arrangement. Furthermore, we show that this scheme, interlaced optical force-fluorescence, does not compromise the trap stiffness or single molecule fluorescence sensitivity at sufficiently high modulation frequencies. Such improvement permits the simultaneous measurement of the mechanical state of a system with optical tweezers and the localization of molecular changes with single molecule fluorescence, as demonstrated by mechanically unzipping a 15-basepair DNA segment labeled with Cy3. | Spectrometry, Fluorescence |
The birth of a baby sibling is a normative life event for many children. Few studies address this important transition period and changes in the older sibling's adjustment and family relationships following the sibling's birth. The present article presents a developmental ecological systems model for studying changes in family life and the older child's adjustment following the birth of a baby sibling. Simultaneous changes occurring in the family and how these changes are interrelated over time to predict patterns of adaptation after the transition to siblinghood are underscored. Recommendations for designing longitudinal studies that take advantage of recent developments in multilevel modeling are also discussed. | Birth Order |
OBJECTIVE: Carisoprodol, a drug used for acute lower back pain, may cause psychomotor impairment. We wanted to investigate if patients using carisoprodol had increased risk of being involved in a traffic accident. METHODS: Data were retrieved from three population-based registries for the period April 2004-September 2005. The Norwegian Prescription Database contained individual information on all dispensed drugs at all pharmacies outside hospitals. The Norwegian Road Accident Registry contained information on all drivers involved in motor vehicle accidents with person injury. The Norwegian Central Population Registry was used to control for emigration or death. The accident incidence among carisoprodol exposed and unexposed subjects was compared by standardized incidence ratio. RESULTS: Having a prescription for carisoprodol dispensed increased the standardized incidence ratio for being involved in an accident with person injury to 3.7 (95% CI 2.9-4.8) the first week after the date of dispensing. This was similar to diazepam (2.8; 2.2-3.6), but higher than for salbutamol (1.1; 0.6-1.8). CONCLUSIONS: Patients receiving carisoprodol seem to have an increased risk of being involved in traffic accidents involving person injury. The study gives support to earlier work published on the impairing effects of carisoprodol. | Carisoprodol |
Procedures developed for in vitro pellicle formation in intact enamel proved useful for relating qualitiative characteristics of dental pellicle to a number of factors. Coronal surfaces of extracted human molars from experimental and control groups were pumiced, sterilized, and incubated for two hours at 37 C in parotid saliva and distilled water, respectively. Pellicle proteins were desorbed sequentially with water and 0.2 M sodium phosphate, with a pH of 7.0. Polyacrylamide disc electrophoresis of the desorbates yielded distinct patterns, indicating selective adsorption of proteins from saliva, varying affinity to enamel, and the presence of proteins not acquired in vitro from saliva. Certain pellicle components, including amylase and IgA, showed a relatively weak affinity for enamel and were eluted in part by water; other proteins were desorbed only by phosphate buffer. Anionic electropherograms of the phosphate desorbates showed an increase in the two most anodic proteins relative to corresponding salivary bands. An intense anodic protein and two minor bands were eluted by water or buffer from the surface of control as well as experimental teeth but not from teeth coated with sealants. Serum albumin and alkaline phosphatase were identified as components of the extra-salivary material. Further investigation of the sources and functions of the constituents of the protein layer generally considered as acquired" dental pellicle appears warranted." | Dental Deposits |
Several chiral thiols, i.e. traditionally used enantiomerically pure SH reagents and novel N-R-mandelyl-L-cysteine (R-NMC) containing additional chiral center, have been applied as co-reagents in precolumn derivatization with o-phthalaldehyde for enantiomeric HPLC analysis of individual alpha-amino acids and their mixtures. The R-NMC-derived isoindoles as well as adducts with other thiols have a characteristic absorption maximum at 340 nm, and are highly fluorescent allowing detection of 10 microg/l of an amino acid. Investigated 19 amino acids were analyzed separately and in a mixture by a gradient HPLC after precolumn derivatization. The chromatographic behavior of formed isoindoles substantially differs for each of the thiols used for modification. In contrast to traditional enantiomeric thiols application of diastereomeric R-NMC provides higher resolution for alpha-amino acid enantiomers, with L,D-elution order (except for Arg). Combined use of R-NMC and other thiol enlarges the possibilities of this method, allowing accurate chiral analysis of complex amino acid mixtures. | Sulfhydryl Reagents |
In this case report, we present a successful outcome of conservative treatment in a patient with oral mucosal necrosis. Quantitative Light induced Fluorescence (QLF) was used to evaluate progression and determine the medication period. Histology revealed microbiological differences between red fluorescing and non-fluorescing sites on QLF images. QLF technology could be widely used for detecting bacterial infections or necrotic lesions in oral and maxillofacial regions." | Quantitative Light-Induced Fluorescence |
PCR assays that can identify the presence of variola virus (VARV) sequences in an unknown DNA sample were developed using principles established for the amplification refractory mutation system (ARMS). The assay's specificity utilised unique single nucleotide polymorphisms (SNP) identified among Orthopoxvirus (OPV) orthologs of the vaccinia virus Copenhagen strain A13L and A36R genes. When a variola virus specific primer was used with a consensus primer in an ARMS assay with different Orthopoxvirus genomes, a PCR product was only amplified from variola virus DNA. Incorporating a second consensus primer into the assay produced a multiplex PCR that provided Orthopoxvirus generic and variola-specific products with variola virus DNA. We tested two single nucleotide polymorphisms with a panel of 43 variola virus strains, collected over 40 years from countries across the world, and have shown that they provide reliable markers for variola virus identification. The variola virus specific primers did not produce amplicons with either assay format when tested with 50 other Orthopoxvirus DNA samples. Our analysis shows that these two polymorphisms were conserved in variola virus genomes and provide a reliable signature of Orthopoxvirus species identification. | Orthopoxvirus |
BACKGROUND: There is currently no consensus regarding microorganisms that may be considered true peri-implant pathogens. Therefore, the aim of this systematic review is to determine the weight of evidence for microorganisms related to peri-implantitis based on results of association studies. METHODS: This review was performed following the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA). Two independent researchers searched PubMed/Medline, Embase, and Cochrane Library databases up to August 4, 2015, for studies comparing microbiologic outcomes of subgingival biofilm samples from healthy implants and implants with peri-implantitis. RESULTS: A total of 799 titles was identified and 11 studies were included in this review. All data were extracted using a predefined form. Microorganisms found in increased count/abundance/frequency in peri-implantitis belonged to Bacteria domain and viruses, and included a total of six bacterial phyla, 17 bacterial genera, 23 bacterial species, and two genera of viruses. The main bacterial species associated with peri-implantitis are recognized as periodontal pathogens. CONCLUSION: Results of this systematic review suggest moderate evidence supporting association of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia and some evidence supporting association of Prevotella intermedia and Campylobacter rectus with the etiology of peri-implantitis." | Gram-Negative Anaerobic Straight, Curved, and Helical Rods |
The amino-terminal region of eukaryotic MCM4 is characteristic of the presence of a number of phosphorylation sites for CDK and DDK, suggesting that the region plays regulatory roles in the MCM2-7 helicase function. However, the roles are not fully understood. We analyzed the role of the amino-terminal region of human MCM4 by using MCM4/6/7 helicase as a model for MCM2-7 helicase. First we found that deletion of 35 amino acids at the amino-terminal end resulted in inhibition of DNA helicase activity of the MCM4/6/7 complex. Conversion of arginine at amino acid no. 10 and 11 to alanine had similar effect to the deletion mutant of Delta1-35, suggesting that these arginine play a role in the DNA helicase activity. The data suggest that expression of these mutant MCM4 in HeLa cells perturbed the progression of the S phase. Substitution of six CDK phosphorylation sites (3, 7, 19, 32, 54 and 110) in the amino-terminal region by phospho-mimetic glutamic acids affected the hexamer formation of the MCM4/6/7 complex. MCM4 phosphorylation by CDK may play a role in DNA replication licensing system, and the present results suggest that the phosphorylation interferes MCM function by lowering stability of MCM complex." | Minichromosome Maintenance Complex Component 4 |
The irritable bowel syndrome (IBS) is a familiar problem in the clinic, but as a disease entity it remains ill defined. Much confusion has arisen in the past, because of the inappropriate inclusion within the category of IBS of almost any patient with unexplained abdominal discomfort. Recent work has established that IBS patients can be positively identified by a cluster of specific symptoms. With the use of these criteria, it seems likely that IBS patients suffer from a diffuse motor abnormality of the gut associated with visceral hypersensitivity; although there is no associated psychopathology, a central nervous system component to the disorder is possible. Better insight into IBS promises more effective management. | Colonic Diseases, Functional |
This paper reports some new structural modifications (branching and lengthening of alkanoic substituent, increase of heterocycle-carboxylate distance) on 1,2,3-triazole derivative 1, a potent in vitro inhibitor of prostaglandin synthesis, and their influence on enzyme activity. Regarding the structural relationship between 1 and Dazoxiben, a selective thromboxane-synthetase inhibitor, the preparation and activity of some Dazoxiben analogs bearing different heterocycles, are also described. | Prostaglandin Antagonists |
The molecular chaperone Hsp90 plays important roles in maintaining malignant phenotypes. Recent studies suggest that Hsp90 exerts high-affinity interactions with multiple oncoproteins, which are essential for the growth of tumor cells. As a result, research has focused on finding Hsp90 probes as potential and selective anticancer agents. In a high-throughput screening exercise, we identified quinoline 7 as a moderate inhibitor of Hsp90. Further hit identification, SAR studies, and biological investigation revealed several synthetic analogs in this series with micromolar activities in both fluorescent polarization (FP) assay and a cell-based Western blot (WB) assay. These compounds represent a new class of Hsp90 inhibitors with simple chemical structures. | Aminoquinolines |
Babesia venatorum was isolated from a captive reindeer calf in Switzerland. The clinical signs consistent with acute babesiosis included hemolytic anemia and hemoglobinuria. The diagnosis was made based on visualization of intraerythrocytic parasites in the stained blood smears and confirmed by PCR analysis of the 18S rRNA gene, with subsequent species identification within Babesia confirmed by sequencing. The reindeer calf was initially treated with supportive care and an antiprotozoal drug (imidocarb dipropionate) but died a few days after hospitalization. Babesia venatorum is also known as Babesia sp. EU1 and can infect different mammalian species, including humans. The current case report aims to increase awareness among veterinarians and reindeer owners about the presence and the associated risk of this zoonotic pathogen. Considering the high morbidity and possible mortality associated with acute babesiosis, captive reindeer should receive tick prevention measures and be tested for subclinical infections in endemic area. | Imidocarb |
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