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This investigation found that genetic inactivation of mouse Atg4b, 1 of the 4 mammalian homologs of the autophagy-related gene Atg4, resulted in amorphous globular bodies in the neuropil of the deep cerebellar nuclei and adjacent vestibular nuclei but nowhere else in the brain or other tissues. The spheroid-like bodies in the deep cerebellar and vestibular nuclei showed heterogeneous composition, reactivity with anti-ubiquitin antibody, and staining characteristics of proteinaceous material. Atg4b-deficient (Atg4b (-/-)) mice also showed a mild but measurable impairment of motor performance on the Rotarod. Atg4b (-/-) mice produced by breeding heterozygous parents were produced at a slightly lower than expected ratio to heterozygous and wild-type siblings but showed no other clear abnormalities in a battery of screening tests. These findings appear to be different than those reported for inactivation of other Atg4 homologs, suggesting that these homologs have tissue-specific functions beyond redundancy. | Rotarod Performance Test |
Fibroblast growth factor 5 (FGF5) is an important molecule required for the transition from anagen to catagen phase of the mammalian hair cycle. We previously reported that Syrian hamsters harboring a 1-bp deletion in the Fgf5 gene exhibit excessive hair growth in males. Herein, we generated Fgf5 mutant mice using genome editing via oviductal nucleic acid delivery (GONAD)/improved GONAD (i-GONAD), an in vivo genome editing system used to target early embryos present in the oviductal lumen, to study gender differences in hair length in mutant mice. The two lines (Fgf5go-malc), one with a 2-bp deletion (c.552_553del) and the other with a 1-bp insertion (c.552_553insA) in exon 3 of Fgf5, were successfully established. Each mutation was predicted to disrupt a part of the FGF domain through frameshift mutation (p.Glu184ValfsX128 or p.Glu184ArgfsX128). Fgf5go-malc1 mice had heterogeneously distributed longer hairs than wild-type mice (C57BL/6J). Notably, this change was more evident in males than in females (p < 0.0001). Immunohistochemical analysis revealed the presence of FGF5 protein in the dermal papilla and outer root sheath of the hair follicles from C57BL/6J and Fgf5go-malc1 mice. Histological analysis revealed that the prolonged anagen phase might be the cause of accelerated hair growth in Fgf5go-malc1 mice. | Fibroblast Growth Factor 5 |
Animals sense light primarily by an opsin-based photopigment present in a photoreceptor cell. Cnidaria are arguably the most basal phylum containing a well-developed visual system. The evolutionary history of opsins in the animal kingdom has not yet been resolved. Here, we study the evolution of animal opsins by genome-wide analysis of the cubozoan jellyfish Tripedalia cystophora, a cnidarian possessing complex lens-containing eyes and minor photoreceptors. A large number of opsin genes with distinct tissue- and stage-specific expression were identified. Our phylogenetic analysis unequivocally classifies cubozoan opsins as a sister group to c-opsins and documents lineage-specific expansion of the opsin gene repertoire in the cubozoan genome. Functional analyses provided evidence for the use of the Gs-cAMP signaling pathway in a small set of cubozoan opsins, indicating the possibility that the majority of other cubozoan opsins signal via distinct pathways. Additionally, these tests uncovered subtle differences among individual opsins, suggesting possible fine-tuning for specific photoreceptor tasks. Based on phylogenetic, expression and biochemical analysis we propose that rapid lineage- and species-specific duplications of the intron-less opsin genes and their subsequent functional diversification promoted evolution of a large repertoire of both visual and extraocular photoreceptors in cubozoans. | Cubozoa |
OBJECTIVE: Using uniform thresholds and a set of variable threshold levels, this study examined the incidence of catastrophe amongst households of different socio-economic status (SES) quintiles. METHODS: A household diary was used to collect illness and household consumption expenditure data from 1128 households over 1 month. Catastrophic health expenditure was examined based on uniform threshold levels of non-food expenditure and a novel set of variable thresholds in which the levels for various SES groups were weighted by the ratio of household expenditure on food. RESULTS: A total of 167 households (14.8%) experienced catastrophe at a non-food expenditure threshold of 40%, with 22.6% and 7.6% of the poorest and richest household quintiles experiencing catastrophe. For the first set of variable scenarios, the thresholds for the poorest and richest household quintiles were 5% and 29.6% and levels of catastrophe were 44.7% and 12.0%, respectively, while the overall level was 36.5%. In the second scenario, the thresholds were 6.8% and 40%, and the levels of catastrophe were 42.5% and 7.6%, respectively, while the overall level was 32.0%. CONCLUSIONS: High levels of catastrophic expenditure exist in Nigeria. Use of variable thresholds to measure catastrophe led to higher overall and disaggregated levels of catastrophe. Such a measure is argued to be more appropriate for the examination of catastrophe. | Catastrophic Illness |
INTRODUCTION: There is an emerging need for telecytology in Colombia as the demand for cytopathology has increased. However, due to economic and technological constraints telecytology services are limited. Our aim was to evaluate the diagnostic feasibility of using whole slide imaging with and without Z-stacking for telecytology in Colombia, South America. METHODS: Archival glass slides from 17 fine needle aspiration smears were digitized employing whole slide imaging (WSI) (Nanozoomer 2.0 HT, Hamamatsu) in one Z-plane at 40x, and panoramic digital imaging (Panoptiq system, ViewsIQ) combining low-magnification digital maps with embedded 40x Z-stacks of representative regions of interest. Fourteen Colombian pathologists reviewed both sets of digital images. Diagnostic concordance, time to diagnosis, image quality (scale 1-10), usefulness of Z-stacking, and technical difficulties were recorded. RESULTS: Image quality scored by pathologists was on average 8.3 for WSI and 8.7 for panoramic images with Z-stacks (P = .03). However, diagnostic concordance was not impacted by image quality ranking. In the majority of cases (72.4%) pathologists deemed Z-stacking to be diagnostically helpful. Technical issues related to Z-stack video performance constituted only a minor proportion of technical problems reported. Slow downloads and crashing of files while viewing were mostly experienced with larger WSI files. CONCLUSION: This study demonstrated that international telecytology for diagnostic purposes is feasible. Panoramic images had to be acquired manually, but were of suitable diagnostic quality and generated smaller image files associated with fewer technical errors. Z-stacking proved to be useful in the majority of cases and is thus recommended for telecytology. | Telepathology |
BACKGROUND: ADPH oxidase-derived reactive oxygen species (ROS) play important roles in redox homeostasis and signal transduction in endothelial cells (ECs). We previously demonstrated that c-Src plays a key role in VEGF-induced, ROS-dependent selective activation of PI3K-Akt but not PLCgamma-1-ERK1/2 signaling pathways. The aim of the present study was to understand how VEGFR-2-c-Src signaling axis 'senses' NADPH oxidase-derived ROS levels and couples VEGF activation of c-Src to the redox state of ECs. METHODOLOGY/PRINCIPAL FINDINGS: Using biotinylated probe that detects oxidation of cysteine thiol (cys-OH) in intracellular proteins, we demonstrate that VEGF induced oxidative modification in c-Src and VEGFR-2, and that reduction in ROS levels using siRNA against p47(phox) subunit of Rac1-dependent NADPH oxidase inhibited this phenomenon. Co-immunoprecipitation studies using human coronary artery ECs (HCAEC) showed that VEGF-induced ROS-dependent interaction between VEGFR-2 and c-Src correlated with their thiol oxidation status. Immunofluorescence studies using antibodies against internalized VEGFR-2 and c-Src demonstrated that VEGF-induced subcellular co-localization of these tyrosine kinases were also dependent on NADPH oxidsase-derived ROS. CONCLUSION/SIGNIFICANCE: These results demonstrate that VEGF induces cysteine oxidation in VEGFR-2 and c-Src in an NADPH oxidase-derived ROS-dependent manner, suggesting that VEGFR-2 and c-Src can 'sense' redox levels in ECs. The data also suggest that thiol oxidation status of VEGFR-2 and c-Src correlates with their ability to physically interact with each other and c-Src activation. Taken together, these findings suggest that prior to activating downstream c-Src-PI3K-Akt signaling pathway, VEGFR-2-c-Src axis requires an NADPH oxidase-derived ROS threshold in ECs. | Genes, src |
Human carbonyl reductases 1 and 3 (CBR1 and CBR3) are monomeric NADPH-dependent enzymes of the short-chain dehydrogenase/reductase superfamily. Despite 72% identity in primary structure they exhibit substantial differences in substrate specificity. Recently, the endogenous low molecular weight S-nitrosothiol S-nitrosoglutathione (GSNO) has been added to the broad substrate spectrum of CBR1. The current study initially addressed whether CBR3 could equally reduce GSNO which was not the case. Neither the introduction of residues which contribute to glutathione binding in CBR1, i.e. K106Q and S97V/D98A, nor the exchange C143S, which prevents a theoretical disulfide bond with C227 in CBR3, could engender activity towards GSNO. However, exchanging amino acids 236-244 in CBR3 to correspond to CBR1 was sufficient to engender catalytic activity towards GSNO. Catalytic efficiency was further improved by the exchanges Q142M, C143S, P230W and H270S. Hence, the same residues previously reported as important for reduction of carbonyl compounds appear to be key to CBR1-mediated reduction of GSNO. Furthermore, for CBR1-mediated reduction of GSNO, considerable substrate inhibition at concentrations >5 K(m) was observed. Treatment of CBR1 with GSNO followed by removal of low molecular weight compounds decreased the GSNO reducing activity, suggesting a covalent modification. Treatment with dithiothreitol, but not with ascorbic acid, could rescue the activity, indicating S-glutathionylation rather than S-nitrosation as the underlying mechanism. As C227 has previously been identified as the reactive cysteine in CBR1, the variant CBR1 C227S was generated, which, in comparison to the wild-type protein, displayed a similar k(cat), but a 30-fold higher K(m), and did not show substrate inhibition. Collectively, the results clearly argue for a physiological role of CBR1, but not for CBR3, in GSNO reduction and thus ultimately in regulation of NO signaling. Furthermore, at higher concentrations, GSNO appears to work as a suicide inhibitor for CBR1, probably through glutathionylation of C227. | S-Nitrosoglutathione |
Interferon regulatory factor-1 (IRF-1) plays important roles in host immunity, cell proliferation and apoptosis. The current GenBank sequence for human IRF-1 (accession number: L05072) was derived from a human placenta DNA library and reported in 1992. In one recent population-based sequence study, we observed consistent discrepancies between our IRF-1 sequence data and GenBank reference sequences suggesting that, current IRF-1 reference sequence was not representative for all populations. By complete gene sequencing, we obtained a representative full-length IRF-1 sequence from a single subject. Compared to submission L05072, our population-based data contains: 35 nucleotide additions, 8 nucleotide removals and another 12 nucleotide replacements. A single nucleotide difference was observed in the IRF-1 promoter sequence compared to GenBank sequence (X53095). These changes were confirmed in 350 Kenyans and 28 non-African donors. The accuracy of a reference sequence is crucial for downstream genetic and functional studies and this study provides more complete and accurate data on the sequence of the human IRF-1 gene and its immediate promoter region." | Interferon Regulatory Factor-1 |
OBJECTIVE: The study contributes to human reliability analysis (HRA) by proposing a method that focuses more on human error causality within a sociotechnical system, illustrating its rationality and feasibility by using a case of the Minuteman (MM) III missile accident. BACKGROUND: Due to the complexity and dynamics within a sociotechnical system, previous analyses of accidents involving human and organizational factors clearly demonstrated that the methods using a sequential accident model are inadequate to analyze human error within a sociotechnical system. METHODS: System-theoretic accident model and processes (STAMP) was used to develop a universal framework of human error causal analysis. To elaborate the causal relationships and demonstrate the dynamics of human error, system dynamics (SD) modeling was conducted based on the framework. RESULTS: A total of 41 contributing factors, categorized into four types of human error, were identified through the STAMP-based analysis. All factors are related to a broad view of sociotechnical systems, and more comprehensive than the causation presented in the accident investigation report issued officially. Recommendations regarding both technical and managerial improvement for a lower risk of the accident are proposed. CONCLUSION: The interests of an interdisciplinary approach provide complementary support between system safety and human factors. The integrated method based on STAMP and SD model contributes to HRA effectively. APPLICATION: The proposed method will be beneficial to HRA, risk assessment, and control of the MM III operating process, as well as other sociotechnical systems. | Causality |
BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) has been associated with vascular tone and blood pressure (BP), however, its role in the genesis of hypertension remains elusive. In the present study, we investigated the regulating effect of CFTR on angiotensin II (Ang II) -induced hypertension and defined the molecular role of CFTR in vasoconstriction. RESULTS: We found that CFTR mRNA and protein expression were markedly down-regulated in the arteries from Ang II induced hypertensive animals. During the development of hypertension, BP of Cftr-â£/- mice was significantly higher than that of Cftr+â£/+ mice. Arteries from Cftr-â£/- mice or pre-incubated with CFTR specific inhibitor CFTR(inh)-172 exhibited a greater contractile response to Ang II. In vascular smooth muscle cells (VSMCs), the phosphorylation of myosin light chain (MLC), which is the core of VSMCs contraction, was negatively modulated by CFTR. Furthermore, intracellular Ca2+ concentration ([Ca2+]i) rise in response to Ang II was negatively modulated by CFTR, while no alteration was observed in resting VSMCs. Ras homolog family member A/Rho-associated protein kinase (RhoA/Rock) mediated phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a regulator of MLC phosphorylation, was negatively modulated by CFTR in both resting and Ang II-stimulated VSMCs. CONCLUSIONS: This study demonstrates that CFTR is a negative regulator of vasoconstriction and hypertension, and the underlying mechanism contains two possible pathways: (1) in resting VSMCs, CFTR altered MLC phosphorylation through RhoA/Rock pathway; (2) in Ang II stimulated VSMCs, the regulating effect was mediated by both Ca2+ influx and RhoA/Rock mediated pathway. | Mice, Inbred CFTR |
AIM: The aim of the present study was to compare the efficacy of herbal mouthwash and chlorine dioxide mouthwash in reduction of plaque and gingivitis. SETTINGS AND DESIGN: In a randomized clinical trial, forty patients were randomly selected and divided equally into two groups. MATERIALS AND METHODS: After professional oral prophylaxis, the clinical parameters plaque index, gingival index, and modified sulcular bleeding index were recorded at baseline, 7(th) day, 14(th) day, and 21(st) day. The plaque samples were collected from gingival sulcus with an absorbent sterile paper point and were stored in a thioglycollate broth, then sent for microbiological examination. The microbial colony-forming units were assessed at baseline, 7(th) day, 14(th) day, and 21(st) day for Streptococcus mutans, Tannerella forsythia, and Fusobacterium nucleatum. RESULTS: There was a statistical significant reduction in both clinical and microbiological parameters were observed with use of both the mouthwashes. However, herbal mouthwash was more effective in reducing the plaque and gingivitis than chlorine dioxide mouthwash. CONCLUSION: Herbal mouthwash was statistically efficacious in controlling plaque and gingivitis with potent antimicrobial activity. | Tannerella forsythia |
The synthesis of (4S-phenylpyrrolidin-2R-yl)methanol and 2S-methyl-4S-phenylpyrrolidine has been achieved via the double reduction of their cyclic sulfonamide precursors which themselves were prepared following the stereoselective intramolecular Heck reaction of a chiral pool derived 2,5-dihydropyrrole. We have recently described a process whereby cyclic aryl sulfonamides, such as 2, are reductively ring-opened to furnish amino products in which the aryl group is incorporated in the final compound. (Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7, 43.) The precursors for this reaction were assembled using an intramolecular Heck reaction followed by reduction of the alkene. Overall, this sequence represents an efficient means to construct molecules of this type in which the aryl sulfonyl moiety acts as both an N-protecting group and as an aryl donor. Use of Benkeser's stronger reducing conditions enables molecules such as 4 to be prepared in which both the sulfonamide functional group and the aromaticity of the aryl substituent have been destroyed. | Methanol |
We investigated individual toxicities of the nitrogen-based energetic materials (EMs) 2,4-dinitrotoluene (2,4-DNT); 2-amino-4,6-dinitrotoluene (2-ADNT); 4-amino-2,6-dinitrotoluene (4-ADNT); and nitroglycerin (NG) on microbial activity in Sassafras sandy loam (SSL) soil, which has physicochemical characteristics that support very high qualitative relative bioavailability for organic chemicals. Batches of SSL soil for basal respiration (BR) and substrate-induced respiration (SIR) assays were separately amended with individual EMs or acetone carrier control. Total microbial biomass carbon (biomass C) was determined from CO(2) production increases after addition of 2500 mg/kg of glucose-water slurry to the soil. Exposure concentrations of each EM in soil were determined using US Environmental Protection Agency method 8330A. Basal respiration was the most sensitive endpoint for assessing the effects of nitroaromatic EMs on microbial activity in SSL, whereas SIR and biomass C were more sensitive endpoints for assessing the effects of NG in soil. The orders of toxicity (from greatest to least) were 4-ADNT > 2,4-DNT = 2-ADNT > NG for BR; but for SIR and biomass C, the order of toxicity was NG > 2,4-DNT > 2-ADNT = 4-ADNT. No inhibition of SIR was found up to and including the greatest concentration of each ADNT tested in SSL. These ecotoxicological data will be helpful in identifying concentrations of contaminant EMs in soil that present acceptable ecological risks for biologically mediated processes in soil. Environ Toxicol Chem 2017;36:2981-2990. Published 2017 Wiley Periodicals Inc. on behalf of SETAC.This article is a US government work and, as such, is in the public domain in the United States of America. | Sassafras |
A schistosomiasis control project was undertaken from 1994 to 1998 in Guruve District, Zimbabwe, based on the active involvement of local communities in the growing and application of the molluscicidal plant Phytolacca dodecandra as a supplement to other control measures such as chemotherapy and health education. The berries of P. dodecandra are highly molluscicidal to the intermediate host snails of schistosomiasis and is rapidly degradable in water. It was observed that plant care fluctuated during the study period. Only a few households participated in snail control activities, although 97% of respondents in a baseline survey had stated a willingness to take part. This invoked an investigation to explore the reality from a user perspective. Focus group discussions, semi-structured interviews and observations were used to solicit information. In spite of a cultural inclination for collective work, many reasons for low-level involvement emerged, inter alia the low perceived value of the project, demands for tangible benefits, inaccessible fields and weak leadership. This study shows that community participation is a complex process upon which a multiplicity of social and cultural determinants have an impact. If community participation is to become successful in development programmes it ought to be viewed as a mutual learning process where obstacles are identified and discussed and solutions shared among community members and project staff. | Phytolacca dodecandra |
Perfluorooctane sulfonate (PFOS) is a pollutant widely found throughout nature and is toxic to animals. We created a PFOS analogue on a polyethylene glycol polyacrylamide copolymer and isolated peptides that preferentially bound the PFOS analogue using a T7 phage display system. Bioinformatic analysis using the FASTAskan program on the RELIC bioinformatics server showed several human proteins that likely bound PFOS. Among them, we confirmed binding between PFOS and a recombinant soluble form of monocyte differentiation antigen CD14 (sCD14) by a surface plasmon biosensor. Furthermore, PFOS inhibited TNF-alpha production induced by the sCD14 in mouse macrophage RAW264.7 cells. | Lipopolysaccharide Receptors |
Hydrogen sulfide (H(2)S) plays an important role in the plant salt stress response. The main component of salt stress is neutral salt (NaCl); NaHCO(3) and Na(2)CO(3) play a key role in soil alkaline due to the influence of pH. Malus hupehensis Rehd. var. pingyiensis Jiang (Pingyi Tiancha, PYTC) is a salt-sensitive apple rootstock. Seedlings of PYTC pretreated with NaHS (an H(2)S donor) were exposed to an alkaline salt solution, and then the plant growth, root architecture, oxidative damage, Na(+)/K(+) homeostasis and gene expression of MhSOS1 and MhSKOR were investigated. The results showed that NaHS pretreatment increased the endogenous H(2)S content in seedlings, significantly alleviated the alkaline salt stress-induced growth inhibition and oxidative damage by inducing antioxidant enzymes activities, and sustained the root activity and root architecture of PYTC in the alkaline salt solution. NaHS pretreatment significantly decreased the root Na(+) content and increased K(+) content to maintain the homeostasis of Na(+)/K(+), and effect the expression of MhSOS1 and MhSKOR at the transcription level in the presence of the alkaline salt. Our study reveals that application of H(2)S could mitigate the toxic effect of alkaline salt stress on Malus hupehensis seedlings, thus providing a foundation for improved plant tolerance to alkaline salt stress. | Malus |
X-chromosome inactivation is established during early development. In mice, transcriptional repression of the paternal X-chromosome (Xp) and enrichment in epigenetic marks such as H3K27me3 is achieved by the early blastocyst stage. X-chromosome inactivation is then reversed in the inner cell mass. The mechanisms underlying Xp reactivation remain enigmatic. Using in vivo single-cell approaches (allele-specific RNAseq, nascent RNA-fluorescent in situ hybridization and immunofluorescence), we show here that different genes are reactivated at different stages, with more slowly reactivated genes tending to be enriched in H3meK27. We further show that in UTX H3K27 histone demethylase mutant embryos, these genes are even more slowly reactivated, suggesting that these genes carry an epigenetic memory that may be actively lost. On the other hand, expression of rapidly reactivated genes may be driven by transcription factors. Thus, some X-linked genes have minimal epigenetic memory in the inner cell mass, whereas others may require active erasure of chromatin marks. | Blastocyst Inner Cell Mass |
Bovine leukemia virus (BLV) is a retrovirus which seems to affect both the humoral and the cellular immune response. Cows affected by enzootic bovine leukemia (EBL) showed a reduction of IgM-producing cells in the spleen and lymph nodes. Experimentally infected calves had lower levels of secretory IgM and a decrease in T lymphocytes in the peripheral blood. The reduction in the amount of T cells was noticed mainly in cells bearing the CD4 markers. BLV-infected animals showed diminished responsiveness to newly encountered antigens. Cows naturally infected by BLV produced Igs with impaired structural or biological reactivity. The primary immune response was shown to be deficient in BLV-infected cows following vaccination with synthetic antigen. A marked shift in the proportion of PBL, especially of the CD5+ subset, was noticed. Peripheral blood mononuclear cells from BLV-infected cows secrete elevated levels of certain cytokines and contain increased levels of cytokine mRNA. High levels of cytokines are also found in the sera of BLV-infected cows compared to non-infected animals. A correlation was found between BLV infection and lack of spontaneous recovery from Trichophyton verrucosum infection. Moreover, some studies ascertained a significant association between the herd BLV infection status and disease incidence. The culling rate was higher and milk production lower in BLV-infected vs. BLV-free herds. It seems that BLV infection affects the immune system of a cow to such an extent that it ceases to be productive enough to be kept and, in most cases, the animal is culled before any symptoms of illness associated with persistent immunodeficiency become apparent. | Leukemia Virus, Bovine |
Two new anthracyclines, tetracenoquinocin (1) and 5-iminoaranciamycin (2), together with the known compounds aranciamycin (3) and antibiotic SM 173B were isolated from the culture of Streptomyces sp. Sp080513GE-26 associated with a marine sponge, Haliclona sp. The structures of 1 and 2 were established on the basis of extensive NMR and MS analyses along with (13)C-labeling experiments. The compounds 1-3 were evaluated for cytotoxicity against two cancer cell lines. | Haliclona |
Spinal cord injury (SCI) causes restrictive ventilatory changes, with reductions in vital capacity, functional residual capacity, and expiratory reserve volume. Vital capacity (VC) often is used as an indicator of overall pulmonary function in these patients. In an effort to determine the extent to which VC correlates with other pulmonary function tests, 52 patients with recent acute traumatic SCI underwent complete pulmonary function testing. Statistical relationships were determined between VC and nine other tests. VC was found to be significantly correlated with forced expiratory volume in 1 s, inspiratory capacity, expiratory reserve volume, functional residual capacity, residual volume (RV), total lung capacity (TLC), and RV/TLC ratio, but not with maximum positive expiratory pressure nor with maximum negative inspiratory pressure. The excellent correlations between vital capacity and nearly all of the other pulmonary function tests support the use of VC as a single global measure of overall ventilatory status in SCI patients. | Respiratory Function Tests |
With the present contribution, we attempt to merge the work of several generations of physiology and psychosomatics. The common denominator in an array of observation levels appear in these works as the relationship between irreversible-structural and dynamic-functional couplings and synchronisations. In this context, studies on the level of the common brainstem system appear to be the base for a neuro-bio-psychic self-organisation. Studies culled from psychosomatics of Heidelberg, notably the Gestaltkreis theory, the Methodenkreis (methodological loop), the Bipersonalitat (bipersonality), and the Simultandiagnostik (simultaneous diagnostics) exhibit the origin of complex functions which have been analyzed and quantified employing nonlinear methods developed in synergetics. Relevance of coupling and synchronisation, desynchronisation, resp., is, however, not limited to the scope of psychosomatic medicine. Fixed or functional, they are essential constituents to neurophysiological processes, such as association, dissociation, resp. This equally holds for evidence based medicine which is to benefit from any dynamic process analysis. | Neurophysiology |
BACKGROUND: The associations between lipocalin-2 (LCN2) with mild cognitive impairment (MCI) and dementia have gained growing interest. However, population-based studies have yielded inconsistent findings. Therefore, we conducted this essential systematic review and meta-analysis to analyze and summarize the existing population-based evidence. METHODS: PubMed, EMBASE, and Web of Science were systematically searched until Mar 18, 2022. Meta-analysis was performed to generate the standard mean difference (SMD) of peripheral blood and cerebrospinal fluid (CSF) LCN2. A qualitative review was performed to summarize the evidence from postmortem brain tissue studies. RESULTS: In peripheral blood, the overall pooled results showed no significant difference in LCN2 across Alzheimer's disease (AD), MCI and control groups. Further subgroup analysis revealed higher serum LCN2 levels in AD compared to controls (SMD =1.28 [0.44;2.13], p = 0.003), while the difference remained insignificant in plasma (SMD =0.04 [-0.82;0.90], p = 0.931). Besides, peripheral blood LCN2 were higher in AD when age difference between AD and controls >/= 4 years (SMD =1.21 [0.37;2.06], p = 0.005). In CSF, no differences were found in LCN2 across groups of AD, MCI and controls. However, CSF LCN2 was higher in vascular dementia (VaD) compared to controls (SMD =1.02 [0.17;1.87], p = 0.018), as well as compared to AD (SMD =1.19 [0.58;1.80], p < 0.001). Qualitative analysis supported that LCN2 was increased in the brain tissue of AD-related areas, especially in astrocytes and microglia; while LCN2 increased in infarct-related brain areas and over-expressed in astrocytes and macrophages in mixed dementia (MD). CONCLUSION: The difference in peripheral blood LCN2 between AD and controls may be affected by the type of biofluid and age. No differences were found in CSF LCN2 across AD, MCI and controls groups. In contrast, CSF LCN2 was elevated in VaD patients. Moreover, LCN2 was increased in AD-related brain areas and cells in AD, while in infarcts-related brain areas and cells in MD. | Mixed Dementias |
Hysteria is an ancient word for a common clinical condition. Although it no longer appears in official diagnostic classifications, hysteria" is used here as a generic term to cover both "somatoform" and "dissociative" disorders as these are related psychopathological states. This paper reviews the clinical features of four hysterical syndromes known to occur in a neurologist's practice, viz conversion, somatization and pain disorders, and psychogenic amnesia. The presence in the clinical history of a multiplicity of symptoms, prodromal stress, a "model" for the symptom(s), and secondary reinforcement all suggest the diagnosis, and minimise the need for extensive investigations to rule out organic disease. Psychodynamic, behavioral, psychophysiologic and genetic factors have been proffered to explain etiology. Appropriate treatment involves psychotherapeutic, behavioral and pharmacological techniques. A basic requirement is to avoid errors of commission such as multiple specialist referrals and invasive diagnostic and treatment procedures. Hysteria is a remediable condition if identified early and managed appropriately." | Hysteria |
The cysteine proteinase cathepsin B (CB) was isolated from immortalized murine BV-2 microglial cells and examined via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting to establish physicochemical properties of CB from what is generally considered the resident CNS macrophage. Microglial proteases have been implicated in several pathological processes occurring in the CNS, including neurodegeneration. Murine microglial CB was observed to consist of two major single-chain species of 32 and 34 kDa, with pls of 5.5-5.2 and 5.1-4.5, respectively. In addition, a minor 24-kDa CB species was also observed in some microglial preparations. The major CB isozymes in microglia differed from those observed in murine liver and brain, which consisted of both single- and double-chain CB variants of 31 and 24-25 kDa/5 kDa, respectively, with pl values of 5.5-4.5. A microglial pro-CB of 37 kDa was also isolated, which could be processed to the 34-kDa single-chain CB species. Cystatin was observed to prevent pro-CB processing, whereas E-64 and leupeptin were only partially inhibitory. The 37-kDa pro-CB species was observed to undergo processing into the 34-kDa CB species when incubated at pH 5.5 but remained stable with respect to molecular mass when incubated at pH 7.0. In contrast, the 34-kDa single-chain CB species was observed to autodegrade when incubated at pH 7.0, whereas incubation at pH 5.5 did not affect the integrity of the species as monitored by immunoblotting. Both pro-CB and 32-kDa single-chain CB species were observed extracellularly following lipopolysaccharide activation of BV-2 microglial cells. | Cathepsin B |
BACKGROUND: Sugammadex (Bridion) is a newly developed agent for the reversal of neuromuscular blockade (NMB) induced by rocuronium or vecuronium. Sugammadex can reverse profound blockade and can be given for immediate reversal and its use would avoid the potentially serious adverse effects of the currently used agent, succinylcholine. Also, sugammadex can reverse NMB more quickly and predictably than existing agents. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of sugammadex for the reversal of muscle relaxation after general anaesthesia in UK practice following routine or rapid induction of NMB. DATA SOURCES: Medical databases [including MEDLINE, EMBASE, CINAHL, Science Citation Index, BIOSIS and Cochrane Central Register of Controlled Trials (CENTRAL), conference proceedings, internet sites and clinical trials registers] were searched to identify published and unpublished studies. The main searches were carried out in May 2008 and supplemented by current awareness updates up until November 2008. REVIEW METHODS: For the clinical effectiveness review, randomised controlled trials of sugammadex against placebo or an active comparator (neostigmine + glycopyrrolate) for the reversal of moderate or profound NMB and for immediate reversal (spontaneous recovery from succinylcholine-induced blockade) were included. The primary effectiveness outcome was speed of recovery from NMB, as measured by objective monitoring of neuromuscular function. For the cost-effectiveness review, a de novo economic assessment considered the routine induction of NMB and the rapid induction and/or reversal of NMB, and threshold analyses were carried out on a series of pairwise comparisons to establish how effective sugammadex needs to be to justify its cost. RESULTS: The review of clinical effectiveness included four randomised active-control trials of sugammadex, nine randomised placebo-controlled trials and five studies in special populations. A total of 2132 titles and abstracts and 265 full-text publications were screened. The included trials indicated that sugammadex produces more rapid recovery from moderate or profound NMB than placebo or neostigmine. Median time to recovery from moderate blockade was 1.3-1.7 minutes for rocuronium + sugammadex, 21-86 minutes for rocuronium + placebo and 17.6 minutes for rocuronium + neostigmine. In profound blockade, median time to recovery was 2.7 minutes for rocuronium + sugammadex, 30 to > 90 minutes for rocuronium + placebo, and 49 minutes for rocuronium + neostigmine. Results for vecuronium were similar. In addition, recovery from NMB was faster with rocuronium reversed by sugammadex 16 mg/kg after 3 minutes (immediate reversal) than with succinylcholine followed by spontaneous recovery (median time to primary outcome 4.2 versus 7.1 minutes). The evidence base for modelling cost-effectiveness is very limited. However, assuming that the reductions in recovery times seen in the trials can be achieved in routine practice and can be used productively, sugammadex [2 mg/kg (4 mg/kg)] is potentially cost-effective at its current list price for the routine reversal of rocuronium-induced moderate (profound) blockade, if each minute of recovery time saved can be valued at approximately 2.40 pounds (1.75 pounds) or more. This is more likely to be achieved if any reductions in recovery time are in the operating room (estimated value of 4.44 pounds per minute saved) rather than the recovery room (estimated value of 0.33 pounds per minute saved). The results were broadly similar for rocuronium- and vecuronium-induced blockade. For rapid reversal of NMB it appeared that any reduction in morbidity from adopting sugammadex is unlikely to result in significant cost savings. LIMITATIONS: The evidence base was not large and many of the published trials were dose-finding and safety studies with very small sample sizes. Also, some relevant outcomes, in particular patient experience/quality of life and resources/costs used, were either not investigated or not reported. In addition, it is likely that the patients included in the efficacy trials were relatively young and in good general health compared with the overall surgical population. Regarding the economic evaluation, there appears to be no evidence linking measures of clinical efficacy to patients' health-related quality of life and mortality risks. CONCLUSIONS: Sugammadex may be a cost-effective option compared with neostigmine + glycopyrrolate for reversal of moderate NMB and also provides the facility to recover patients from profound blockade. Rocuronium + sugammadex could be considered as a replacement for succinylcholine for rapid induction (and reversal) of NMB, although this may not be a cost-effective option in some types of patient at current list prices for sugammadex. Considerable uncertainties remain about whether the full benefits of sugammadex can be realised in clinical practice. | gamma-Cyclodextrins |
OBJECTIVES: Clinical laboratories perform a variety of tests for which biomedical waste is a byproduct. Of these, the complete metabolic panel (CMP) produces a significant portion of this waste. We investigated specific waste subsequent to performing CMPs over the course of a year and analyzed what percentage of the waste produced could have been recycled. METHODS: Patient testing volumes were collected retrospectively from July 14, 2021, to July 14, 2022, for individual assays within the CMP performed on Abbott Alinity c instruments (n = 6). The average weights for components of the reagent kits, which includes wedges, boxes, and package inserts, were calculated. These weights, in conjunction with total patient testing volumes, were used to determine the amount of waste produced. RESULTS: A total of 1089.2 kg of reagent kit waste was estimated to be produced by performing CMPs throughout a year. Of this waste, most (855.5 kg) was not recyclable, but a subset (233.6 kg) was. Overall, 21.4% of the total specific waste weight was found to be recyclable. CONCLUSIONS: The CMP contributes a substantial amount of waste when performed on chemistry analyzer platforms in the clinical laboratory. Paper inserts and cardboard packaging, however, presented opportunities for recycling. | Comprehensive Metabolic Panel |
Soil contamination with arsenic (As) can cause phytotoxicity and elevated As accumulation in rice grain. Here, we used a forward genetics approach to investigate the mechanism of arsenate (As(V)) tolerance and accumulation in rice. A rice mutant hypersensitive to As(V), but not to As(III), was isolated. Genomic resequencing and complementation tests were used to identify the causal gene. The function of the gene, its expression pattern and subcellular localization were characterized. OsHAC4 is the causal gene for the As(V)-hypersensitive phenotype. The gene encodes a rhodanase-like protein that shows As(V) reductase activity when expressed in Escherichia coli. OsHAC4 was highly expressed in roots and was induced by As(V). In OsHAC4pro-GUS transgenic plants, the gene was expressed exclusively in the root epidermis and exodermis. OsHAC4-eGFP was localized in the cytoplasm and the nucleus. Mutation in OsHAC4 resulted in decreased As(V) reduction in roots, decreased As(III) efflux to the external medium and markedly increased As accumulation in rice shoots. Overexpression of OsHAC4 increased As(V) tolerance and decreased As accumulation in rice plants. OsHAC4 is an As(V) reductase that is critical for As(V) detoxification and for the control of As accumulation in rice. As(V) reduction, followed by As(III) efflux, is an important mechanism of As(V) detoxification. | Arsenate Reductases |
A 56-year-old man sustained an intraocular injury by a piece of steel followed by endophthalmitis, which resolved after lensectomy, vitrectomy, and intravitreal injections of gentamicin. Acinetobacter anitratus was the organism responsible for the endophthalmitis. It is a Gram-negative polymorphic organism that can resemble several other pathogens and possesses unpredictable antibiotic susceptibility. A. anitratus is an important cause of nosocomial infection but has not previously been reported as a cause of endophthalmitis following trauma. | Moraxellaceae Infections |
Gene therapies aim to deliver a therapeutic payload to specified tissues with underlying protein deficiency. Since the 1990s, gene therapies have been explored as potential treatments for chronic conditions requiring lifetime care and medical management. Ocular gene therapies target a range of ocular disorders, but retinal diseases are of particular importance due to the prevalence of retinal disease and the current treatment burden of such diseases on affected patients, as well as the challenge of properly delivering these therapies to the target tissue. The purpose of this review is to provide an update on the most current data available for five different retinal gene therapies currently undergoing clinical trials for use against age-related macular degeneration (AMD) and the development of novel delivery routes for the administration of such therapies. Research has been performed and compiled from PubMed and the select authors of this manuscript on the treatment and effectiveness of five current retinal gene therapies: Luxturna, ADVM-022, RGX-314, GT-005, and HMR59. We present the available data of current clinical trials for the treatment of neovascular and dry age-related macular degeneration with different AAV-based gene therapies. We also present current research on the progress of developing novel routes of administration for ocular gene therapies. Retinal gene therapies offer the potential for life-changing treatment for chronic conditions like age-related macular degeneration with a single administration. In doing so, gene therapies change the landscape of treatment options for these chronic conditions for both patient and provider. | Macular Degeneration |
OBJECTIVE: To characterize the dermoscopic features of acral congenital melanocytic nevi (CMN). DESIGN: Retrospective independent evaluation of dermoscopic images by 2 dermoscopists. SETTING: A dermatology clinic at a university hospital. PATIENTS: Using the files of the clinic from January 1, 2004, through February 28, 2009, we selected cases with CMN lesions affecting acral volar skin that were present at birth or developed within the first few months of life. MAIN OUTCOME MEASURES: Characteristic dermoscopic features and their frequencies. RESULTS: We collected a total of 24 acral CMN lesions. Dermoscopically, 9 lesions (38%) showed a combination of the crista dotted pattern and the parallel furrow pattern. Of these 9 lesions, 1 also had a fibrillar pattern. The remaining 15 lesions showed the following single-component patterns: the parallel furrow pattern in 6 (25%), the crista dotted pattern in 3 (12%), the fibrillar pattern in 2 (8%), and the globular, globulostreaklike, nontypical, and parallel ridge patterns in 1 each (4%). We also followed up 6 lesions for several years. Changes in the dermoscopic features were observed in 4 CMN lesions from patients younger than 14 years. Three lesions had a combination of the crista dotted and parallel furrow patterns on the first visit that changed to the nontypical pattern; in addition, the degrees of pigmentation decreased during follow-up. In the remaining lesion, the globulostreaklike pattern changed to the parallel furrow pattern. CONCLUSIONS: Most CMN lesions affecting acral volar skin show characteristic dermoscopic features distinguishable from acral melanoma. The combination of the crista dotted and parallel furrow patterns (ie, peas-in-a-pod pattern) is the most common feature in acral CMN. Some lesions of acral CMN fade during childhood. | Palmar Plate |
IMPORTANCE: With declining use of institutional postacute care, more patients are going directly home after hospital discharge. The consequences on the amount of help needed at home after discharge are unknown. OBJECTIVE: To estimate trends in the frequency and duration of receipt of help with activities of daily living (ADLs) among older adults discharged home. DESIGN, SETTING, AND PARTICIPANTS: Repeated cross-sectional study of a national sample of community-dwelling older adults who returned home after hospital discharge from 2011 to 2017. Participants included respondents to National Health and Aging Trends Study (NHATS), an annual population-based, nationally representative survey of Medicare beneficiaries, who were 69 years or older and were discharged from an acute care hospital to home during the years of the study. A nationally representative sample was estimated using NHATS' analytic weights. Unweighted frequencies and weighted and unweighted percentages are reported. The analysis was conducted from September 2020 to October 2021. EXPOSURES: Discharge from an acute care hospitalization. MAIN OUTCOMES AND MEASURES: Receipt of help with ADLs during the 3 months after hospital discharge. RESULTS: Of the 3591 survey participants who were discharged home from an acute care hospital during the study period, 53.3% were female, 54.8% were married or living with a partner, and the mean (SD) age was 78.5 (7.0) years. Of these, 1710 (44.1%) reported receiving help within 3 months of discharge. Compared with people not receiving help, those receiving help were older (mean [SD] years, 79.7 [7.5] years vs 77.6 [6.3] years), had worse self-rated health at baseline (47.1% with fair or poor health vs 26.5%) and were more likely to have dementia (21.8% vs 5.5%). The percentage of respondents who reported receiving help increased during the study period from 38.1% of hospital discharges in 2011 to 51.5% in 2017. For those who were independent in their ADLs before hospitalization, the percentage receiving help after discharge more than doubled over the study period increasing from 9.3% receiving help in 2011 to 31.8% in 2017. Among patients who did not receive Medicare-reimbursed home health, the percentage receiving help also increased from 22.1% to 28.1%. Among those who received help after discharge, the need for help slowly declined to prehospitalization levels over the ensuing 9 months. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, older adults' receipt of help at home after hospital discharge increased from 2011 to 2017, including patients relying on non-Medicare funded sources of care. As payers steer patients away from inpatient postacute care facilities, policymakers will need to pay attention to this shifting burden of care. | Hospital to Home Transition |
The early response of mammalian cells to growth factors consists of a combination of protein assemblages and kinase cascades. In the study of how signal specificity of different growth factors is determined, PC12 cells represent an elective experimental model to compare the signaling of differentiative nerve growth factor (NGF) and mitogenic epidermal growth factor (EGF). Focusing on Shc as established regulator of the Ras-ERK cascade, whose sustained activation is known to critically shape the neuronal differentiation of PC12 cells, the present manuscript describes two novel sources of divergence in the signaling of NGF and EGF: a differential phosphorylation of p66-Shc at early time points and a differential duration in the recruitment of the overall pool of Shc. | Epidermal Growth Factor |
In order to evaluate the potential role of gastrin in the etiology of pyloric stenosis, serum gastrin levels were measured in cord blood of affected infants, matched controls, and mothers of both. No differences were identified when values from infants with pyloric stenosis were compared with those from control infants. Mean cord serum gastrin levels of the infants were significantly greater than the mean maternal gastrin levels. The data effectively dismiss the possibility that elevated serum gastrin concentration in mother or infant at the time of delivery can be implicated as a cause of pyloric stenosis. | Gastrins |
Histone acetyltransferase complexes have been shown to be key regulators of gene expression. Among these, the NuA4 complex, first characterized in yeast, stands out as it controls multiple key nuclear functions in eukaryotic cells. Many subunits of this protein assembly have been directly linked to global and targeted acetylation of histone H4 tails in vivo, regulation of transcription, cell-cycle progression as well as to the process of DNA repair. Recent studies presented here have established its remarkable structural conservation from yeast to human cells and contributed to the understanding of its diverse functions. | Acetyltransferases |
It has been suggested that tensor tympani muscle (TTM) contraction may be involved in the development of ear-related pathologies such as tinnitus, hyperacusis and otalgia, called the tonic tensor tympani syndrome (TTTS). However, as there is no precise measure of TTM function under normal and pathological states, its involvement remains speculative. When the TTM or the stapedius muscle (SM) contracts, they both generate an increase of middle ear stiffness that can be measured through middle ear admittance. However, this technique cannot differentiate the contraction between the two muscles. On the other hand, the air pressure measured in a sealed external auditory canal can provide a measure of the eardrum displacement that may be able to differentiate SM from TTM contraction. TTM is attached to the malleus, and its contraction causes a retraction of the eardrum inside the middle ear cavity, while SM can have a small but reversed effect on TTM displacement. To investigate this issue, we compared the middle ear admittance and air pressure in a sealed external ear canal upon auditory stimulation (sMEMC) and voluntary middle ear muscle contraction (vMEMC). In addition, we assessed the perceptual effect of vMEMC, including pitch and loudness matching of the fluttering noise produced by vMEMC and the threshold shifts, were measured. Out of the 14 ears tested, sMEMC was associated with a decrease of admittance in 93% (mean peak average: -0.06 ml, SD:0.04) and an increase of air pressure in 29% of ears (mean peak average: 8.1 Pa, SD:5.1). No decrease in air pressure was found upon sMEMC. For vMEMC (n = 8 ears), decreases were found for both admittance and air pressure in 100% and 88%, with a mean peak average of -0.38 ml, SD: 0.54 and -149 Pa, SD:156, for admittance and pressure respectively. These results suggest that SM and TTM are involved in sMEMC and vMEMC, respectively. In addition, vMEMC was associated with perceptual effects including a low-frequency sound, pitch-matched at approximately 30 Hz (>15 dB SL), and a low-frequency hearing loss of at least 10 dB between 20 and 200 Hz. In conclusion, admittance and air pressure recordings provide useful and complementary information on middle ear muscle contraction and can be used to explore the middle ear function. | Tensor Tympani |
In autumn of 2010 we collected fecal samples from the rectums of 89 trapped or road-killed Pennsylvania raccoons (Procyon lotor). Similar samples were collected in the summer and autumn of 2011 from 383 raccoons. Fecal samples were stored in 10% formalin until examined. Using saturated sugar flotation and a direct smear, we found Baylisascaris procyonis eggs in 38% of 2010 samples and 32.9% of 2011 samples. Prevalence in raccoons was greater in autumn than in summer and greater in juveniles than in adults; there was not a statistically significant difference between sexes. Infected raccoons were found in 54 of the 65 counties from which samples were recovered (a mean of 5.9 [range 1-12] raccoons were examined per county). The prevalences were similar in all regions of the state. | Ascaridida Infections |
Polysaccharides from feijoa fruit were extracted and analyzed; the composition of these polysaccharides conforms to those typically found in the primary cell walls of eudicotyledons. The two major polysaccharide extracts consisted of mainly pectic polysaccharides and hemicellulosic polysaccharides [xyloglucan (77%) and arabinoxylan (16%)]. A collection of commensal Bacteroides species was screened for growth in culture using these polysaccharide preparations and placed into five categories based on their preference for each substrate. Most of the species tested could utilize the pectic polysaccharides, but growth on the hemicellulose was more limited. Constituent sugar and glycosyl linkage analysis showed that species that grew on the hemicellulose fraction showed differences in their preference for the two polysaccharides in this preparation. Our data demonstrate that the members of the genus Bacteroides show differential hydrolysis of pectic polysaccharides, xyloglucan, and arabinoxylan, which might influence the structure and metabolic activities of the microbiota in the human gut. | Feijoa |
Herein, the synthesis of ferrocene-containing salts is presented. Acylation of ferrocene (Fc) according to the Friedel-Crafts method led to omega-bromoacyl ferrocenes. The omega-bromoacyl ferrocenes were subsequently introduced to quaternization reaction with tri-tert-butyl phosphine, which resulted in phosphonium salts. Obtained phosphonium salts were characterized by physical methods. The electrochemical properties of phosphonium salts were studied by cyclic voltammetry (CV). It was found that the replacement of n-butyl fragments at the phosphorus atom by tert-butyl leads to a more anodic potential shift. In contrast to isolobal structures Fc-C(O)(CH(2))(n)P(+)(n-Bu)(3)X(-) and Fc-(CH(2))(n+1)P(+)(n-Bu)(3)X(-), the CV curves of Fc-C(O)(CH(2))(n)P(+)(t-Bu)(3)X(-) and Fc-(CH(2))(n+1)P(+)(t-Bu)(3)X(-) did not show a large discrepancy between forward and reverse currents. The transformation of the C=O groups to CH(2) fragments had a significant effect on the electrochemical properties of ferrocene salts, the oxidation potential of which is close to that of pure ferrocene. | Metallocenes |
A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, resulting in a negligible net change in the PK of the active metabolite. CYP2C19 inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that are either CYP450 inhibitors or inducers with clobazam in the treatment of LGS patients had negligible to no effect on clobazam PK in this study, dosage adjustments may not be required for clobazam in the presence of the AEDs investigated here." | Cytochrome P-450 CYP2C19 Inducers |
An Air Sampling Link (ASL), employed in conjunction with an Air Sampling Device (ASD) or a laser particle counter, has been developed for sampling flowing air for viable and non-viable particulate analyses. Typically, the ASL could be used to sample filtered air supplied to an air shower of a Blow/Fill/Seal machine operating in the dynamic state. The ASL allows sample volumes of air to be taken from flowing air without significant loss from the sample flow of airborne particles possessing aerodynamic sizes relevant to those found in practice. The link has no moving parts, is steam sterilizable in-situ, and allows for the taking of continuous samples of air without the need for intervention into the 'critical zone' of the filling machine. This article describes (i) the design criteria for the ASL and the ASD, (ii) the rationale underlying the concept of the ASL design, (iii) the collection performance of the ASL against that of a conventional sampling arrangement, and (iv) a functionality assessment of the ASL-based sampling system installed on a Rommelag style 305 B/F/S machine over a seven week period. | Air Microbiology |
Thirty four distinct breeds and many non-descript populations represent the caprine diversity of India. Genetic characterization of breeds is an essential element in designing breeding strategies and preserving genetic diversity. Considering the popularity of mitochondrial DNA for phylogeographical studies, this study involved an extensive analysis of population structure and genetic diversity of 28 defined breeds and 5 lesser known populations representing all four major agro-climatic zones of India using mitochondrial DNA markers. Analysis of hypervariable region 1 of mtDNA control region in 443 goats together with 22 reference sequences, delineated 341 distinct haplotypes belonging to four maternal haplogroups; A, B, C and D, with haplogroup A representing 90% of the individuals. The haplotype and nucleotide diversity indices of Indian goats were 0.998 +/- 0.001 and 0.028 +/- 0.001, respectively indicating abundant genetic variability. Estimates of population demographic parameters from mismatch analysis suggested a relatively good fit to the model of either spatial or demographic expansion of Indian goats. AMOVA analysis and topology of MJ network suggested lack of phylogeographic structure in domestic goats, which can be attributed to unstructured animal breeding, dwindling pastures and nomadic pastoralism. Genetic differentiation between goats from different agro-ecological regions was in accordance with their geographical propinquity. | Goats |
Mulibrey nanism is an autosomal recessive disease with severe growth failure and multiple organ involvement. Heart manifestations include constrictive pericarditis and restrictive cardiomyopathy. The purpose of this study was to evaluate left ventricular (LV) diastolic and systolic function in children with mulibrey nanism utilizing two- and three- dimensional (2-D and 3-D) echocardiography and measurement of serum levels of natriuretic peptides. Of the 30 children diagnosed with mulibrey nanism in Finland, 26 participated. The control group comprised 26 children. In 2-D echocardiography, the interventricular septum and LV posterior wall were thicker in patients. The left atrium/aorta ratio measured a median 1.8 (range, 1.4-2.5) in patients and 1.3 (range, 1.0-1.7) in controls (p < 0.001). Patients differed from controls in several indices of diastolic LV function. In 3-D echocardiography, LV end diastolic volume measured a median of 51.9 ml/m(2) (range, 33.3-73.4) in patients and 59.7 ml/m(2) (range, 37.6-87.6) in controls (p = 0.040), and serum levels of N-terminal proatriopeptide and N-terminal pro-brain natriuretic peptide measured, respectively, a median of 0.54 nmol/L (range, 0.04-4.7) and 289 ng/L (range, 18-9170) in patients and 0.28 nmol/L (range, 0.09-0.72; p < 0.001) and 54 ng/L (range, 26-139; p < 0.001) in controls. They correlated with several indices of diastolic LV function. In a significant proportion of children with mulibrey nanism, myocardial function is impaired. Significant correlations appeared between indices of LV function, size of the left atrium, and levels of natriuretic peptides, showing that measurement of serum levels of natriuretic peptides is a useful follow-up method despite its dependence on loading conditions. | Mulibrey Nanism |
We discuss a mathematical model of growth of two types of phytoplankton, non-nitrogen-fixing and nitrogen-fixing, that both require light in order to grow. We use general functional responses to represent the inhibitory effect their biomass has on the exposure to light. We give conditions for the existence and local stability of all of the possible steady-states (die out, single species survival, and coexistence). We derive conditions for global stability of the die out and single-species steady-states and for persistence of both species when the coexistence steady-state exists. Numerical investigation illustrates the qualitative dynamics demonstrating that even under constant environmental conditions, both stable intrinsic oscillatory behavior and a period doubling route to chaotic dynamics are possible. We also show that competitor-mediated coexistence can occur due to the positive feedback resulting from recycling by the nitrogen-fixing phytoplankton. To show the impact of seasonal change in water depth, we also allow the water depth to vary in an annual cycle and discuss echo blooms in this context. | Trichodesmium |
Nicotine abstinence following chronic exposure is associated with impairments in memory and variety of cognitive functions. Daily nicotine (2â¯mg/kg, sc, four times daily) administration for 14â¯days and its abrupt withdrawal significantly impaired avoidance learning in inhibitory avoidance task as indicated by a significant decrease in the step through latency. Animals injected with agmatine (10-40â¯mug/rat, icv) from day 7 to 14 before the first daily dose of nicotine (2â¯mg/kg, sc) showed increased step through latencies during retrieval test. Similarly Intracerebroventricular injection of l-arginine (25-100â¯mug/rat), a biosynthetic precursor of agmatine and arcaine (50â¯mug -100â¯mug/rat), an agmatinase inhibitor, also increased the step through latency during retrieval test in nicotine withdrawn animals. In separate experiments, alpha(2)-adrenoceptor agonist, clonidine (0.5-1â¯mug/rat, icv) not only demonstrated significant increase in the step through latency as in nicotine withdrawn rats but also potentiated the pharmacological effect of agmatine. In contrast, pre-treatment of alpha(2)-adrenoceptor antagonist, yohimbine (0.5â¯mug/rat, icv) antagonized the memory enhancing effect of agmatine (20â¯mug/rat, icv) in nicotine withdrawn rats. In addition, brain agmatine analysis carried out at 72â¯h time point of nicotine withdrawal showed marked decrease in basal brain agmatine content as compared to control. Overall, the data indicate that agmatine attenuates nicotine withdrawal induced memory impairment through modulation of alpha(2)adrenergic receptors. Thus, agmatine might have therapeutic implications in the treatment of cognitive deficits following nicotine withdrawal. | Agmatine |
BACKGROUND: Research into nanoparticles has increased markedly during the last decade, especially in light of their potential diagnostic and therapeutic use. While silver has been used since ancient times, a detailed understanding of the kinetics of its dermal absorption requires further study. Thus far, only in vitro and animal models have been used to analyse the absorption characteristics of nanocrystalline silver particles and no in vivo study using intact human skin has demonstrated silver absorption. METHOD: A nanocrystalline silver dressing was applied to a sample of 16 healthy patients with normal intact skin approximately 5 days prior to surgery. The treated skin samples, removed as surgical waste, were then analysed with a tissue mass spectrometry, light microscopy, scanning electron microscopy (SEM) and an X-ray diffusion spectrography (XRD). Silver serum levels were also analysed before and after application of the dressing. RESULTS: A limited amount of silver penetration could be noted even with light microscopy. However, definitive analysis required SEM and XRD confirmation. With SEM, metallic particles could be seen within the dermis. XRD confirmed that these were silver species, possible in oxide form. Furthermore, silver clusters as large as 750 nm could be discerned. In addition, there was no demonstrable rise in serum silver levels post-treatment with the silver dressing. CONCLUSION: Our results suggest that silver nanoparticles are able to penetrate intact human skin in vivo beyond the stratum corneum and can be found as deep as the reticular dermis. The absorbed silver might be in silver oxide form and the silver species appear to form sizeable clusters once absorbed across the epidermis. However, despite silver deposition into the dermis, the silver nanoparticles did not reach systemic circulation and should thus have no end organ consequences. | Silver |
Objective: To summarize the clinical characteristics of occupational asthma and provide a basis for revising the diagnosis of occupational asthma in China. Methods: Taking occupational asthma" , "occupational bronchial asthma" and "bronchial provocation test at work site" as key words, the case reports of occupational asthma in China were retrieved. The general data, latent period, allergen, clinical manifestation, and diagnostic methods were analyzed. Results: A total 318 cases from 14 published literatures were reported.The incidence of male and female is basically similar. The average age of onset is 38 years, and the latent period is from 2 months to 19 years. The top 3 allergens were isocyanates, penicillin and cephalosporins, formaldehyde. During the diagnosis process, 48.8% of the patients were diagnosed by bronchial provocation test, and 19 cases were diagnosed according to the specific IgE antibody. Only 1 case was diagnosed according to the specific skin test. Conclusion: The etiological diagnosis of occupational asthma is not easy. Nearly half of the patients in our country have been diagnosed as occupational asthma by bronchial provocation test at work site. How to identify the relationship between occupational exposure and the occurrence of asthma is one of the main problems we need to solve." | Asthma, Occupational |
INTRODUCTION: Simulation workshops for surgical training of residents are becoming popular. The gold standard for teaching thoracolumbar pedicle screw placement are cadaver labs; however, the availability of human bodies is limited. The primary objective of this study was to determine if training on a synthetic bone model improves the apprenticeship of accurate pedicle screw placement. The secondary objective was to check the influence of residents' previous experience in spine surgery. HYPOTHESIS: The main hypothesis was that theoretical learning with practical application on synthetic bone was superior to theoretical learning alone. METHODS: Twenty-three orthopedic residents were taught about free-hand pedicle screw placement using a theoretical presentation. Six residents had previous experience with screwing techniques. After randomization in two groups, 11 residents (group 1) participated in a workshop on synthetic bone, whereas 12 residents received only theoretical instruction (group 2). Each resident was asked to place two thoracic screws (T7-T11) and two lumbar screws (L1-L5) on a cadaver. Screw placement accuracy was analyzed using the Gertzbein classification on computed tomography (grades 0 and 1=accurate positioning; grades 2 and 3=malposition>2mm). RESULTS: Rates of accurate screw positioning were 64.0% and 62.5% for thoracic levels, and 72.7% and 66.6% for lumbar levels in group 1 and 2, respectively. There was no significant difference in malposition rates on cadavers between the groups (p=0.1809). A resident who was first trained by simulation had a chance of decreasing the Gertzbein score with an odds-ratio of 1.7714 [0.7710-4.1515]. The odds ratio was 4.5188 [0.0456-0.8451] when comparing residents with previous experience in spinal surgery to novice residents. DISCUSSION: Theoretical teaching associated with a simulation model is relevant for learning a surgical technique. A single simulation workshop on synthetic bone seems insufficient to improve pedicle screw placement accuracy compared to theoretical teaching alone. Progressive experience and the repetition of technical gestures during hands-on supervised learning in spine surgery with a senior surgeon had an influence on the accuracy of pedicle screw placement. LEVEL OF EVIDENCE: II. | Pedicle Screws |
Others have shown that leptin and cholecystokinin (CCK) act synergistically to suppress food intake. Experiments described here tested whether leptin in the ventromedial hypothalamus (VMH) contributes to the synergy with peripheral CCK in male Sprague Dawley rats. A subthreshold injection of 50-ng leptin into the VMH 1 h before a peripheral injection of 1 microg/kg CCK did not change the response to CCK in rats offered chow or low-fat purified diet, but did exaggerate the reduction in intake of high-fat diet 30 min and 1 h after injection in rats that had been food deprived for 8 h. By contrast, deletion of leptin receptor-expressing cells in the VMH using leptin-conjugated saporin (Lep-Sap) abolished the response to peripheral CCK in chow-fed rats. Lateral ventricle injection of 2-microg leptin combined with peripheral CCK exaggerated the inhibition of chow intake for up to 6 h in control rats treated with Blank-saporin, but not in Lep-Sap rats. Blank-Saporin rats offered low- or high-fat purified diet also demonstrated a dose-response inhibition of intake that reached significance with 1 microg/kg of CCK for both diets. CCK did not inhibit intake of Lep-Sap rats in either low- or high-fat-fed rats. Thus, although basal activation of VMH leptin receptors makes a significant contribution to the synergy with CCK, increased leptin activity in the VMH does not exaggerate the response to CCK in intact rats offered low-fat diets, but does enhance the response in those offered high-fat diet.NEW & NOTEWORTHY Leptin is a feedback signal in the control of energy balance, whereas cholecystokinin (CCK) is a short-term satiety signal that inhibits meal size. The two hormones synergize to promote satiety. We tested whether leptin receptors in the ventromedial nucleus of the hypothalamus (VMH) contribute to the synergy. The results suggest that there is a requirement for a baseline level of activation of leptin receptors in the VMH in order for CCK to promote satiety. | Saporins |
While antibody-based therapies have emerged as clinically effective approaches for several hematologic and solid malignancies, they have not played a significant role to date in the treatment of acute myeloid leukemia (AML). More recently, improvements in antibody-drug conjugate technology, bispecific antibodies, as well as identification of novel AML antigens have re-invigorated enthusiasm for antibody-based therapies for AML. This review describes experiences with former and existing antibody-based therapies for AML, including unconjugated antibodies, antibody-drug conjugates (ADCs), radio-labelled antibodies, and immune-engaging antibodies, and discusses the promise and challenges associated with each. | Calicheamicins |
Lysates of Leishmania promastigotes can metabolise arachidonic acid to prostaglandins. Prostaglandin production was heat sensitive and not inhibited by aspirin or indomethacin. We cloned and sequenced the cDNA of Leishmania major, Leishmania donovani, and Leishmania tropica prostaglandin F(2alpha) synthase, and overexpressed their respective 34-kDa recombinant proteins that catalyse the reduction of 9,11-endoperoxide PGH(2) to PGF(2alpha). Database search and sequence alignment alignment showed that L. major prostaglandin F(2alpha) synthase exhibits 61, 99.3, and 99.3% identity with Trypanosoma brucei, L. donovani, and L. tropica prostaglandin F(2alpha) synthase, respectively. Using polymerase chain reaction amplification, Western blotting, and immunofluorescence, we have demonstrated that prostaglandin F(2alpha) synthase protein and gene are present in Old World and absent in New World Leishmania, and that this protein is localised to the promastigote cytosol. | Prostaglandins H |
This paper illustrates a method for determining trace amounts of CO, CH4 and CO2 with the detection limit of 0.15, 0.15 and 0.20 microg/l, respectively, in refinery hydrogen gases or in air. A simple modification of a gas chromatograph equipped with a flame-ionization detector is presented. A Porapak Q column, additionally connected with a short molecular sieve 5A packed column and a catalytic hydrogenation reactor on the Ni catalyst have been applied. The principle of the analytical method proposed is the separation of CO from O2 before the introduction of CO to the methanizer. The analytical procedure and examples of the results obtained have been presented. The modification applied makes it possible to use the GC instrument for other determinations, requiring utilization of the Porapak Q column and the flame-ionization detector. In such cases, the short molecular sieve 5A column and the methanizer can be by-passed. | Gases |
Computational analysis of cellular activity has developed largely independently of modern transcriptomic cell typology, but integrating these approaches may be essential for full insight into cellular-level mechanisms underlying brain function and dysfunction. Applying this approach to the habenula (a structure with diverse, intermingled molecular, anatomical, and computational features), we identified encoding of reward-predictive cues and reward outcomes in distinct genetically defined neural populations, including TH(+) cells and Tac1(+) cells. Data from genetically targeted recordings were used to train an optimized nonlinear dynamical systems model and revealed activity dynamics consistent with a line attractor. High-density, cell-type-specific electrophysiological recordings and optogenetic perturbation provided supporting evidence for this model. Reverse-engineering predicted how Tac1(+) cells might integrate reward history, which was complemented by in vivo experimentation. This integrated approach describes a process by which data-driven computational models of population activity can generate and frame actionable hypotheses for cell-type-specific investigation in biological systems. | Reward |
The review is devoted to the patterns of evolution of alpha- and beta-globin gene domains. A hypothesis is presented according to which segregation of the ancestral cluster of alpha/beta-globin genes in Amniota occurred due to the performance by alpha-globins and beta-globins of non-canonical functions not related to oxygen transport. | Hemoglobin Subunits |
The handstand is an uncommon posture, highly demanding in terms of muscle and joint stability, used in sporting and artistic practices in a variety of disciplines. Despite its becoming increasingly widespread, there is no specific way to perform a handstand, and the neuromuscular organizational mechanisms involved are unknown. The objective of this study was to determine the muscle synergy of four handstand postures through a semblance analysis based on wavelets of electromyographic signals in the upper limbs of experienced circus performers between 18- and 35-year old. The results show that there is a large difference in positive and negative correlations depending on the posture, which suggests that the more asymmetrical the position of the lower limbs, the greater the number of strategies to maintain the posture. Although it is not a statistically significant data, it is observed that the posture 3 in particular, possesses the greatest number of positive correlations, which suggests it has the greatest synergy. | Wavelet Analysis |
Lymph node metastasis is an important prognostic factor in gastric cancer. Vascular endothelial growth factor-D (VEGF-D) is a lymphangiogenic growth factor that activates VEGF receptor (VEGFR)-3, a receptor expressed in the lymphatic endothelium. We investigated the clinical value of VEGF-D expression and VEGFR-3 positive vessel density in gastric carcinoma with regard to lymphangiogenesis. Immunohistochemical staining was used to determine the expression of VEGF-D and VEGFR- 3 in specimens from 104 cases of resected gastric cancer. VEGF-D expression was observed in 62.5% of the gastric cancers and in 9.6% of the non-neoplastic gastric tissue. The VEGFR-3-positive vessel density was significantly greater in the VEGFD positive group than the negative group. VEGF-D expression was significantly associated with lymph node metastasis, increased serum CEA levels, and the nonsignet ring cell type. The VEGFR-3-positive vessel density was correlated with tumor size, lymphatic invasion, and lymph node metastasis. The VEGF-D expression and high VEGFR-3-positive vessel density were significant poor prognostic factors for relapse-free survival. These results suggest that VEGF-D and VEGFR-3-positive vessel density are potential molecular markers that predict lymphatic involvement in gastric carcinoma." | Vascular Endothelial Growth Factor D |
The aim of this study was to determine a heart rate deflection point (HRdp) in competitive agility dogs. Fourteen healthy border collies underwent progressive incremental treadmill exercise--modified Conconi test protocol. Heart rate was continuously recorded, and the HRdp was estimated using two methods: subjective and computer aided regression. Maximal heart rate (HRmax), achieved running speed at the anaerobic threshold and at the end of test were also determined. Statistical analysis showed a very high positive correlation between HRdp determined by two methods. The mean HRdp in this research corresponded to 80% of HRmax. The wide range of individual HRdp (162-229 BPM) indicates the need of an individual approach in assessing physiological parameters. To the authors' knowledge, this is the first application of Conconi modified test for estimating anaerobic threshold in agility dogs since the standard for dogs is yet undetermined. Future studies need to detect the most appropriate and reliable technique for its determination as well as its applicability in programming of the optimal training intensity. | Anaerobic Threshold |
OBJECTIVE: To correlate uterine artery Doppler findings with maternal and neonatal outcomes in early- and late-onset preeclampsia with severe features. METHODOLOGY: Doppler scan was done in both uterine arteries. Maternal and neonatal outcomes in women with abnormal and normal Doppler results were compared. RESULTS: Abnormal Doppler results were present in 45 women (75%). Thirty-four (56.7%) women had abnormal RI, 19 (31.6%) had abnormal PI, and 36 (60%) had diastolic notch. Of the women who participated in the study, 21.6% developed maternal complications, and the majority belonged to the early-onset severe preeclampsia group. Diastolic notch was twofold more frequent in the early group. RI was abnormal in 63% of the early-onset and 50% of the late-onset group. CONCLUSION: Pregnancies with early-onset preeclampsia who had abnormal uterine artery Doppler findings were at high risk for both maternal and neonatal complications, whereas those who had late-onset preeclampsia with abnormal Doppler findings only had an increased risk of perinatal complications. | Uterine Artery |
Three cases of possible acute cardiopulmonary toxicity following the administration of vinorelbine are reported. The symptoms mimicked acute cardiac ischemia. However, neither ECG changes nor elevations of serum enzymes were observed. The outcome is favorable in 90% of patients developing this adverse event. The putative mechanism remains to be elucidated. | Vinorelbine |
Porcine epidemic diarrhea (PED) is a severe diarrhea disease in swine that is caused by porcine epidemic diarrhea virus (PEDV). Nucleocapsid (N) protein is the RNA-binding protein of PEDV, which plays an important role for virus life cycle. The aim of this research was to screen and characterize the compounds that could inhibit the activity of PEDV N protein. The gene encoding PEDV N protein obtained from PEDV Thai isolate was cloned and expressed in E. coli. Its amino acid sequence was employed to generate the three dimensional structure by homology modeling. There were 1,286 compounds of FDA-approved drug database that could virtually bind to the RNA-binding region of N protein. Three compounds, trichlormethiazide, D-(+) biotin, and glutathione successfully bound to the N protein, in vitro, with the IC(50) at 8.754 mg/mL, 0.925 mg/mL, and 2.722 mg/mL. Antiviral activity in PEDV-infected Vero cells demonstrated that the effective concentration of trichlormethiazide, D-(+) biotin, and glutathione in inhibiting PEDV replication were 0.094, 0.094 and 1.5 mg/mL. This study demonstrated a strategy applied for discovery of antiviral agents capable of inhibiting PEDV N protein and PEDV replication. The compounds identified here exhibited a potential use as therapeutic agents for controlling PEDV infection." | Porcine epidemic diarrhea virus |
BACKGROUND: Increasing prior authorization (PA) requirements for immunosuppression remain a burden for solid organ transplant (SOT) recipients and transplant staff. The objective of this study was to evaluate the number of PAs required and the approval rates at an academic, urban transplant center. METHODS: This was a retrospective study of SOT recipients at the University of Illinois Hospital and Health Sciences System (UI Health) that required PAs between 11/1/2019 and 12/1/2020. Inclusion criteria were SOT recipients greater than 18 years of age and prescribed a medication by the transplant team that required PA. Duplicate PA requests were excluded from the analysis. RESULTS: A total of 879 PAs were included in the study. Of these PAs, 85% (747/879) were approved. Seventy-four percent of the denials were overturned by an appeal. Most PAs were in black (45.4%), kidney transplant (62%), Medicare (31.7%), and Medicaid recipients (33.2%). The median approval time was 1 day for PAs and 5 days for appeals. Tacrolimus extended release (XR) (35.4%), tacrolimus immediate release (IR) (9.7%),and mycophenolic acid (7%) required most PAs. Black recipients and immunosuppression were identified as predictors of eventual PA approval, whereas recipients with Medicaid were less likely to obtain approval. CONCLUSIONS: At our transplant center, there was a high approval rate of PAs for immunosuppression, which calls into question the utility of PAs in this patient population, where these medications are standard of care. More black recipients and patients with Medicare and Medicaid had increased PA requirements, highlighting further disparities within the current system. | Prior Authorization |
BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a congenital anomaly characterized by hypohydrosis, hypotrichosis and hypodontia. Mutations in at least four genes (EDAR, EDARADD, WNT10A, TRAF6) have been reported to cause both autosomal recessive and autosomal dominant forms of HED. Mutations in two other genes (EDA and IKBKG) have been reported to cause X-linked HED. OBJECTIVES: To clinically characterize three consanguineous families (A-C) segregating with autosomal recessive HED and identify possible disease-causing variants of EDAR and EDARADD genes. MATERIALS AND METHODS: The genes, EDAR and EDARADD, were sequenced in Family A and C, and exome sequencing was performed in Family B. Additionally, in Family A and C, the effect of the identified variants was examined by analysis of EDAR mRNA, extracted from hair follicles from both affected and unaffected members. RESULTS: Sequence analysis revealed three possible disease-causing EDAR variants including a novel splice acceptor site variant (IVS3-1G > A) in Family A and two previously reported mutations (p.[Ala26Val], p.[Arg25*]) in the two other families. Previously, the nonsense variant p.(Arg25*) was reported only in the heterozygous state. Analysis of the RNA, extracted from hair follicles, revealed skipping of a downstream exon in EDAR and complete degradation of EDAR mRNA in affected members in family A and C, respectively. Computational modelling validated the pathogenic effect of the two variants identified in Family B and C. CONCLUSION: The three variants reported here expand the spectrum of EDAR mutations associated with HED which may further facilitate genetic counselling of families segregating with similar disorders in the Pakistani population." | Edar-Associated Death Domain Protein |
OBJECTIVES: Exposure to arsenic and hexavalent chromium is a major public health concern especially in the developing part of the world and there is paucity of information on reliable treatment modalilities. It is in this regard that this study evaluates the efficacy of methanol leaf extract of Rauvolfia vomitoria (MRV) when used as pretreatment agent against potassium dichromate (K(2)Cr(2)O(7)) and sodium arsenite (NaAsO(2)) exposure. METHODS: Swiss albino mice between 7 and 10 weeks old were divided into eight cohorts of five animals each. Treatment groups consisted of a distilled water control, MRV alone (275 mg/kg po daily), K(2)Cr(2)O(7) (12.0 mg/kg, single ip injection) +/- MRV pretreatment, NaAsO(2) (2.5 mg/kg, single ip injection) +/- MRV pretreatment, Na(2)AsO(2) + K(2)Cr(2)O(7) +/- MRV pretreatment. MRV was given for seven consecutive days, while K(2)Cr(2)O(7) and NaAsO(2) were injected on day seven of the experiment. The frequency of micronucleated polychromatic erythrocytes (mPCEs) was determined in bone marrow cells, while aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were assessed in the plasma. Hepatic glutathione (GSH), malondialdehyde (MDA), catalase (CAT) and glutathione-S-transferase (GST) levels were also determined. RESULTS: The NaAsO(2) and K(2)Cr(2)O(7) significantly (p<0.05) increased mPCE formation, AST, ALT, and CAT when compared with the control. Simultaneous exposure to NaAsO(2) and K(2)Cr(2)O(7) further increased the levels of the markers. Furthermore, GSH and GST were significantly reduced by NaAsO(2) or K(2)Cr(2)O(7) or their combination. Pretreatment with MRV reversed the markers towards that of control. CONCLUSIONS: Methanol extract of Rauvolfia vomitoria may therefore ameliorate NaAsO(2) and K(2)Cr(2)O(7)-induced toxicities via reduction of oxidative stress and fortification of anti-oxidant system. | Potassium Dichromate |
Although many Archaea have AMP-Acs (acetyl-coenzyme A synthetase) and ADP-Acs, the extant methanogenic genus Methanosarcina is the only identified Archaeal genus that can utilize acetate via acetate kinase (Ack) and phosphotransacetylase (Pta). Despite the importance of ack as the potential urkinase in the ASKHA phosphotransferase superfamily, an origin hypothesis does not exist for the acetate kinase in Bacteria, Archaea, or Eukarya. Here we demonstrate that Archaeal AMP-Acs and ADP-Acs contain paralogous ATPase motifs previously identified in Ack, which demonstrate a novel relation between these proteins in Archaea. The identification of ATPase motif conservation and resulting structural features in AMP- and ADP-acetyl-CoA synthetase proteins in this study expand the ASKHA superfamily to include acetyl-CoA synthetase. Additional phylogenetic analysis showed that Pta and MaeB sequences had a common ancestor, and that the Pta lineage within the halophilc archaea was an ancestral lineage. These results suggested that divergence of a duplicated maeB within an ancient halophilic, archaeal lineage formed a putative pta ancestor. These results provide a potential scenario for the establishment of the Ack/Pta pathway and provide novel insight into the evolution of acetate metabolism for all three domains of life. | Acetate-CoA Ligase |
Since enkephalins were discovered in 1975, it has become clear that they play an antisecretory role in the gastrointestinal tract. Hence a rational research programme was directed at the development of a drug that would preserve these neurotransmitter peptides in the gut by preventing their inactivation. This research programme has resulted in the development of the enkephalinase inhibitor, racecadotril. Preclinical studies have demonstrated the efficacy of racecadotril in two models of hypersecretory diarrhoea: infusion of cholera toxin and castor oil-induced diarrhoea. Moreover, unlike loperamide, racecadotril did not prolong transit time in the small intestine or colon. Further experiments have shown that racecadotril does not promote bacterial overgrowth in the small intestine. Racecadotril lacks any potential for neurotoxicity, and radiolabelled studies have demonstrated that the drug does not enter the brain after oral administration. No potential for abuse or physical dependence has been seen. It is concluded that racecadotril demonstrates specificity of antisecretory action on the gastrointestinal tract without any adverse effect on gastrointestinal motility, and that the results of the preclinical studies indicate the potential usefulness in the treatment of hypersecretory diarrhoea in man. | N-substituted Glycines |
Alzheimer's disease is a chronic neurodegenerative disease affecting more than 30 million people worldwide. Development of small molecule inhibitors of human beta-secretase 1 (hBACE-1) is being the focus of pharmaceutical industry for the past 15-20 years. Here, we successfully applied multiple ligand-based in silico modeling techniques to understand the inhibitory activities of a diverse set of small molecule hBACE-1 inhibitors reported in the scientific literature. Strikingly, the use of only a small subset of 230 (13%) molecules allowed us to develop quality models that performed reasonably well on the validation set of 1,476 (87%) inhibitors. Varying the descriptor sets and the complexity of the modeling techniques resulted in only minor improvements to the model's performance. The current results demonstrate that predictive models can be built by choosing appropriate modeling techniques in spite of using small datasets consisting of diverse chemical classes, a scenario typical in triaging of high-throughput screening results to identify false negatives. We hope that these encouraging results will help the community to develop more predictive models that would support research efforts for the debilitating Alzheimer's disease. Additionally, the integrated diversity of the techniques employed will stimulate scientists in the field to use in silico statistical modeling techniques like these to derive better models to help advance the drug discovery projects faster. | Aspartic Acid Endopeptidases |
OBJECTIVES: Acute appendicitis is a common surgical emergency. The etiology and pathophysiology of appendicitis have been well investigated. Aggregatibacter aphrophilus is a fastidious gram-negative coccobacilli. Detection of this organism in clinical samples and its differentiation from Haemophilus aphrophilus or from Aggregatibacter actinomycetemcomitans in routine microbiology settings could be difficult. METHODS: In this rare case, we report the isolation of Aggregatibacter aphrophilus from the appendix of a 14-year-old boy presented with acute appendicitis. The genotypic method using 16S rRNA sequencing was used for identification of the organism at species level. CONCLUSION: This case highlights the importance of detecting fastidious and rare microorganisms such as Aggregatibacter aphrophilus that could be associated with acute appendicitis. | Haemophilus paraphrophilus |
Cattle, vaccinated as calves with Cowdria ruminantium-infected tick stabilate, were challenged 6, 12 and 24 months later. In the absence of tick challenge, vaccination of calves induced a partial immunity against subsequent challenge at 12 and 24 months. In animals exposed to ticks, the resistance was no better than that of control, unvaccinated cattle. When they were challenged at 6 months of age there was no difference between vaccinated and unvaccinated calves, either in the absence or presence of tick challenge, and all the animals manifested a high degree of natural resistance. This study therefore suggests that the value of vaccinating Afrikander-cross calves in heartwater endemic areas should be further investigated. The indirect fluorescent antibody (IFA) test proved to be a valuable means of monitoring the serological response of vaccinated animals and detecting the sero-conversion of animals exposed to tick infection. On one hand, there was good correlation between the febrile reaction and the results of the IFA test on the sera of vaccinated and control cattle challenged with the heartwater agent, in that all sero-positive animals were resistant to challenge. On the other hand, though, a considerable percentage of the animals that were serologically negative were also resistant to challenge. | Rickettsial Vaccines |
OBJECTIVE: Emergency department (ED) patients with psychiatric chief complaints undergo medical screening to rule out underlying or comorbid medical illnesses prior to transfer to a psychiatric facility. This systematic review attempts to determine the clinical utility of protocolized laboratory screening for the streamlined medical clearance of ED psychiatric patients by determining the clinical significance of individual laboratory results. METHODS: We searched PubMed, Embase, and Scopus using the search terms emergency department, psychiatry, diagnostic tests, laboratories, studies, testing, screening, and clearance" up to June 2017 for studies on adult psychiatric patients. This systematic review follows the recommendations of Meta-analysis of Observational Studies in Epidemiology (MOOSE) statement. The quality of each study was rated according to the Newcastle-Ottawa quality assessment scale. RESULTS: Four independent reviewers identified 2,847 publications. We extracted data from three studies (n = 629 patients). Included studies defined an abnormal test result as any laboratory result that falls out of the normal range. A laboratory test result was deemed as "clinically significant" only when patient disposition or treatment plan was changed because of that test result. Across the three studies the prevalence of clinically significant results were low (0.0%-0.4%). CONCLUSIONS: The prevalence of clinically significant laboratory test results were low, suggesting that according to the available literature, routine laboratory testing does not significantly change patient disposition. Due to the paucity of available research on this subject, we could not determine the clinical utility of protocolized laboratory screening tests for medical clearance of psychiatric patients in the ED. Future research on the utility of routine laboratory testing is important in a move toward shared decision making and patient-centered health care." | Surgical Clearance |
Left ventricular noncompaction is a rare cardiomyopathy characterized by prominent ventricular hypertrabeculation. Here, we discuss the case of a 30-year-old man who presented with rapidly conducted atrial fibrillation. The images we present demonstrate appearances characteristic of this cardiomyopathy, with prominent trabeculations and an end-diastolic noncompacted to compacted myocardial thickness ratio of more than 2 noted on echocardiography and magnetic resonance imaging." | Isolated Noncompaction of the Ventricular Myocardium |
This article examines the advances made by neuroscience in the attempt to find an answer to the question regarding the origin and foundation of moral judgements and of human behaviour in compliance with them. The conception of the brain as something dynamic and capable of adapting to the social and cultural surroundings is seen to be an important point for philosophy. At the same time, the complexity of ethical issues that cannot be reduced to observations based strictly on neurons alone also becomes quite apparent. Nevertheless, scientists and philosophers should get together and communicate with one another so as to be able to pose their questions with greater rigour and take advantage of each other's respective knowledge. | Moral Development |
We generated C57BL/6NTac mice carrying a tyrosinase loss-of function mutation and a reversion of the nonagouti locus to agouti. This strain has a high superovulation response, allows visual detection of chimeric coat color contribution of C57BL/6 ES-cells and provides a simplified breeding format that generates black G1 offspring of pure inbred C57BL/6 background in one step, providing the ideal host for genetically manipulated C57BL/6 ES cells. | Agouti Signaling Protein |
Hepatocellular carcinoma (HCC) has been one of the most fatal malignant tumors worldwide and its associated morbidity and mortality remain of significant concern. Based on in-depth reviews of serological diagnosis of HCC, in addition to AFP, there are other biomarkers: Lens culinaris agglutinin-reactive AFP (AFP-L3), des- carboxyprothrombin (DCP), tyrosine kinase with Ig and eprdermal growth factor (EGF) homology domains 2 (TIE2)-espressing monocytes (TEMs), glypican-3 (GPC3), Golgi protein 73 (GP73), interleukin-6 (IL-6), and squamous cell carcinoma antigen (SCCA) have been proposed as biomarkers for the early detection of HCC. The diagnosis of HCC is primarily based on noninvasive standard imaging methods, such as ultrasound (US), dynamic multiphasic multidetector-row CT (MDCT) and magnetic resonance imaging (MRI). Some experts advocate gadolinium diethyl-enetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and contrast-enhanced US as the promising imaging madalities of choice. With regard to recent advancements in tissue markers, many cuting-edge technologies using genome-wide DNA microarrays, qRT-PCR, and proteomic and inmunostaining studies have been implemented in an attempt to identify markers for early diagnosis of HCC. Only less than half of HCC patients at initial diagnosis are at an early stage treatable with curative options: local ablation, surgical resection, or liver transplant. Transarterial chemoembolization (TACE) is considered the standard of care with palliation for intermediate stage HCC. Recent innovative procedures using drug-eluting-beads and radioembolization using Yttrium-90 may exhibit beneficial effects in HCC treatment. During the past few years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. Sorafenib is currently the only approved systemic treatment for HCC. It has been approved for the therapy of asymptomatic HCC patients with well-preserved liver function who are not candidates for potentially curative treatments, such as surgical resection or liver transplantation. In the USA, Europe and particularly Japan, hepatitis C virus (HCV) related HCC accounts for most liver cancer, as compared with Asia-Pacific regions, where hepatitis B virus (HBV) may play a more important role in HCC development. HBV vaccination, while a vaccine is not yet available against HCV, has been recognized as a best primary prevention method for HBV-related HCC, although in patients already infected with HBV or HCV, secondary prevention with antiviral therapy is still a reasonable strategy. In addition to HBV and HCV, attention should be paid to other relevant HCC risk factors, including nonalcoholic fatty liver disease due to obesity and diabetes, heavy alcohol consumption, and prolonged aflatoxin exposure. Interestingly, coffee and vitamin K2 have been proven to provide protective effects against HCC. Regarding tertiary prevention of HCC recurrence after surgical resection, addition of antiviral treatment has proven to be a rational strategy. | Liver Neoplasms |
Mitochondria are ATP-producing organelles of bacterial ancestry that played a key role in the origin and early evolution of complex eukaryotic cells. Most modern eukaryotes transmit mitochondrial genes uniparentally, often without recombination among genetically divergent organelles. While this asymmetric inheritance maintains the efficacy of purifying selection at the level of the cell, the absence of recombination could also make the genome susceptible to Muller's ratchet. How mitochondria escape this irreversible defect accumulation is a fundamental unsolved question. Occasional paternal leakage could in principle promote recombination, but it would also compromise the purifying selection benefits of uniparental inheritance. We assess this tradeoff using a stochastic population-genetic model. In the absence of recombination, uniparental inheritance of freely-segregating genomes mitigates mutational erosion, while paternal leakage exacerbates the ratchet effect. Mitochondrial fusion-fission cycles ensure independent genome segregation, improving purifying selection. Paternal leakage provides opportunity for recombination to slow down the mutation accumulation, but always at a cost of increased steady-state mutation load. Our findings indicate that random segregation of mitochondrial genomes under uniparental inheritance can effectively combat the mutational meltdown, and that homologous recombination under paternal leakage might not be needed. | Genome, Mitochondrial |
Aquatic organisms, such as microalgae (Chlorella, Arthrospira (Spirulina), Tetrasselmis, Dunalliela etc.) and duckweed (Lemna spp., Wolffia spp. etc.) are a potential source for the production of protein-rich biomass and for numerous other high-value compounds (fatty acids, pigments, vitamins etc.). Their cultivation using agro-industrial wastes and wastewater (WaW) is of particular interest in the context of a circular economy, not only for recycling valuable nutrients but also for reducing the requirements for fresh water for the production of biomass. Recovery and recycling of nutrients is an unavoidable long-term approach for securing future food and feed production. Agro-industrial WaW are rich in nutrients and have been widely considered as a potential nutrient source for the cultivation of microalgae/duckweed. However, they commonly contain various hazardous contaminants, which could potentially taint the produced biomass, raising various concerns about the safety of their consumption. Herein, an overview of the most important contaminants, including heavy metals and metalloids, pathogens (bacteria, viruses, parasites etc.), and xenobiotics (hormones, antibiotics, parasiticides etc.) is given. It is concluded that pretreatment and processing of WaW is a requisite step for the removal of several contaminants. Among the various technologies, anaerobic digestion (AD) is widely used in practice and offers a technologically mature approach for WaW treatment. During AD, various organic and biological contaminants are significantly removed. Further removal of contaminants could be achieved by post-treatment and processing of digestates (solid/liquid separation, dilution etc.) to further decrease the concentration of contaminants. Moreover, during cultivation an additional removal may occur through various mechanisms, such as precipitation, degradation, and biotransformation. Since many jurisdictions regulate the presence of various contaminants in feed or food setting strict safety monitoring processes, it would be of particular interest to initiate a multi-disciplinary discussion whether agro-industrial WaW ought to be used to cultivate microalgae/duckweed for feed or food production and identify most feasible options for doing this safely. Based on the current body of knowledge it is estimated that AD and post-treatment of WaW can lower significantly the risks associated with heavy metals and pathogens, but it is yet unclear to what extent this is the case for certain persistent xenobiotics. | Animal Feed |
CLINICAL CONTEXT: Sensitive tools are available to diagnose occult ischemic and atherosclerotic coronary disease, yet screening for coronary artery disease (CAD) has not been shown to reduce cardiac events in patients with type 2 diabetes mellitus (T2DM). Professional guidelines are inconsistent regarding CAD screening recommendations, but it is suggested that those at highest risk (10-yr risk >/=20%) for cardiac events may benefit. EVIDENCE ACQUISITION: We reviewed bibliographies of professional CAD screening guidelines, review articles, and clinical trials published within the last 10 yr, although we have included relevant older studies. We excluded studies that did not focus on T2DM or explicitly analyze that subgroup. EVIDENCE SYNTHESIS: Although screening for coronary ischemia or atherosclerosis does provide incremental prognostic information in patients with T2DM and previously undiagnosed CAD, this has not been found to significantly impact outcomes. This appears to result from comparable efficacy of revascularization and optimal medical therapy in stable CAD. Limited evidence supports the hypothesis that those with more severe CAD (three-vessel, left main, proximal left anterior descending) amenable to bypass surgery may be potential beneficiaries of screening. However, the low prevalence of such candidates in the asymptomatic population, continuing advances with percutaneous intervention, and the lack of prospective trials makes such a recommendation currently unsupportable. CONCLUSIONS: Findings to date do not support widespread screening for CAD in patients with T2DM. A future strategy identifying those at highest risk as screening candidates may ultimately be effective, but the optimal method for selecting those subjects or subsequent treatment is unknown. | Coronary Artery Disease |
Heteroplasmy is the presence of two or more organellar genomes (mitochondrial or plastid DNA) in an organism, tissue, cell or organelle. Heteroplasmy can be detected by visual inspection of Sanger sequencing chromatograms, where it appears as multiple peaks of fluorescence at a single nucleotide position. Visual inspection of chromatograms is both consuming and highly subjective, as heteroplasmy is difficult to differentiate from background noise. Few software solutions are available to automate the detection of point heteroplasmies, and those that are available are typically proprietary, lack customization or are unsuitable for automated heteroplasmy assessment in large datasets. Here, we present PHFinder, a Python-based, open-source tool to assist in the detection of point heteroplasmies in large numbers of Sanger chromatograms. PHFinder automatically identifies point heteroplasmies directly from the chromatogram trace data. The program was tested with Sanger sequencing data from 100 humpback whales (Megaptera novaeangliae) tissue samples with known heteroplasmies. PHFinder detected most (90%) of the known heteroplasmies thereby greatly reducing the amount of visual inspection required. PHFinder is flexible and enables explicit specification of key parameters to infer double peaks (i.e., heteroplasmies). | Heteroplasmy |
Basic-laboratory assessments of renewal may inform clinical efforts to maintain reduction of severe destructive behavior when clients transition between contexts. The contextual changes arranged during standard renewal procedures, however, do not necessarily align with those that clients experience during outpatient therapy. More specifically, clients transition between clinical (associated with extinction for target behavior) and home/community (associated with reinforcement for target behavior) contexts during outpatient treatment. Standard renewal assessments do not incorporate these contextual alternations during treatment. The present experiment aimed to directly compare renewal of rats' lever pressing following a standard (sequential") ABA renewal procedure (i.e., baseline in Context A, extinction in Context B, renewal test in Context A) and a "nonsequential" renewal assessment wherein treatment consisted of daily alternation between Context A (associated with reinforcement for lever pressing) and Context B (associated with extinction). Lever pressing renewed to a greater extent for rats in the Nonsequential group than for rats in the Sequential group, suggesting the contextual changes that clients experience during outpatient treatment for severe destructive behavior may be a variable that is important to consider in translational research on renewal. Potential implications of these findings for basic and clinical research on renewal are discussed." | Rats, Long-Evans |
A series of amides of ethacrynic acid was prepared and evaluated for their ability to inhibit Wnt signaling and decrease the survival of CLL cells. Several of the most potent derivatives were active in the low micromolar range. Reduction of the alpha,beta-unsaturated carbon-carbon double bond of EA abrogated both the inhibition of Wnt signaling as well as the decrease in CLL survival. Preliminary mechanism of action studies suggest that these derivatives covalently modify sulfhydryl groups present on transcription factors important for Wnt/beta-catenin signaling. | Ethacrynic Acid |
The cannabinoid receptor type 1 (CB1) is abundantly expressed in the central nervous system where it negatively controls the release of several neurotransmitters. CB1 activity plays a crucial role in learning and memory and in synaptic plasticity. In the present study, the role of CB1 was investigated in three different hippocampus-dependent memory tasks and in in vivo hippocampal synaptic plasticity in knockout (CB1-ko) and wildtype mice. There was no difference in short-term and long-term social and object recognition memory between CB1-ko and wildtype mice. In contrast, in background contextual fear conditioning CB1-ko mice showed enhanced freezing levels in the conditioning context and increased generalised contextual fear after a high-intensity conditioning foot shock of 1.5 mA, but not after 0.7 mA. In in vivo field potential recordings in the dentate gyrus, CB1-ko mice displayed a decreased paired-pulse facilitation of the populations spikes, suggesting an altered inhibitory synaptic drive onto hippocampal granule cells. Furthermore, CB1-ko mice displayed significantly higher levels of in vivo long-term potentiation (LTP) in the dentate gyrus. In conclusion, CB1 deficiency leads to enhanced contextual fear memory and altered synaptic plasticity in the hippocampus, supporting the key role of endocannabinoid signalling in learning and memory, in particular following highly aversive encounters. | Receptor, Cannabinoid, CB1 |
The third meeting of WHO's Product Development for Vaccines Advisory Committee (PDVAC) was held in June 2016, with a remit to revisit the pathogen areas for which significant progress has occurred since recommendations from the 2015 meeting, as well as to consider new advances in the development of vaccines against other pathogens. Since the previous meeting, significant progress has been made with regulatory approvals of the first malaria and dengue vaccines, and the first phase III trials of a respiratory syncytial virus (RSV) vaccine candidate has started in the elderly and pregnant women. In addition, PDVAC has also supported vaccine development efforts against important emerging pathogens, including Middle Eastern Coronavirus (MERS CoV) and Zika virus. Trials of HIV and tuberculosis vaccine candidates are steadily progressing towards pivotal data points, and the leading norovirus vaccine candidate has entered a phase IIb efficacy study. WHO's Immunization, Vaccine and Biologicals (IVB) department is actively working in several pathogen areas on the recommendation of PDVAC, as well as continuing horizon scanning for advances in the development of vaccines that may benefit low and middle income countries (LMICs), such as the recent licensure of the enterovirus 71 (EV71) vaccine in China. Following on from discussions with WHO's Strategic Advisory Group of Experts (SAGE) on Immunization, PDVAC will also look beyond licensure and consider data needs for vaccine recommendation and implementation to reduce the delay between vaccine approval and vaccine impact. | Vaccines |
BACKGROUND: Massive hemobilia is a rare but potentially life-threatening cause of upper gastrointestinal hemorrhage. In this retrospective analysis, we have evaluated the challenges involved in the diagnosis and management of massive hemobilia. METHODS: Between 2001 and 2011, a total of 20 consecutive patients (14 males) who were treated in our department for massive hemobilia were included in the study and their records were retrospectively analyzed. RESULTS: Causes of hemobilia were blunt liver trauma (n = 9), hepatobiliary intervention (n = 4), post-laparoscopic cholecystectomy hepatic artery pseudoaneurysm (n = 3), hepatobiliary tumors (n = 3), and vascular malformation (n = 1). Melena, abdominal pain, hematemesis, and jaundice were the leading symptoms. All patients had undergone upper GI endoscopy, abdominal ultrasound, and computerized tomography of the abdomen. An angiogram and therapeutic embolization were done in 12 patients and was successful in nine but failed in three, requiring surgery. Surgical procedures performed were right hepatectomy (n = 4), extended right hepatectomy (n = 1), segmentectomy (n = 1), extended cholecystectomy (n = 1), repair of the pseudoaneurysm (n = 3), and right hepatic artery ligation (n = 1). CONCLUSION: The successful diagnosis of hemobilia depends on a high index of suspicion for patients with upper GI bleeding and biliary symptoms. Although transarterial embolization is the therapeutic option of choice for massive hemobilia, surgery has a definitive role in patients with hemodynamic instability, after failed embolization, and in patients requiring laparotomy for other reasons. | Hemobilia |
The CA1 region of the hippocampus plays a critical role in spatial and contextual memory, and has well-established circuitry, function and plasticity. In contrast, the properties of the flanking CA2 pyramidal neurons (PNs), important for social memory, and lacking CA1-like plasticity, remain relatively understudied. In particular, little is known regarding the expression of voltage-gated K(+) (Kv) channels and the contribution of these channels to the distinct properties of intrinsic excitability, action potential (AP) waveform, firing patterns and neurotransmission between CA1 and CA2 PNs. In the present study, we used multiplex fluorescence immunolabeling of mouse brain sections, and whole-cell recordings in acute mouse brain slices, to define the role of heterogeneous expression of Kv2 family Kv channels in CA1 versus CA2 pyramidal cell excitability. Our results show that the somatodendritic delayed rectifier Kv channel subunits Kv2.1, Kv2.2, and their auxiliary subunit AMIGO-1 have region-specific differences in expression in PNs, with the highest expression levels in CA1, a sharp decrease at the CA1-CA2 boundary, and significantly reduced levels in CA2 neurons. PNs in CA1 exhibit a robust contribution of Guangxitoxin-1E-sensitive Kv2-based delayed rectifier current to AP shape and after-hyperpolarization potential (AHP) relative to that seen in CA2 PNs. Our results indicate that robust Kv2 channel expression confers a distinct pattern of intrinsic excitability to CA1 PNs, potentially contributing to their different roles in hippocampal network function. | CA2 Region, Hippocampal |
The limited capacity and resources of a Field Hospital Intensive Care Unit may necessitate the triage or prioritisation of critically ill patients requiring admission. The use of critical care resources by members of the local population in certain Areas of Operation, who can not be discharged or transferred to equivalent care in their local health service, impacts significantly on bed occupancy. Therefore available resources must be distributed efficiently and equitably with decisions guided by the principles of advocacy for the patient. Patients must be admitted only on the concept of potential benefit and reasonable chance of recovery, which would not be available elsewhere. Discriminating between seriously ill patients before admission and decision making regarding withdrawal of care is very difficult. Senior clinicians working regularly in a critical care setting demonstrate a better level of discrimination in assessing outcome of seriously ill patients and are best placed to make decisions regarding admission, continuation and withdrawal of treatment. | Mobile Health Units |
OBJECTIVE: To measure the neuromagnetic fields of carpal tunnel syndrome patients after electrical digital nerve stimulation and evaluate median nerve function with high spatial resolution. METHODS: A superconducting quantum interference device magnetometer system was used to record neuromagnetic fields at the carpal tunnel after electrical stimulation of the middle digital nerve in 10 hands of nine patients with carpal tunnel syndrome. The patients were diagnosed based on symptoms (numbness, tingling, and pain) supported by a positive Phalen or Tinel sign. A novel technique was applied to remove stimulus-induced artifacts, and current distributions were calculated using a spatial filter algorithm and superimposed on X-ray. RESULTS: In 6 of the 10 hands, the amplitude of the inward current waveform attenuated to <70% or the nerve conduction velocity was <40 m/s. The results of conventional nerve conduction studies were normal for two of these six hands. All four hands that could not be diagnosed by magnetoneurography had severe carpal tunnel syndrome superimposed on peripheral neuropathy secondary to comorbidities. CONCLUSIONS: Technical improvements enabled magnetoneurography to noninvasively visualize the electrophysiological nerve activity in carpal tunnel syndrome patients. SIGNIFICANCE: Magnetoneurography may have the potential to contribute to the detailed diagnosis of various peripheral nerve disorders. | Neural Conduction |
Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR function. While excessive formation of RNA:DNA hybrids under these conditions was tightly associated with replication-stress-induced DNA damage, inhibition of transcription rescued fork speed, origin activation, and alleviated replication catastrophe. Uncoupling of pre-mRNA cleavage from co-transcriptional processing and export also protected cells from replication-stress-associated DNA damage, suggesting that pre-mRNA cleavage provides a mechanism to efficiently release nascent transcripts and thereby prevent gene gating-associated genomic instability. | RNA Cleavage |
Understanding Macrobrachium rosenbergii ovarian maturation control at the genome level is an important aspect for increasing larvae production. In this study, an ovarian maturation related gene, M. rosenbergii vWD domain and three Kazal-type domains of a gene (MrvWD-Kazal) have been studied. The MrvWD-Kazal gene was isolated using a rapid amplification of cDNA end (RACE) method and the relative abundances of MrvWD-Kazal mRNA in the ovary, hepatopancreas, stomach, intestine and gill were determined by using the quantitative PCR technique. The MrvWD-Kazal gene is composed of 2194 bp with an open reading frame (ORF) of 1998 bp encoding 665 amino acids and has great similarity to the M. nipponense vWD-Kazal gene (91%). The qPCR analyses indicated the relative abundance of MrvWD-Kazal mRNA transcript varied among different stages of ovarian function (P < 0.05), but there were no differences abundance in hepatopancreas, stomach, intestine and gill (P> 0.05). In the ovary, relative abundance of MrvWD-Kazal mRNA transcript gradually increased with ovarian maturation from Stages 1 (Spent; 1.00-fold), to 2 (Proliferative; 3.47-fold) to 3 (Premature; 6.18-fold) and decreased at Stage 4 (Mature; 1.31-fold). Differential relative abundances of MrvWD-Kazal mRNA transcript in the ovary indicate the MrvWD-Kazal protein may have an important function in ovarian maturation of M. rosenbergii. The results of this study also indicate the MrvWD-Kazal is not involved in regulation of the reproductive related function of the hepatopancreas, digestive system (stomach and intestine) and respiratory system (gill). | Kazal Motifs |
Current cooperative group trails in non-Hodgkin's lymphoma have been analyzed for their overall methods and strategies. There has been more frequent application of staging procedures and individualization of protocols for favorable and unfavorable histologies according to the Rappaport classification. Early-stage protocols are evaluating the extent of radiotherapy and the need for chemotherapy as maintenance. In later stages the incorporation of new agents in induction regimens, use of cycle-active agents, development of non-cross-resistant combinations, and use of radiation in bulk disease are being examined. In childhood lymphoma, strategies using both leukemia- or lymphoma-type approaches are being tested. Cooperative group trials should also serve as an extensive repository of data on late effects of treatment and on alterations of the course of the disease for future analysis. | Lymphoma |
This study examines Health Savings Account (HSA) effects on health-related debt outcomes. Applying the health lifestyles theory, a subset of 12,686 respondents from three years (2010, 2012, and 2014) of secondary quantitative data from the National Longitudinal Surveys of Youth (NLSY) was drawn. The sample included respondents who answered survey questions about owning an HSA, chronic disease status, health behavior, and health-related debt. Descriptive, bivariate, and generalized estimating equation (GEE) analyses were conducted. Results indicate HSA ownership status (p = .76) is not significantly associated with reporting health-related debt. Implications for social work practice are discussed. | Medical Savings Accounts |
Two sesterterpenoids, possessing an unusual 10,11-seco-gentianellane skeleton, gentianelloids A and B, were isolated from a traditional Uighur medicine Gentianella turkestanorum. Through extensive spectroscopic analysis and single-crystal X-ray diffraction, their structures including absolute configurations were unambiguously determined. A plausible biosynthetic pathway for the two compounds was proposed. Both compounds showed remarkable immunosuppressive activity, including inhibition of the proliferation, activation, and cytokine IFN-gamma production of T cells. The findings suggested that sesterterpenoids could contribute positively to the therapeutic effects of this popular traditional Uighur medicine. | Gentianella |
Age-related macular degeneration (AMD) has been described as a progressive eye disease characterized by irreversible impairment of central vision, and unfortunately, an effective treatment is still not available. It is well-known that amyloid-beta (Abeta) peptide is one of the major culprits in causing neurodegeneration in Alzheimer's disease (AD). The extracellular accumulation of this peptide has also been found in drusen which lies under the retinal pigment epithelium (RPE) and represents one of the early signs of AMD pathology. Abeta aggregates, especially in the form of oligomers, are able to induce pro-oxidant (oxidative stress) and pro-inflammatory phenomena in RPE cells. ARPE-19 is a spontaneously arising human RPE cell line validated for drug discovery processes in AMD. In the present study, we employed ARPE-19 treated with Abeta oligomers, representing an in vitro model of AMD. We used a combination of methods, including ATPlite, quantitative real-time PCR, immunocytochemistry, as well as a fluorescent probe for reactive oxygen species to investigate the molecular alterations induced by Abeta oligomers. In particular, we found that Abeta exposure decreased the cell viability of ARPE-19 cells which was paralleled by increased inflammation (increased expression of pro-inflammatory mediators) and oxidative stress (increased expression of NADPH oxidase and ROS production) along with the destruction of ZO-1 tight junction protein. Once the damage was clarified, we investigated the therapeutic potential of carnosine, an endogenous dipeptide that is known to be reduced in AMD patients. Our findings demonstrate that carnosine was able to counteract most of the molecular alterations induced by the challenge of ARPE-19 with Abeta oligomers. These new findings obtained with ARPE-19 cells challenged with Abeta1-42 oligomers, along with the well-demonstrated multimodal mechanism of action of carnosine both in vitro and in vivo, able to prevent and/or counteract the dysfunctions elicited by Abeta oligomers, substantiate the neuroprotective potential of this dipeptide in the context of AMD pathology. | Carnosine |
To investigate the genetic diversity of porcine reproductive and respiratory syndrome virus (PRRSV) in Northern Ireland, the ORF5 gene from nine field isolates was sequenced and phylogenetically analysed. The results revealed relatively high diversity amongst isolates, with 87.6-92.2% identity between farms at the nucleotide level and 84.1-93.5% identity at the protein level. Phylogenetic analysis confirmed that all nine isolates belonged to the European (type 1) genotype and formed a cluster within the subtype 1 subgroup. This study provides the first report on PRRSV isolate diversity in Northern Ireland." | Porcine respiratory and reproductive syndrome virus |
A patient with Kleine-Levin syndrome, typical except that onset was at 39 years of age, died during a symptomatic period. Autopsy disclosed recent and old lesions in the medial thalamus involving intralaminar, medial, and some dorsal nuclei as well as the pulvinar. Despite massive microglial infiltration, there was minimal neuronal loss. The hypothalamus was not involved. The findings suggest a viral cause for Kleine-Levin syndrome. | Thalamic Diseases |
During the Persian Gulf War, the U.S. Army Medical Department (AMEDD) found evacuation distances for patients increasing as a result of the fast movement of the forward line of troops. Thus, there is a need for a trauma and intensive care transport system that avoids the medical dangers that accompany such evacuation distances. In 1998, after a few years of research and development, the AMEDD introduced a prototype transport trauma pod" called the LSTAT (Life Support for Trauma and Transport). In March 2000, the LSTAT was issued to the 212th Mobile Army Surgical Hospital that deployed to Camp Bondsteel, Kosovo, for its first real-world fielding. This article describes the initial Kosovo fielding phase, highlighting the LSTAT benefits, advantages to military medicine, and recommended enhancements." | Life Support Care |
BACKGROUND: Recent data suggest a beneficial effect of add-on treatment with Viscum album L (VA) on the survival in cancer patients. The objective of this study was to compare the impact of standard oncological therapy plus add-on VA treatment (S+VA) versus standard oncological therapy alone (S) on the overall survival (OS) of patients with nonmetastasized non-small cell lung carcinoma (NSCLC). METHODS: The multicenter real-world data study was conducted using data from the Network Oncology Clinical Registry. The primary end point was OS. OS and impact on hazard in both treatment groups were compared. RESULTS: A total of 275 patients with stages I to IIIA NSCLC were enrolled (mean age = 67.6 years, 57.2% male patients). No significant difference of OS was observed between both groups. Even though not significant, for a subgroup of unresected patients with stage I NSCLC, adenocarcinoma or squamous cell carcinoma, a medium effect size OS improvement was observed for S+VA compared to S. CONCLUSIONS: Our findings support the importance of surgery as the most effective intervention in nonmetastasized NSCLC patients. Add-on VA therapy shows here no additional effect in resected patients. However, a small subgroup analysis suggests a possible role of add-on VA for nonresected subgroups. Our results complement existing knowledge on the clinical impact of add-on VA therapy in NSCLC patients and may serve as hypothesis-generating data for further examinations in this cohort. Further research could be directed towards the role of combined therapy for nonresected early-stage NSCLC. | Viscum album |
We investigated whether a standardized saw palmetto extract (SP, mixture of supercritical extract and ethanol extract at a ratio of 9.5 to 0.5) can relieve the symptoms of andropause, including metabolic syndrome, and decreases in muscle endurance and spermatogenesis, in old rats. Twenty-four-week-old male Sprague Dawley rats received oral supplementation of SP at 40, 80, and 160 mg/kg body weight (bw) for 4 weeks. We found that SP supplementation reduced body weight gain by decreasing visceral and epididymal fat weights and the levels of serum triglycerides, total cholesterol, and low-density lipoprotein/very low-density lipoprotein cholesterol. In addition, SP supplementation increased muscle endurance, sperm counts, and testosterone biosynthesis through hormonal regulation. In Leydig cells under hydrogen peroxide-induced oxidative stress, SP treatment directly induced testosterone biosynthesis by activating the mRNA expression of the genes encoding 17,20-desmolase and 3beta-hydroxysteroid dehydrogenase 4. In conclusion, our results suggest that supplementation of SP may be useful for alleviating the symptoms of andropause via direct and indirect regulation of testosterone biosynthesis. | Serenoa |
Histamine antagonists have various effects on H1, H2, cholinergic, adrenergic and serotoninergic receptors. In childhood side effects may be different and central agitation may be more pronounced than in adults. Histamine antagonists should be avoided in the fetal and neonatal periods. They are not indicated in common cold. The use of histamine antagonists in childhood will be discussed. | Histamine Agents |
This article historically reviews the limited potential of articular cartilage to heal or regenerate, past emphasis on rest as opposed to motion, and the reasoning that led the author to create the biologic concept of continuous passive motion (CPM) in 1970. The basic premises and hypotheses of CPM are stated. A brief summary is provided of 19 scientific investigations of CPM in rabbits, with particular emphasis on the beneficial short-term and long-term effects of CPM in intra-articular fractures. The conclusions from the basic research are summarized. The clinical applications of CPM to the care of patients are discussed with respect to the indications and the results." | Motion Therapy, Continuous Passive |
The oculomotor accessory nucleus, often referred to as the Edinger-Westphal nucleus [EW], was first identified in the 17th century. Although its most well known function is the control of pupil diameter, some controversy has arisen regarding the exact location of these preganglionic neurons. Currently, the EW is thought to consist of two different parts. The first part [termed the preganglionic EW-EWpg], which controls lens accommodation, choroidal blood flow and pupillary constriction, primarily consists of cholinergic cells that project to the ciliary ganglion. The second part [termed the centrally projecting EW-EWcp], which is involved in non-ocular functions such as feeding behavior, stress responses, addiction and pain, consists of peptidergic neurons that project to the brainstem, the spinal cord and prosencephalic regions. However, in the literature, we found few reports related to either ascending or descending projections from the EWcp that are compatible with its currently described functions. Therefore, the objective of the present study was to systematically investigate the ascending and descending projections of the EW in the rat brain. We injected the anterograde tracer biotinylated dextran amine into the EW or the retrograde tracer cholera toxin subunit B into multiple EW targets as controls. Additionally, we investigated the potential EW-mediated innervation of neuronal populations with known neurochemical signatures, such as melanin-concentrating hormone in the lateral hypothalamic area [LHA] and corticotropin-releasing factor in the central nucleus of the amygdala [CeM]. We observed anterogradely labeled fibers in the LHA, the reuniens thalamic nucleus, the oval part of the bed nucleus of the stria terminalis, the medial part of the central nucleus of the amygdala, and the zona incerta. We confirmed our EW-LHA and EW-CeM connections using retrograde tracers. We also observed moderate EW-mediated innervation of the paraventricular nucleus of the hypothalamus and the posterior hypothalamus. Our findings provide anatomical bases for previously unrecognized roles of the EW in the modulation of several physiologic systems. | Neurons, Efferent |
The poor prognosis and rising incidence of esophageal cancer highlight the need for improved detection and prediction methods that are essential prior to treatment. Esophageal cancer is one of the most fatal malignancies worldwide, with a dramatic increase in incidence in the Western world occurring over the past few decades. Despite improvements in the management and treatment of esophageal cancer patients, the general outcome remains very poor for overall 5-year survival rates ( approximately 10%) and 5-year postesophagectomy survival rates ( approximately 15-40%). Esophageal cancer is often diagnosed during its advanced stages, the main reason being the lack of early clinical symptoms. In an attempt to improve the outcome of patients after surgery, such patients are often treated with neoadjuvent concurrent chemoradiotherapy (CCRT) in order to decrease tumor size. However, CCRT may enhance toxicity levels and possibly cause a delay in surgery for patients who respond poorly to CCRT. Thus, precise biomarkers that could predict or identify patients who may or may not respond well to CCRT can assist physicians in choosing the appropriate therapy for patients. Identifying susceptible gene and biomarkers can help in predicting the treatment response of patients while improving their survival rates. | Esophageal Neoplasms |
A review of the use of live attenuated varicella vaccine in immunocompromised children, particularly those with underlying leukemia in remission, is presented. Data concerning safety, immunogenicity, and efficacy of this vaccine in high-risk children are reviewed. The unique contributions toward our understanding of varicella vaccine, including spread of vaccine-type virus, incidence of zoster, and immune correlates provided by studies of immunocompromised patients are discussed. The importance of protecting high-risk children against severe varicella by the use of varicella vaccine is apparent. | Chickenpox Vaccine |
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