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Interstitial cystitis is a clinical entity that has been known for a century, but its pathophysiology remains largely unknown and the optimal treatment is a matter of ongoing discussion. A successful strategy for treatment relies on precise appraisal of symptoms, clinical findings and histology, as well as on the patient's individual personality. The least invasive treatment possible should be chosen, and only after conservative options have been exhausted should a surgical solution be considered. In this respect, anatomical bladder capacity plays an important role. A large capacity indicates the potential for conservative treatment and may be regarded as a negative predictor for the outcome of orthotopic bladder substitution. In contrast, a small anatomical capacity is unlikely to respond to conservative therapy, but is associated with a high probability of successful orthotopic bladder substitution. | Urodynamics |
Disconnecting a patient from artificial life support, on their request, is often if not always a matter of letting them die, not killing them-and sometimes, permissibly doing so. Stopping a patient's heart on request, by contrast, is a kind of killing, and rarely if ever a permissible one. The difference seems to be that procedures of the first kind remove an unwanted external support for bodily functioning, rather than intervening in the body itself. What should we say, however, about cases at the boundary-procedures involving items that seem bodily in some respects, but not others? When, for instance, does deactivating an implanted device like a pacemaker count as killing, and when as letting die? Contra existing proposals, I argue that the boundaries of the body for this purpose are not drawn at the boundaries of the self, or (if this is different) the human organism. Nor should we determine when we are killing and when we are letting die by deferring to existing practices for distinguishing ongoing from completed treatment. Rather, I argue that whether something (organic or inorganic) counts as body part for purposes of this distinction depends on the results of a normative analysis of the particular character of our rights in it-particularly, whether and in what way these rights ought to be alienable. I conclude by arguing that there are likely good reasons to recognize distinctively bodily" rights and restrictions in at least some implantable devices." | Euthanasia |
Research has demonstrated that many chemical constituents dominated by piperidine alkaloids and flavonoids, such as lobelanidine, lobeline, and lobelanine, have been obtained from Lobelia chinensis Lour. Experimental studies and clinical applications have also indicated that L. chinensis possesses a number of pharmacological activities (e.g., diuretic, choleretic, breathing excitement, anti-venom, anti-bacterial, and anticancer). This paper focuses on the properties, chemical constituents, and anticancer activity of L. chinensis to clarify the connection among them, and identify the active anticancer compounds. This work serves as the foundation for further research and development of L. chinensis. | Lobelia |
Mediation analyses are valuable for examining mechanisms underlying an association, investigating possible explanations for nonintuitive results, or identifying interventions that can improve health in the context of nonmanipulable exposures. However, designing a study for the purpose of answering a mediation-related research question remains challenging because sample size and power calculations for mediation analyses are typically not conducted or are crude approximations. Consequently, many studies are probably conducted without first establishing that they have the statistical power required to detect a meaningful effect, potentially resulting in wasted resources. In an effort to advance more accurate power calculations for estimating direct and indirect effects, we present a tutorial demonstrating how to conduct a flexible, simulation-based power analysis. In this tutorial, we compare power to estimate direct and indirect effects across various estimators (the Baron and Kenny estimator (J Pers Soc Psychol. 1986;51(6):1173-1182), inverse odds ratio weighting, and targeted maximum likelihood estimation) using various data structures designed to mimic important features of real data. We include step-by-step commented R code (R Foundation for Statistical Computing, Vienna, Austria) in an effort to lower implementation barriers to ultimately improving power assessment in mediation studies. | Factor Analysis, Statistical |
Intravenous mannitol was introduced as an effective treatment for ciguatera in 1988. Clinicians have used intravenous mannitol with success in several geographic areas. However, there remains a general skepticism and reluctance to use mannitol to treat ciguatera amongst clinicians. The possible reasons for the clinician's reluctance to use intravenous mannitol to treat ciguatera are reviewed. | Mannitol |
PUF proteins are eukaryotic RNA-binding proteins that repress specific mRNAs. The mechanisms and corepressors involved in PUF repression remain to be fully identified. Here, we investigated the mode of repression by Saccharomyces cerevisiae Puf5p and Puf4p and found that Puf5p specifically requires Eap1p to repress mRNAs, whereas Puf4p does not. Surprisingly, we observed that Eap1p, which is a member of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein (4E-BP) class of translational inhibitors, does not inhibit the efficient polyribosome association of a Puf5p target mRNA. Rather, we found that Eap1p accelerates mRNA degradation by promoting decapping, and the ability of Eap1p to interact with eIF4E facilitates this activity. Deletion of EAP1 dramatically reduces decapping, resulting in accumulation of deadenylated, capped mRNA. In support of this phenotype, Eap1p associates both with Puf5p and the Dhh1p decapping factor. Furthermore, recruitment of Eap1p to downregulated mRNA is mediated by Puf5p. On the basis of these results, we propose that Puf5p promotes decapping by recruiting Eap1p and associated decapping factors to mRNAs. The implication of these findings is that a 4E-BP can repress protein expression by promoting specific mRNA degradation steps in addition to or in lieu of inhibiting translation initiation." | Eukaryotic Initiation Factor-4E |
Mutations in cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED/EDM1). Because COMP exists as a homopentamer, only one mutant COMP subunit may result in an abnormal complex that is accumulated in expanded rough endoplasmic reticulum (rER) cisternae, a hallmark of PSACH. Type IX collagen and matrilin-3 (MATN3), also accumulate in the rER cisternae of PSACH chondrocytes, but it is unknown how mutant COMP interacts with these proteins. The studies herein focus on defining the organization of these intracellularly retained proteins using fluorescence deconvolution microscopy. A unique matrix organization was identified in which type II procollagen formed a central core surrounded by a protein network of mutant COMP, type IX collagen, and MATN3. This pattern of matrix organization was found in multiple cisternae from single chondrocytes and in chondrocytes with different COMP mutations, indicating a common pattern of interaction. This suggests that stalling of mutant COMP and an interaction between mutant COMP and type II procollagen are initiating events in the assembly of matrix in the rER, possibly explaining why the material is not readily cleared from the rER. Altogether, these data suggest that mutant COMP initiates and perhaps catalyzes premature intracellular matrix assembly. | Endoplasmic Reticulum, Rough |
Exercise has an anxiolytic activity and it increases the concentrations of atrial natriuretic peptide (ANP). Because ANP has an anxiolytic activity, this hormone might contribute to the anxiolytic effects of aerobic exercise. Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks were studied in 10 healthy subjects after quiet rest" or 30 min of aerobic exercise. Plasma ANP concentrations were measured before and after exercise or quiet rest using a commercial IRMA kit. Compared to quiet rest, CCK-4-induced anxiety was reduced and plasma ANP concentrations were increased by prior exercise. This anxiolytic activity of exercise was correlated with the increase in plasma ANP concentrations. Our results suggest that besides other mechanisms, ANP might be a physiologically relevant humoral link between the heart and anxiety-related behavior contributing to the acute anxiolytic effects of exercise." | Tetragastrin |
Foster care is a system created to protect children from an unsafe home environment yet multiple foster home placements, conflictual or nonexistent relationships between foster parents and birth parents, long, drawn out court battles, and living in an on-going state of not knowing when or if they will be going home are just some of the challenges many children in care are expected to manage. This paper presents a guide for therapists working with families involved in foster care. Utilizing ideas from the postmodern therapies and structural family therapy, suggestions will be provided about who needs to talk to whom about what, when to have these necessary conversations, and how to talk to people in a way that mobilizes adults to take action for the children, with the goal of minimizing postplacement trauma, strengthening and repairing relational bonds, and moving children out of foster care and into permanent homes as quickly as possible. | Foster Home Care |
The fragile sites at 10q25, 16q22, and 17p12 can all be induced in lymphocyte culture by BrdU or BrdC added 6-12 hrs prior to harvest. Without induction, fra(10)(q25) is rarely expressed spontaneously, whereas fra(16)(q22) is frequently expressed spontaneously. Fra(17)(p12) is frequently expressed spontaneously but is probably expressed only after induction in some individuals. Distamycin A, netropsin, and Hoechst 33258 induced high levels of expression of fra(16)(q22) and fra(17)(p12) but did not enhance expression of fra(10)(q25). The mechanisms of induction of fra(16)(q22) by BrdU and distamycin A appear to be different, since the time of induction by BrdU reaches a maximum about 12 hrs prior to harvest whereas induction by distamycin A requires much longer exposure. The fragile sites at 10q25 and 16q22 were both induced in fibroblast culture by BrdU. Fra(17)(p12) is accepted as a fragile site because preliminary studies show that it behaves similarly in lymphocyte culture to fra(16)(q22); however, there is only limited evidence for fragility at 17p12. | Bromodeoxycytidine |
Spatial learning and memory are typically assessed to evaluate hippocampus-dependent cognitive and memory functions in vivo. Protein phosphorylation and dephosphorylation by kinases and phosphatases play critical roles in spatial learning and memory. Here we report that the Wip1 phosphatase is essential for spatial learning, with knockout mice lacking Wip1 phosphatase exhibiting dysfunctional spatial cognition. Aberrant phosphorylation of the Wip1 substrates p38, ATM, and p53 were observed in the hippocampi of Wip1(-/-) mice, but only p38 inhibition reversed impairments in long-term potentiation in Wip1-knockout mice. p38 inhibition consistently ameliorated the spatial learning dysfunction caused by Wip1 deficiency. Our results demonstrate that deletion of Wip1 phosphatase impairs hippocampus-dependent spatial learning and memory, with aberrant downstream p38 phosphorylation involved in this process and providing a potential therapeutic target. | Morris Water Maze Test |
Sarcophaga peregrina is an important flesh fly species for estimating the minimum postmortem interval (PMImin) in forensic entomology. The accurate determination of the developmental age is a crucial task for using necrophagous sarcophagids to estimate PMImin. During larval development, the age determination is straight forward by the morphological changes and variation of length, weight, and width; however, the age estimation of sarcophagid intrapuparial is more difficult due to anatomical and morphological changes not being visible. The analysis of differentially expressed genes (DEGs) during sarcophagid metamorphosis is a potential method for age estimation of intrapuparial. In the present study, real-time quantitative polymerase chain reaction (RT-qPCR) was used to analyze the differential gene expression level of S. peregrina intrapuparial in different constant temperatures (35 degrees C, 25 degrees C, and 15 degrees C). In addition, the appropriate reference genes of S. peregrina were selected in the intrapuparial and at different temperatures to obtain reliable and valid gene expression profiles. The results indicated that two candidate genes (18S rRNA and 28S rRNA) were the most reliable reference genes, and four DEGs (Hsp90, A-alpha, AFP, AFBP) have the potential to be used to more accuracy estimate the age of S. peregrina intrapuparial. | Forensic Entomology |
Idiopathic pulmonary fibrosis (IPF) is a specific type of fibrosing interstitial pneumonia of unknown cause. It is usually chronic and progressive, tends to affect mainly adults over age 60, has a predilection for men, and is often fatal. The condition is still underappreciated by pulmonologists and primary care physicians. This article attempts to close that information gap by reviewing the natural course of IPF and presenting an algorithmic approach to diagnosis and treatment based on evidence-based international guidelines. New treatment options are briefly discussed, to raise awareness of new medications that target pulmonary fibrosis. | Pulmonologists |
Mitochondria contain an endogenous set of chaperones and proteases that form a complex and functionally interconnected protein quality control system responsible for maintenance of mitochondrial enzyme content and function (protein homeostasis). Here the functional roles of the ATP-dependent protease Pim1/LON and the ClpB-type chaperone Hsp78, both members of the ubiquitous AAA+ (ATPases associated with a wide variety of cellular activities) protein family, are described and discussed in the context of protein homeostasis processes under normal and stress conditions. Particular emphasis is set on cooperative mechanisms of protein quality control components in the specific recognition of damaged polypeptides and their subsequent removal. The coordinated biochemical activities of both Hsp78 and Pim1/LON prevent the accumulation of toxic protein aggregates in mitochondria and thereby indirectly ensure survival of the eukaryotic cell. | Protease La |
OBJECTIVE: To systematically assess the literature to ascertain the pharmacokinetics, pharmacodynamics, and clinical efficacy and safety associated with administration of a vancomycin loading dose (LD). DATA SOURCES: MEDLINE (1948-December 31, 2014), EMBASE (1980-December 31, 2014), Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts (1970-December 31, 2014), Google and Google Scholar, and International Clinical Trials Registry Platform were searched using the following terms: vancomycin, glycopeptides, loading dose, dose-response relationship. STUDY SELECTION AND DATA EXTRACTION: Pharmacokinetic, pharmacodynamic, and clinical efficacy studies using vancomycin LDs to achieve trough concentrations of 15 to 20 mg/L were included. Nonhuman, non-English, oral vancomycin, and dialysis patient studies were excluded. Abstracts were included. Study quality was ranked using US Preventative Services Task Force 1996 classification system. Data on study design, baseline characteristics, exclusion criteria, dosing, study outcomes, and conclusions were extracted. DATA SYNTHESIS: A total of 8 studies (5 manuscripts [2 level I, 3 level II-3] and 3 abstracts) were cited. Of 6 adult studies, 4 concluded that administration of vancomycin LDs resulted in significantly more patients achieving troughs of 15 to 20 mg/L. Studies in children found that LDs did not lead to rapid attainment of vancomycin levels >/=15 mg/L. No studies assessed clinical or microbiological outcomes. Limitations included heterogeneity and inconsistent timing of concentration measurements. CONCLUSIONS: High-quality data to guide the use of vancomycin LDs are lacking. LDs may more rapidly attain vancomycin troughs of 15 to 20 mg/L in adults, but information in pediatrics, obesity, and renal impairment is limited. Further studies are required to determine benefit of LDs on clinical and microbiological outcomes. | Vancomycin |
State-of-the-art papers from around the globe addressing current topics in education were published in the FEMS Microbiology Letters virtual Thematic Issue 'Education' in November 2015 (http://femsle.oxfordjournals.org/content/thematic-issue-education), which was innovative and well received by microbiologists and other educators. Its unique content is reviewed here to facilitate broader access and further discussions in the professional community. Best practice in supporting school teaching and exposing students to concepts from other disciplines is presented in context of inspiring the next generations, where also historical microbiology can be drawn upon. Technology-enhanced education is discussed including its applications (e.g. lecture podcasts for flipped learning, learning from experts via videoconference). Authentic learning is covered with examples of research-led teaching, water and showerhead biofilm analyses and participation in the International Genetically Engineered Machines competition. Enhancing employability is focussed on, including supporting personal development and work-readiness in general and for the changing nature of the microbiology profession. International mobility develops international awareness but challenges teachers. Teaching training, teaching excellence and dissemination of best practice are reviewed. Times of challenge and change in the Higher Education landscape motivate us to improve educational approaches and frameworks, so that we are prepared for new topics to emerge as current topics in education. | Microbiology |
The proto-oncogene bcl-3 is a member of the IkappaB family. The Bcl-3 protein is known to interact specifically with the p50 and p52 subunits of NFkappaB. However, the function of this interaction is not well understood. To determine the in vivo role of Bcl-3, mice were generated that lack the bcl-3 gene, Bcl 3(-/-). Here we report that Bcl 3(-/-) mice appear developmentally normal, but exhibit severe defects in humoral immune responses and protection from in vivo pathogenic challenges. Relative to wild-type mice, Bcl 3(-/-) mice are unable to clear L. monocytogenes and are more susceptible to infection with S. pneumoniae. This phenotype is similar to that observed in the p50(-/-) mice and the cross between the Bcl-3(-/-) and p50(-/-) mice generates animals with an enhanced phenotype. In accordance with the observed defects in their immune response, the Bcl 3(-/-) mice have normal immunoglobulin levels before and after immunization, but fail to produce antigen-specific antibodies. Additionally, spleens from Bcl-3(-/-) mice are abnormal and void of germinal centers. In contrast, the p50(-/-) mice have normal germinal centers. We propose that in in vivo, Bcl-3 can function independently of p50. | B-Cell Lymphoma 3 Protein |
Now-a-days, plant species are consumed globally for various purposes and this increasing demand leads to adulteration due to gradually exploitation in natural resources. The major causes of adulteration may be confusion in nomenclature, unawareness of authentic sources, unavailability of authentic sources, color resemblances, deficiencies in collection procedures, and misidentification. This study aims to use the microscopic techniques such as scanning electron microscopy for the authentication of the oil yielding seeds of four important and traditionally used species Prunus persica, Prunus domestica, and Eruca sativa and Argemone Mexicana from their adulterants. All of these are versatile in usage. Locally, these four plants are adulterated badly and there is need to provide a criteria and a complete monograph for correct identification. This research may prove to be helpful for quality control and as well for future studies to explore other novel aspects of these plants. | Argemone |
BACKGROUND: Intracoronary administration of an abciximab bolus during a primary percutaneous coronary intervention results in a high local drug concentration, improved perfusion, and reduction of infarct size compared with intravenous bolus application. However, the safety and efficacy of intracoronary versus standard intravenous bolus application in patients with ST-elevation myocardial infarction (STEMI) undergoing this intervention has not been tested in a large-scale clinical trial. METHODS: The AIDA STEMI trial was a randomised, open-label, multicentre trial. Patients presenting with STEMI in the previous 12 h with no contraindications for abciximab were randomly assigned in a 1:1 ratio by a central web-based randomisation system to intracoronary versus intravenous abciximab bolus (0.25 mg/kg bodyweight) during percutaneous coronary intervention with a subsequent 12 h intravenous infusion 0.125 mug/kg per min (maximum 10 mug/min). The primary endpoint was a composite of all-cause mortality, recurrent infarction, or new congestive heart failure within 90 days of randomisation. Secondary endpoints were the time to occurrence of the primary endpoint, each individual component of that endpoint, early ST-segment resolution, thrombolysis in myocardial infarction (TIMI) flow grade, and enzymatic infarct size. A masked central committee adjudicated the primary outcome and its components. Treatment allocation was not concealed from patients and investigators. This trial is registered with ClinicalTrials.gov, NCT00712101. FINDINGS: Between July, 2008, and April, 2011, 2065 patients were randomly assigned intracoronary abciximab (n=1032) or intravenous abciximab (n=1033). Intracoronary, as compared with intravenous abciximab, resulted in a similar rate of the primary composite clinical endpoint at 90 days in 1876 analysable patients (7.0%vs 7.6%; odds ratio [OR] 0.91; 95% CI 0.64-1.28; p=0.58). The incidence of death (4.5%vs 3.6%; 1.24; 0.78-1.97; p=0.36) and reinfarction (1.8%vs 1.8%; 1.0; 0.51-1.96; p=0.99) did not differ between the treatment groups, whereas less patients in the intracoronary group had new congestive heart failure (2.4%vs 4.1%; 0.57; 0.33-0.97; p=0.04). None of the secondary endpoints or safety measures differed significantly between groups. INTERPRETATION: In patients with STEMI undergoing primary percutaneous coronary intervention, intracoronary as compared to intravenous abciximab did not result in a difference in the combined endpoint of death, reinfarction, or congestive heart failure. Since intracoronary abciximab bolus administration is safe and might be related to reduced rates of congestive heart failure the intracoronary route might be preferred if abciximab is indicated. FUNDING: Lilly, Germany. University of Leipzig-Heart Centre. University of Leipzig, Clinical Trial Centre Leipzig, supported by the Federal Ministry of Education and Research (BMBF). | Abciximab |
Necrotizing fasciitis (NF) is a life-threatening condition, consisting of a soft-tissue infection with rapidly progressive, widespread fascial necrosis. NF may be caused by a wide variety of microbes. Indeed, NF may be an infection of one species of bacteria or may be polymicrobial. Prompt diagnosis and treatment are essential. Surgical debridement and antibiotic therapy are the primary treatment options. | Fasciitis, Necrotizing |
The double immunodiffusion technique was applied to avian encephalomyelitis virus (AEV). Agar gel medium containing such a high concentration of NaCl as 15% was more preferable for highly diluted quantities of reactants than any other NaCl-containing medium. A single precipitin line appeared on the 1st to 7th days of diffusion at room temperature. The specificity of reaction between AEV antigen and homologous immune chicken serum has been demonstrated by no cross reaction between heterologous viruses and specific absorption by homologous virus. The antigen was produced in the brain, viscera, eyeball, whole body and yolk sac of chick embryos inoculated via yolk sac, as well as in the thigh muscles of chicks subcutaneously inoculated at 2 days of age. Antigenicity was detectable in 50% emulsion of these organs with a virus titer more than 10(5.0) per 0.1 g of tissue weight." | Encephalomyelitis Virus, Avian |
OBJECTIVE: To investigate the association between maternal use of sulfamethizole near term and the risk of neonatal jaundice. METHODS: We conducted a nationwide population-based retrospective cohort study using Danish registers. All Danish women giving birth between 1995 and 2007 were included from the Danish Fertility Database. Women redeeming a prescription for sulfamethizole up to 4 weeks before giving birth were identified from the National Prescription Register. The primary outcome was the number of neonates diagnosed with jaundice between birth and age 28 days identified in the National Hospital Register. Risk of neonatal jaundice was calculated as odds ratios (ORs) with linear logistic regression with and without adjustment for confounders. RESULTS: We identified 841,900 births. Of 1,823 (0.2%) neonates exposed to sulfamethizole up to 4 weeks before birth, 197 (10.8%) developed neonatal jaundice. The OR of developing neonatal jaundice after exposure to sulfamethizole was 2.35 (95% confidence interval [CI] 2.02-2.72). Adjustment for maternal age, education, household income, parity, and period of conception left OR unchanged at 2.29 (95% CI 1.97-2.67). After further adjustment for gestational age, the risk associated with sulfamethizole was rendered insignificant (OR 1.03, 95% CI 0.86-1.22). Narrowing exposure time to the last week before birth did not change the estimates. Broken into gestational age groups, the rate of neonates with jaundice after exposure was similar to the rate of unexposed neonates with jaundice. CONCLUSIONS: We found no association between redeeming a prescription of sulfamethizole near term and increased risk of neonatal jaundice. We showed that the presumed association is the result of preterm birth, which can be caused by maternal urinary tract infection. LEVEL OF EVIDENCE: II. | Sulfamethizole |
PURPOSE: Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting. PATIENTS AND METHODS: Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments. RESULTS: In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide v 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided P = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide v 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided P = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone. CONCLUSION: The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity. | Abiraterone Acetate |
FRET is a powerful approach to study the interactions of fluorescent molecules, and numerous methods have been developed to measure FRET in cells. Here, we present a method based on a donor molecule's photoswitching properties, which are slower in the presence vs. the absence of an acceptor. The technique, photoswitching FRET (psFRET), is similar to an established but underutilized method called photobleaching FRET (pbFRET), with the major difference being that the molecules are switched off" rather than photobleached. The psFRET technique has some of the FRET imaging advantages normally attributed to fluorescence lifetime imaging microscopy (FLIM), such as monitoring only donor fluorescence. However, it can be performed on a conventional widefield microscope, requires less illumination light to photoswitch off than photobleaching, and can be photoswitched "on" again to repeat the experiment. We present data testing the validity of the psFRET approach to quantify FRET in cells and demonstrate its use in imaging protein-protein interactions and fluorescent protein-based biosensors." | COS Cells |
A patient with well-controlled HIV-1 infection presented with fever and rigors, a widespread maculopapular rash, and severe generalised arthralgia. Sepsis of unknown aetiology was diagnosed, and treatment with broad-spectrum antimicrobials commenced. Following initial clinical improvement, a right knee septic arthritis developed. Microscopy and culture of the joint aspirate were negative for organisms but 16S rDNA PCR identified Neisseria meningitidis DNA, subsequently verified as capsular genogroup C, thus confirming a diagnosis of disseminated meningococcal sepsis with secondary septic arthritis." | Neisseria meningitidis, Serogroup C |
Jamestown Canyon (JC) virus of the California (CAL) serogroup has been isolated in 12 American states and 6 Canadian provinces. A study was undertaken to produce monoclonal antibodies (MAbs) to JC virus and to use these MAbs to assay for possible heterogeneity among naturally occurring JC topotypes in Canada. MAbs were produced to the prototype strain of JC virus using BALB/c mice. Twenty-seven secreting MAbs were obtained and three of these MAbs were propagated and studied. All three MAbs, M1 (IgG1), M2 (IgG2b), and M3 (IgG2a), were reactive by immunofluorescent antibody assay against JC-infected vero cells and by ELISA against JC antigen. MAb M2 reacted with all members of the Melao complex, MAb M1 reacted only with Keystone virus, while MAb M3 exhibited no reactivity with other CAL serogroup viruses. Only MAb M3 possessed neutralization and hemagglutination inhibition activities against JC virus. The MAbs were also tested by ELISA and for neutralizing activity against 13 JC topotypes isolated in 5 provinces from Newfoundland to Saskatchewan. ELISA confirmed closer identity of the Canadian topotypes to JC as opposed to the closely related South River virus. The MAbs verified all Canadian topotypes to be JC virus but revealed different patterns of reactivity between these topotypes and prototype JC virus. | Hemagglutination, Viral |
Groove pancreatitis is a rare form of segmental chronic pancreatitis that involves the anatomic space between the head of the pancreas, the duodenum, and the common bile duct. We report 2 cases of groove pancreatitis with pancreatic heterotopia in the minor papilla. Patients were a 44-year-old woman and a 47-year-old man. Both had a past history of alcohol consumption and presented with abdominal pain, vomiting, and weight loss caused by duodenal stenosis. Abdominal computed tomography revealed thickening of the duodenal wall and enlargement of the pancreatic head in both patients. In 1 patient, ultrasound endoscopy showed a dilated duct in the head of the pancreas. Pancreaticoduodenectomy was performed to rule out pancreatic adenocarcinoma and because of the severity of the symptoms. In both cases, gross and microscopic examinations showed fibrous scar of the groove area. The Santorini duct was dilated and contained protein plugs in both patients, with abscesses in 1 of them. In both cases, there were microscopic foci of heterotopic pancreas with mild fibrosis in the wall of the minor papilla. Groove pancreatitis is often diagnosed in middle-aged alcoholic men presenting with clinical symptoms caused by duodenal stenosis. The pathogenesis of this rare entity could be because of disturbance of the pancreatic secretion through the minor papilla. Pancreatitis in heterotopic pancreas located in the minor papilla and chronic consumption of alcohol seem to be important pathogenic factors. | Pancreatitis, Alcoholic |
OBJECTIVE: To describe aspects in clinical and genetic presentation in five patients with episodic ataxia type 2 (EA2). METHODS: CACNA1A gene screening identified a mutation in three probands and in two of their children. RESULTS: The three probands had attacks of imbalance, associated with dizziness/vertigo and/or headache. Two of them had independent migraine attacks. Interictal oculomotor examination revealed a gaze evoked nystagmus and central oculomotor signs. Two probands had a history of strabismus. All responded well to acetazolamide. Two children were found to have both clinical and genetic abnormalities. At 23 months, one child started to have short attacks of imbalance mimicking benign paroxysmal vertigo of childhood. Then, the frequency and duration of his attacks increased and some were associated with headache. The other child developed permanent imbalance with falls at the age of 2 years, strabismus, hyperactivity and slight to moderate cognitive deficiency. When aged 10 years, this was further complicated by episodic ataxia. Genetic analysis revealed three novel mutations in the calcium channel gene CACNA1A (chromosome 19p13). The two children had the same genetic abnormality as their parents. CONCLUSION: EA2 may present with still unknown genetic mutations in adults, and with large and various phenotypes in children, such as short attacks of imbalance or permanent imbalance, cognitive deficiency, and possibly strabismus and hyperactivity. | Chromosomes, Human, Pair 19 |
BACKGROUND CONTEXT: A herniated vertebral disc is a common cause of paralysis. Other causes include infections, tumors, and neurologic diseases. A rare and dangerous but in most cases easily treatable cause is hypokalemia. Clinically, the acute symptoms may resemble a herniated vertebral disc, but hypokalemia per se is life-threatening by causing heart arrest through ventricular tachycardia or fibrillation. PURPOSE: A patient with back pain and neurologic deficit in the lower extremities after a history of a herniated vertebral disc presented, who finally receives the diagnosis of hypokalemia. STUDY DESIGN: Case report. METHODS: A 25-year-old female patient presenting after a fall with muscle weakness in both legs was followed clinically and radiographically. RESULTS: Neurological examination showed a lower extremity muscle weakness with three-fifths muscular strength of the quadriceps and tibialis anterior muscle on both sides. Reflexes were diminished bilaterally, anal sphincter tone was normal. Plain radiography suggested a posterior rim fracture of L5, but computed tomography did not confirm this diagnosis. The laboratory investigation revealed a hypokalemia of 1.7 mEq/L. On electrolyte replacement, the patient recovered immediately. CONCLUSION: This report describes a misleading diagnostic case of back pain and neurologic deficit after a trauma and sensitizes for the possible life-threatening diagnosis hypokalemia, which is rare but easily treatable. | Hypokalemia |
PURPOSE: To describe the adverse effects associated with energy drink consumption among adolescents and young adults. DATA SOURCES: Review of literature utilizing Medscape, the Internet, MD Consult, and CINAHL. The following search terms were used: Energy drinks, caffeine, guarana, taurine, ginseng, sugar, and caffeine toxicity. Search was limited to English language sources from 2005 to 2010. CONCLUSIONS: The popularity of energy drinks and the rapid growth of their excessive consumption among adolescents and young adults have brought about great concern in regards to overall health and well-being. Caffeine, which is readily available to minors, is the most commonly used psychoactive substance in the world and imposes a potentially harmful influence on health, academic performance, and personal adjustments. Teens and young adults account for nearly $2.3 billion of energy drink sales. Adolescents and young adults are often unaware that various products, such as energy drinks, herbal medications, and various other medications that promote alertness, contain caffeine. When these products are taken together, caffeine toxicity and severe adverse effects can occur. IMPLICATIONS FOR PRACTICE: Practitioners need to be aware of the consequences of energy drink consumption and be prepared to provide appropriate patient education. | Energy Drinks |
The total synthesis of alcyonolide, an antitumor xenicn diterpenoid, has been achieved. The inverse electron demand hetero-Diels-Alder reaction using a dienophile possessing an electron-withdrawing group provided the endo adduct which included a condensed lactone and dihydropyran rings with the desired three stereogenic centers. After introduction of the side chain by the Negishi coupling, the lactone ring was opened to form a Weinreb amide. The sequential transformation including conversion of Weinreb amide to aldehyde, PMB to acetate, and allylation of the aldehyde gave a mixture of separable four diastereomers. The desired stereoisomer was submitted to the 2,2,6,6-tetramethylpiperidine 1-oxyl oxidation, which afforded the delta-lactone and the methyl ketone side chain. Finally, the olefin metathesis of the desired isomer gave racemic alcyonolide. | Cycloaddition Reaction |
OBJECTIVE: To study the genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) among the Han, Buyi and Miao populations in Guizhou and to provide genetic data for establishment of the genetic polymorphism bank of Guizhou Minorities. METHODS: The technique of polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype and allele frequencies at two mononucleotide sites (677 and 1298) of MTHFR among the Han population in Libo county, the Buyi population in Libo county and the Miao population in Leishan county. RESULTS: At the site of 677, the T allele frequencies were found to be 22.8%, 16.1%, 10.6%, for the Han, Buyi, Miao populations respectively. At the site of 1298, the C allele frequencies were 28.9%, 39.1%, 48.7% for the Han, Buyi, Miao populations respectively. The frequencies for the combined heterozygote of 677CT/1298AC were 16.66%, 22.7%, 11.1% for the three populations respectively. Moreover, one case with combined homozygote of 677TT/1298CC was seen in the Miao population. CONCLUSION: The polymorphisms of the two mononucleotide sites (677 and 1298) of MTHFR are diverse in different populations. The C allele frequencies at the site of MTHFR 1298 of the Miao population in Leishan county and the Buyi population in Libo county are high, and the C allele frequency in the Miao population is higher than those hitherto reported in literature. | Polymorphism, Genetic |
The major acquired immunodeficiency syndrome (AIDS) clinical trials groups in the Division of AIDS of the National Institutes of Health have been investigating weight loss and wasting in persons with the human immunodeficiency virus (HIV) and AIDS. Both the AIDS Clinical Trials Group (ACTG) and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) have developed research projects to study the pathogenesis, diagnosis, prevention, and treatment of HIV-related malnutrition and wasting. This article reviews multicenter trials concerning HIV-related malnutrition and wasting conducted by the AIDS clinical trials groups. CPCRA trials will examine the effects of caloric supplements and triglycerides, or the use of megestrol acetate, oxandrolone, and progressive resistance training, on weight loss in patients with HIV-associated wasting. Planned ACTG trials will study the effects of the combination of megestrol acetate and testosterone, the testosterone derivative nandrolone decanoate, or highly active antiretroviral therapy on weight loss. Results from these studies may also have relevance to clinical oncologists who are treating patients with cancer-related cachexia. | Nandrolone Decanoate |
Eggs of leaf beetles of the tribe Galerucini, subfamily Galerucinae, contain polyketides that are unusual in insects: 1,8-dihydroxylated anthraquinones (chrysazin, chrysophanol) and anthrones (dithranol, chrysarobin) deterring predators. The host plants do not contain these compounds. In the present study, we tested the hypothesis that the beetles, but not bacterial or fungal microorganisms living as endosymbionts within the beetles, produce the anthraquinones. The tansy leaf beetle Galeruca tanaceti was used as Galerucini model organism. It was treated with antimicrobial substances to eradicate the microorganisms and inhibit the hypothesised endosymbiotic anthraquinone production. Despite treatment, female G. tanaceti laid eggs containing anthraquinones. Although broad spectrum antimicrobials were used, it cannot be excluded that the potential endosymbiotic microorganisms are resistant. Given that the hypothesised endosymbionts are transferred via the eggs from one generation to the next, bacterial or fungal DNA was expected to be present in the eggs. With the exception of Wolbachia pipientis, however, no further 16S rDNA from bacteria responsible for anthraquinone biosynthesis was detected in eggs of untreated beetles. Because Wolbachia were also found in closely related anthraquinone-free insects, we exclude these bacteria as producers of the defensive polyketides. Nor was any 18S rDNA from fungi with anthraquinone biosynthetic abilities detected. Our results indicate that anthraquinones and anthrones in eggs of Galerucini are produced by beetle enzymes and not by endosymbiotic microorganisms within the eggs. | Ovum |
BACKGROUND: The aim of our study was to investigate the impact of abdominal wall reconstruction surgery on tissue anatomy and to explore how flap surgery influences the patient's immune status. METHODS: Experimental abdominal wall defects were created in 8 Sus scrofa (swine) animal models. The animals were divided into two groups: 4 swine were euthanized one month after surgery for the biopsies retrieval purpose and the other 4 swine were kept alive and the collection of blood samples has been done 6 months after surgery. In order to evaluate the relative gene expression in operated-on animal cohorts we compared them with samples from 4 healthy swine used as controls. RESULTS: The inflammatory process was present in all types of repairs. Collagen I deposition was higher in the flap repairs. The expression level for the genes related to immune response after 6 months from surgery was relatively similar to the control group except minor alteration registered in the case of two swine models. CONCLUSION: Our findings indicate a less pronounced proinflammatory response to surgical trauma in animal models after flap surgery. The postoperative levels of the inflammatory cytokines did not show significant differences after abdominal wall reconstruction using flap surgery. | Abdominal Wall |
At present, the adrenogenital syndrome must surely be reckoned among the most widely known conditions in endocrine pathology. It may come as a surprise that no unambiguous cases of adrenogenitalism are on record before the end of the 19th century. While granting that impressive clinical descriptions may be found in isolated instances, postmortem findings are either totally missing or were not recorded in sufficient detail, thus greatly diminishing their value for retrospective study. This, however, does not apply to a case published by Luigi de Crecchio, a Naples anatomist, in 1865, of a female pseudo-hermaphrodite. De Crecchio provides, for the first time ever, a clear description of a rare pathology, underpinned by an exemplary postmortem examination, detailed clinical findings, and biographical data. Based on a complete translation of De Crecchio's article, our study comments on this almost forgotten case history, placing it, at the same time, in the context of the history of endocrine research. | Adrenogenital Syndrome |
PREMISE OF THE STUDY: Philodendron is a large genus of ~560 species and among the most conspicuous epiphytic components of Neotropical forests, yet its phylogenetic relationships, timing of divergence, and diversification history have remained unclear. We present a comprehensive phylogenetic study for Philodendron and investigate its diversification, including divergence-time estimates and diversification rate shift analyses. METHODS: We performed the largest phylogenetic reconstruction for Philodendron to date, including 125 taxa with a combined dataset of three plastid regions (petD, rpl16, and trnK/matK). We estimated divergence times using Bayesian evolutionary analysis sampling trees and inferred shifts in diversification rates using Bayesian analysis of macroevolutionary mixtures. KEY RESULTS: We found that Philodendron, its three subgenera, and the closely related genus Adelonema are monophyletic. Within Philodendron subgenus Philodendron, 12 statistically well-supported clades are recognized. The genus Philodendron originated ~25 mya and a diversification rate upshift was detected at the origin of subgenus Philodendron ~12 mya. CONCLUSIONS: Philodendron is a species-rich Neotropical lineage that diverged from Adelonema during the late Oligocene. Within Philodendron, the three subgenera currently accepted are recovered in two lineages: one contains the subgenera Meconostigma and Pteromischum and the other contains subgenus Philodendron. The lineage containing subgenera Meconostigma and Pteromischum underwent a consistent diversification rate. By contrast, a diversification rate upshift occurred within subgenus Philodendron ~12 mya. This diversification rate upshift is associated with the species radiation of the most speciose subgenus within Philodendron. The sections accepted within subgenus Philodendron are not congruent with the clades recovered. Instead, the clades are geographically defined. | Philodendron |
Nalbuphine reverses opioid-induced respiratory depression, but the effect on analgesia is unclear. The analgesic interaction between subcutaneous (sc) nalbuphine and intrathecal morphine in conscious, male, Sprague-Dawley rats implanted with chronic intrathecal catheters was investigated. Nalbuphine (10 mg/kg) injected 30 min after intrathecal morphine (4 micrograms) significantly antagonized the effect of morphine in the tail flick test. The antagonism was rapid in onset and persisted beyond the experimental period of 240 min. The magnitude and the duration of the effect were comparable to that observed with sc naloxone (1 mg/kg). In contrast to the results in the tail flick test, nalbuphine enhanced the effect of intrathecal morphine in the noninflamed paw pressure test. Nalbuphine (10 mg/kg) alone had no effect on the time course of tail flick latency but significantly increased paw pressure threshold during the 15-90 min interval after sc injection. Nalbuphine (0.5 mg/kg, sc) alone had no antinociceptive effect in either pain test and did not antagonize the antinociceptive effect of intrathecal morphine (4 micrograms) in the tail flick test. However, sc nalbuphine (0.5 mg/kg), injected 30 min after intrathecal morphine (1.5 micrograms), significantly enhanced the effect of morphine in the paw pressure test compared with intrathecal morphine + sc saline-treated rats. The results indicate a complex analgesic interaction between intrathecal morphine and sc nalbuphine. The net analgesic effect during the interaction was determined by the following: 1) the doses of morphine and nalbuphine; 2) the time after nalbuphine administration; and 3) the nature of the nociceptive stimulus. At lower doses, sc nalbuphine appeared to potentiate the effect of intrathecal morphine in the noninflamed paw pressure test. | Nalbuphine |
BACKGROUND: Iatrogenic induced hypothyroidism had been described in newborns and more particularly in preterm infants after cutaneous or intravenous exposure to iodine. CASE-DIAGNOSIS : We reported a new risk of iodine intoxication with the cases of two newborns who developed hypothyroidism after intra vesical iodine injection during a cystography, which was performed to confirm antenatal diagnosis of posterior urethral valves (PUV). The newborns both developed transient hypothyroidism due to an iodine overdose. CONCLUSIONS: These two observations suggest that voiding cystourethrography (VCUG) should be carefully considered in newborns with severe uropathy, particularly in the case of renal insufficiency. If indicated, thyroid function should be monitored in the following weeks, and in case of hypothyroidism treatment should be started. | Cystography |
A set of recombinant, live attenuated human parainfluenza virus type 1 (rHPIV1) vaccine candidates was evaluated for attenuation, immunogenicity, and protective efficacy in African green monkeys (AGMs). Temperature sensitive (ts) and non-ts attenuating (att) mutations in the P/C and L genes were introduced individually or in various combinations into rHPIV1, including the C(R84G) and HN(T553A) mutations identified in the present work and the C(F170S), L(Y942A), and L(L992C) mutations identified previously. The rHPIV1 vaccine candidates exhibited a spectrum of attenuation in AGMs. One genetically and phenotypically stable vaccine candidate, rC(R84G/F170S)L(Y942A/L992C), was attenuated and efficacious in AGMs and is a promising live attenuated intranasal HPIV1 vaccine candidate suitable for clinical evaluation. | Parainfluenza Virus 1, Human |
Lingual thyroid is a rare embryological aberration with incidence of 1:100,000. It is an ectopic thyroid tissue. In most cases, it is diagnosed in childhood and young adulthood but frequently around menopause. It appears as a mass on the base of the tongue causing mostly local symptoms often with hypothyroidism, rarely with thrive and mental retardation. Authors describe the features, diagnosis and therapy of lingual thyroid with the case of a 23-year-old woman. They analyze the probable pathomechanism and potential risk of malignant transformation of lingual thyroid. In this case, the diagnosis was described at the age of 17, but therapy or further investigation did not take place then. Six years later the patient visited our surgery with local complaints in euthyroid phase. Since the suppression therapy proved to be unsuccessful, the problem was finally solved by operation. | Tongue Diseases |
Accumulation of genetic changes characterizes the progression of cells, initiated by carcinogens, to full malignancy. Various epigenetic mechanisms, such as high polyamine synthesis, aberrant DNA methylation, and production of reactive oxygen species, may favor this process by stimulating growth and inducing DNA damage. We observed a decrease in S-adenosyl-L-methionine (SAM) content in the liver, associated with DNA hypomethylation in rat liver, during the development of preneoplastic foci, and in neoplastic nodules and hepatocellular carcinomas, induced in diethylnitrosamine-initiated rats by resistant hepatocyte" (RH) protocol. Reconstitution of the methyl donor level in the liver by SAM administration inhibits growth and induces phenotypic reversion and apoptosis of preneoplastic cells. A 6-month SAM treatment results in a sharp and persistent decrease in development of neoplastic nodules, suggesting a long duration of SAM chemopreventive effect. Various observations support the suggestion of a role of DNA methylation in chemoprevention by SAM: (1) Exogenous SAM reconstitutes the SAM pool in preneoplastic and neoplastic liver lesions. (2) DNA methylation is positively correlated with SAM:S-adenosylhomocysteine (SAH) ratio in these lesions. (3) 5-Azacytidine, a DNA methyltransferase inhibitor, inhibits chemoprevention by SAM. (4) c-Ha-ras, c-Ki-ras, and c-myc are hypomethylated and overexpressed in preneoplastic liver. Their expression is inversely correlated with SAM:SAH ratio in SAM-treated rats. (5) S-Adenosyl-L-methionine treatment results in overall DNA methylation and partial methylation of these genes. Other possible mechanisms of SAM treatment include inhibition of polyamine synthesis, linked to partial transformation of SAM into 5'-methylthioadenosine (MTA), and antioxidant and antifibrogenic activities of both SAM and MTA." | S-Adenosylmethionine |
Oxaliplatin (OXA) is a third-generation platinum anticancer drug that is mainly used for the treatment of metastatic colorectal cancer (CRC). Of note, hepatic sinusoidal obstruction syndrome (HSOS) induced by OXA has become a key concern for patients with CRC receiving chemotherapy with OXA in recent years. Splenomegaly, thrombocytopenia, abnormal liver function, and portal hypertension are some of the main clinical characteristics seen in patients with OXA-induced HSOS. Previous studies have suggested that oxidative stress, inflammatory damage, liver fibrosis, and platelet aggregation and adhesion may be involved in the pathogenesis of OXA-induced HSOS. Currently, there are no specific drugs for prevention and treatment of OXA-induced HSOS. In this review, we summarized the epidemiology, pathological characteristics, clinical predictive indicators, related mechanisms, possible prevention and treatment of OXA-related HSOS." | Hepatic Veno-Occlusive Disease |
The present paper revisits and extends the examination of the long-run relationship between UK life expectancy and income provided by Tapia Granados (2012). Adopting a more detailed form of analysis, a clear break corresponding to the 1918-1919 Influenza Pandemic is identified in the long span of data examined. This finding of structural change, along with detected uncertainty regarding the orders of integration of the series examined, results in the application of split-sample analysis employing autoregressive distributed lag (ARDL) modelling. The results obtained reverse the 'no long-run relationship' conclusion of Tapia Granados (2012) with overwhelming evidence presented in support of a negative relationship between life expectancy and income. Our findings add to both health-income research and a burgeoning literature on the reproduction and replication of previously published empirical research. | Carbon Dioxide |
BACKGROUND: Plants have remarkable diversity in petal colour through the biosynthesis and accumulation of various pigments. To better understand the mechanisms regulating petal pigmentation in Lonicera japonica, we used multiple approaches to investigate the changes in carotenoids, anthocyanins, endogenous hormones and gene expression dynamics during petal colour transitions, i.e., green bud petals (GB_Pe), white flower petals (WF_Pe) and yellow flower petals (YF_Pe). RESULTS: Metabolome analysis showed that YF_Pe contained a much higher content of carotenoids than GB_Pe and WF_Pe, with alpha-carotene, zeaxanthin, violaxanthin and gamma-carotene identified as the major carotenoid compounds in YF_Pe. Comparative transcriptome analysis revealed that the key differentially expressed genes (DEGs) involved in carotenoid biosynthesis, such as phytoene synthase, phytoene desaturase and zeta-carotene desaturase, were significantly upregulated in YF_Pe. The results indicated that upregulated carotenoid concentrations and carotenoid biosynthesis-related genes predominantly promote colour transition. Meanwhile, two anthocyanins (pelargonidin and cyanidin) were significantly increased in YF_Pe, and the expression level of an anthocyanidin synthase gene was significantly upregulated, suggesting that anthocyanins may contribute to vivid yellow colour in YF_Pe. Furthermore, analyses of changes in indoleacetic acid, zeatin riboside, gibberellic acid, brassinosteroid (BR), methyl jasmonate and abscisic acid (ABA) levels indicated that colour transitions are regulated by endogenous hormones. The DEGs involved in the auxin, cytokinin, gibberellin, BR, jasmonic acid and ABA signalling pathways were enriched and associated with petal colour transitions. CONCLUSION: Our results provide global insight into the pigment accumulation and the regulatory mechanisms underlying petal colour transitions during the flower development process in L. japonica." | Geranylgeranyl-Diphosphate Geranylgeranyltransferase |
Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general. | Pimelic Acids |
Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of urokinase type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), and as such is thought to play an important role in the regulation of extracellular matrix remodeling. In blood, PAI-1 is bound to the adhesion protein vitronectin and is associated with vitronectin in fibrin clots and the provisional matrix. Elevated levels of PAI-1 are associated with atherosclerosis and an increased thrombotic tendency, while PAI-1 deficiency leads to increased fibrinolysis and bleeding. PAI-1 is also elevated in many solid tumors and is associated with a poor prognosis in cancer. PAI-1 has been shown to be a potent regulator of both vascular cell migration in vitro and of angiogenesis and tumor growth in vivo. PAI-1 can both promote and inhibit tumor growth and angiogenesis. Low concentrations of PAI-1 can stimulate tumor angiogenesis while treatment of animals with high doses of PAI-1 inhibits angiogenesis and tumor growth. Hence, PAI-1 appears to have a multifunctional role in regulating the migratory and fibrinolytic activity of vascular cells, and this, in turn, may help to explain the many varied actions of PAI-1. | Plasminogen Inactivators |
In wastewater-based epidemiology (WBE), nicotine metabolites have been used as biomarkers for monitoring tobacco use. Recently, the minor tobacco alkaloids anabasine and anatabine have been suggested as more specific biomarkers for tobacco use since nicotine use can be from both tobacco and non-tobacco sources. This study aimed to provide an in-depth evaluation of the suitability of anabasine and anatabine as WBE biomarkers of tobacco and subsequently estimate their excretion factors for WBE applications. Pooled urine (n = 64) and wastewater samples (n = 277), collected between 2009 and 2019 in Queensland, Australia, were analyzed for nicotine and its metabolites (cotinine and hydroxycotinine), as well as anabasine and anatabine. Anabasine performed as the better biomarker, showing a similar per capita load in pooled urine (2.2 +/- 0.3 mug/day/person) and wastewater samples (2.3 +/- 0.3 mug/day/person), while the per capita load of anatabine in wastewater was 50% higher than its load in urine. It is estimated that 0.9 mug of anabasine was excreted per cigarette smoked. Triangulation of tobacco sales data and tobacco use estimated from either anabasine or cotinine showed that anabasine-based estimates were 5% higher than sales data, while cotinine-based estimates were between 2 and 28% higher. Our results provided concrete evidence to confirm the suitability of anabasine as a specific biomarker for monitoring tobacco use by WBE. | Anabasine |
Cyanobacterial harmful algal blooms (cyanoHABs) are a global problem with serious consequences for public health and many sectors of the economy. The use of algicidal bacteria as natural antagonists to control bloom-forming cyanobacteria is a topic of growing interest. However, there are still unresolved questions that need to be addressed to better understand their mode of action and to implement effective mitigation strategies. In this study, thirteen bacterial strains isolated from both scums and concentrated bloom samples exhibited algicidal activity on three Microcystis aeruginosa strains with different characteristics: the axenic microcystin (MC)-producing strain M. aeruginosa PCC7820 (MaPCC7820), and two environmental (non-axenic) M. aeruginosa strains isolated from two different water bodies in Poland, one MC-producer (MaSU) and another non-MC-producer (MaPN). The bacterial strain SU7S0818 exerted the highest average algicidal effect on the three cyanobacterial strains. This strain was identified as Morganella morganii (99.51% similarity) by the 16S rRNA gene analyses; hence, this is the first study that demonstrates the algicidal properties of these ubiquitous bacteria. Microscopic cell counting and qPCR analyses showed that M. morganii SU7S0818 removed 91%, 96%, and 98.5% of MaPCC7820, MaSU and MaPN cells after 6 days of co-culture, respectively. Interestingly, the ultra-high-performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS) analyses showed that this bacterium was involved on the release of several substances with algicidal potential. It was remarkable how the profile of some compounds evolved over time, as in the case of cadaverine, tyramine, cyclo[Pro-Gly] and cyclo[Pro-Val]. These dynamic changes could be attributed to the action of M. morganii SU7S0818 and the presence of associated bacteria with environmental cyanobacterial strains. Therefore, this study sheds light on how algicidal bacteria may adapt their action on cyanobacterial cells by releasing a combination of compounds, which is a crucial insight to exploit them as effective biological tools in the control of cyanoHABs. | Morganella morganii |
This paper describes the synthesis, characterization, and modeling of a series of molecules having four protein domains attached to a central core. The molecules were assembled with the megamolecule" strategy, wherein enzymes react with their covalent inhibitors that are substituted on a linker. Three linkers were synthesized, where each had four oligo(ethylene glycol)-based arms terminated in a para-nitrophenyl phosphonate group that is a covalent inhibitor for cutinase. This enzyme is a serine hydrolase and reacts efficiently with the phosphonate to give a new ester linkage at the Ser-120 residue in the active site of the enzyme. Negative-stain transmission electron microscopy (TEM) images confirmed the architecture of the four-armed megamolecules. These cutinase tetramers were also characterized by X-ray crystallography, which confirmed the active-site serine-phosphonate linkage by electron-density maps. Molecular dynamics simulations of the tetracutinase megamolecules using three different force field setups were performed and compared with the TEM observations. Using the Amberff99SB-disp + pH7 force field, the two-dimensional projection distances of the megamolecules were found to agree with the measured dimensions from TEM. The study described here, which combines high-resolution characterization with molecular dynamics simulations, will lead to a comprehensive understanding of the molecular structures and dynamics for this new class of molecules." | Protein Domains |
The fingernail and toenail are unique to primates. The anatomy and physiology of the nail must be understood for nail care to be effective. The most common cause of deformity of the nail bed is trauma, which requires careful suturing and postoperative care if the desired results are to be achieved. Congenital anomalies, tumors, and infection can also cause nail deformities and can frequently be corrected or improved surgically. | Nails |
PURPOSE: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. RESULTS: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. CONCLUSION: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS. | Salpingo-oophorectomy |
Sirtuins are a conserved family of deacetylases whose activities are dependent on nicotinamide adenine dinucleotide (NAD+). Sirtuins act in different cellular compartments, such as the nucleus where they deacetylate histones and transcriptional factors, in the cytoplasm where they modulate cytoskeletal and signaling molecules, and in the mitochondria where they engage components of the metabolic machinery. Collectively, they tune metabolic processes to energy availability, and modulate stress responses, protein aggregation, inflammatory processes, and genome stability. As such, they have garnered much interest and have been widely studied in aging and age-related neurodegeneration. In this chapter, we review the identification of sirtuins and their biological targets. We focus on their biological mechanisms of action and how they might be regulated, including via NAD metabolism, transcriptional and posttranscriptional control, and as targets of pharmacological agents. Lastly, we highlight the numerous studies suggesting that sirtuins are efficacious therapeutic targets in neurodegenerative disease and injury." | Group III Histone Deacetylases |
One demographic indicator is the structure of mortality by cause. Analysis of the causes of death allows you to define the fight against the disease, efforts should be focused to reduce mortality and on the effectiveness of measures against those or other diseases. The basis of information about the causes of death is a medical certificate of death, filling it depends on the correct diagnosis, the choice of the original cause of death, coding, as well as on policy documents aimed at reducing mortality from a particular cause. In the Russian Federation, in contrast to the countries of the European region, there is a fairly high proportion of inaccurately marked conditions, which account for 6.9% of all causes (in 2010 - 5%), the main reason for this is <<old age>>, which ranks 4th among the leading causes of death (5% of all causes, in 2010 - 2.8%), as well as damage with uncertain intentions, which are on the 7th rank place of the leading causes of death (2.3% of all causes, in 2010 - 2%). | Mortality |
The isoschizomer pair MspI and HpaII were used to investigate whether the putative specificity of restriction endonucleases would be maintained when they were introduced into mammalian cells. Although both enzymes recognize the sequence CCGG, HpaII will cut only if the internal cytosine is unmethylated, whereas MspI will cut regardless of the methylation status. Cleavage results in a cohesive-end DNA double-strand break, which can lead to the formation of chromosome aberrations. Since mammalian DNA is heavily methylated, one would expect MspI to be much more effective than HpaII at inducing chromosome aberrations in Chinese hamster ovary cells. In fact, during G1, MspI induced a greater than 90-fold higher number of aberrations than did HpaII. Cell cycle studies indicated that during early S there was a 30-fold increase in HpaII-induced aberrations. This increase may be due to increased accessibility of replicating hypomethylated DNA. Cells that were treated with the demethylating agent 5-aza-2'-deoxycytidine (AzdC) displayed only a moderate increase in HpaII-induced aberrations during G1. This observation, together with the results of restriction enzyme analysis of genomic DNA, indicated that demethylation was incomplete. The effects of AzdC on the induction of aberrations by MspI suggested that AzdC increases chromatin accessibility. Our results were consistent with the expected specificity of MspI and HpaII. Thus, it appears that restriction endonucleases can play a useful role in determining the biological consequences of DNA double-strand breaks. | Azacitidine |
BACKGROUND: Failure to differentiate supraventricular from ventricular arrhythmias is the most frequent cause of inappropriate implantable cardioverter-defibrillator therapies. Although a sudden-onset criterion is available to differentiate sustained monomorphic ventricular tachycardias (SMVTs) and sinus tachycardias (STs), SMVTs arising during ST and SMVTs gradually accelerating above the cutoff rate can remain undetected. Regular paroxysmal atrial tachycardias (ATs) also can be undetected by onset and stability algorithms. We hypothesized that the first postpacing interval (FPPI) variability after overdrive right ventricular pacing may differentiate SMVTs from STs and ATs. METHODS AND RESULTS: FPPI variability was measured in 23 SMVTs (cycle length [CL] 366+/-50 ms [VT group]), 27 supraventricular tachycardias, 15 episodes of induced or simulated ATs (CL 376+/-29 ms [AT group]), and 12 exercise-related STs (CL 381+/-24 [ST group]). Sequences of trains of 5, 10, and 15 beats were delivered with a CL 40 ms shorter than the tachycardia CL. An FPPI absolute mean difference between consecutive trains of 5 and 10 beats (deltaFPPI) < or =25 ms identified all VTs (mean difference 5+/-7 ms). In the AT group, the deltaFPPI was >25 ms in all sequences (mean difference 129+/-60 ms, P<0.01). In the ST group, the deltaFPPI was >50 ms in all STs (mean difference 118+/-47 ms, P<0.01). CONCLUSIONS: FPPI variability may differentiate SMVT from AT and ST. This criterion is potentially useful in implantable devices that use a single ventricular lead." | Cardiac Conduction System Disease |
Colonization of mycorrhizal and root endophytic fungi in 14 Pedicularis species from northwest of Yunnan Province, southwest China, was examined. These species included: Pedicularis gracilis Wall., Pedicularis longipes Maxim., Pedicularis axillaris Franch., Pedicularis cephalantha Franch., Pedicularis tenuisecta Franch., Pedicularis tapaoensis Tsoong, Pedicularis likiangensis Franch., Pedicularis dichotoma Bonati, Pedicularis yui Li, Pedicularis rhinanthoides Schrenk, Pedicularis rex C.B. Clarke, Pedicularis longiflora Rudolph., Pedicularis siphonantha Don, and Pedicularis oxycarpa Franch., among which nine are endemic to China (one to Yunnan). Three types of potentially beneficial fungi associated with roots of these species were observed, namely, arbuscular mycorrhizal fungi, ectomycorrhizal fungi, and dark septate endophytic fungi (DSEF), with DSEF as the most common colonizers. An unexpected high colonization level was detected in this hemiparasitic genus. Of the 19 sampling sites examined, 10 gave colonization frequency of above 50% and 6 showed a colonization index of above 50. Heavy colonization suggested a significant ecological role of these fungi and their potential to be applied to successful cultivation of these intractable plants. | Pedicularis |
Action spectra for simulated sunlight were measured in clear water for two viruses: PRD1, a double-stranded DNA bacteriophage, and MS2, a single-stranded RNA bacteriophage. Viruses were diluted into phosphate buffered saline (20 mM PBS, pH 7.5) and exposed for 22 h to simulated sunlight either directly or through one of six glass filters with 50% cutoff wavelengths ranging from 280 to 350 nm. Virus survival was measured using the double agar layer plaque method. Both UVA (320-400 nm) and UVB (280-320 nm) light were found to contribute to PRD1 inactivation, while only UVB inactivated MS2. A computational model was developed for interpreting these action spectra with 3-nm resolution. Using these methods, we provide detailed estimates of the sensitivity of MS2 and PRD1 to photoinactivation from 285 to 345 nm. The resulting sensitivity coefficients can be combined with solar spectra to estimate inactivation rates in clear water under different sunlight conditions. This approach will be useful for modeling the inactivation of viruses and other microorganisms in sunlit natural and engineered systems. | Levivirus |
Perineuronal nets (PNNs) are highly organized components of the extracellular matrix that surround a subset of mature neurons in the CNS. These structures play a critical role in regulating neuronal plasticity, particularly during neurodevelopment. Consistent with this role, their presence is associated with functional and structural stability of the neurons they ensheath. A loss of PNNs in the prefrontal cortex (PFC) has been suggested to contribute to cognitive impairment in disorders such as schizophrenia. However, the direct consequences of PNN loss in medial PFC (mPFC) on cognition has not been demonstrated. Here, we examined behavior after disruption of PNNs in mPFC of Long-Evans rats following injection of the enzyme chondroitinase ABC (ChABC). Our data show that ChABC-treated animals were impaired on tests of object oddity perception. Performance in the cross-modal object recognition (CMOR) task was not significantly different for ChABC-treated rats, although ChABC-treated rats were not able to perform above chance levels whereas control rats were. ChABC-treated animals were not significantly different from controls on tests of prepulse inhibition (PPI), set-shifting (SS), reversal learning, or tactile and visual object recognition memory. Posthumous immunohistochemistry confirmed significantly reduced PNNs in mPFC due to ChABC treatment. Moreover, PNN density in the mPFC predicted performance on the oddity task, where higher PNN density was associated with better performance. These findings suggest that PNN loss within the mPFC impairs some aspects of object oddity perception and recognition and that PNNs contribute to cognitive function in young adulthood." | Receptors, N-Acetylglucosamine |
Although the treatment of obsessive-compulsive disorder (OCD), a common, chronic, and disabling psychiatric condition, has significantly improved in the last decades, with the demonstration of the specific effectiveness of serotonin reuptake inhibitors (SRIs), a large proportion of patients still show high relapse rates. In addition, pharmacological treatments should be maintained for years, so that the clinicians should take into account the pharmacokinetic changes in the long-term, which may be responsible for dangerous side effects or interactions. Areas covered: The aim of this paper was to review the literature on the pharmacokinetics of SSRIs and clomipramine, and on their pharmacokinetic parameters in OCD patients. Expert opinion: Although the literature on the pharmacokinetics of both clomipramine and SSRIs is consistent, data on pharmacokinetic parameters in OCD patients are very few. Given the impact of OCD, its chronicity requiring long-term treatments, together with the need to increase the clinical response rate, more studies in this field are urgently required. | Clomipramine |
The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease. | Complement System Proteins |
Epithelial cell migration is a crucial event in wound healing, yet little is known about mechanisms whereby integrins regulate epithelial cell polarization and migration. In the present work, we demonstrate the importance of adhesion through the alpha3beta1 integrin in promoting the stabilization of leading lamellipodia in migrating keratinocytes. We demonstrate that this integrin is found at the leading edge of migrating keratinocytes and that inhibition of alpha3beta1 binding to laminin-5 prevents the formation of stable leading lamellipodia. Consistent with this observation, keratinocytes derived from alpha3beta1-deficient mice fail to form stable leading lamellipodia but retain the ability to form actin-containing protrusions that rapidly extend and retract from the cell membrane. Formation of a leading lamellipodium also requires alpha3beta1-dependent activation of Rac1, because alpha3beta1-deficient keratinocytes show decreased activation of Rac1 compared with alpha3beta1-expressing cells, and formation of stable leading lamellipodia can be inhibited in the latter cells by expression of the dominant negative Rac1 mutant Rac1N17. Furthermore, alpha3beta1-deficient keratinocytes expressing constitutively active Rac1L61 failed to form stable lamellipodia when plated onto laminin-5, demonstrating that alpha3beta1 is required for Rac1-mediated formation of a stable lamellipodium. These observations identify a crucial role for integrin-mediated adhesion and signaling in the formation of large, polarized, stable lamellipodia by migrating epithelial cells. To our knowledge, this study is the first to demonstrate that signal transduction through a specific integrin is required to direct the development of a lamellipodium from an initial protrusion and promote persistent epithelial cell migration. | Integrin alpha3beta1 |
The size and surface area of the mammalian brain are thought to be critical determinants of intellectual ability. Recent studies show that development of the gyrated human neocortex involves a lineage of neural stem and transit-amplifying cells that forms the outer subventricular zone (OSVZ), a proliferative region outside the ventricular epithelium. We discuss how proliferation of cells within the OSVZ expands the neocortex by increasing neuron number and modifying the trajectory of migrating neurons. Relating these features to other mammalian species and known molecular regulators of the mouse neocortex suggests how this developmental process could have emerged in evolution. | Neocortex |
The Northern Snakehead Channa argus is an introduced species that now inhabits the Chesapeake Bay. During a preliminary survey for introduced pathogens possibly harbored by these fish in Virginia waters, a filterable agent was isolated from five specimens that produced cytopathic effects in BF-2 cells. Based on PCR amplification and partial sequencing of the major capsid protein (MCP), DNA polymerase (DNApol), and DNA methyltransferase (Mtase) genes, the isolates were identified as Largemouth Bass virus (LMBV). Nucleotide sequences of the MCP (492 bp) and DNApol (419 pb) genes were 100% identical to those of LMBV. The nucleotide sequence of the Mtase (206 bp) gene was 99.5% identical to that of LMBV, and the single nucleotide substitution did not lead to a predicted amino acid coding change. This is the first report of LMBV from the Northern Snakehead, and provides evidence that noncentrarchid fishes may be susceptible to this virus. | Iridoviridae |
The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), are highly lethal zoonotic agents of concern as emerging pathogens and potential bioweapons. Antigen-presenting cells (APCs), particularly macrophages and dendritic cells, are targets of filovirus infection in vivo. Infection of these cell types has been proposed to contribute to the inflammation, activation of coagulation cascades and ineffective immune responses characteristic of filovirus hemorrhagic fever. However, many aspects of filovirus-APC interactions remain to be clarified. Among the unanswered questions: What determines the ability of filoviruses to replicate in different APC subsets? What are the cellular signaling pathways that sense infection and lead to production of copious quantities of cytokines, chemokines and tissue factor? What are the mechanisms by which innate antiviral responses are disabled by these viruses, and how may these mechanisms contribute to inadequate adaptive immunity? A better understanding of these issues will clarify the pathogenesis of filoviral hemorrhagic fever and provide new avenues for development of therapeutics. | Filoviridae |
To distinguish between different models of vesicular release in brain synapses, it is necessary to know the number of vesicles of transmitter that can be released immediately at individual synapses by a high-calcium stimulus, the readily releasable pool (RRP). We used direct stimulation by calcium uncaging at identified, single-site inhibitory synapses to investigate the statistics of vesicular release and the size of the RRP. Vesicular release, detected as quantal responses in the postsynaptic neuron, showed an unexpected stochastic variation in the number of quanta from stimulus to stimulus at high intracellular calcium, with a mean of 1.9 per stimulus and a maximum of three or four. The results provide direct measurement of the RRP at single synaptic sites. They are consistent with models in which release proceeds from a small number of vesicle docking sites with an average occupancy around 0.7. | Synaptic Vesicles |
A QuEChERS based methodology was developed for the simultaneous identification and quantification of acetamiprid, imidacloprid, and spirotetramat and their relevant metabolites in pistachio by liquid chromatography-tandem mass spectrometry for the first time. First, sample extraction was done with MeCN:citrate buffer:NaHCO(3) followed by phase separation with the addition of MgSO(4):NaCl. The supernatant was then cleaned by a primary-secondary amine (PSA), GCB, and MgSO(4). The proposed method provides a linearity in the range of 5-200microgL(-1), and the linear regression coefficients were higher than 0.99. LOD and LOQ were obtained to be 2 and 5microgkg(-1) for the studied insecticides, respectively, with the exception of imidacloprid-olefin (5 and 10microgkg(-1)). Acceptable recoveries (91-110%) were obtained for all the analytes with good intra- and inter-precisions (0.4>/=RSD </=11.0). The method was then used for the pistachio samples collected from a field trial to estimate the maximum residue limits (MRLs) in next step. | Anacardiaceae |
The protistan parasite Ichthyophonus sp. occurs in coastal populations of Pacific Herring Clupea pallasii throughout the northeast Pacific region, but the route(s) by which these planktivorous fish become infected is unknown. Several methods for establishing Ichthyophonus infections in laboratory challenges were examined. Infections were most effectively established after intraperitoneal (IP) injections with suspended parasite isolates from culture or after repeated feedings with infected fish tissues. Among groups that were offered the infected tissues, infection prevalence was greater after multiple feedings (65%) than after a single feeding (5%). Additionally, among groups that were exposed to parasite suspensions prepared from culture isolates, infection prevalence was greater after exposure by IP injection (74%) than after exposure via gastric intubation (12%); the flushing of parasite suspensions over the gills did not lead to infections in any of the experimental fish. Although the consumption of infected fish tissues is unlikely to be the primary route of Ichthyophonus sp. transmission in wild populations of Pacific Herring, this route may contribute to abnormally high infection prevalence in areas where juveniles have access to infected offal. | Mesomycetozoea Infections |
We describe a rare case of type II achondrogenesis (gestational age = thirty-two weeks) dead forty-five minutes after birth. This congenital skeletal dysplasia is classified among the lethal osteochondrodysplasias. Clinical features were enough for diagnosis and autopsy added nothing to our clinical knowledges. | Abnormalities, Multiple |
The molecular mechanisms by which bone cells transduce mechanical stimuli into intracellular biochemical responses have yet to be established. There is evidence that mechanical stimulation acts synergistically with parathyroid hormone PTH(1-34) in mediating bone growth. Using picosecond time-resolved fluorescence microscopy and G protein-coupled receptor conformation-sensitive fluorescence resonance energy transfer (FRET), we investigated conformational transitions in parathyroid hormone type 1 receptor (PTH1R). 1) A genetically engineered PTH1R sensor containing an intramolecular FRET pair was constructed that enabled detection of conformational activity of PTH1R in single cells. 2) The nature of ligand-dependent conformational change of PTH1R depends on the type of ligand: stimulation with the PTH(1-34) leads to conformational transitions characterized by decrease in FRET efficiency while NH(2)-terminal truncated ligand PTH(3-34) stimulates conformational transitions characterized by higher FRET efficiencies. 3) Stimulation of murine preosteoblastic cells (MC3T3-E1) with fluid shear stress (FSS) leads to significant changes in conformational equilibrium of the PTH1R in MC3T3-E1 cells, suggesting that mechanical perturbation of the plasma membrane leads to ligand-independent response of the PTH1R. Conformational transitions induced by mechanical stress were characterized by an increase in FRET efficiency, similar to those induced by the NH(2)-terminal truncated ligand PTH(3-34). The response to the FSS stimulation was inhibited in the presence of PTH(1-34) in the flow medium. These results indicate that the FSS can modulate the action of the PTH(1-34) ligand. 4) Plasma membrane fluidization using benzyl alcohol or cholesterol extraction also leads to conformational transitions characterized by increased FRET levels. We therefore suggest that PTH1R is involved in mediating primary mechanochemical signal transduction in MC3T3-E1 cells." | Receptor, Parathyroid Hormone, Type 1 |
Caloric and nutrient requirements significantly increase in a pediatric patient with severe injury. This is attributable to catabolism and metabolic features in children cause postoperative complications, increases mortality rates in pediatric surgical patients. This generates the need for early administration of diet therapy using specialized formulas that correct nutrient deficiency. Therefore, the aim of our study was to evaluate the effect of enteral feeding in the early postoperative period: early enteral feeding caused a more rapid increase in the concentrations of transferin and albumin, decreases in C-reactive protein and orosomucoid, and a reduction in the number of the patients who were on early enteral nutrition versus those on a routine postsurgical diet. | Shock, Traumatic |
The relationship between soluble and membrane-bound endothelin-converting enzyme (ECE) activity with the level of endothelin-1 (ET-1) synthesis was investigated in cultured endothelial cells. Escherichia coli lipopolysaccharide (LPS) was used to stimulate ET-1 synthesis, and brefeldin A, monensin, colchicine or cytochalasin B, which disrupt peptide biosynthetic pathways in a variety of ways, were tested for their ability to modify changes in ET-1 synthesis and ECE levels. LPS increased ET-1 secretion by more than twofold. Levels of soluble ECE activity, but not those of membrane-bound ECE activity, correlated with ET-1 synthesis. These results suggest the soluble ECE activity is likely to play a role in ET-1 biosynthesis. | Endothelin-Converting Enzymes |
Interleukin 12 (IL-12) and/or interleukin 18 (IL-18) gene ablated mice were applied for the investigation of the tissue expression of interferon gamma (IFN-gamma). For IL-12(-/-), IL-18(-/-), IL-12(-/-)/18(-/-) and wt mice, reproductive performance were recorded and IFN-gamma concentrations in heart, lung, liver, spleen, kidney and serum were quantified by ELISA. There were no significant differences of IFN-gamma in heart, lung and kidney between 4 strains although control group was higher. It was observed that for IL-12(-/-) mice, compared with other 3 groups, IFN-gamma in liver and spleen were decreased (p < 0.05) and reproductive performance appeared to be impaired. Serum IFN-gamma level of IL-12(-/-)/18(-/-) mice was significantly higher (p < 0.05). It was showed that IFN-gamma productions under the normal condition were independent upon IL-12 and IL-18, its expressions in various tissues were different, and optimal IFN-gamma is necessary for the normal growth and development of mammals. This study is helpful for clinical cytokines therapy. | Interleukin-12 |
Acyclovir [9-(2-hydroxyethoxymethyl)guanine, ZoviraxTM] is a selective antiviral agent with indications for the treatment of the herpes virus group of injections. In a cross-over design study, three male beagle dogs were given acyclovir i.v. and p.o. (capsule) at 5, 20 and 50 mg/kg doses. Additionally, dogs received acyclovir by gavage at these three doses. After i.v. injection, the acyclovir plasma concentration-time profile, determined by radioimmunoassay, exhibited a biexponential decay with a terminal t1/2 of 2.2 to 3.6 hr. Plasma clearance (3.48-5.83 ml/min/kg) approximated the normal glomerular filtration rate in dogs and the Vd beta (0.97-1.17 liters/kg) indicated distribution of the drug into tissues. Similar kinetic findings were obtained after i.v. administration of [8-14C]acyclovir to dogs. The radioactivity recovered in the urine was 95% of the dose and 92% of the urinary 14C was identified as acyclovir. The remainder of 14C corresponded to minor urinary metabolites. The plasma acyclovir concentration-time curves generated from oral (capsule and gavage) data were fit to a one-compartment open pharmacokinetic model. The half-life and Vd parameters were similar to those calculated for the i.v. route. Peak plasma drug concentrations were reached within 2 hr of dosing. Good oral bioavailability (91 and 80%) was observed after the administration of a capsule at the lower doses (5 and 20 mg/kg, respectively) but bioavailability declined (52%) at the 50 mg/kg dose, indicating the possibility that the gastrointestinal absorption of acyclovir is a saturable process. | Purinones |
As saliva is an easily accessible biological material, compared with 24-hour urine and blood, the salivary concentration of estriol was studied from the 30th to the 41st week of gestation in 268 samples from 124 normal pregnancies. At the same time, venous blood samples were drawn and analyzed for total and unconjugated estriol. The mean values for the concentration of total estriol in saliva in the 30th and 41st weeks were 2.8 and 7.2 nmol/l respectively. The salivary estriol concentration appears to increase in perfect conformity with its serum concentration in the course of gestation. If estriol in saliva also reflects low serum values and an impaired function of the feto-placental unit, analyses of the saliva may be applicable as a screening procedure in high-risk pregnancies. | Estriol |
BACKGROUND: Internal iliac artery aneurysms (IIAAs) are rare, comprising 0.3% of all aortoiliac aneurysms. Endovascular management is associated with lower morbidity and mortality than open repair. We present a 91-year-old female with a rapidly expanding 8.2-cm IIAA who previously underwent incomplete endovascular treatment, using endovascular aneurysm repair, to exclude the right internal iliac artery (IIA). Transarterial access to the IIAA was not possible secondary to the iliac limb of the endograft over the origin of the IIA. We recommended that the patient undergo embolization and coiling of the IIAA via a direct percutaneous transgluteal approach. METHODS: With the patient in a prone position, under fluoroscopic guidance, a 10-cm long, 18-gauge needle was placed through the gluteus muscle into the right IIAA. Needle location was confirmed by angiography and a 6-French sheath was advanced into the aneurysm. Selective catheterization of the native aorta was accomplished around the occluded limb of the previously placed endograft. Aortography confirmed robust filling of 2 large lumbar arteries with brisk runoff through branches of the IIA. Coil embolization was used to treat both the lumbar arteries causing aortic endoleak, as well as the outflow branches of the IIAA. RESULTS: Completion angiography revealed static flow in the aorta and aneurysm, with minimal flow through the inflow and outflow tracts. At a 1-month follow-up appointment, repeat computed tomography angiography revealed resolution of the endoleak and no blood flow within the aneurysm. There have only been a few case reports utilizing alternative access to an IIAA. Although computed tomography and ultrasound-guided techniques have been described in the literature, a percutaneous, fluoroscopy-guided, transgluteal approach to access the IIAA is a new and unique approach. CONCLUSIONS: In patients who are not candidates for open or standard endovascular repair with a large, inaccessible IIAA, a transgluteal approach to directly access the aneurysm sac may offer a less invasive and successful management strategy. | Iliac Aneurysm |
BACKGROUND: Microphthalmia-associated transcription factor (MITF) suppresses the expression of enzymes controlling the production of melanin. Phytosphingosine is a well-known cosmetic agent, but its anti-melanogenic activity and mechanism of action remain unclear. OBJECTIVE: This study was designed to investigate the effects of phytosphingosine on melanin synthesis and elucidate the plausible mechanism of actions in vitro and ex vivo systems. METHODS: Melanin content, cell viability, tyrosinase activity, p-CREB DNA binding activity, and the protein gene expression levels of the enzymes and proteins involved in melanogenesis were measured with the treatment of phytosphingosine. RESULTS: Phytosphingosine inhibits melanin synthesis in cultured melan-a cells and a reconstructed human skin model. One possible mechanism of the anti-melanogenic activity of phytosphingosine appears to be associated with the modulation of MITF, which suppresses the expression of tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2. Further analysis revealed that phytosphingosine suppressed paired box 3 and SRY-related HMG-box 10, critical transcription factors of MITF. Phytosphingosine also effectively downregulated the protein levels of beta-catenin and the phospho-cAMP response element binding protein, an upstream regulatory factor of MITF. These results are closely related to the suppression of MITF gene expression. In addition, treatment with phytosphingosine for over 12h, which is a relatively long period of time, did not directly suppress these MITF transcriptional factors. Instead, phytosphingosine induced ERK activation, which led to MITF phosphorylation, followed by its degradation. Therefore, the downregulation of MITF protein levels by phytosphingosine with a long time exposure is in part associated with MITF protein degradation through the MAPK kinase activation pathway. CONCLUSION: The modulation of MITF by phytosphingosine is closely related with the signaling pathways, such as the suppression of the MITF gene expression and the degradation of the MITF protein, depending on the duration of treatment time. These results suggest that phytosphingosine might serve as an effective melanogenesis inhibitor in melanocytes via the regulation of the MITF signaling pathways." | Microphthalmia-Associated Transcription Factor |
With a long history of promoting pathological inflammation, eosinophils are now emerging as important regulatory cells. Yet, findings from controlled laboratory experiments so far lack translation to animals, including humans, in their natural environment. In order to appreciate the breadth of eosinophil phenotype under non-laboratory, uncontrolled conditions, we exploit a free-living population of the model organism Mus musculus domesticus. Eosinophils were present at significantly higher proportions in the spleen and bone marrow of wild mice compared with laboratory mice. Strikingly, the majority of eosinophils of wild mice exhibited a unique Ly6G(hi) phenotype seldom described in laboratory literature. Ly6G expression correlated with activation status in spleen and bone marrow, but not peritoneal exudate cells, and is therefore likely not an activation marker per se. Intermediate Ly6G expression was transiently induced in a small proportion of eosinophils from C57BL/6 laboratory mice during acute infection with the whipworm Trichuris muris, but not during low-dose chronic infection, which better represents parasite exposure in the wild. We conclude that the natural state of the eosinophil is not adequately reflected in the standard laboratory mouse, which compromises our attempts to dissect their functional relevance. Our findings emphasize the importance of studying the immune system in its natural context - alongside more mechanistic laboratory experiments - in order to capture the entirety of immune phenotypes and functions. | Antigens, Ly |
Soil water transported via the petiole is a primary rehydration pathway for leaves of water-stressed plants. Leaves may also rehydrate by absorbing water via their epidermal surfaces. The mechanisms and physiological relevance of this water pathway, however, remain unclear, as the associated hydraulic properties are unknown. To gain insight into the foliar water absorption process, we compared rehydration kinetics via the petiole and surface of Prunus dulcis and Quercus lobata leaves. Petiole rehydration could be described by a double exponential function suggesting that 2 partly isolated water pools exist in leaves of both species. Surface rehydration could be described by a logistic function, suggesting that leaves behave as a single water pool. Whereas full leaf rehydration via the petiole required approximately 20 min, it took over 150 and 300 min via the surface of P. dulcis and Q. lobata, respectively. Such differences were attributed to the high resistance imposed by the leaf surface and especially the cuticle. The minimum resistance to surface rehydration was estimated to be 6.6 x 10(2) (P. dulcis) and 2.6 x 10(3) MPa.m(2) .s.g(-1) (Q. lobata), which is remarkably higher than estimated for petiole rehydration. These results are discussed in a physiological context. | Prunus dulcis |
We describe a Japanese girl with Bernard-Soulier syndrome and 22q11.2 microdeletion. She had viral infections and recurrent thrombocytopenia and hemorrhagic diathesis after cardiac surgery. As congenital heart defects and abnormal immunity are the most common clinical manifestations associated with 22q11.2 deletion, patients with this association may have a greater risk of developing a severe bleeding disorder. | Bernard-Soulier Syndrome |
Pythiosis is a serious disease caused by the aquatic oomycete Pythium insidiosum that mainly affects mammals. Unlike fungal and bacterial resistance induced by the indiscriminate use of drugs, P. insidiosum has low susceptibility to antifungal drugs. In this sense, essential oils and their major components emerge as a promising treatment line for this disease. Given the above, this study sought to verify P. insidiosum (n = 34) susceptibility to the bioactive compounds eugenol, alpha-terpineol, menthol, and carvacrol and correlate them with the respective essential oils of Eugenia caryophyllata, Melaleuca alternifolia, Mentha piperita, and Origanum vulgare. The essential oils and bioactive compounds were purchased commercially and tested according to the Clinical and Laboratory Standards Institute protocol M38-A2. Our findings showed that eugenol, alpha-terpineol, and carvacrol had superior anti-P. insidiosum action than their respective essential oils, suggesting that they may be responsible for inhibitory activity against P. insidiosum. Notably, the major compound with the best anti-P. insidiosum activity was alpha-terpineol; nonetheless, menthol showed less activity than its essential oil. The results imply that essential oils and their major compounds may be important allies in treating pythiosis, expanding the perspectives of developing new drugs with anti-P. insidiosum activity. | Menthol |
BACKGROUND: In the era of global surgery, there are limited data regarding the available surgical workforce in South Africa. METHODS: This aim of this study was to determine the orthopaedic surgeon density in South Africa. This involved a quantitative descriptive analysis of all registered specialist orthopaedic surgeons in South Africa, using data collected from various professional societal national databases. RESULTS: The results showed 1.63 orthopaedic surgeons per 100,000 population. The vast majority were male (95%) with under two-thirds (65%) being under the age of 55 years. The majority of the orthopaedic surgeons were found in Gauteng, followed by the Western Cape and Kwa-Zulu Natal. The majority of specialists reportedly worked either full time or part time in the private sector (95%), and the orthopaedic surgeon density per uninsured population (0.36) was far below that of the private sector (8.3). CONCLUSION: Interprovincial differences as well as intersectoral differences were marked indicating geographic and socio-economic maldistribution of orthopaedic surgeons. This parallels previous studies which looked at other surgical sub-disciplines in South Africa. Addressing this maldistribution requires concerted efforts to expand public sector specialist posts as well as quantifying the burden of orthopaedic disease in both private and public sectors before recommendations can be made regarding workforce allocation in the future. LEVEL OF EVIDENCE: IV. | Orthopedic Surgeons |
PURPOSE: In ocular drug development, an early estimate of drug behavior before any in vivo experiments is important. The pharmacokinetics (PK) and bioavailability depend not only on active compound and excipients but also on physicochemical properties of the ocular drug formulation. We propose to utilize PK modelling to predict how drug and formulational properties affect drug bioavailability and pharmacokinetics. METHODS: A physiologically relevant PK model based on the rabbit eye was built to simulate the effect of formulation and physicochemical properties on PK of pilocarpine solutions and fluorometholone suspensions. The model consists of four compartments: solid and dissolved drug in tear fluid, drug in corneal epithelium and aqueous humor. Parameter values and in vivo PK data in rabbits were taken from published literature. RESULTS: The model predicted the pilocarpine and fluorometholone concentrations in the corneal epithelium and aqueous humor with a reasonable accuracy for many different formulations. The model includes a graphical user interface that enables the user to modify parameters easily and thus simulate various formulations. CONCLUSIONS: The model is suitable for the development of ophthalmic formulations and the planning of bioequivalence studies. | Ocular Absorption |
BACKGROUND: SHP2 is a protein tyrosine phosphatase that is extensively involved in several signaling pathways related to cancer occurrence, and thus SHP2 has been proposed as an attractive target for cancer treatment. METHODS: After a brief introduction of SHP2, we provided a short overview of the structure, function and regulation mechanism of SHP2 in cancer occurrence. Then, this perspective focused on the current therapeutic strategies targeting SHP2, including SHP2 PTP inhibitors, SHP2 allosteric inhibitors and SHP2-targeting PROTACs, and discussed the benefits and defects of these strategies. Finally, the opportunities and challenges were presented. RESULTS: SHP2 regulated RAS-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 signaling pathways involved in the pathogenesis of cancer via conformations conversion. Current therapeutic strategies targeting SHP2, especially SHP2 allosteric inhibitors, hold significant potency and have broad application prospects for cancer therapy. CONCLUSION: In summary, SHP2 is a promising therapeutic target, and strategies targeting SHP2 offer an alternative program for cancer patients." | SH2 Domain-Containing Protein Tyrosine Phosphatases |
OBJECTIVE: To evaluate the frequency with which relevant and accurate information about the benefits and related uncertainties of anticancer drugs are communicated to patients and clinicians in regulated information sources in Europe. DESIGN: Document content analysis. SETTING: European Medicines Agency. PARTICIPANTS: Anticancer drugs granted a first marketing authorisation by the European Medicines Agency, 2017-19. MAIN OUTCOME MEASURES: Whether written information on a product addressed patients' commonly asked questions about: who and what the drug is used for; how the drug was studied; types of drug benefit expected; and the extent of weak, uncertain, or missing evidence for drug benefits. Information on drug benefits in written sources for clinicians (summaries of product characteristics), patients (patient information leaflets), and the public (public summaries) was compared with information reported in regulatory assessment documents (European public assessment reports). RESULTS: 29 anticancer drugs that received a first marketing authorisation for 32 separate cancer indications in 2017-19 were included. General information about the drug (including information on approved indications and how the drug works) was frequently reported across regulated information sources aimed at both clinicians and patients. Nearly all summaries of product characteristics communicated full information to clinicians about the number and design of the main studies, the control arm (if any), study sample size, and primary measures of drug benefit. None of the patient information leaflets communicated information to patients about how drugs were studied. 31 (97%) summaries of product characteristics and 25 (78%) public summaries contained information about drug benefits that was accurate and consistent with information in regulatory assessment documents. The presence or absence of evidence that a drug extended survival was reported in 23 (72%) summaries of product characteristics and four (13%) public summaries. None of the patient information leaflets communicated information about the drug benefits that patients might expect based on study findings. Scientific concerns about the reliability of evidence on drug benefits, which were raised by European regulatory assessors for almost all drugs in the study sample, were rarely communicated to clinicians, patients, or the public. CONCLUSIONS: The findings of this study highlight the need to improve the communication of the benefits and related uncertainties of anticancer drugs in regulated information sources in Europe to support evidence informed decision making by patients and their clinicians. | Document Analysis |
Removal of the eye may be necessary after severe ocular trauma, to control pain in a blind eye, to treat some intraocular malignancies, in endophthalmitis unresponsive to medical therapy, and for cosmetic improvement of a disfigured eye. The choice of procedure to accomplish this is best made by an informed patient. Enucleation and evisceration can each achieve the desired goals, but several factors must be considered in choosing the most appropriate procedure. | Eye Evisceration |
Cholesterol-rich lipid rafts act as signaling microdomains and can regulate receptor function. We have shown in HEK293 cells recombinant P2X1-4 receptors (ATP-gated ion channels) are expressed in lipid rafts. Localization to flotillin-rich lipid rafts was reduced by the detergent Triton X-100. This sensitivity to Triton X-100 was concentration- and subunit-dependent, demonstrating differential association of P2X1-4 receptors with lipid rafts. The importance of raft association to ATP-evoked P2X receptor responses was determined in patch clamp studies. The cholesterol-depleting agents methyl-beta-cyclodextrin or filipin disrupt lipid rafts and reduced P2X1 receptor currents by >90%. In contrast, ATP-evoked P2X2-4 receptor currents were unaffected by lipid raft disruption. To determine the molecular basis of cholesterol sensitivity, we generated chimeric receptors replacing portions of the cholesterol-sensitive P2X1 receptor with the corresponding region from the insensitive P2X2 receptor. These chimeras identified the importance of the intracellular amino-terminal region between the conserved protein kinase C site and the first transmembrane segment for the sensitivity to cholesterol depletion. Mutation of any of the variant residues between P2X1 and P2X2 receptors in this region in the P2X1 receptor (residues 20-23 and 27-29) to cysteine removed cholesterol sensitivity. Cholesterol depletion did not change the ATP sensitivity or cell surface expression of P2X1 receptors. This suggests that cholesterol is normally needed to facilitate the opening/gating of ATP-bound P2X1 receptor channels, and mutations in the pre-first transmembrane segment region remove this requirement." | Purinergic P2X Receptor Agonists |
Prostaglandin E2 (PGE2) has been proposed to be a potent stimulator of bone resorption. However, PGE2 itself has been shown to directly inhibit bone-resorbing activity of osteoclasts. We examined the role of PGE2 in the function of mouse osteoclasts formed in vitro. Bone marrow macrophage osteoclast precursors expressed PGE2 receptors EP1, EP2, EP3beta, and EP4, and the expression of EP2 and EP4 was down-regulated during osteoclastic differentiation induced by receptor activator of NF-kappaB ligand and macrophage colony-stimulating factor. In contrast, functional EP1 was continuously expressed in mature osteoclasts. PGE2 as well as calcitonin caused intracellular Ca2+ influx in osteoclasts. However, PGE2 and 17-phenyltrinol-PGE2 (an EP1 agonist) failed to inhibit actin-ring formation and pit formation by osteoclasts cultured on dentine slices. When EP4 was expressed in osteoclasts using an adenovirus carrying EP4 cDNA, both actin-ring and pit-forming activities of osteoclasts were inhibited in an infectious unit-dependent manner. Treatment of EP4-expressing osteoclasts with PGE2 further inhibited their actin-ring and pit-forming activities. Such inhibitory effects of EP4-mediated signals on osteoclast function are similar to those that are calcitonin receptor-mediated. Thus, osteoclast precursors down-regulate their own EP2 and EP4 levels during their differentiation into osteoclasts to escape inhibitory effects of PGE2 on bone resorption. | Receptors, Prostaglandin E |
BACKGROUND: We assessed the feasibility of administering a neuroprotective drug, vigabatrin (VGB; gamma-vinyl-gamma-aminobutyric acid) with multimodality monitoring, including cerebral microdialysis, in severe head injury patients, to measure surrogate endpoints and blood-brain barrier (BBB) penetration. METHODS: Patients (n = 20) were randomised to VGB (0.5 g twice-daily, enteric) or control. ICP, ABP, CPP and cerebrovascular pressure reactivity index (PRx) were monitored. Microdialysate glucose, lactate, pyruvate, glutamate, glycerol, amino acids, VGB and GABA were analysed. RESULTS: Preliminary evaluation of results (five VGB-treated patients) showed that VGB levels rose in brain microdialysates, followed by a modest increase in GABA. VGB and GABA increased more in abnormal brain than in sites further from lesions, and were higher after multiple VGB doses. Highest VGB and GABA microdialysate levels were 75 and 4 mumol/L respectively. Microdialysate glucose and glycerol sometimes decreased, and glutamate and tyrosine sometimes increased, following VBG administration; causation unproven. VGB did not overtly affect ICP, ABP, CPP, PRx, or microdialysate lactate, pyruvate and lactate/pyruvate ratio. CONCLUSION: Multimodality monitoring, including cerebral microdialysis, is feasible for studying surrogate endpoints following drug administration. VGB crosses the BBB, leading to modest increases in extracellular GABA. Further analyses are ongoing. Microdialysis may assist the development of neuroprotective agents by determining penetration into extracellular fluid of the brain. | Vigabatrin |
The present letter to editor is related to Bohra A et al Prognostic significance of hepatic encephalopathy in patients with cirrhosis treated with current standards of care. World J Gastroenterol 2020; 26(18): 2221-2231. Hepatic encephalopathy (HE) is a significant and frequent major decompensating event in cirrhosis. However clinical studies examining the clinical outcome of HE are lacking despite its high prevalence. | Hepatic Encephalopathy |
Smoking continues to be a burden to economies and health-care systems across the world. One proposed solution to the problem has been e-cigarettes; however, because they are a relatively new product in the market, little is known about their potential health impacts. Furthermore, e-cigarettes continue to evolve at a rapid rate, making it necessary to regularly review and summarize available studies. Although e-cigarettes are marketed as a smoking cessation tool by some manufacturers, the reality is that many nonsmokers, including youth, are using them. This review focuses on two major demographic groups (smokers and nonsmokers) and evaluates the most recent data (early 2017 to mid 2019) regarding the potential health effects of e-cigarettes. We assessed peer-reviewed studies on the health impacts of e-cigarettes, with a particular focus on common questions asked by policy makers, clinicians, and scientists: (1) What are the effects of e-cigarettes compared with air/not smoking?; (2) Is there any direct evidence of harm or benefit to humans?; (3) Is there a risk from secondhand exposure?; (4) What are the risks and/or benefits of e-cigarettes compared with tobacco cigarette use?; (5) Are there risks or benefits to specific populations (eg, people with COPD or asthma, pregnant women [and their offspring])?; (6) What are the effects of flavoring chemicals?; (7) What are the effects of including nicotine in e-liquids?; (8) How often is nicotine concentration labeling incorrect?; and (9) What are the risks when e-cigarettes explode? | E-Cigarette Vapor |
The general aim of this thesis was to broaden our knowledge of the signs and symptoms, genetics, and outcomes of dental implant treatment in individuals with oligodontia or ectodermal dysplasia. Article I is a population-based study in three Swedish counties of 162 individuals with oligodontia, which was a prevalence of 0.09%. The intent was to explore ways for dentists to assess symptoms from other ectodermal structures than teeth through a clinical interview and chair-side analyses. Thirty per cent had low salivary secretion rates while only 11% with no known syndrome reported symptoms from hair, nails, or sweat glands. These are, together with teeth, the ectodermal structures on which it is proposed that a clinical diagnosis of ectodermal dysplasia (ED) be based. Article II screened 93 probands with oligodontia for mutations in six genes known to cause oligodontia and hypohidrotic ED. Sequence alterations predicted to be damaging or potentially damaging were revealed in the AXIN2, MSX1, PAX9, and EDARADD genes in 14 (15%) of the probands. All mutations but one were novel. For the first time, EDARADD mutations were shown to cause isolated oligodontia. No individual who had reported ectodermal symptoms from hair, nails, or sweat glands had a mutation. Article III assessed orofacial function in individuals with different types of EDs using the Nordic Orofacial Test-Screening (NOT-S) protocol. Individuals with ED scored significantly higher in orofacial dysfunction than a healthy reference sample, especially in the Chewing and swallowing, Dryness of the mouth, and Speech domains. Article IV surveyed treatment outcome of dental implants in Swedish children up to age 16 years. In a 20-year period, only 26 patients were treated, 5 of whom had hypohidrotic ED and anodontia of the mandible. Individuals with ED had 64% failed implants compared to 6% among subjects with teeth missing due to trauma or agenesis. The main conclusions of this thesis were that (i) a check of whether one or more permanent incisors are missing will identify 65% of individuals with oligodontia and 84% of individuals missing nine teeth or more, (ii) evaluation of salivary secretion is indicated in children with oligodontia, (iii) a majority of individuals with oligodontia did not report other abnormal ectodermal organ function besides teeth, (iv) no clinical indicator discriminated between individuals with and without mutations in the tested genes, and more unidentified genes are involved in tooth morphogenesis, (v) EDARADD mutations are associated with isolated oligodontia, (vi) evaluation of orofacial function is indicated in individuals with ED, and many individuals with ED would benefit from orofacial skills training, (vii) dental implant placement is a rare treatment modality in children, (viii) individuals with hypohidrotic ED seem to present special challenges due to structural as well as direct effects of the mutations on bone, which seem to compromise osseointegration, (ix) central registers on signs and symptoms in individuals with rare disorders would help establish prevalences of various diagnoses and define treatment needs, and (x) quality registers for monitoring treatment outcomes of dental implants would promote early detection of risks and side-effects in individuals with rare disorders. | Ectodermal Dysplasia |
Trypanosoma cruzi, causative agent of Chagas disease, co-infects its triatomine vector with its sister species Trypanosoma rangeli, which shares 60% of its antigens with T. cruzi. Additionally, T. rangeli has been observed to be pathogenic in some of its vector species. Although T. cruzi-T. rangeli co-infections are common, their effect on the vector has rarely been investigated. Therefore, we measured the fitness (survival and reproduction) of triatomine species Rhodnius prolixus infected with just T. cruzi, just T. rangeli, or both T. cruzi and T. rangeli. We found that survival (as estimated by survival probability and hazard ratios) was significantly different between treatments, with the T. cruzi treatment group having lower survival than the co-infected treatment. Reproduction and total fitness estimates in the T. cruzi and T. rangeli treatments were significantly lower than in the co-infected and control groups. The T. cruzi and T. rangeli treatment group fitness estimates were not significantly different from each other. Additionally, co-infected insects appeared to tolerate higher doses of parasites than insects with single-species infections. Our results suggest that T. cruzi-T. rangeli co-infection could ameliorate negative effects of single infections of either parasite on R. prolixus and potentially help it to tolerate higher parasite doses. | Trypanosoma rangeli |
This paper describes the first empirical analysis of the personalities of crosscountry hitchhikers. One hundred and four young adults were tested in 32 states using the Myers-Briggs Type Indicator (MBTI) as the measuring instrument. The results display the predominance of the intuitive and feeling functions among subjects, and also the utilization of the perceptual function in dealing with the environment. These findings suggest a personality which is impulsive and autonomous, having a high degree of tolerance for complexity and change, and strong interest in interpersonal relations. These young hitchhikers also differ on a number of personality dimensions from three comparison groups previously obtained by the Center for Applications of Psychological Type, but are most similar to students in psychological and counseling training services. Implications of the results in explaining this nomadic behavior" are discussed." | Personality Development |
Bartonella spp. are facultative intracellular bacteria that typically cause a long-lasting intraerythrocytic bacteremia in their mammalian reservoir hosts, thereby favoring transmission by blood-sucking arthropods. In most cases, natural reservoir host infections are subclinical and the relapsing intraerythrocytic bacteremia may last weeks, months, or even years. In this review, we will follow the infection cycle of Bartonella spp. in a reservoir host, which typically starts with an intradermal inoculation of bacteria that are superficially scratched into the skin from arthropod feces and terminates with the pathogen exit by the blood-sucking arthropod. The current knowledge of bacterial countermeasures against mammalian immune response will be presented for each critical step of the pathogenesis. The prevailing models of the still-enigmatic primary niche and the anatomical location where bacteria reside, persist, and are periodically seeded into the bloodstream to cause the typical relapsing Bartonella spp. bacteremia will also be critically discussed. The review will end up with a discussion of the ability of Bartonella spp., namely Bartonella henselae, Bartonella quintana, and Bartonella bacilliformis, to induce tumor-like vascular deformations in humans having compromised immune response such as in patients with AIDS. | Bartonellaceae |
Gene therapy is one of the promising treatment modalities in cancer therapy. The current gene therapy modalities are mainly focused on the introduction of suppressed tumor suppressor genes into cancer cells, modulation of anti-tumoral immune response, and the suicide gene therapy by introducing pro-drug-activating enzyme genes into the tumor cells. Currently, various gene therapy trials are being conducted in cancer patients. However, the early results of these trials conducted so far are not so encouraging. Combination of gene therapy strategies with conventional treatment modalities such as chemotherapy, immunotherapy or radiotherapy has yielded encouraging results in experimental models and early clinical trials. | Genes, Transgenic, Suicide |
PURPOSE: To investigate the risk of posterior capsular rupture (PCR) during cataract surgery in eyes with previous intravitreal injection (IVI). DESIGN: Retrospective cohort study. METHODS: The Moorfields Patient Administrative System and OpenEyes electronic databases were used to study all cataract surgery procedures undertaken between January 1, 2012 and August 31, 2015 in the Moorfields main and satellite sites. Clinical data were anonymized and extracted, including prior occurrence and number of intravitreal injections. Logistic regression was performed with the Hosmer-Lemeshow test for goodness of fit to generate odds ratios for possible risk factors. RESULTS: In total, 62 994 cataract surgery procedures were undertaken over the study period, of which 1035 (1.64%) were in eyes with previous intravitreal injection(s). PCR occurred in 650 (1.04%) eyes. After logistic regression, prior intravitreal injection was associated with an increased risk of PCR (P = .037), with an odds ratio of 1.66. The number of prior injections, indication for injections, and service undertaking the surgery were not associated with increased risk of PCR (P > .1). CONCLUSIONS: Eyes with previous IVI have a higher risk of PCR. This is not affected by number of previous injections, indication for injections, or the specialty undertaking the surgery." | Posterior Capsular Rupture, Ocular |
The inhibitory effects of sulfide on microbial processes during anaerobic digestion have been widely addressed. However, other effects of sulfide are less explored, given that sulfide is a potential sulfur source for microorganisms and its high reactivity triggers a suit of abiotic reactions. We demonstrated that sulfide interaction with Fe regulates the dynamics and activities of microbial community during anaerobic digestion. This was manifested by the S:Fe molar ratio, whose increase adversely influenced the acetoclastic methanogens, Methanosaeta, and turnover of acetate. Dynamics of hydrogenotrophic methanogens, Methanoculleus and Methanobrevibacter, were presumably influenced by sulfide-induced changes in the partial pressure of hydrogen. Interestingly, conversion of the long-chain fatty acid (LCFA), oleate, to methane was enhanced together with the abundance of LCFA-degrading, beta-oxidizing Syntrophomonas at an elevated S:Fe molar ratio. The results suggested that sulfur chemical speciation is a controlling factor for microbial community functions in anaerobic digestion processes. | Methanomicrobiaceae |
The authors describe the principal methods of assisted ventilation of the lungs used for smooth and safe transition from artificial ventilation to spontaneous respiration: trigger method, intermittent forced ventilation of the lungs, pressure support, permanent positive pressure respiration, jet high-frequency ventilation of the lungs, and two systems of the respirator response to spontaneous attempts of the patient: to pressure change and flow-by change. Basing on their own experience, the authors claim that patients with parenchymatous respiratory insufficiency better tolerate the method of pressure support, whereas those with ventilation respiratory insufficiency can be best treated by intermittent forced ventilation of the lungs. Jet high-frequency ventilation of the lungs may serve a full-value alternative to the flow-by method. | Respiratory Therapy |
Subcutaneous injections of angiotensin (ANG) II or III in the periphery reduce alcohol intake and raise water intake. These peptides do not cross the blood-brain barrier and cannot reach the angiotensin receptor-rich sites surrounding the lateral and third ventricles. To examine the effect on alcohol intake of ANG II and III at these ventricular sites, groups of rats were first trained to drink alcohol using a limited access procedure, then surgically prepared with chronic indwelling lateral or third ventricular cannulae, and then reoffered daily 40-min access to alcohol. Neither ANG II (25-200 ng) nor ANG III (25-100 ng) had any effect on alcohol consumption at either of the two ventricular sites. Water consumption was significantly enhanced by both peptides at both sites and could be attenuated by prior treatment with the ANG II antagonist Sar1Thr8-ANG II. The SC administration of ANG II was able to produce a significant reduction in alcohol drinking. These findings demonstrate that ICV administered ANG II or ANG III do not modulate alcohol drinking and that changes in alcohol intake do not result from the thirst promoted by ANG II. Sites in the periphery may be more involved in the interaction between angiotensin and alcohol consumption. | Angiotensin III |
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