text
stringlengths 11
9.77k
| label
stringlengths 2
104
|
|---|---|
RAC1 is a member of the Rac/Rho GTPase subfamily within the RAS superfamily of small GTP-binding proteins, comprising 3 paralogs playing a critical role in actin cytoskeleton remodeling, cell migration, proliferation and differentiation. De novo missense variants in RAC1 are associated with a rare neurodevelopmental disorder (MRD48) characterized by DD/ID and brain abnormalities coupled with a wide range of additional features. Structural and functional studies have documented either a dominant negative or constitutively active behavior for a subset of mutations. Here, we describe two individuals with previously unreported de novo missense RAC1 variants. We functionally demonstrate their pathogenicity proving a gain-of-function (GoF) effect for both. By reviewing the clinical features of these two individuals and the previously published MRD48 subjects, we further delineate the clinical profile of the disorder, confirming its phenotypic variability. Moreover, we compare the main features of MRD48 with the neurodevelopmental disease caused by GoF variants in the paralog RAC3, highlighting similarities and differences. Finally, we review all previously reported variants in RAC proteins and in the closely related CDC42, providing an updated overview of the spectrum and hotspots of pathogenic variants affecting these functionally related GTPases. | rac1 GTP-Binding Protein |
Ectopic eruption of a tooth is common in the dental arch, palate, and nose, but it is rare in the maxillary antrum. We present the case of a 35-year-old man with an ectopic canine and an associated dentigerous cyst in the maxillary sinus that masqueraded as an antrochoanal polyp. | Tooth Eruption, Ectopic |
OBJECTIVES: Only 4% of brief resolved unexplained events (BRUE) are caused by a serious underlying illness. The American Academy of Pediatrics (AAP) guidelines do not distinguish patients who would benefit from further investigation and hospitalization. We aimed to derive and validate a clinical decision rule for predicting the risk of a serious underlying diagnosis or event recurrence. METHODS: We retrospectively identified infants presenting with a BRUE to 15 children's hospitals (2015-2020). We used logistic regression in a split-sample to derive and validate a risk prediction model. RESULTS: Of 3283 eligible patients, 565 (17.2%) had a serious underlying diagnosis (n = 150) or a recurrent event (n = 469). The AAP's higher-risk criteria were met in 91.5% (n = 3005) and predicted a serious diagnosis with 95.3% sensitivity, 8.6% specificity, and an area under the curve of 0.52 (95% confidence interval [CI]: 0.47-0.57). A derived model based on age, previous events, and abnormal medical history demonstrated an area under the curve of 0.64 (95%CI: 0.59-0.70). In contrast to the AAP criteria, patients >60 days were more likely to have a serious underlying diagnosis (odds ratio:1.43, 95%CI: 1.03-1.98, P = .03). CONCLUSIONS: Most infants presenting with a BRUE do not have a serious underlying pathology requiring prompt diagnosis. We derived 2 models to predict the risk of a serious diagnosis and event recurrence. A decision support tool based on this model may aid clinicians and caregivers in the discussion on the benefit of diagnostic testing and hospitalization (https://www.mdcalc.com/calc/10400/brief-resolved-unexplained-events-2.0-brue-2.0-criteria-infants)." | Brief, Resolved, Unexplained Event |
Muscle fibers from individuals with hyperkalemic periodic paralysis generate repetitive trains of action potentials (myotonia) or large depolarizations and block of spike production (paralysis) when the extracellular K+ is elevated. These pathologic features are thought to arise from mutations of the sodium channel alpha subunit which cause a partial loss of inactivation (steady-state Popen approximately 0.02, compared to < 0.001 in normal channels). We present a model that provides a possible mechanism for how this small persistent sodium current leads to repetitive firing, why the integrity of the T-tubule system is required to produce myotonia, and why paralysis will occur when a slightly larger proportion of channels fails to inactivate. The model consists of a two-compartment system to simulate the surface and T-tubule membranes. When the steady-state sodium channel open probability exceeds 0.0075, trains of repetitive discharges occur in response to constant current injection. At the end of the current injection, the membrane potential may either return to the normal resting value, continue to discharge repetitive spikes, or settle to a new depolarized equilibrium potential. This after-response depends on both the proportion of noninactivating sodium channels and the magnitude of the activity-driven K+ accumulation in the T-tubular space. A reduced form of model is presented in which a two-dimensional phase-plane analysis shows graphically how this diversity of after-responses arises as extracellular [K+] and the proportion of noninactivating sodium channels are varied. | Myotonia |
BACKGROUND: The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches. OBJECTIVES: We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them. METHODS: An expert working group was convened to discuss mechanisms associated with CV toxicity. RESULTS: The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1-4 below), the vascular system (5-7), or both (8-12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling. DISCUSSION: These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM </= 2.5 mum in aerodynamic diameter (PM2.5)] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321. | Toxic Actions |
Nipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genus Henipavirus. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as heparan sulfate for both Nipah virus and Hendra virus. Cells devoid of heparan sulfate were not able to mediate henipavirus trans-infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound heparan sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the heparan sulfate and to block cell-mediated trans-infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cells in vitro. Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal heparan sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections. IMPORTANCE: The Henipavirus genus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified heparan sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with heparan sulfate and to block cell-mediated trans-infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cells in vitro. Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of heparan sulfate in henipavirus infection and open novel perspectives for the development of heparan sulfate-targeting therapeutic approaches for these emerging infections. | Henipavirus Infections |
Three triazole-linked nonionic xylo-nucleoside dimers T(L)-t-T(xL), T(L)-t-A(BzxL) and T(L)-t-C(BzxL) have been synthesized for the first time by Cu(I) catalyzed azide-alkyne [3 + 2] cycloaddition reaction (CuAAC) of 1-(3'-azido-3'-deoxy-2'-O,4'-C-methylene-beta-D-ribo-furanosyl)thymine with different alkynes, i.e., 1-(5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-beta-D-xylofuranosyl)thymine, 9-(5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-beta-D-xylo-furanosyl)-N6-benzoyladenine and 1-(5'-deoxy-5'-C-ethynyl-2'-O,4'-C-methylene-beta-D-xylofuranosyl)-N4-benzoylcytosine in 90%-92% yields. Among the two Cu(I) reagents, CuSO4.5H2O-sodium ascorbate in THF:(t)BuOH:H2O (1:1:1) and CuBr.SMe2 in THF used for cycloaddition (click) reaction, the former one was found to be better yielding than the latter one. | Pyrimidine Nucleosides |
Data from two epidemiological studies are used to measure the degree to which two well-known guidelines agree in measuring hyperlipidemia in population samples in the US and Poland. The epidemiological studies are the US Lipid Research Clinics Program Prevalence Study and the Pol-MONICA project in Poland and the guidelines are those adopted by the US National Cholesterol Program (USNCEP) and by the European Atherosclerosis Society (EAS). EAS guidelines were analyzed in two ways: Method 1 used triglycerides and total cholesterol only in classifying persons as hyperlipidemics or non-hyperlipidemics; Method 2 used triglycerides, total cholesterol and nine additional risk factors in the classification process. USNCEP guidelines used total cholesterol, low density lipoprotein cholesterol and the same additional nine risk factors used in EAS Method 2 in classifying hyperlipidemics. Classification differences between the two sets of guidelines were high when EAS Method 1 guidelines were compared with USNCEP guidelines. However, EAS Method 2 which included risk factors, compared favorably with USNCEP guidelines in all three populations under study. | Hyperlipidemias |
The water-soluble polysaccharide (AMP), with a molecular mass of 7.8x10(3)Da as determined by high-performance size-exclusion chromatography (HPSEC), was obtained from the fruiting body of Armillaria mellea. Methylation, Smith degradation, acetolysis, (1)H and (13)C NMR spectroscopy and acid hydrolysis studies were conducted to elucidate its structure. The results indicated that AMP consisted of a backbone composed of (1-->6)-linked-alpha-D-glucopyranosyl, (1-->2,6)-linked-alpha-D-glucopyranosyl and (1-->6)-linked-alpha-D-galactopyranosyl residues in the ratio of 3:1:1, and terminated with one single terminal (1-->)-beta-D-glucopyranosyl at the O-2 position of (1-->2,6)-linked-alpha-D-glucopyranosyl, on average, along the main chain. Preliminary tests in vitro showed that AMP has stimulating effects on murine lymphocyte proliferation induced by concanavalin A or lipopolysaccharide in a dose-dependent manner. It is a possible potential immunopotentiating agent for use in health-care food or medicine. | Armillaria |
Death-associated protein kinase (DAPK) is a key player in multiple cell death signaling pathways. We report that DAPK is regulated by DANGER, a partial MAB-21 domain-containing protein. DANGER binds directly to DAPK and inhibits DAPK catalytic activity. DANGER-deficient mouse embryonic fibroblasts and neurons exhibit greater DAPK activity and increased sensitivity to cell death stimuli than do wild-type control cells. In addition, DANGER-deficient mice manifest more severe brain damage after acute excitotoxicity and transient cerebral ischemia than do control mice. Accordingly, DANGER may physiologically regulate the viability of neurons and represent a potential therapeutic target for stroke and neurodegenerative diseases." | Death-Associated Protein Kinases |
To determine whether K(ATP) channels control liver growth, we used primary rat hepatocytes and several human cancer cell lines for assays. K(ATP) channel openers (minoxidil, cromakalim, and pinacidil) increased cellular DNA synthesis, whereas K(ATP) channel blockers (quinidine and glibenclamide) attenuated DNA synthesis. The channel inhibitor glibenclamide decreased the clonogenicity of HepG2 cells without inducing cytotoxicity or apoptosis. To demonstrate the specificity of drugs for K(+) channels, whole-cell patch-clamp recordings were made. Hepatocytes revealed K(+) currents with K(ATP) channel properties. These K(+) currents were augmented by minoxidil and pinacidil and attenuated by glibenclamide as well as tetraethylammonium, in agreement with established responses of K(ATP) channels. Reverse transcription of total cellular RNA followed by polymerase chain reaction showed expression of K(ATP) channel-specific subunits in rat hepatocytes and human liver cell lines. Calcium fluxes were unperturbed in glibenclamide-treated HepG2 cells and primary rat hepatocytes following induction with ATP and hepatocyte growth factor, respectively, suggesting that the effect of K(ATP) channel activity upon hepatocyte proliferation was not simply due to indirect modulation of intracellular calcium. The regulation of mitogen-related hepatocyte proliferation by K(ATP) channels advances our insights into liver growth control. The findings have implications in mechanisms concerning liver development, regeneration, and oncogenesis. | Cromakalim |
Mast cells (MCs) are effector cells of the immune system commonly known for their role in asthma and allergy. They are present throughout biological systems in various tissues, serving as an interface between the biological system and environment. Previous work characterizing the impact of malaria on MCs revealed contradictory results, showing minimal to strong correlation between MC degranulation and disease progression. This work seeks to reveal how MC degranulation is impacted in the presence of malaria, induced by Plasmodium chabaudi, using a mouse model and a single cell measurement technique that reveals exquisite biophysical detail about any impacts to the degranulation process. It was hypothesized that the malaria parasites would impact MC degranulation response during live infection, and the differences would be revealed via carbon-fiber microelectrode amperometry. In fact, the data collected show that different stages of malaria infection affect MC degranulation differently, affirming the importance of considering different infection stages in future studies of malarial immune response. Furthermore, a comparison of MC degranulation response to that measured from platelets under similar circumstances shows similar trends in quantitative degranulation, suggesting that MC and platelet exocytosis machinery are affected similarly despite their distinct biological roles. However, based on the small number of mouse replicates, the studies herein suggest that there should be further study about cellular and disease processes. Overall, the work herein reveals important details about the role of MCs in malaria progression, relevant during treatment decisions, as well as a potentially generalizable impact on chemical messenger secretion from cells during malarial progression. | Cell Degranulation |
A novel exopolysaccharide-producing bacterium, designated strain k53(T), was isolated from sediment from the Arabia Sea, Indian Ocean. The strain was Gram-negative, motile, strictly aerobic, oxidase-positive and catalase-positive, and required Na(+) for growth. Its major isoprenoid quinone was ubiquinone-8 (Q-8), and its cellular fatty acid profile mainly consisted of C16 : 1omega7c, C16 : 0 and C18 : 1omega7c. The DNA G+C content was 43 mol%. 16S rRNA gene sequence analysis suggested that strain k53(T) is a member of the genus Pseudoalteromonas. Strain k53(T) exhibited close phylogenetic affinity to Pseudoalteromonas lipolytica LMEB 39(T) (98.0% 16S rRNA gene sequence similarity) and Pseudoalteromonas donghaensis HJ51(T) (97.3 %).The DNA-DNA reassociation values between strain k53(T) and P. lipolytica JCM 15903(T) and P. donghaensis LMG 24469(T) were 17 % and 12 %, respectively. Owing to the significant differences in phenotypic and chemotaxonomic characteristics, and phylogenetic analysis based on the 16S rRNA gene sequence and DNA-DNA relatedness data, the isolate merits classification as a representative of a novel species, for which the name Pseudoalteromonas arabiensis is proposed. The type strain of this species is k53(T) ( = JCM 17292(T) = NCIMB 14688(T)). | Pseudoalteromonas |
Papers published on ion-selective electrodes (ISEs) generally report on the performance characteristics of these devices after long, extensive conditioning. Conditioning refers to the equilibration of the ion-selective electrode in an aqueous solution before the measurement of the sample. The requirement for long and repeated conditioning is a significant burden in a variety of applications, for example, single-use sensors aimed for in vivo or field applications and solid contact (SC) ISEs, which were developed to provide simple, mass-produced sensors that have the potential to be implemented without calibration and extensive conditioning. In this study we recorded the potential of SC K(+), Na(+), and H(+) ISEs as a function of time following their first contact with an aqueous electrolyte solution and used these transients to determine their equilibration times. The SC electrodes were built on Au, Pt, and glassy carbon (GC) substrates using galvanostatically deposited conductive polymer (PEDOT(PSS(-)), poly(3,4-ethylenedioxythiophene) polystyrenesulfonate) as ion-to-electron transducer (solid internal contact) between the ion-selective membrane and the substrate. The SC electrodes built on GC and Au had significantly shorter equilibration times (between 5 and 13 min) than the SC electrodes built on Pt substrates (>60 min). Such significant differences in the equilibration times of SC ISEs built on different substrate electrodes are reported here for the first time. These unexpected findings suggest that the interface between the conductive polymer and the electron-conducting substrate (EC) has significant influence on the long-term dynamic behavior of SC ISEs. | Ion-Selective Electrodes |
OBJECTIVE: To compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3. DESIGN: A prospective, open, randomised multicentre trial. SETTING: 32 general hospitals located in Wales and England. POPULATION OR SAMPLE: 180 patients were randomised consecutively between 21 October 2009 and 11 January 2013, 89 to cidofoovir (of whom 41 completely responded to treatment) and 91 to imiquimod (of whom 42 completely responded to treatment). METHODS: After 24 weeks of treatment, complete responders were followed up at 6-monthly intervals for 24 months. At each visit, the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was assessed and any new lesions were biopsied for histology. MAIN OUTCOME MEASURES: Time to histologically confirmed disease recurrence (any grade of VIN). RESULTS: The median length of follow up was 18.4 months. At 18 months, more participants were VIN-free in the cidofovir arm: 94% (95% CI 78.2-98.5) versus 71.6% (95% CI 52.0-84.3) [univariable hazard ratio (HR) 3.46, 95% CI 0.95-12.60, P = 0.059; multivariable HR 3.53, 95% CI 0.96-12.98, P = 0.057). The number of grade 2+ events was similar between treatment arms (imiquimod: 24/42 (57%) versus cidofovir: 27/41 (66%), chi2 = 0.665, P = 0.415), with no grade 4+. CONCLUSIONS: Long-term data indicates a trend towards response being maintained for longer following treatment with cidofovir than with imiquimod, with similar low rates of adverse events for each drug. Adverse event rates indicated acceptable safety of both drugs TWEETABLE ABSTRACT: Long-term follow up in the RT3VIN trial suggests cidofovir may maintain response for longer than imiquimod. | Cidofovir |
Based on different reactivity of the (pseudo)halide substituents in the 2-pyrone (3-Br and 4-OTs), palladium-catalyzed sequential site-selective Suzuki-Miyaura cross-coupling reactions of 3-bromo-6-methyl-4-tosyloxy-2-pyrone are described, which afford the diverse 2-pyrones in good yields. | Pyrones |
This article reviews the recent advancements and future potential of optical surface imaging (OSI) in clinical applications as a four-dimensional (4D) imaging modality for surface-guided radiotherapy (SGRT), including OSI systems, clinical SGRT applications, and OSI-based clinical research. The OSI is a non-ionizing radiation imaging modality, offering real-time 3D surface imaging with a large field of view (FOV), suitable for in-room interactive patient setup, and real-time motion monitoring at any couch rotation during radiotherapy. So far, most clinical SGRT applications have focused on treating superficial breast cancer or deep-seated brain cancer in rigid anatomy, because the skin surface can serve as tumor surrogates in these two clinical scenarios, and the procedures for breast treatments in free-breathing (FB) or at deep-inspiration breath-hold (DIBH), and for cranial stereotactic radiosurgery (SRS) and radiotherapy (SRT) are well developed. When using the skin surface as a body-position surrogate, SGRT promises to replace the traditional tattoo/laser-based setup. However, this requires new SGRT procedures for all anatomical sites and new workflows from treatment simulation to delivery. SGRT studies in other anatomical sites have shown slightly higher accuracy and better performance than a tattoo/laser-based setup. In addition, radiographical image-guided radiotherapy (IGRT) is still necessary, especially for stereotactic body radiotherapy (SBRT). To go beyond the external body surface and infer an internal tumor motion, recent studies have shown the clinical potential of OSI-based spirometry to measure dynamic tidal volume as a tumor motion surrogate, and Cherenkov surface imaging to guide and assess treatment delivery. As OSI provides complete datasets of body position, deformation, and motion, it offers an opportunity to replace fiducial-based optical tracking systems. After all, SGRT has great potential for further clinical applications. In this review, OSI technology, applications, and potential are discussed since its first introduction to radiotherapy in 2005, including technical characterization, different commercial systems, and major clinical applications, including conventional SGRT on top of tattoo/laser-based alignment and new SGRT techniques attempting to replace tattoo/laser-based setup. The clinical research for OSI-based tumor tracking is reviewed, including OSI-based spirometry and OSI-guided tumor tracking models. Ongoing clinical research has created more SGRT opportunities for clinical applications beyond the current scope. | Radiotherapy Setup Errors |
Synaptic boutons are highly plastic structures undergoing experience-dependent changes in their number, volume, and shape. Their plasticity has been intensively studied in the insect mushroom bodies by manually counting the number of boutons in small regions of interest and extrapolating this number to the volume of the mushroom body neuropil. Here we extend this analysis to the synaptic bouton distribution within a larger subregion of the mushroom body olfactory neuropil of honey bees (Apis mellifera). This required the development of an automated method combining two-photon imaging with advanced image post-processing and multiple threshold segmentation. The method was first validated in subregions of the mushroom body olfactory and visual neuropils. Further analyses in the olfactory neuropil suggested that previous studies overestimated the number of synaptic boutons. As a reason for that, we identified boundaries effects in the small volume samples. The application of the automated analysis to larger volumes of the mushroom body olfactory neuropil revealed a corrected average density of synaptic boutons and, for the first time, their 3D spatial distribution. This distribution exhibited a considerable heterogeneity. This additional information on the synaptic bouton distribution provides the basis for future studies on brain development, symmetry, and plasticity. | Synapsins |
Hallux valgus-the most common forefoot deformity-can cause both pain and decreased mobility. The development and progress of the hallux valgus is a multifactorial process. Different intrinsic and extrinsic causes are responsible. Various conservative and operative treatment options exist and have to been chosen regarding the stage of the disease. Conservative orthopedic measures may prevent a deterioration of hallux valgus only at an early stage of the disease. Concerning operative techniques, more than 150 different surgical procedures are described in the literature, which can be reduced to some common procedures. These are dependent on the manifestation of the bunion as well as on associated foot and ankle pathologies. Patients should be informed that postoperative follow-up treatment until complete recovery is time-consuming. | Hallux Valgus |
Spiral ligament fibrocytes (SLFs) play an important role in normal hearing as well as in several types of sensorineural hearing loss attributable to inner ear homeostasis disorders. Our previous study showed that transplantation of mesenchymal stem cells (MSCs) into the inner ear of rats with damaged SLFs significantly accelerates hearing recovery compared with rats without MSC transplantation. To elucidate this mechanism of SLF repair and to determine the contribution of transplanted MSCs in this model, we investigated the mutual effects on differentiation and proliferation between MSCs and SLFs in a coculture system. Factors secreted by SLFs had the ability to promote the transdifferentiation of MSCs into SLF-like cells, and the factors secreted by MSCs had a stimulatory effect on the proliferation of SLFs. Cytokine antibody array analysis revealed the involvement of transforming growth factor-beta (TGF-beta) in SLF proliferation induced by MSCs. In addition, a TGF-beta inhibitor reduced SLF proliferation induced by MSC stimulation. Our results suggest that there are two mechanisms of hearing recovery following transplantation of MSCs into the inner ear: 1) MSCs transdifferentiate into SLF-like cells that compensate for lost SLFs, and 2) transplanted MSCs stimulate the regeneration of host SLFs. Both mechanisms contribute to the functional recovery of the damaged SLF network. | Spiral Ligament of Cochlea |
Phagocytosis and macropinocytosis are actin-dependent clathrin-independent processes primarily performed by cells like neutrophils and macrophages that result in the internalization of particles or the formation of fluid-filled macropinosomes, respectively. Phagocytosis consists of a number of stages, including attachment of particles to cell surface receptors, engulfment of the particle dependent on actin polymerization and membrane exocytosis, and formation of phago-lysosomes. In contrast, the molecular steps regulating macropinocytosis are only just now being deciphered. Much remains to be learned concerning the signaling pathways that regulate these processes. Dictyostelium is a genetically and biochemically tractable professional phagocyte that has proven to be a powerful system with which to determine the nature of the molecular steps involved in regulating these internalization processes. This review summarizes what is currently understood concerning the molecular mechanisms governing phagocytosis and macropinocytosis in Dictyostelium and describes recent data concerning the common and distinct pathways that regulate these processes. | Pinocytosis |
In bacteria, the canonical mechanism of translational repression by small RNAs (sRNAs) involves sRNA-mRNA base pairing that occludes the ribosome binding site (RBS), directly preventing translation. In this mechanism, the sRNA is the direct regulator, while the RNA chaperone Hfq plays a supporting role by stabilizing the sRNA. There are a few examples where the sRNA does not directly interfere with ribosome binding, yet translation of the target mRNA is still inhibited. Mechanistically, this non-canonical regulation by sRNAs is poorly understood. Our previous work demonstrated repression of the mannose transporter manX mRNA by the sRNA SgrS, but the regulatory mechanism was unknown. Here, we report that manX translation is controlled by a molecular role-reversal mechanism where Hfq, not the sRNA, is the direct repressor. Hfq binding adjacent to the manX RBS is required for sRNA-mediated translational repression. Translation of manX is also regulated by another sRNA, DicF, via the same non-canonical Hfq-dependent mechanism. Our results suggest that the sRNAs recruit Hfq to its binding site or stabilize the mRNA-Hfq complex. This work adds to the growing number of examples of diverse mechanisms of translational regulation by sRNAs in bacteria. | Host Factor 1 Protein |
Studies of the hyaluronan (HA) tetrasaccharides are important for understanding hydrogen-bonding in the HA polymer, as they are probably the smallest oligomers in which characteristics of the constituent monosaccharides and the polymer are simultaneously exhibited. Here we present extensive molecular dynamics simulations of the two tetrasaccharides of HA in dilute aqueous solution. These simulations have confirmed the existence of intramolecular hydrogen-bonds between the neighboring sugar residues of HA in solution, as proposed by Scott (1989). However, our simulations predict that these intramolecular hydrogen-bonds are not static as previously proposed, but are in constant dynamic exchange on the sub-nanosecond time-scale. This process results in discrete internal motion of the HA tetrasaccharides where they rapidly move between low energy conformations. Specific interactions between water and intramolecular hydrogen-bonds involving the hydroxymethyl group were found to result in differing conformations and dynamics for the two alternative tetrasaccharides of HA. This new observation suggests that this residue may play a key role in the entropy and stability of HA in solution, allowing it to stay soluble up to high concentration. The vicinal coupling constants3 J NHCH of the acetamido groups have been calculated from our aqueous simulations of HA. We found that high values of 3J NHCH approximately 8 Hz, as experimentally measured for HA, are consistent with mixtures of both trans and cis conformations, and thus3 J NHCH cannot be used to imply a purely trans conformation of the acetamido. The rapid exchange of intramolecular hydrogen-bonds indicates that although the structure is at any moment stabilized by these hydrogen-bonds, no one hydrogen-bond exists for an extended period of time. This could explain why NMR often fails to provide evidence for intramolecular hydrogen-bonds in HA and other aqueous carbohydrate structures. | Carbohydrate Sequence |
The study examined the effects of dopaminergic agonists on the extracellularly recorded spontaneous activity of CA1 neurons in hippocampal slices of the rat. Dopamine evoked excitation or inhibition of the neuronal firing rate, the first reaction being more sensitive to the substance. Having used selective dopaminergic agonists (pergolide and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepines) and selective antagonists (haloperidol, spiperone, sulpiride and (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepine-7-ol), it was concluded that the excitation evoked by dopamine was due to activation of D2 dopamine receptors, while the inhibition was the result of D1 receptor activation. The effects of the dopamine agonists on the firing of CA1 neurons were long-lasting, which suggests a modulating role of dopamine in the hippocampus. | Pergolide |
OBJECTIVE: To clarify the relationships between the varying clinical or radiographic features of cherubism. STUDY DESIGN: Nonparametric statistics were used in a long-term follow-up of 18 patients through 2 generations from 6 Danish families. RESULTS: The radiographic grade of cherubism was significantly related to sex, maximal buccal bone expansion, course of cherubism, and number of aplasia or ectopic impacted teeth, but it was not related to families. Normal dentition in nonaffected regions was present or was obtained in 14 of 14 patients (age, >14 years). Surgical treatment did not provoke growth of lesional tissue in 22 of 22 cases. Radiographically, the bone structure in the lesional areas was related to age in all grades of cherubism: new bone formation in radiolucent areas (age, >20 years), normal bone structure with multilocular sketches (age, 32 to 39 years), and completely normal bone structure (age, >41 years), also found in 7 of 7 carriers of cherubism (age, >32 years). CONCLUSIONS: This group analysis verifies the knowledge of cherubism previously based on cumulative reviews of findings in single-family and case reports. | Cherubism |
An endophytic strain (designated as SYPF 7195T) was isolated from a branch of a ginkgo tree in Liaoning province of China. Strain SYPF 7195T was characterized by its grey to greyish-green aerial mycelium, velvety to floccose surface and swelling near the septa. Phylogenetic analyses, which were inferred from the internal transcribed spacer (ITS) and partial sequences of the LSU and SSU of the rDNA and translation elongation factor 1-alpha (TEF1), showed that strain SYPF 7195T belonged to the genus Pseudochaetosphaeronema, and was distinct from all other species with high bootstrap-supported values (92 %). Strain SYPF 7195T constitutes a separate evolutionary clade with Pseudochaetosphaeronema larense and Pseudochaetosphaeronema martinelli, with P. martinelli as its closest phylogenetic neighbour. The nucleotide differences between strain SYPF 7195T and P. martinelli were 71 substitutions in the ITS region. Strain SYPF 7195Tcould also be distinguished from P. martinelli by a number of physiological characteristics. Combined with morphology and molecular analyses, strain SYPF 7195T merits recognition as a representative of a novel species of the genus Pseudochaetosphaeronema, for which the name Pseudochaetosphaeronemaginkgonis sp. nov. is proposed. The type strain is CBS 140953T (=CGMCC 3.17865T=SYPF 7195T). The Mycobank number is MB 816567. | Endophytes |
Induction of labour is a common obstetrical procedure and is undertaken when the benefits of delivery are considered to outweigh the risks of continuation of pregnancy. However, more than one-fifth of induction cases fail to result in vaginal births and lead to unplanned caesarean deliveries, which compromise the birth experience and have negative clinical and resource implications. The need for accurate prediction of successful labour induction is increasingly recognised and many researchers have attempted to evaluate the potential predictability of different factors including maternal characteristics, Bishop score, various biochemical markers and ultrasound markers and derive predictive models to address this issue. | Delivery, Obstetric |
In eye movement desensitization and reprocessing (EMDR), a treatment for post-traumatic stress disorder (PTSD), patients make eye movements (EM) during trauma recall. Earlier experimental studies found that EM during recall reduces memory vividness during future recalls, and this was taken as laboratory support for the underlying mechanism of EMDR. However, reduced vividness was assessed with self-reports that may be affected by demand characteristics. We tested whether recall+EM also reduces memory vividness on a behavioural reaction time (RT) task. Undergraduates (N=32) encoded two pictures, recalled them, and rated their vividness. In the EM group, one of the pictures was recalled again while making EM. In the no-EM group one of the pictures was recalled without EM. Then fragments from both the recalled and non-recalled pictures, and new fragments were presented and participants rated whether these were (or were not) seen before. Both pictures were rated again for vividness. In the EM group, self-rated vividness of the recalled+EM picture decreased, relative to the non-recalled picture. In the no-EM group there was no difference between the recalled versus non-recalled picture. The RT task showed the same pattern. Reduction of memory vividness due to recall+EM is also evident from non-self-report data." | Eye Movement Desensitization Reprocessing |
To assess the influence of graft vs host disease (GVHD) on T cell development and thymic repertoire selection, a murine transplantation model was chosen, in which donor (B10.BR: Mls-1b, Mls-2b) and recipient (CBA/J: Mls-1a, Mls-2a) mice differ in their minor lymphocyte-stimulating Ag. Mature splenic T cells of donor origin were added to the T cell-depleted bone marrow cells to induce moderate GVHD. When analyzed 5 and 10 wk after transplantation, animals with GVHD, but not disease-free controls, demonstrated aberrant thymic maturation with an increase in single positive, TCRhigh+ thymocytes. Phenotypic analysis of TCR V beta expression in mature thymocytes and peripheral T cells revealed a disruption of negative thymic selection of Mls-reactive T cells with the subsequent emergence of V beta 3+ and V beta 6+ T cells in mice with GVHD but not in controls. Using retroviral-mediated gene transfer to tag mature T cells, these V beta 3+ and V beta 6+ T cells could be shown to be derived from donor bone marrow precursors. Thymocytes expressing V beta 3 and V beta 6 were efficiently activated upon cross-linking of their TCRs and peripheral T cells from mice with GVHD proliferated to host-derived splenocytes in a MLR. When transferred to sublethally irradiated CBA/J recipients, only T cells from mice with GVHD expanded dramatically. These data suggest that the lack of proper thymic selection after bone marrow transplantation results in the survival and persistence of self-reactive T cells, which might be responsible for the autoimmune manifestations of chronic GVHD." | Minor Lymphocyte Stimulatory Antigens |
Isolated human pancreatic islets converted [3H8]arachidonate to compounds with the high-performance liquid-chromatographic mobility of cyclooxygenase products, including prostaglandin E2 (PGE2), PGF2 alpha, and the lipoxygenase product 12-HETE. Human islet synthesis of PGE2, PGF2 alpha, and 12-HETE from endogenous arachidonate was demonstrated with stable isotope dilution-gas chromatographic-negative ion-chemical ionization-mass spectrometric analysis. Pharmacologic inhibition of arachidonate metabolism by both lipoxygenase and cyclooxygenase pathways with BW 755C strongly suppressed glucose-induced insulin secretion from perifused human islets, and the selective cyclooxygenase inhibitor indomethacin enhanced insulin secretion. These findings are similar to those reported for islets isolated from rats and suggest that arachidonate metabolites may modulate glucose-induced insulin secretion in humans." | 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine |
Paresis of the left side upper plexus brachialis is diagnosed to a boy of 2;8 years. The trouble appeared after a smallpox vaccination, which had been carried out successfully. There are no symptoms of CNS-disturbance. serumneuritis and virogenic radiculatis are discussed as pathogenic variants. Although postvaccinal peripheral nervous lesions very seldom occur, it does seem possible that the ailment in question could be a consequence of the smallpox vaccination. | Smallpox Vaccine |
The approach to care in dentistry has evolved over the past couple of decades from a narrow focus on oral disease to addressing the psychosocial determinants of oral health. Subsequently, there have been many attempts to reform dental curricula through alternative models of education, such as competency-based and community-based educational models and problem-based learning. These efforts aim to improve the abilities of dental students in problem-solving, critical thinking, professionalism, and social and cultural competence to help them cope with the complexity of dealing with oral health-related issues and the constantly changing evidence underlying the practice of dentistry. However, it is not yet clear how well these educational initiatives meet their objectives or how they influence the reasoning skills of dental students. There is now a need to develop a conceptual framework for clinical reasoning in dentistry grounded on empirical evidence to direct the future evolution of dental education. | Evidence-Based Dentistry |
Spinal muscular atrophy (SMA) is a progressive disease of the lower motor neurons associated with recessive loss of the SMN1 gene, and which leads to worsening weakness and disability, and is fatal in its most severe forms. Over the past six years, three treatments have emerged, two drugs that modify exon splicing and one gene therapy, which have transformed the management of this disease. When treated pre-symptomatically, many children show normal early motor development, and the benefits extend from the newborn period to adulthood. Similar treatment approaches are now under investigation for rare types of SMA associated with genes beyond SMN1. | Muscular Atrophy, Spinal |
Brattleboro rats without diabetes insipidus were subjected to sodium chloride enrichment (20-fold increase in dietary salt) at various stages of their development. Salt supplementation in the adult rat produced higher systolic blood pressure (SBP), particularly in males (142 +/- 3 versus 110 +/- 3 mmHg in control. The blood pressures of females on salt-supplemented diets during pregnancy decreased from 136 +/- 1 to 121 +/- 2 mmHg, although throughout this period the blood pressures for these rats were greater than for the control pregnant rats. Pregnant females on salt-supplemented diets also showed higher sodium concentrations in the amniotic fluid compared with controls (155 +/- 3.4 versus 134.1 +/- 6.0 mmol/l). Salt supplemented lactating mothers produced milk with similar sodium concentrations to those of the controls, but the urinary sodium concentrations of pups suckling on the former were greater than in the controls. It is concluded that the suckling pups were also salt-enriched. Rats were submitted to salt-enriched regimes in utero, during suckling, post-weaning and post-pubertally, or permutations thereof. Salt supplementation post-weaning led to consistent elevation in arterial blood pressure with males being more susceptible than females. The degree of elevation was increased if the salt-supplement was present during suckling (132 +/- 1 versus 112 +/- 1 mmHg) and was greatest when the salt-supplemented regime was administered both in utero and during the post-weaning period (154 +/- 2 versus 112 +/- 1 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)" | 18-Hydroxydesoxycorticosterone |
The wake-promoting drug Modafinil has been used for treatment of sleep disorders, such as Narcolepsy, excessive daytime sleepiness and sleep apnea, due to its stimulant action. Despite the known effect of Modafinil on brain neurochemistry, particularly on brain dopamine system, recent evidence support an immunomodulatory role for Modafinil treatment in neuroinflammatory models. Here, we aimed to study the effects of in vitro and in vivo Modafinil treatment on activation, proliferation, cell viability, and cytokine production by immune cells in splenocytes culture from mice. The results show that in vitro treatment with Modafinil increased Interferon (IFN)-gamma, Interleukin (IL)-2 and IL-17 production and CD25 expression by T cells. In turn, in vivo Modafinil treatment enhanced splenocyte production of IFN-gamma, IL-6 and tumor necrosis factor (TNF), and increased the number of IFN-gamma producing cells. Next, we addressed the translational value of the observed effects by testing PBMCs from Narcolepsy type 1 patients that underwent Modafinil treatment. We reported increased number of IFN-gamma producing cells in PBMCs from Narcolepsy type 1 patients following continuous Modafinil treatment, corroborating our animal data. Taken together, our results show, for the first time, a pro-inflammatory action of Modafinil, particularly on IFN-mediated immunity, in mice and in patients with Narcolepsy type 1. The study suggests a novel effect of this drug treatment, which should be taken into consideration when given concomitantly with an ongoing inflammatory or autoimmune process. | Wakefulness-Promoting Agents |
Ankle-foot orthoses (AFOs) are devices that support ankle motion. An AFO's sagittal plane rotational stiffness can affect gait kinematics. Because AFOs are often made from viscoelastic materials, their properties may vary at different walking speeds. The influence of rotational speed on AFO properties has not been thoroughly investigated. Therefore, the purpose of this study was to determine the impact of rotational speed on AFO stiffness about the ankle. We tested a sample of one thermoplastic off-the-shelf AFO and two 3-D printed carbon fiber enforced nylon AFOs. Each AFO's dynamic resistance torque was measured as it was flexed at five speeds (5-100 degrees /s) using a custom-built measurement apparatus. We compared loading stiffness, neutral angle, and energy dissipation parameters for each AFO across speeds. Parameter values were generally greater at higher speeds. These effects were statistically significant for all AFOs (p</=0.002). However, differences in AFO stiffness and neutral angle across speeds were quite small (<0.6 Nm/ degrees and <2.2 degrees ). Changes in the thermoplastic AFO's stiffness were lower than the minimum detectable difference. Energy dissipation, as indicated by hysteresis area, increased by up to 6.3 J (about 250%) at the highest speed. This demonstrates that AFO flexion speed can influence the properties of different AFOs over the range typically achieved in human walking. Future work should assess whether the observed small variations of stiffness and neutral angle have a clinically meaningful impact on user performance, as well as explore effects of angular speed on a variety of AFO materials and designs. | Foot Orthoses |
o-Phthaldialdehyde was used in combination with a series of six thiosugars for the pre-column chiral derivatization of selected primary amino acids. The diastereomers were resolved on a conventional reversed-phase column and with fluorescence detection. A surprisingly effective resolution of 1-isoindolyl-(1-thioglycosides) derived from 1-thio-beta-L-fucose was observed. | Thiosugars |
BACKGROUND: My career goal in 1971 was to learn about the causes of malformations. Attending the annual meetings of the Teratology Society and reading the articles in Teratology exposed me to the scientists and clinicians involved in this research and the methods being used. METHODS: Over a period of 49 years (1972-2020), I heard many presentations about several exposures in pregnancy that can cause birth defects. Symposia and platform presentations provided unique and stimulating information on the fetal effects of the teratogen thalidomide. RESULTS: I developed research studies and presented the results from our studies on teratogenic exposures, such as anticonvulsant drugs, the prenatal diagnosis procedure chorionic villus sampling, and the abortifacient misoprostol. The annual Pregnancy Registry Workshop was developed as a forum for discussing issues related to this new method of evaluating potential teratogenic exposures in pregnancy. CONCLUSION: Attending the annual meetings and reading the articles in the journal Teratology (now Birth Defects Research) have been an instructive and enjoyable way to learn about the causes of malformations. | Teratogens |
OBJECTIVES: Previous studies have found little association between objective measures and the subjective experience of opioid-induced constipation. The subjective experience of opioid-induced constipation may be influenced by treatment expectations. While most trials control for treatment expectations through blinding, success rate is generally low. This study aimed to explore the association between objective measures and the subjective experience of opioid-induced constipation, while considering blinding success and treatment expectations, and other psychological factors. METHODS: Data from a randomized, double-blinded, placebo-controlled crossover trial including 21 healthy male participants was analyzed. Participants received either placebo, tapentadol, or oxycodone (in equipotent doses) for 14 days. They were assessed on objective and subjective measures of opioid-induced constipation (gastrointestinal transit time and the Patient Assessment of Constipation-Symptoms questionnaire, respectively), treatment guesses to indicate blinding success, and psychological factors. RESULTS: There was a strong association between objective and subjective measures of opioid-induced constipation when participants were treated with oxycodone (r=0.676, p=0.006). Furthermore, participants were able to guess that they received active treatment when treated with oxycodone (p<0.001), suggesting that treatment expectations may have influenced the subjective experience of symptoms. Finally, patterns of moderate associations between opioid-induced constipation and other psychological factors emerged, although none reached significance (p>0.05). CONCLUSIONS: Results indicate that treatment expectations could play an important role in the subjective experience of opioid-induced constipation, and support the importance of assessing blinding success in study trials. Besides expectations, other psychological factors may be associated with opioid-induced constipation. | Opioid-Induced Constipation |
Delta-amino acids are very attractive in drug discovery, especially in the peptidomimetic area, because of their capability to act as dipeptide isosteres and reverse turn mimetics. Herein we report the synthesis of a rigid delta-amino acid constrained by a 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffold, which can be considered as a Gly-Asn dipeptide mimetic. Key steps are the condensation of glycidol and tartaric acid derivatives, and the intramolecular trans-acetalization of the oxidized adduct to give the bicyclic delta-amino acid. Starting from L-tartaric acid derivative, it was achieved the corresponding Gly-D-Asn isostere, whereas from the enantiomeric D-tartaric acid derivative the corresponding Gly-L-Asn isostere could be obtained, thus giving access to both enantiomeric dipeptide sequences. | Amino Acids, Cyclic |
Atractylodis Macrocephalae Rhizoma (AMR) is one of commonly used medicinal and edible herbs in China. It is often sulfur-fumigated during post-harvest processing. Carbohydrates are important active components of AMR. However, it is unknown whether sulfur-fumigation would induce changes on carbohydrates. Here, carbohydrates including polysaccharides, oligosaccharides and free monosaccharides were comprehensively analyzed to characterize the quality changes of sulfur-fumigated AMR. Determination of both homemade sulfur-fumigated AMR samples and commercial samples from market revealed that sulfur-fumigation did not affect molecular weight distribution of polysaccharides, but altered polysaccharides content and its ratios of constituent monosaccharides, especially glucose (Glc) and fructose (Fru), as well as the contents of oligosaccharides DP2-10 and free monosaccharide Fru. Moreover, the variations enhanced with the increasing of residual SO(2) content. The potential transformation mechanisms could be due to the hydrolysis of polysaccharides. The research outcomes could provide a chemical basis for the safety and efficacy evaluations of sulfur-fumigated AMR. | Rhizome |
The Coatomer protein complex subunit beta 2 (COPB2) is involved in the formation of the COPI coatomer protein complex and is responsible for the transport of vesicles between the Golgi apparatus and the endoplasmic reticulum. It plays an important role in maintaining the integrity of these cellular organelles, as well as in maintaining cell homeostasis. More importantly, COPB2 plays key roles in embryonic development and tumor progression. COPB2 is regarded as a vital oncogene in several cancer types and has been implicated in tumor cell proliferation, survival, invasion, and metastasis. Here, we summarize the current knowledge on the roles of COPB2 in cancer development and progression in the context of the hallmarks of cancer. | Coat Protein Complex I |
Quantitative assay for fibrin monomer was done by use of a chromogenic substrate (S-2390, Coa set fibrin monomer). Samples from DIC prone patients with the underlying disease were assayed and classified into four groups. The pre DIC group showed higher FM values than the control with no laboratory coagulation abnormality, although the FDP . D-dimer showed no significant rise. FM assay is a useful marker for the detection of early coagulopathy in DIC. Administration of the AT III concentrate in the case of low level of plasma ATIII, thrombin . antithrombin complex I (TAT) caused a significant transient rise. The clinical course of DIC by TAT is often affected by the fluctuation of ATIII level in plasma, the usefulness of FM is that it reflects the real thrombin generation in DIC." | Fibrin Fibrinogen Degradation Products |
Migraine is a common, disabling, neurovascular disorder characterized by episodic attacks of head pain and associated disability plus systemic autonomic and neurologic symptoms. The advent of the triptan class of medication in the 1990s revolutionized the acute treatment of migraine, but many migraineurs do not respond optimally or at all to triptans, have intolerable adverse effects, or have contraindications to their use. Preventive pharmacotherapy has advanced mostly through serendipity, with new drugs being found effective while being used for other indications. There remains a significant need for new medications and devices that can provide effective, rapid, and sustained pain relief without adverse effects or recurrence. Several new acute and preventive therapies for the treatment of migraine and cluster headaches have shown promise and are currently under investigation. This article covers innovative delivery mechanisms, calcitonin gene-related peptide receptor antagonists, antibodies to calcitonin gene-related peptide and its receptor, 5-HT1F receptor agonists, transient receptor potential vanilloid receptor modulators, orexin receptor antagonists, glial cell modulators, and neurostimulation. | Orexin Receptor Antagonists |
The ultrafast deactivation processes in the excited state of biomolecules, such as the most stable tautomers of guanine, forbid any state-of-the-art gas phase spectroscopic studies on these species with nanosecond lasers. This drawback can be overcome by grafting a chromophore having a long-lived excited state to the molecule of interest, allowing thus a mass-selective detection by nanosecond R2PI and therefore double resonance IR/UV conformer-selective spectroscopic studies. The principle is presently demonstrated on the keto form of a modified 9-methylguanine, for which the IR/UV double resonance spectrum in the C horizontal lineO stretch region, reported for the first time, provides evidence for extensive vibrational couplings within the guanine moiety. Such a successful strategy opens up a route to mass-selective IR/UV spectroscopic investigations on molecules exhibiting natural chromophores having ultrashort-lived excited states, such as DNA bases, their complexes as well as peptides containing short-lived aromatic residues. | Guanine |
PURPOSE: The aim of this study was to evaluate the integrity of the corticospinal tracts (CST) in patients with SCA3 and age- and gender-matched healthy control subjects using diffusion tensor imaging (DTI). We also looked at the clinical correlates of such diffusivity abnormalities. METHODS: We assessed 2 cohorts from different Brazilian centers: cohort 1 (n = 29) scanned in a 1.5 T magnet and cohort 2 (n = 91) scanned in a 3.0 T magnet. We used Pearson's coefficients to assess the correlation of CST DTI parameters and ataxia severity (expressed by SARA scores). RESULTS: Two different results were obtained. Cohort 1 showed no significant between-group differences in DTI parameters. Cohort 2 showed significant between-group differences in the FA values in the bilateral precentral gyri (p < 0.001), bilateral superior corona radiata (p < 0.001), bilateral posterior limb of the internal capsule (p < 0.001), bilateral cerebral peduncle (p < 0.001), and bilateral basis pontis (p < 0.001). There was moderate correlation between CST diffusivity parameters and SARA scores in cohort 2 (Pearson correlation coefficient: 0.40-0.59). CONCLUSION: DTI particularly at 3 T is able to uncover and quantify CST damage in SCA3. Moreover, CST microstructural damage may contribute with ataxia severity in the disease. | Machado-Joseph Disease |
Humans are involved in various real-life networked systems. The most obvious examples are social and collaboration networks but the language and the related mental lexicon they use, or the physical map of their territory can also be interpreted as networks. How do they find paths between endpoints in these networks? How do they obtain information about a foreign networked world they find themselves in, how they build mental model for it and how well they succeed in using it? Large, open datasets allowing the exploration of such questions are hard to find. Here we report a dataset collected by a smartphone application, in which players navigate between fixed length source and destination English words step-by-step by changing only one letter at a time. The paths reflect how the players master their navigation skills in such a foreign networked world. The dataset can be used in the study of human mental models for the world around us, or in a broader scope to investigate the navigation strategies in complex networked systems. | Mental Navigation Tests |
A survey of 100 samples of sorghum grains was carried out to determine Phoma spp. and tenuazonic acid (TA) contamination using molecular tools and LC-MS/MS. Sorghum samples were obtained at the following four grain maturity stages: milk (S1), soft dough (S2), hard dough (S3), and physiological maturity (S4). The results revealed a good correlation between Phoma and TA occurrence during grain development. The samples showed Phoma contamination with frequencies ranging from 2.4% (S1) to 87.4% (S4), and the molecular identification revealed P. sorghina as the only Phoma specie isolated. Tenuazonic acid was found in sorghum grains at all maturity stages. In S2, S3 and S4, 100% of the samples showed TA contamination with levels ranging from 20 to 1234microg/kg. Low levels of TA were detected in 36% of the samples collected at S1 stage. This is the first report of tenuazonic acid in Brazilian sorghum grains. | Tenuazonic Acid |
Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer's disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with heat shock 70 kDa protein (Hsp70) and the ubiquitin-proteasome machinery. While inhibition of VCP activity stabilizes large Tau aggregates, disaggregation by VCP generates seeding-active Tau species as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies. | Valosin Containing Protein |
Ocular hypertension is a significant risk factor for vision loss in glaucoma due to the death of retinal ganglion cells (RGCs). This study investigated the effects of the antiapoptotic peptides peptain-1 and peptain-3a on RGC death in vitro in rat primary RGCs and in mouse models of ocular hypertension. Apoptosis was induced in primary rat RGCs by trophic factor deprivation for 48 h in the presence or absence of peptains. The effects of intravitreally injected peptains on RGC death were investigated in mice subjected to retinal ischemic/reperfusion (I/R) injury and elevated intraocular pressure (IOP). I/R injury was induced in mice by elevating the IOP to 120 mm Hg for 1 h, followed by rapid reperfusion. Ocular hypertension was induced in mice by injecting microbeads (MB) or silicone oil (SO) into the anterior chamber of the eye. Retinal flatmounts were immunostained with RGC and activated glial markers. Effects on anterograde axonal transport were determined by intravitreal injection of cholera toxin-B. Peptain-1 and peptain-3a inhibited neurotrophic factor deprivation-mediated RGC apoptosis by 29% and 35%, respectively. I/R injury caused 52% RGC loss, but peptain-1 and peptain-3a restricted RGC loss to 13% and 16%, respectively. MB and SO injections resulted in 31% and 36% loss in RGCs following 6 weeks and 4 weeks of IOP elevation, respectively. Peptain-1 and peptain-3a inhibited RGC death; the loss was only 4% and 12% in MB-injected eyes and 16% and 15% in SO-injected eyes, respectively. Anterograde transport was defective in eyes with ocular hypertension, but this defect was substantially ameliorated in peptain-injected eyes. Peptains suppressed ocular hypertension-mediated retinal glial activation. In summary, our results showed that peptains block RGC somal and axonal damage and neuroinflammation in animal models of glaucoma. We propose that peptains have the potential to be developed as therapeutics against neurodegeneration in glaucoma. | Ocular Hypertension |
HSP47 is a 47-kDa collagen-binding heat shock protein, the expression of which is always correlated with that of collagens in various cell lines. We examined the effects of TGF-beta 1, which is reported to induce the collagen genes, on the expression of HSP47 in mouse osteoblast MC3T3-E1 cells. Treatment of the cells with 5 ng/ml TGF-beta 1 for 24 h increased the level of HSP47 mRNA three-fold. Dose-dependent induction by TGF-beta 1 was observed for both HSP47 mRNA and collagen alpha 1 (I) mRNA, and actinomycin D inhibited this increase of HSP47 mRNA. To elucidate the TGF-beta 1 responsive element(s) in the mouse HSP47 gene, we generated a series of 5'-deletion promoters fused to luciferase reporter constructs. Transient transfection assays showed that TGF-beta 1 induced 4-6 fold the promoter activity of a region approximately -5.5 kbp upstream of the HSP47 gene. Two upstream regions, -3.9 to -2.7 kbp and -280 to -50 bp were shown to be involved in the activation in response to TGF-beta 1 treatment. | HSP47 Heat-Shock Proteins |
Altitude illness refers to a group of environmentally mediated pathophysiologies. Many people will suffer acute mountain sickness shortly after rapidly ascending to a moderately hypoxic environment, and an unfortunate few will develop potentially fatal conditions such as high altitude pulmonary edema or high altitude cerebral edema. Some individuals seem to be predisposed to developing altitude illness, suggesting an innate contribution to susceptibility. The implication that there are altitude-sensitive and altitude-tolerant individuals has stimulated much research into the contribution of a genetic background to the efficacy of altitude acclimatization. Although the effect of altitude attained and rate of ascent on the etiology of altitude illness is well known, there are only tantalizing, but rapidly accumulating, clues to the genes that may be involved. In 2006, we reviewed what was then known about the genetics of altitude illness. This article updates that review and attempts to tabulate all the available genetic data pertaining to these conditions. To date, 58 genes have been investigated for a role in altitude illness. Of these, 17 have shown some association with the susceptibility to, or the severity of, these conditions, although in many cases the effect size is small or variable. Caution is recommended when evaluating the genes for which no association was detected, because a number of the investigations reviewed in this article were insufficiently powered to detect small effects. No study has demonstrated a clear-cut altitude illness gene, but the accumulating data are consistent with a polygenic condition with a strong environmental component. The genes that have shown an association affect a variety of biological pathways, suggesting that either multiple systems are involved in altitude pathophysiology or that gene-gene interactions play a role. Although numerous studies have been performed to investigate specific genes, few have looked for evidence of heritability or familial transmission, or for epidemiological patterns that would be consistent with genetically influenced conditions. Future trends, such as genome-wide association studies and epigenetic analysis, should lead to enhanced understanding of the complex interactions within the genome and between the genome and hypoxic environments that contribute to an individual's capacity to acclimatize rapidly and effectively to altitude." | 5,10-Methylenetetrahydrofolate Reductase (FADH2) |
A red body morph with reddish-orange body and brownish-red eyes is described in the terrestrial isopod, Venezillo evergladensis. The alternate, non-red morph, has a brown body and black eyes and either gray or orange antennae. Breeding results show three alleles, rg, ro and r at an autosomal locus control the variation. The dominance hierarchy is rg less than ro less that r; the genotypes, rg/rg, rg/ro, and rg/r are non-red, grey, ro/ro and ro/r are non-red, orange, and r/r are red. The gray antennae of non-red, gray individuals is variable in expression although still objectively recognized. The red body morph and its inheritance is paralleled in related species, while the antennal variation identifies a new allele. Sperm storage, exceeding a full year, and multiple matings in nature are documented. | Crosses, Genetic |
N-acetyl-N-formyl-5-methoxykynuramine (AFMK) is a melatonin metabolite identified in rat brain by Hirata et al. (The Journal of Biological Chemistry 249 (1974) 1311). Since no assay has been described for its routine measurement, we have developed and validated such a radioimmunoassay. We synthesized AFMK and N-acetyl-5-methoxykynuramine (AMK), in order to produce anti-AFMK antibodies and to standardize the assay. The tracer [3H]-AFMK was obtained from [3H]-melatonin. The assay was preceded by a chromatographic step on Celite microcolumn in order to increase its specificity. The assay was suitable for the measurement of AFMK levels ranging from 59 to 1894 pmol/L. The detection limit of the assay was routinely set at 65 pmol/L. The intra- and inter-assay coefficients of variation were 3.5% and 11% respectively. Investigation of the 24 h plasma pattern in healthy volunteers did not reveal any AFMK levels in plasma samples. In rats, plasma AFMK showed a peak after melatonin injection, which confirmed the in vivo AFMK production as a melatonin metabolite. This AFMK assay is suitable for studies on melatonin metabolism. | Kynuramine |
BACKGROUND: Laser microbeam microdissection has greatly facilitated the procurement of specific cell populations from tissue sections. However, the fact that a coverslip is not used means that the morphology of the tissue sections is often poor. AIMS: To develop a mounting method that greatly improves the morphological quality of tissue sections for laser microbeam microdissection purposes so that the identification of target cells can be facilitated. METHODS: Fresh frozen tissue and formalin fixed, paraffin wax embedded tissue specimens were used to test the morphological quality of mounted and unmounted tissue. The mounting solution consisted of an adhesive gum and blue ink diluted in water. Interference of the mounting solution with DNA quality was analysed by the polymerase chain reaction using 10-2000 cells isolated by microdissection from mounted and unmounted tissue. RESULTS: The mounting solution greatly improved the morphology of tissue sections for laser microdissection purposes and had no detrimental effects on the isolation and efficiency of amplification of DNA. One disadvantage was that the mounting solution reduced the cutting efficiency of the ultraviolet laser. To minimise this effect, the mounting solution should be diluted as much as possible. Furthermore, the addition of blue ink to the mounting medium restores the cutting efficiency of the laser. CONCLUSIONS: The mounting solution is easy to prepare and apply and can be combined with various staining methods without compromising the quality of the DNA extracted. | Tissue Embedding |
We report a case in which strict anticoagulant therapy management was useful for a recurrent in-stent thrombosis after carotid artery stenting (CAS). An 84-year-old man presented with cognitive decline that progressed rapidly over two months. Head magnetic resonance imaging showed an acute-stage infarct occurring frequently in the right cerebral hemisphere, and he underwent hospitalization and treatment. On neck magnetic resonance angiography (MRA), severe stenosis was found at the origin of the right internal carotid artery. Since he took aspirin, clopidogrel, and a statin after placement of an indwelling coronary stent, we treated him by adding argatroban and edaravone drip therapy to his existing medication. CAS was performed on day 15 of the hospitalization. A small in-stent thrombosis with plaque protrusion was observed on a carotid sonogram performed at the second day after CAS, and re-examination at the seventh day confirmed enlargement of the lesion and an increase in peak systolic velocity; thus, a second CAS procedure was performed on the same day. After the second CAS, oral cilostazol was added for triple antiplatelet therapy (TAPT), but as the in-stent thrombosis increased further, we started a continuous infusion of heparin with the goal of an activated partial thromboplastin time (APTT) of 50 to 65 seconds. After starting heparin, the lesion did not progress; after 14 days of continuous heparin infusion, the patient was switched to TAPT, and regression of the plaque was confirmed. This case demonstrated to us that controlled anticoagulation therapy can be an effective treatment for cases in which a thrombus recurs within a stent after CAS. | Carotid Artery Thrombosis |
Organized in 1922, the Lovelace Clinic successfully provided health care services throughout the Southwest utilizing a group practice format under the aegis of a nonprofit foundation. In 1984, the Foundation contracted with Hospital Corporation of America to form a for-profit health care organization which allows the provision of high quality health care through a group practice professional corporation, a 238-bed inpatient facility, a 70,000-member health maintenance organization, and an independent research and education foundation. | Health Facilities |
INTRODUCTION: It is the responsibility of certification organizations to provide psychometrically sound and legally defensible examinations. Practice research serves as the certification framework for validating advanced practice roles and updating national qualifying examinations. This national study describes the practice of the acute care pediatric nurse practitioner (ACPNP) since the inception of the certified pediatric nurse practitioner-acute care (CPNP-AC) examination in 2005. METHOD: A descriptive analysis of the 2009 practice survey of U.S. ACPNPs (291 respondents) was performed. RESULTS: Most ACPNP respondents were White women; the mean age was 40 years, and 47.9% had been formally educated as ACPNPs. More than 40% practiced in the Midwestern United States. Most respondents (86.2%) practiced in urban areas. Respondents reported spending 71% of practice time in inpatient settings. The most frequently cited areas of practice were critical care (27.5%), followed by emergency department (10.7%) and specialty practices. DISCUSSION: In light of recent advanced practice regulatory role distinctions, this re-examination of the ACPNP practice 5 years after initiation of the CPNP-AC certification examination demonstrates changes in clinical practice and educational preparation requirements. | Pediatric Nurse Practitioners |
Silicosis is a well acknowledged occupational lung disorder with considerable negative impact on the patients' quality of life. Various signaling pathways have been reported to interplay in the pathogenesis of pulmonary fibro-proliferative disorders; of which, P-AKT/mTOR signaling pathway. The current study highlights the potential pulmonary protective effect of carvedilol; a non-selective alpha/beta blocker against experimental silicosis-induced in rats by the intranasal installation of silica (50â¯mg/rat, 1â¯ml 0.9% NaCl). Carvedilol (20â¯mg/kg, orally) was administered for 8â¯weeks post intranasal silica installation. Carvedilol significantly attenuated silica-induced pulmonary damage on all the investigated scales. Inflammatory, oxidative/anti-oxidative and fibrotic incidences significantly improved with a significant histopathological restoration of lung architecture and attenuation of inflammatory and fibrotic biomarkers expression. Carvedilol significantly reduced lung contents of P-AKT and mTOR which, appears to be the main mechanism underlying the pulmonary protective effect of carvedilol. In conclusion; carvedilol attenuated silica-induced pulmonary fibrosis by modulating P-AKT/mTOR/TGFbeta1 signaling and underlying inflammatory and fibrotic sequel. | Carvedilol |
Twenty-eight unselected patients with histologically proven aplastic anaemia were electively treated with anabolic steroids (75-150 mg orally q.d.) Additional supportive treatment with blood cell components and antibiotics was given if indicated. Response to therapy was defined as favourable if after 3 months of anabolic therapy overt bleeding tendency had disappeared, there was no need for transfusion therapy, a spontaneous increase of haemoglobin had occurred of greater than 3 g/dl above the initial level, and a platelet rise of twofold the initial count (up to at least greater than 30 x 10(9) /L) had occurred. Of 22 patients evaluable for the results of long-term (greater than 3 months) anabolic treatment, six showed a partial response and eleven responded favourably. These 11 are all alive at the end of the study. Five of these patients proved to be anabolic steroid-dependent. The 50% actuarial survival is approximately 4 years after diagnosis, which compares favourably with the best published results from bone marrow transplantation for aplastic anaemia. It is concluded that anabolic therapy in aplastic anaemia should be tried for 2-3 months before the bone marrow transplantation or immunosuppressive therapy is taken into consideration. | Methenolone |
Stillbirth is a major obstetric complication, with 3.2 million stillbirths worldwide and 26,000 stillbirths in the United States every year. The Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop from October 22-24, 2007, to review the pathophysiology of conditions underlying stillbirth to define causes of death. The optimal classification system would identify the pathophysiologic entity initiating the chain of events that irreversibly led to death. Because the integrity of the classification is based on available pathologic, clinical, and diagnostic data, experts emphasized that a complete stillbirth workup should be performed. Experts developed evidence-based characteristics of maternal, fetal, and placental conditions to attribute a condition as a cause of stillbirth. These conditions include infection, maternal medical conditions, antiphospholipid syndrome, heritable thrombophilias, red cell alloimmunization, platelet alloimmunization, congenital malformations, chromosomal abnormalities including confined placental mosaicism, fetomaternal hemorrhage, placental and umbilical cord abnormalities including vasa previa and placental abruption, complications of multifetal gestation, and uterine complications. In all cases, owing to lack of sufficient knowledge about disease states and normal development, there will be a degree of uncertainty regarding whether a specific condition was indeed the cause of death. | Death |
Cauda equina syndrome (CES) is a rare and severe type of spinal stenosis, where all the nerves in the lower back suddenly become severely compressed. It is a serious medical emergency, and compression of the nerves in the lower portion of the spinal canal can lead to permanent loss of bowel and bladder control, paraesthesia, and paralysis of the legs if left untreated. Causes of CES include: trauma, spinal stenosis, herniated discs, spinal tumour, cancerous tumour, inflammatory and infectious conditions or due to an accidental medical intervention. CES patients typically present with symptoms of: saddle anaesthesia, pain, incontinence and numbness. Any of these are red flag symptoms and require immediate investigation and treatment. | Cauda Equina Syndrome |
The lack of antiviral drugs for the treatment of orthopoxvirus disease represents an unmet medical need, particularly due to the threat of variola virus (the causative agent of smallpox) as an agent of biowarfare or bioterrorism (Henderson, 283:1279-1282, 1999). In addition to variola, monkeypox, cowpox, and vaccinia viruses are orthopoxviruses of concern to human health (Lewis-Jones, 17:81-89, 2004). Smallpox vaccination, using the closely related vaccinia virus, is no longer provided to the general public leading to a worldwide population increasingly susceptible not only to variola but to monkeypox, cowpox, and vaccinia viruses as well. Orthopoxviruses share similar life cycles (Fenner et al., WHO, Geneva, 1988), and significant nucleotide and protein homology, and are immunologically cross-protective against other species within the genus, which was the basis of the highly successful vaccinia virus vaccine. These similarities also serve as the basis for screening for antivirals for dangerous pathogens such as variola and monkeypox virus using generally safer viruses such as cowpox and vaccinia. Methods for preliminary screening and initial characterization of potential orthopoxvirus antivirals in vitro, using vaccinia virus as a relatively safe surrogate for more pathogenic orthopoxviruses, are described herein. They include candidate identification in a viral cytopathic effect (CPE) assay as well as evaluation of the antiviral activity in inhibition assays to determine mean effective (or inhibitory) concentrations (EC(50) or IC(50)). These assays were utilized in the identification and early characterization of tecovirimat (ST-246) (Yang et al., 79:13,139-13,149, 2005). These initial steps in identifying and characterizing the antiviral activity should be followed up with additional in vitro studies including specificity testing (for other orthopoxviruses and against other viruses), single-cycle growth curves, time of addition assays, cytotoxicity testing, and identification of the drug target. | Variola virus |
During the past decade, dozens of countries, regions, and cities have enacted taxes on sugar-sweetened beverages (SSBs). They have been primarily motivated by a desire to raise prices, reduce sales and consumption, improve population health, and raise revenue. This review outlines the economic rationale for SSB taxes and illustrates their predicted effects. It reviews the research on the effects of these taxes on retail prices, sales, cross-border shopping, consumption, and product availability. The evidence indicates that the amount by which taxes increase retail prices (also called the pass-through of the tax) varies by jurisdiction, ranging from less than 50% to 100% of the tax. Sales tend to decrease significantly in the taxing jurisdiction, although this seems to be partly offset by residents increasingly shopping outside of the taxing jurisdiction (i.e., engaging in cross-border shopping).Overall, taxes lower consumption of the taxed beverages by adults, although not for all types of beverages or all groups of consumers. We conclude with suggestions for improving the design of such taxes and directions for future research. | Consumer Behavior |
To investigate the roles of mammary PTHrP in calcium uptake and/or release in the mammary gland of cows, plasma PTHrP and Ca levels, and their arterial-venous differences were examined in a Jersey cow during the periparturient period. Levels of Ca in both abdominal aorta and abdominal subcutaneous vein blood slightly decreased around the parturition and at 24 days after the parturition, however, no remarkable arterial-venous differences were observed. Plasma PTHrP levels in both arterial and venous samples were below the detection limit (0.57 pmol/l) during the experimental period. Milk PTHrP and Ca levels were measured in 9 Holstein dairy cows. Although plasma PTHrP levels in all arterial and venous samples were also below the detection limit, milk PTHrP and Ca levels were remarkably high, ranging from 14,900 pmol/l to 41,200 pmol/l and from 772 mg/l to 1,200 mg/l, respectively. In addition, a significant positive correlation (P<0.01) was observed between milk PTHrP and Ca levels. These results suggested that mammary PTHrP is closely related to Ca concentration in the milk." | Parathyroid Hormone-Related Protein |
An intravenous bolus injection of 0.1 ml alpha-endorphin (1 x 10(-8)-1 x 10(-4) g/ml) didn't change the heart rate in frogs. The parasympathetic bradycardia induced by the peripheral vagus stimulation was decreased by alpha-endorphin. This vago-inhibitory action was dose-dependent (1 x 10(-5)-1 x 10(-4) g/ml). The maximal inhibitory action was watched in 4-8 and 9-15 minutes after bolus injection of alpha-endorphin in concentration of 1 x 10(-5) and 1 x 10(-4) g/ml accordingly. | alpha-Endorphin |
Recent studies have shown that metals such as copper, zinc, aluminum, cadmium, chromium, iron and lead cause severe dose-dependent disturbances in growth, morphogenesis, photosynthetic and respiratory activity as well as on ultrastructure and function of organelles in the algal model system Micrasterias denticulata (Volland et al., 2011, 2012; Andosch et al., 2012). In the present investigation we focus on amelioration of these adverse effects of cadmium, chromium and lead by supplying the cells with different antioxidants and essential micronutrients to obtain insight into metal uptake mechanisms and subcellular metal targets. This seems particularly interesting as Micrasterias is adapted to extremely low-concentrated, oligotrophic conditions in its natural bog environment. The divalent ions of iron, zinc and calcium were able to diminish the effects of the metals cadmium, chromium and lead on Micrasterias. Iron showed most ameliorating effects on cadmium and chromium in short- and long-term treatments and improved cell morphogenesis, ultrastructure, cell division rates and photosynthesis. Analytical transmission electron microscopic (TEM) methods (electron energy loss spectroscopy (EELS) and electron spectroscopic imaging (ESI)) revealed that chromium uptake was decreased when Micrasterias cells were pre-treated with iron, which resulted in no longer detectable intracellular chromium accumulations. Zinc rescued the detrimental effects of chromium on net-photosynthesis, respiration rates and electron transport in PS II. Calcium and gadolinium were able to almost completely compensate the inhibiting effects of lead and cadmium on cell morphogenesis after mitosis, respectively. These results indicate that cadmium is taken up by calcium and iron transporters, whereas chromium appears to enter the algae cells via iron and zinc carriers. It was shown that lead is not taken up into Micrasterias at all but exerts its adverse effects on cell growth by substituting cell wall bound calcium. The antioxidants salicylic acid, ascorbic acid and glutathione were not able to ameliorate any of the investigated metal effects on the green alga Micrasterias when added to the culture medium. | Micrasterias |
BACKGROUND: Although R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard chemotherapy regimen for diffuse large B cell lymphoma (DLBCL) patients, not all patients are responsive to the scheme, and there is no effective method to predict treatment response. METHODS: We utilized 5hmC-Seal to generate genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) from 86 DLBCL patients before they received R-CHOP chemotherapy. To investigate the correlation between 5hmC modifications and curative effectiveness, we separated patients into training (n = 56) and validation (n = 30) cohorts and developed a 5hmC-based logistic regression model from the training cohort to predict the treatment response in the validation cohort. RESULTS: In this study, we identified thirteen 5hmC markers associated with treatment response. The prediction performance of the logistic regression model, achieving 0.82 sensitivity and 0.75 specificity (AUC = 0.78), was superior to existing clinical indicators, such as LDH and stage. CONCLUSIONS: Our findings suggest that the 5hmC modifications in cfDNA at the time before R-CHOP treatment are associated with treatment response and that 5hmC-Seal may potentially serve as a clinical-applicable, minimally invasive approach to predict R-CHOP treatment response for DLBCL patients. | DNA Demethylation |
CONTEXT: Synonymous mutations are usually nonpathogenic. OBJECTIVE: We report here a family with X-linked hypophosphatemia (XLH) due to a novel synonymous PHEX variant with a unique mechanism. METHODS: We studied a 4-member family (a mother, a son, and 2 daughters), all affected with XLH. Genomic DNA was extracted from peripheral leucocytes. Whole exome sequencing (WES) was used to identify the underlying genetic variant in the proband (the son). Sanger sequencing was used to confirm this variant in the proband and his family members. RT-PCR and sequencing of the cDNA revealed the effect of this variant on the PHEX structure and function. RESULTS: A synonymous variant in the PHEX gene (c.1701A>C) was identified in all affected members. This variant changes the first nucleotide of exon 17 from adenine to cytosine. Using RT-PCR, this variant was shown to interfere with splicing of exons 16 with 17 resulting in a single shorter PHEX transcript in the proband compared to normal control. Sanger sequencing of the cDNA revealed a complete skipping of exon 17 and direct splicing of exons 16 and 18. This led to a frameshift and an introduction of a new stop codon in the next codon (codon 568), which ultimately led to truncation and loss of the final 183 amino acids of PHEX. CONCLUSION: This novel variant shows how a synonymous exonic mutation may induce a complex series of changes in the transcription and translation of the gene and causes a disease, a mechanism that is not commonly recognized." | PHEX Phosphate Regulating Neutral Endopeptidase |
Protein tyrosine phosphatases (PTPs) have been challenging targets for inhibitor design, because all PTPs share a highly conserved active site structure, which is positively charged and requires negatively charged moieties for tight binding. In this study, we developed cell-permeable bicyclic peptidyl inhibitors against T-cell PTP (TCPTP), which feature a cell-penetrating motif in one ring and a target-binding sequence in the second ring." | Protein Tyrosine Phosphatase, Non-Receptor Type 2 |
Numerous filling defects may be detected in the colon during interpretation of data sets obtained with computed tomographic (CT) colonography. A series of 230 patients were evaluated with thin-section multidetector row CT colonography immediately before conventional colonoscopy. In all cases, the interpreting radiologist and gastroenterologist reviewed the imaging findings as well as the results of histologic analysis of biopsy specimens to determine the causes of filling defects. In many cases, the cause of a filling defect can be confidently determined at CT colonography by using combinations of two- and three-dimensional images. However, lesions will occasionally be indeterminate because of overlapping features and will require further evaluation with endoscopy. With knowledge of the morphologic and attenuation characteristics of the various filling defects in the colon, one should be able to differentiate those filling defects detected at CT colonography that require no further evaluation from those that require endoscopic interrogation." | Colonography, Computed Tomographic |
For viruses to productively infect their hosts, they must evade or inhibit important elements of the innate immune system, namely the type I interferon (IFN) response, which negatively influences the subsequent development of antigen-specific adaptive immunity against those viruses. Dengue virus (DENV) can inhibit both type I IFN production and signaling in susceptible human cells, including dendritic cells (DCs). The NS2B3 protease complex of DENV functions as an antagonist of type I IFN production, and its proteolytic activity is necessary for this function. DENV also encodes proteins that antagonize type I IFN signaling, including NS2A, NS4A, NS4B and NS5 by targeting different components of this signaling pathway, such as STATs. Importantly, the ability of the NS5 protein to bind and degrade STAT2 contributes to the limited host tropism of DENV to humans and non-human primates. In this review, we will evaluate the contribution of innate immunity evasion by DENV to the pathogenesis and host tropism of this virus. | STAT2 Transcription Factor |
Breast cancer is the highest incidence of female malignant tumor in the world, and it shows an increasing trend year by year. It poses a great threat to women's life and health and has become a public health issue of global concern. Paying attention to the psychological response of cancer patients is of definite value in helping patients cope with the disease, return to society, reshape an active and healthy life, and improve their quality of life with cancer. In recent years, researchers have increasingly focused on the positive changes experienced by cancer patients from the perspective of positive psychology, namely post-traumatic growth. It is of great significance to explore individual and social resources to help patients grow and improve their survival ability and quality of life by paying attention to the potential resources and positive forces in the process of patients' fighting against diseases. This paper summarizes the influencing factors and intervention measures of post-traumatic growth of breast cancer patients, providing ideas and reference for clinical medical staff to carry out relevant intervention." | Posttraumatic Growth, Psychological |
Three cases of ruptured intracranial aneurysm during pregnancy are presented. Rupture occurred near term in all three cases. Simultaneous elective cesarean section and clipping of the aneurysm was performed in two cases. Successful maternal and perinatal outcome was achieved in all three patients. The diagnosis and management of the cases are described and discussed. | Aneurysm, Ruptured |
BACKGROUND: Previous analyses evaluating alvimopan included patients at varying risk for ileus after intestinal resection, which may have precluded its widespread adoption. We assess the early and delayed effects of alvimopan in patients stratified by risk for ileus after intestinal and colon resection. METHODS: From the Premier Perspective database, patients with elective small and large bowel resections from 2012 to 2014 were identified. Multivariable analysis identified 14 perioperative risk factors for postoperative ileus. Within low- (0-4 factors), intermediate- (5 factors), and high-risk (6-12 factors) ileus categories, alvimopan and no-alvimopan patients were propensity-score matched for demographics, morbidities, diagnosis, surgery and approach, postoperative complications, surgeon specialty, and hospital features. In-hospital postoperative ileus, length of stay, discharge destination, and ileus-related readmission were compared. RESULTS: Of 52,948 patients, 15,719 (29.7%) received alvimopan. Risk for ileus in low- (18,784), intermediate- (14,370), and high-risk (19,794) categories was 8.9, 13, and 22% (p </= .0001) respectively. After matching, alvimopan was associated with significantly reduced in-hospital postoperative ileus in all (low, 6%; intermediate, 9.4%; and high risk, 16.2%) categories. Hospital stay and 30-, 60-, and 90-day postdischarge ileus were also significantly lower with alvimopan. For low-risk patients, alvimopan increased discharge to home, while 90-day emergency readmission was reduced. CONCLUSIONS: Alvimopan, regardless of ileus risk, improves ileus, hospital stay, and ileus-related readmission after intestinal resection and these effects are sustained over the long term. Since fewer than a third of patients currently receive alvimopan, its routine adoption with small and large intestinal resection will significantly impact patients and health systems. | Ileus |
Patients treated with 10 mCi of I-131 for toxic diffuse goiter in the period January 1974--June 1976 were evaluated for development of hypothyroidism. Fifty percent were hypothyroid within 3 mo and 69% within 1 yr of treatment. Our data suggest that there is a higher incidence of hypothyroidism after standard doses of I-131 in the 1970s as contrasted with treatment groups in the 1950s and 1960s. The pathophysiology of this increased incidence is not known with certainty; however, infrequent use of thionamide medication, together with recent increases in dietary iodine, may render the gland more radiosensitive. | Methylthiouracil |
NEED AND PURPOSE OF REVIEW: Biliary atresia is a progressive obstructive cholangiopathy and is fatal if left untreated within 2 years of life. Delay in referral is because of difficulties in differentiating it from physiologic jaundice and identifying an abnormal stool color. This paper presents an overview on the diagnosis and discusses the current strategies in the management of this disease in developing countries. METHODS: Articles were retrieved from the PubMed database using the terms biliary atresia, Kasai portoenterostomy and pediatric liver transplantation. Contents of the article are also based on personal experience of the authors. CONCLUSION: A national screening program using stool color cards as part of standard care in the neonatal period will greatly improve early detection of biliary atresia. Outcomes will improve if it is diagnosed at the earliest after birth, the child is referred to an experienced pediatric hepatobiliary unit for evaluation, and undergoes an early Kasai procedure. If an early Kasai portoenterostomy is performed, nearly half of all children survive into adolescence, and about one-third are likely to have a long-term, symptom-free life with normal liver biochemistry. Sequential treatment combining Kasai as first line and liver transplantation as second line results in 90% survival for children with biliary atresia. | Biliary Atresia |
PURPOSE: To examine the outcomes of arthroscopic treatment of the hip in a young, active military population. Specifically, the ability to return to duty was the prime indicator of success. In addition, an objective evaluation of various demographic and surgery-related variables was performed to identify predictors for success or failure of treatment in this military population. METHODS: A retrospective chart review was undertaken to ascertain the results of hip arthroscopy at a single academic military medical center. A total of 206 patients underwent 223 hip arthroscopies during a 13-year period (2000-2013). Of these, 159 patients met the inclusion criteria, which included active duty military service and at least 12-month follow-up. Veterans Affairs Beneficiaries, active duty dependents, and those with less than 12 months of follow-up were excluded. Surgeries were performed by 1 of 5 fellowship-trained orthopaedic surgeons. Data were collected from the Armed Forces Health Longitudinal Technology Application, Electronic profiling system, and Physical Evaluation Board. RESULTS: A total of 159 patients were available for the study, 102 males and 57 females. The average age of the patients overall was 30.9 +/- 8.3 years (range, 18-52 years). Junior enlisted, which is considered entry level, made up 64.2% of the subjects. The most common diagnosis was femoroacetabular impingement, and the most common procedure performed was acetabuloplasty. Twenty-two percent of patients underwent evaluation by the medical retention board after hip arthroscopy and were separated from military service. Seventy-eight percent of soldiers were maintained on active duty after hip arthroscopy. The overall complication rate was 15.7%, with a major complication rate of 1.25% defined as femoral neck fracture, abdominal compartment syndrome, osteonecrosis, deep vein thrombosis and/or pulmonary embolus, and septic arthritis. Univariate analysis of risk factors showed the presence of a complication to be a significant predictor for failure to return to active duty (odds ratio [OR] 4.04, P = .0035) as was senior noncommissioned officer rank (OR 0.20, P = .0347). Multivariate analysis showed only the presence of a complication to be a significant predictor for failure to return to active duty (OR 3.71, P = .0083). CONCLUSIONS: Hip arthroscopy in a military population is effective in treating multiple causes and retaining soldiers on active duty status. Complications of any kind from surgery or postoperatively are significant predictors of medical separation and may warrant earlier initiation of a medical evaluation board. LEVEL OF EVIDENCE: Level IV, therapeutic case series. | Acetabuloplasty |
IgG4-related sclerosing cholangitis (IgG4-SC) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4-related disease. Although clinical diagnostic criteria of IgG4-SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4-SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions (CQs) with clinical statements were developed regarding diagnosis (14 CQs) and treatment (4 CQs). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4-SC. | Cholangitis, Sclerosing |
The velogenic Newcastle disease virus (NDV) causes highly infectious and economically significant Newcastle disease (ND) in birds of various species. In cell culture NDV induces cytopathic effect (CPE) characterized by rounding, vacuolation, syncytia formation and cell death. Aside from cell to cell fusion caused by the F and HN glycoprotein of the virus molecular events leading to cell death are not known. In the current study, NDV-infected Vero cells, at 48 h p.i., showed nuclear condensation, cytoplasm blebbing, DNA fragmentation, and phosphatidylserine translocation to the cell surface. In addition, virus-infected cells demonstrated decreased DNA content and an increased Bax to Bcl-2 ratio, p53 level and caspase 3, 8, 9 expression compared to mock-infected cells. Based on these results, it was concluded that CPE in NDV-infected cells was caused by to the induction of apoptosis with the involvement of p53 and the Bax, dependent apoptotic pathways. | Newcastle Disease |
An original method for the culture of granulosa and thecal cells of the domestic hen was developed and used to investigate the effects of serum, of EGF and of IGFI on the multiplication of these cell types and on their secretion of steroid hormones. The growth of the cultures (measured by the accumulation of DNA in the culture wells) over a 72 hour period was judged to be satisfactory although slower without serum. Both growth factors stimulated cell growth and EGF inhibited steroidogenesis in both cell types. IGFI inhibits the secretion of oestrogens by thecal cells but it stimulates the secretion of progesterone by granulosa cells towards the end of the period of culture. | Ovary |
Malonyl-thioesters are reactive centers of malonyl-CoA and malonyl- S-acyl carrier protein, essential to fatty acid, polyketide and various specialized metabolite biosynthesis. Enzymes that create or use malonyl-thioesters spontaneously hydrolyze or decarboxylate reactants on the crystallographic time frame preventing determination of structure-function relationships. To address this problem, we have synthesized a panel of methylmalonyl-CoA analogs with the carboxylate represented by a sulfonate or nitro and the thioester retained or represented by an ester or amide. Structures of Escherichia coli methylmalonyl-CoA decarboxylase in complex with our analogs affords insight into substrate binding and the catalytic mechanism. Counterintuitively, the negatively charged sulfonate and nitronate functional groups of our analogs bind in an active site hydrophobic pocket. Upon decarboxylation the enolate intermediate is protonated by a histidine preventing CO(2)-enolate recombination, yielding propionyl-CoA. Activity assays support a histidine catalytic acid and reveal the enzyme displays significant hydrolysis activity. Our structures also provide insight into this hydrolysis activity. Our analogs inhibit decarboxylation/hydrolysis activity with low micromolar K(i) values. This study sets precedents for using malonyl-CoA analogs with carboxyate isosteres to study the complicated structure-function relationships of acyl-CoA carboxylases, trans-carboxytransferases, malonyltransferases and beta-ketoacylsynthases. | Sulfonic Acids |
Sterectal is a new antihemorrhoidal drug which contains prednacinolone, lidocaine hidrochloride and ephedrine hidrochloride. The results of the double blind, between patient, clinical study carried out in order to detect effectiveness of Sterectal compared with placebo show that the new drug owns a more rapid onset of therapeutic activity and exhibits a greater reduction in symptom severity than placebo. Both treatments were well tolerated. | Desonide |
The clinical isolate Corynebacterium xerosis M82B carries the 50-kb R-plasmid pTP10 that confers resistance to the antibiotics chloramphenicol, kanamycin, erythromycin, and tetracycline. A detailed restriction map of pTP10 was constructed by cloning and analyzing restriction fragments of pTP10 in Escherichia coli. The resistance determinants of pTP10 were located by studying the phenotype of the recombinant plasmids in E. coli and Corynebacterium glutamicum. Restriction patterns of fragments encoding the kanamycin and erythromycin resistances revealed striking similarity to the kanamycin resistance of transposon Tn903 and the erythromycin resistance on plasmid pNG2 from Corynebacterium diphtheriae, respectively. Expression of the resistance determinants in E. coli and C. glutamicum ATCC 13032 led to high resistance levels in both strains, with the exception of the tetracycline resistance gene, which could be expressed only in C. glutamicum. Furthermore, the erythromycin resistance gene was found to be located on a transposable element which is functional in C. glutamicum strains. | Kanamycin Resistance |
BACKGROUND: Access to washroom facilities and a place to dispose of menstrual waste are prerequisites for optimal menstrual hygiene management in schools. Like other low- and middle-income countries, Bangladeshi schools lack facilities for girls to change and dispose of their menstrual absorbents. We explored existing systems for disposing of menstrual absorbent wastes in urban and rural schools of Bangladesh and assessed the feasibility and acceptability of alternative disposal options. METHODS: We explored how girls dispose of their menstrual products, identified girls' preferences and choices for a disposal system and piloted four disposal options in four different schools. We then implemented one preferred option in four additional schools. We explored girls', teachers', and janitors' perspectives and evaluated the acceptability, feasibility, and potential for sustainability of the piloted disposal system. RESULTS: Barriers to optimal menstrual hygiene management included lack of functional toilets and private locations for changing menstrual products, and limited options for disposal. Girls, teachers, and janitors preferred and ranked the chute disposal system as their first choice, because it has large capacity (765 L), is relatively durable, requires less maintenance, and will take longer time to fill. During implementation of the chute disposal system in four schools, girls, teachers, and janitors reported positive changes in toilet cleanliness and menstrual products disposal resulting from the intervention. CONCLUSIONS: The chute disposal system for menstrual products is a durable option that does not require frequent emptying or regular maintenance, and is accepted by schoolgirls and janitors alike, and can improve conditions for menstrual hygiene management in schools. However, regular supervision, motivation of girls to correctly dispose of their products, and a long-term maintenance and management plan for the system are necessary. | Menstrual Hygiene Products |
Crop contamination by mycotoxins is a global problem that poses significant economic burdens due to the food/feed losses that are caused by reduced production rates; the resulting adverse effects on human and animal health and productivity; and the trade losses associated with the costs incurred by inspection, sampling, and analysis before and after shipments [...]. | Mycotoxins |
The oil extracted from the bean of Balanites aegyptiaca was characterized, and its photochemical and thermal stabilization were evaluated. The chemical composition was determined using gas chromatography (GC), revealing that the oil is very rich in unsaturated fatty acids (72% omega-6 and omega-9). The photochemical stability was assessed by subjecting it to artificially accelerated photo-aging and then examining the changes using infrared spectroscopy. The thermal stability was studied at six different temperatures ranging from 130 to 200 degrees C and monitored in situ by differential scanning calorimetry (DSC). The kinetic parameters (EA and k) describing the thermal degradation of this oil were calculated. It has been shown that the antioxidants present in the oil delay the oxidation process (induction period). The degradation of the Toogga oil was compared with that of oleic and linoleic fatty acids. In addition, the degradation of the Toogga oil extracted with hexane was compared to that of the neat oil. | Balanites |
Glycolipid transfer proteins (GLTPs) are small (24 kDa), soluble, ubiquitous proteins characterized by their ability to accelerate the intermembrane transfer of glycolipids in vitro. GLTP specificity encompasses both sphingoid- and glycerol-based glycolipids, but with a strict requirement that the initial sugar residue be beta-linked to the hydrophobic lipid backbone. The 3D architecture of GLTP reveals liganded structures with unique lipid-binding modes. The biochemical properties of GLTP action at the membrane surface have been studied rather comprehensively, but the biological role of GLTP remains enigmatic. What is clear is that GLTP differs distinctly from other known glycolipid-binding proteins, such as nonspecific lipid transfer proteins, lysosomal sphingolipid activator proteins, lectins, lung surfactant proteins as well as other lipid-binding/transfer proteins. Based on the unique conformational architecture that targets GLTP to membranes and enables glycolipid binding, GLTP is now considered the prototypical and founding member of a new protein superfamily in eukaryotes. | Lactosylceramides |
Recent years have seen renewed interest in the permeability transition pore, a high conductance channel responsible for permeabilization of the inner mitochondrial membrane, a process that leads to depolarization and Ca(2+) release. Transient openings may be involved in physiological Ca(2+) homeostasis while long-lasting openings may trigger and/or execute cell death. In this review we specifically focus (i) on the hypothesis that the PTP forms from the F-ATP synthase and (ii) on the mechanisms through which Ca(2+) can reversibly switch this energy-conserving nanomachine into an energy-dissipating device." | Mitochondrial Proton-Translocating ATPases |
We report 4 cases of acute corneal edema with subsequent thinning and hyperopic shift following routine selective laser trabeculoplasty (SLT) for the treatment of primary open-angle glaucoma. Four women from 3 clinical sites developed acute corneal edema and haze within 2 days of uneventful SLT. In the following weeks to months, all treated corneas thinned to below pre-procedure thicknesses with resultant hyperopic shifts of nearly 2.0 diopters (D) to greater than 6.0 D. All eyes were moderately to highly myopic prior to SLT (spherical equivalent from -5.00 to -12.5 D). The corrected distance visual acuity 6 to 11 months after SLT was within 2 Snellen lines of the pre-procedure acuity in all patients; 2 patients required contact lenses. Corneal edema with subsequent corneal thinning and resultant hyperopic shift is an uncommon but possibly underrecognized complication of SLT, the etiology of which remains unknown but may be associated with moderate to high myopia. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. | Corneal Edema |
INTRODUCTION: Spinal cord stimulation is an effective method of treatment for chronic pain. We previously showed that programming using accelerometry was advantageous for paresthesia-based stimulation. However, programming can be labor intensive. OBJECTIVE: Here we focus on standardized programming for both accelerometer-based paresthesia-induced programming (termed shuffle") and high-dose (HD) subthreshold programming with stimulation delivered over the T9-10 interspace. METHODS: In this prospective cross-over study, patients received 4 weeks of shuffle programming and 4 weeks of HD programming in a randomized order. In both intervals, contacts overlying T9-10 were programmed. Pain scales with measurements of activity and sleep were collected at the end of each study arm and compared with preoperative baseline scores. RESULTS: Twelve patients were enrolled, with 10 patients completing this study. Compared with baseline, during the HD study period, significant improvements were seen in worst pain of week (P = 0.03) and current pain (P = 0.04) as rated on Numeric Rating Scale scores and walking on the Activity Test (P = 0.012). No difference was seen from baseline compared with shuffle stimulation or in shuffle stimulation compared with HD stimulation. CONCLUSION: In this pilot study, we demonstrated that HD stimulation at T9-10 is superior to algorithmic programming of paresthesia-based stimulation. These results compared with our previous work with shuffle suggest that paresthesia-based stimulation may necessitate stimulation of additional contact locations and additional programming to optimize. This algorithmic programming of paresthesia-based stimulation continues to warrant exploration." | Paresthesia |
BACKGROUND: Treatments currently used for patients with myasthenia gravis (MG) include steroids, non-steroid immune suppressive agents, plasma exchange, intravenous immunoglobulin and thymectomy. Data from randomized controlled trials (RCTs) support the use of some of these therapeutic modalities and the evidence for non-surgical therapies are the subject of other Cochrane reviews. Significant uncertainty and variation persist in clinical practice regarding the potential role of thymectomy in the treatment of people with MG. OBJECTIVES: To assess the efficacy and safety of thymectomy in the management of people with non-thymomatous MG. SEARCH METHODS: On 31 March 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2013, Issue 3), MEDLINE (January 1966 to March 2013), EMBASE (January 1980 to March 2013) and LILACS (January 1992 to March 2013) for RCTs. Two authors (RS and GC) read all retrieved abstracts and reviewed the full texts of potentially relevant articles. These two authors checked references of all manuscripts identified in the review to identify additional articles that were of relevance and contacted experts in the field to identify additional published and unpublished data. Where necessary, authors were contacted for further information. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of thymectomy against no treatment or any medical treatment, and thymectomy plus medical treatment against medical treatment alone, in people with non-thymomatous MG.We did not use measured outcomes as criteria for study selection. DATA COLLECTION AND ANALYSIS: We planned that two authors would independently extract data onto a specially designed data extraction form and assess risk of bias; however, there were no included studies in the review. We would have identified any adverse effects of thymectomy from the included trials. MAIN RESULTS: We did not identify any RCTs testing the efficacy of thymectomy in the treatment of MG. In the absence of data from RCTs, we were unable to do any further analysis. AUTHORS' CONCLUSIONS: There is no randomized controlled trial literature that allows meaningful conclusions about the efficacy of thymectomy on MG. Data from several class III observational studies suggest that thymectomy could be beneficial in MG. An RCT is needed to elucidate if thymectomy is useful, and to what extent, in MG. | Myasthenia Gravis |
BACKGROUND: Insulin receptors are widely expressed in the brain and may represent a crossroad between metabolic and cognitive disorders. Although antipsychotics, such as olanzapine, are the cornerstone treatment for schizophrenia, they are associated with high rates of type 2 diabetes and lack efficacy for illness-related cognitive deficits. Historically, this risk of diabetes was attributed to the weight gain propensity of antipsychotics, but recent work suggests antipsychotics can have weight-independent diabetogenic effects involving unknown brain-mediated mechanisms. Here, we examined whether antipsychotics disrupt central insulin action, hypothesizing that olanzapine would impair the well-established ability of central insulin to supress hepatic glucose production. METHODS: Pancreatic euglycemic clamps were used to measure glucose kinetics alongside a central infusion of insulin or vehicle into the third ventricle. Male rats were pretreated with olanzapine or vehicle per our established model of acute olanzapine-induced peripheral insulin resistance. Groups included (central-peripheral) vehicle-vehicle (n = 11), insulin-vehicle (n = 10), insulin-olanzapine (n = 10) and vehicle-olanzapine (n = 8). RESULTS: There were no differences in peripheral glucose or insulin levels. Unexpectedly, we showed that central insulin increased glucose uptake, and this effect was not perturbed by olanzapine. We replicated suppression of glucose production by insulin (clamp relative to basal: 77.9% +/- 13.1%, all p < 0.05), an effect abolished by olanzapine (insulin-olanzapine: 7.7% +/- 14%). LIMITATIONS: This study used only male rats and an acute dose of olanzapine. CONCLUSION: To our knowledge, this is the first study suggesting olanzapine may impair central insulin sensing, elucidating a potential mechanism of antipsychotic-induced diabetes and opening avenues of investigation related to domains of schizophrenia psychopathology. | Subcutaneous Absorption |
Some of the readjustment problems of Vietnam veterans have been attributed to posttraumatic stress disorder (PTSD). This case-control study compared demographic and military characteristics of 374 Vietnam veterans who had PTSD with 373 healthy Vietnam veterans. Veterans were chosen from the Agent Orange Registry, a Department of Veterans Affairs computerized database of approximately 200,000 Vietnam veterans who volunteered for a physical examination. Case patients and control subjects were frequently-matched by age, year of Registry examination, and race. Crude odds ratios (OR) were used to evaluate the risk of PTSD associated with certain characteristics of Vietnam service, as there was no apparent confounding by other military factors. Being wounded in Vietnam (OR, 2.33; 95% confidence interval (CI), 1.49-3.65) and having a combat job in Vietnam (OR, 1.54; 95% CI, 1.15-2.06) were the only risk factors for PTSD. Those who had noncombat jobs but were wounded had the highest risk of PTSD (OR, 3.56; 95% CI, 1.26-10.06). | Defoliants, Chemical |
This paper is the fourth of a five-part series that describes the principles of construction and evaluation of valid decision models. In this review, the authors describe the key principles of detecting and eliminating structural and programming errors in decision trees (debugging). In addition, they offer guidelines to facilitate the interpretation of analytic results of decision models. | Decision Support Techniques |
Tics wax and wane in severity. Although the understanding of the natural course of symptoms in tic disorder (TD) is important for planning and assessing therapeutic interventions, neurophysiological mechanisms and predictors of tic exacerbation and remission have not been sufficiently investigated. In each of seven children suffering from TD, contingent negative variation (CNV) was recorded on 10 occasions over a period of 2 months. CNV parameters of children with TD were compared with CNV data of healthy, age-matched children. During the entire time of observation, tic severity was assessed by parents and the investigator using a scale developed from the Yale Global Tic Severity Scale. Moreover, tic severity was also evaluated using video assessments. Patients with TD were characterized by significantly lower amplitude of the total CNV and more pronounced habituation of the early CNV component as compared to healthy children. Correlation analysis between tic severity and CNV parameters demonstrated that the more severe the tics were, the lower the amplitude of the total CNV. Since CNV amplitude represents processes of resource mobilization and control over neuronal excitability, tic severity may result from less ability to control neurophysiological functions in patients with TD. | Contingent Negative Variation |
The metal resistance of 350 subsurface bacterial strains from two U.S. Department of Energy facilities, the Savannah River Site (SRS), South Carolina, and the Hanford site, Washington, was determined to assess the effect of metal toxicity on microorganisms in the deep terrestrial subsurface. Resistance was measured by growth inhibition around discs containing optimized amounts of Hg(II), Pb(II), and Cr(VI). A broad range of resistance levels was observed, with some strains of Arthrobacter spp. demonstrating exceptional tolerance. A higher level of resistance to Hg(II) and Pb(II) (P < 0.05) and a higher occurrence of multiple resistances suggested that metals more effectively influenced microbial evolution in subsurface sediments of the SRS than in those of the Hanford site. Common resistance to heavy metals suggests that toxic metals are unlikely to inhibit bioremediation in deep subsurface environments that are contaminated with mixed wastes. | Bacteria, Aerobic |
BACKGROUND: The Royal College of Pathologists of Australasia Cytopathology Quality Assurance Program has operated an external quality assurance program in nongynecologic cytopathology since 1993. Glass slide preparations of a wide range of nongynecologic cases were circulated to approximately 200 cytopathology laboratories in 16 countries. METHODS: General nongynecologic cytology cases were manufactured from residual specimens after routine diagnosis. Fine-needle aspiration (FNA) cases were made by sampling fresh tissue and making direct specimens. The majority of cases consisted of both air-dried and fixed preparations. Results returned to laboratories included illustrated case discussions highlighting diagnostic features, key differential diagnoses, and useful adjunctive tests. RESULTS: The current study reviewed >22,000 results for 123 nongynecologic cases. Cases found to cause the most diagnostic difficulties included serous effusion cases with metastatic carcinoma in a dispersed pattern, well-differentiated carcinoma, and cellular reactive cases; urine specimens with sparse malignant cells; reactive pneumocytes in a bronchoalveolar lavage; breast FNA cases with papillary lesions; gestational specimens; and fibroadenoma. FNA specimens from the lung and thyroid, particularly papillary thyroid carcinoma, generally were well reported. CONCLUSIONS: The use of multiple preparations of the same specimen has allowed interlaboratory comparison, and the quality assurance program has played an educational role as well as informing the laboratory accreditation process. Cancer Cytopathol 2017;125:349-361. (c) 2017 American Cancer Society. | Pericardial Fluid |
Pertussis toxin, an ADP-ribosylating toxin, interacts with vertebrate cells of many types and inhibits the ability of these cells to respond to certain hormones and neurotransmitters, resulting in a multitude of biological effects. The structure and mechanism of action of this toxin are described. | Virulence Factors, Bordetella |
Regulatory differences between countries are an important driver of the cross-border trade in assisted reproduction as people move to seek services unavailable in their home countries. The development of a lucrative global trade in non-medical sex selection needs to be considered in ethical debates over its availability. I suggest that depictions of non-medical sex selection as a means of 'family balancing' or supportive of reproductive autonomy serve to distance the technologies rhetorically from the gender stereotyping inherent in their use and the commodification upon which they depend. They construct new social categories such as the 'unbalanced' family, the pathologization of 'gender disappointment' and a limited and highly individualized definition of reproductive freedom that permits medical interventions on healthy bodies. Orientalism pervades ethical debate depicting non-medical sex selection in the West as more acceptable to practices in 'Asia'. A case study of the interconnections between Australia and Thailand highlights the global economy sustaining the practice. | Commodification |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.