text
stringlengths 11
9.77k
| label
stringlengths 2
104
|
|---|---|
Cranial sutures connect adjacent bones of the skull and play an important role in the absorption of stresses that may occur during different activities. The Late Triassic temnospondyl amphibian Metoposaurus krasiejowensis has been extensively studied over the years in terms of skull biomechanics, but without a detailed description of the function of cranial sutures. In the present study, 34 thin sections of cranial sutures were examined in order to determine their histovariability and interpret their biomechanical role in the skull. The histological model was compared with three-dimensional-finite element analysis (FEA) simulations of the skull under bilateral and lateral biting as well as skull-raising loads for maximum and minimum principal stress. Histologically, only two sutural morphologies were recognised in the skull of Metoposaurus: interdigitated sutures (commonly associated with compressive stresses) are dominant along the entire length of the skull roof and palate; tongue-and-groove sutures (commonly associated with tensile stresses) are present across the maxilla. FEA shows a much more complex picture of stress type and distribution than predicted by sutures. Common to both methods is a predominance of compressive stresses which act on the skull during biting. The methods predict different stress regimes during biting in the posterior part of the skull: where histological analysis suggests compression, FEA predicts tension. For lateral biting and skull raising, histological and digital reconstructions show similar general patterns but with some variations. | Skull |
OBJECTIVE: Lichen nitidus (LN) is an uncommon inflammatory skin eruption. The present study aims to describe a case series of children with LN seen at a tertiary-care health center. METHODS: Retrospective study of 17 children with biopsy-proven LN between January 2007 and March 2017. Data related with epidemiologic, clinical, and histopathologic characteristics were recorded. RESULTS: The mean age for the onset of LN was 9 years (range: 5-17 years), and the mean duration of the skin lesions was 13 months (range: 1-48 months). Fifteen were boys (88.2%). Seven children had a generalized form of LN (41.1%) and of these, two children had severe pruritus (11.8%). Seven children had a history of co-morbid skin conditions (41.1%), including lichen planus in one patient (5.9%), lichen striatus in one patient (5.9%), psoriasis and longitudinal ridges in the nails in one patient (5.9%), and cutaneous features of atopic skin in four patients (23.5%). All of the reviewed patients had lymphohistiocytic infiltration in the dermis and basal vacuolar degeneration. Multinucleated giant cells were present in 11 (64.7%). CONCLUSION: This case series found LN in a generalized form as well as other concurrent dermatologic conditions in nearly half of those reported. The boy predominance was also noteworthy. | Lichen Nitidus |
Liver-directed gene therapy is appropriate for many conditions. Recent work established that liver repopulation with transplanted cells can be effective in treating genetic disorders. Although hepatocytes express therapeutic genes with considerable efficiency, correction of genetic disorders is constrained by limitations in permanent gene transfer into hepatocytes and repopulation of the liver with transplanted cells. Adenoviral vectors are highly efficient for hepatic gene transfer but the onset of deleterious host immune responses against adenoviral vectors, along with clearance of transduced hepatocytes have caused problems. Nonetheless, recent work concerning engraftment and proliferation of transplanted hepatocytes in the liver has provided significant new information, which should refocus interest in hepatocyte-based therapies. Moreover, hepatocyte transplantation systems offer creative tools for defining critical mechanisms in gene regulation and survival of transduced cells. | Animals, Congenic |
The major contribution of molecular biology to the study of antibiotic resistance has been the elucidation of nearly all biochemical mechanisms of resistance and the routes for dissemination of genetic information among bacteria. In this review, we consider the potential contribution of molecular biology to counteracting the evolution of resistant bacteria. In particular, we emphasize the fact that fundamental approaches have had direct practical effects on minimizing potential resistance: by improving interpretation of resistance phenotypes, by providing more adequate human therapy, by fostering more prudent use of antibiotics, and by allowing the rational design of new drugs that evade existing resistance mechanisms or address unexploited targets." | Drug Resistance, Multiple, Bacterial |
PURPOSE: To evaluate the frequency of protective lens wear by anophthalmic patients and identify factors that influence compliance. METHODS: An IRB approved descriptive retrospective chart review of patients undergoing surgery with the senior author (PLC) with an anophthalmic orbit and one remaining sighted eye. Results were tabulated and analyzed using age, indication for procedure, duration of visual symptoms, safety glasses wear, number of postoperative visits, and evidence of new trauma to the remaining eye. All patients underwent counseling on the importance of protective lens wear preoperatively and each subsequent visit. RESULTS: Etiologies for loss of the eye in the 132 study patients included trauma (33.3%), blind painful eye (33.3%), congenital disorders (14.4%), adult-onset malignancy (14.4%), and retinoblastoma (4.5%). At the final visit, protective lenses were worn in the following patterns: full-time (55.3%), frequently (11.4%), occasional (6%), and never (28.8%). The regular use of protective eyewear at last visit was more common in patients wearing glasses at presentation (79.7%), than in those who did not (32.9%; p </= 0.001). Increased number of office encounters correlated with more frequent use of protective eyewear (p </= 0.01). Patient age (p = 0.95), indication for surgery (p = 0.97), and duration of visual loss (p = 0.85) were not predictive of safety glasses wear. Three patients had evidence of subsequent ocular trauma to the remaining eye, with 2 having resultant decrease in acuity; none of these 3 patients wore safety glasses full-time. CONCLUSIONS: A significant number of anopthalmic patients were not wearing protective lenses at presentation. Overall compliance was poor; but repeated education on the importance of safety glasses appears to improve compliance. Educating referring providers and primary care physicians about the importance of early and repeated counseling is vital to increasing compliance. | Eye Protective Devices |
The aim of this study was to compare the efficacy and safety of intravenous JR-131, a darbepoetin alfa biosimilar, to darbepoetin alfa in hemodialysis patients with renal anemia. In this 24-week, multicenter, randomized, double-blinded, parallel-group phase 3 study, 334 hemodialysis patients with renal anemia who had been receiving darbepoetin alfa were randomized to either JR-131 or darbepoetin alfa group. The initial dose was set based on the darbepoetin alfa dose during the observation period. The primary endpoint was change in hemoglobin level from baseline to end of treatment. The 95% confidence interval of the difference in the change in hemoglobin level between the groups was -0.19 to -0.20 g/dL, within the equivalent margin of -0.5 to 0.5 g/dL. No notable treatment-emergent adverse events were observed in either group. JR-131 was therapeutically equivalent to darbepoetin alfa, and the safety profile of JR-131 was similar to that of darbepoetin alfa. | Darbepoetin alfa |
A fungal nitrilase gene from Fusarium proliferatum AUF-2 was cloned through reverse transcription-PCR. The open reading frame consisted of 903 bp and potentially encoded a protein of 301 amino acid residues with a theoretical molecular mass of 33.0 kDa. The encoding gene was expressed in Escherichia coli strain BL21 and the recombinant protein with His6-tag was purified to electrophoretic homogeneity. The purified enzyme exhibited optimal activity in the range of 35-40 degrees C and pH 8.0. EDTA, Mg(2+), Zn(2+), Ca(2+), Fe(2+), Fe(3+) and Mn(2+) stimulated hydrolytic activity, whereas Cu(2+), Co(2+) and Ni(2+) had inhibitory effect on nitrilase activity. Ag(+) ions showed a strong inhibitory effect on the recombinant nitrilase activity. This nitrilase was specific towards aliphatic, heterocyclic and aromatic nitriles. The kinetic parameters V(max) and K(m) for benzonitrile substrate were determined to be 14.6 mumol/min/mg protein and 1.55 mM, respectively. Homology modelling and molecular docking studies provided an insight into the substrate specificity and the proposed catalytic triad for recombinant nitrilase consisted of Glu-54, Lys-133 and Cys-175. This is the first report on the cloning and heterologous expression of nitrilase from Fusarium proliferatum. | Aminohydrolases |
The development of chimeric antigen receptor (CAR) T cells began as a means toward specific yet modular therapies against cancer. Recent advancements in several CAR T cell therapies show the promise of cellular immunotherapy in cancer treatment. CAR T cell therapy is still immature, however, and improvements are needed to fully realize its curative potential. The approved CAR T cells are designed with simple logic capabilities; an antigen sensor that, when bound to the target antigen, triggers costimulation domains and native T cell activation. This single-type sensor and native activation design, although capable, also has severe limitations. Reliance on a single-type sensor leads to unwanted toxicity toward antigen-expressing normal tissues, and unmodulated activation leads to unwanted cytokine toxicity. Synthetic biology (SB) offers a powerful solution to these limitations: modular receptors with customizable sensors and output behaviors that enable higher Boolean logic. SB T cells already have shown incredible capabilities, such as multiple-antigen discrimination and improved persistence. In light of these results, cellular immunotherapy may already be branching into a new subfield that we term here as synthetic immunotherapy." Here we review the current logic capabilities of CAR T cells, the resulting limitations, and the engineering undertaken to address these issues. We then discuss several tools of SB and show how SB CAR T cells pave the way for synthetic immunotherapy." | Adoptive Transfer |
In this paper, we are presenting a synthetic version of the third updated version of Guidelines for the first-line management by the non-sexologist practitioner of a man with erectile dysfunction (ED). This work applied the methodology recommended by the French High Authority of Health (in-depth documentary search of medical and scientific bibliographic data and review by a group of experts). Among the points to be highlighted since 2010, an important part has been devoted to updating epidemiological data that focus on the strong correlation between ED and vulnerable populations, on the question of the role of the partner's role in triggering or maintaining erectile dysfunction, previously poorly documented, and on the evolution of ED treatments and management algorithms. | Erectile Dysfunction |
OBJECTIVE: This study was designed to investigate the prognosis of restorative caries therapy applied in nursing home residents. METHOD AND MATERIALS: In 25 consecutive patients a total of 42 restorations were placed, 23 of composite resin (APX/SE Bond) and 19 of compomer (Dyract). The working conditions, such as patient cooperation, quantity of saliva, location of cavity margins, cavity size, and gingival inflammation, were evaluated prior to treatment. The restorations were evaluated qualitatively at baseline, after 6 months, and after 12 months. RESULTS: At 12 months, all examined restorations were clinically acceptable (6 patients had died). There was no significant difference between the quality of the restorations in composite resin and compomer. The plaque scores increased significantly during the study period. CONCLUSIONS: The study showed that, within the limitation of a short-term follow-up, restorative caries therapy using composite resin or compomer was successful in nursing home residents although rubber dam was not used. | Compomers |
Kinesins are microtubule-based motor proteins that are involved in cargo transport and mitosis. They are called motors" because they convert chemical energy to mechanical energy (i.e. force and motion). They use the energy of ATP hydrolysis for their enzymatic processes by walking on microtubules. However, the mechanism underlying their motion has been unclear. Recently, conventional kinesin, which was the first-identified member of the family, has been shown to walk by swapping its two heads in a "hand-over-hand" mechanism. There is also experimental evidence supporting an asymmetric walking of kinesin in which two identical heads of the motor take alternate slow and fast steps. Other cargo-carrier and mitotic kinesins remain uninvestigated and are of great interest to biophysicists." | Kinesins |
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored. METHODS: We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA. RESULTS: Low muM concentrations of Nintedanib (1 muM) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs. CONCLUSIONS: Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients. | Alveolar Epithelial Cells |
Adults with paraphilic infantilism may desire to wear diapers or engage in infant-like role play. Erotic target identity inversions (ETII) and childhood maltreatment have been hypothesized to cause regressive interests. To evaluate these two etiological hypotheses, we surveyed the online adult baby/diaper lover community. Data from 1904 cis-gender men revealed a prevalence of pedophilic interests comparable with the general male population, arguing against ETIIs as common in paraphilic infantilism. In contrast, self-reported childhood neglect and abuse were highly prevalent, suggesting that infantilism might be correlated with childhood maltreatment. Additionally, some participants described repetition and/or sexualization of negative childhood experiences. | Diapers, Infant |
A new two-piece plastic split cast consisting of an assembly plate and a disposable part was described; its use as a diagnostic an control device was discussed. The split is available for all standard articulators. | Dental Casting Technique |
The identification and cloning of full-length homologs of circadian clock genes from Picea abies represent a first step to study the function and evolution of the circadian clock in gymnosperms. Phylogenetic analyses suggest that the sequences of key circadian clock genes are conserved between angiosperms and gymnosperms. though fewer homologous copies were found for most gene families in P. abies. We detected diurnal cycling of circadian clock genes in P. abies using quantitative real-time PCR; however, cycling appeared to be rapidly dampened under free-running conditions. Given the unexpected absence of transcriptional cycling during constant conditions, we employed a complementary method to assay circadian rhythmic outputs and measured delayed fluorescence in seedlings of Norway spruce. Neither of the two approaches to study circadian rhythms in Norway spruce could detect robust approximately 24 h cycling behavior under constant conditions. These data suggest gene conservation but fundamental differences in clock function between gymnosperms and other plant taxa. | Picea |
Characteristic genetic aberrations have been identified in many soft tissue tumors, and it is likely that several of these aberrations, e.g., the translocation of chromosomes X and 18 in synovial sarcoma, will play an increasing diagnostic role. It is fascinating that most of the consistent soft tissue tumor translocations result in fusion genes, and these fusion genes encode proteins, which in turn regulate the expression of other genes. Thus, many soft tissue tumor translocations represent the first steps in complicated cascades of events contributing to deregulated tumor cell growth. Although a number of translocations appear to be useful in diagnosis, it should be emphasized that cytogenetic and molecular detection of chromosome translocations and gene fusions is not always straightforward. Cytogenetic and molecular analyses are perhaps best reserved for the subgroup of undifferentiated small round cell or spindle cell sarcomas, which remain unclassified after histological, immunohistochemical, and ultrastructural studies. Tumor specimens frozen at -70 degrees C can be used subsequently for FISH and PCR studies, although the opportunity to karyotype such specimens is lost upon freezing. | Genes, Tumor Suppressor |
Genome-scale metabolic models (GEMs) provide a functional view of the complex network of biochemical reactions in the living cell. Initially mainly applied to reconstruct the metabolism of model organisms, the availability of increasingly sophisticated reconstruction methods and more extensive biochemical databases now make it possible to reconstruct GEMs for less well-characterized organisms, and have the potential to unravel the metabolism in pathogen-host systems. Here, we present a GEM for the oomycete plant pathogen Phytophthora infestans as a first step towards an integrative model with its host. We predict the biochemical reactions in different cellular compartments and investigate the gene-protein-reaction associations in this model to obtain an impression of the biochemical capabilities of P. infestans. Furthermore, we generate life stage-specific models to place the transcriptomic changes of the genes encoding metabolic enzymes into a functional context. In sporangia and zoospores, there is an overall down-regulation, most strikingly reflected in the fatty acid biosynthesis pathway. To investigate the robustness of the GEM, we simulate gene deletions to predict which enzymes are essential for in vitro growth. This model is an essential first step towards an understanding of P. infestans and its interactions with plants as a system, which will help to formulate new hypotheses on infection mechanisms and disease prevention. | Phytophthora infestans |
Calcineurin (CaN) is a heterodimer composed of a catalytic subunit A (CaNA) and a regulatory subunit B (CaNB). We report here an active truncated mutation of the rat CaNAdelta that contains only the catalytic domain (residues 1-347, also known as a/CaNA). The p-nitrophenyl phosphatase activity and protein phosphatase activity of a/CaNA were higher than that of CaNA. Both p-nitrophenyl phosphatase activity and protein phosphatase activity of a/CaNA were unaffected by CaM and the B-subunit; the B-subunit and CaM have relatively little effect on p-nitrophenyl phosphatase activity and a crucial effect on protein phosphatase activity of CaNA. Mn2+ and Ni2+ ions effeciently activated CaNA. The Km of a/CaNA was about 16 mM, and the k(cat) of a/CaNA was 10.03 s(-1) using pNPP as substrate. With RII peptide as a substrate, the Km of a/CaNA was about 21 microM and the k(cat) of a/CaNA was 0.51 s(-1). The optimum reaction temperature was about 45 degrees C, and the optimum reaction pH was about 7.2. Our results indicate that a/CaNA is the catalytic core of CaNA, and CaN and the B-subunit binding domain itself might play roles in the negative regulation of the phosphatase activity of CaN. The results provide the basis for future studies on the catalytic domain of CaN. | Calcineurin |
BACKGROUND: Cellular metabolism and exposure to solar irradiation result in generation of free radicals which are destructive and can lead to premature aging. Antioxidants and free radical scavengers such as carotenoids successfully protect from these free radicals by quenching and neutralizing them thereby strengthening skin barrier which leads to improved skin moisturization, desquamation, and a more youthful look. This study was designed to evaluate the consumer-perceived efficacy of an oral supplement (Lumenato) containing a mix of tomato carotenoids and oil-soluble vitamins in improving skin appearance after 12 weeks of supplement use. MATERIALS AND METHODS: Plasma levels of phytoene, phytofluene, zeta-carotene, and lycopene were quantitated before and after 1-, 2-, 3-, and 4-week administration of Lumenato by 24 healthy volunteers. Part II of the study addressed skin visual attributes as assessed by validated tools (questionnaires). A total of 60 females, aged 35 to 55 years, completed part II of the study. The subjects answered questionnaires pertaining to their assessment of skin appearance before and after 12 weeks of taking the supplement. RESULTS: There was a significant increase (p < 0.001) in plasma levels of phytoene, phytofluene, and zeta-carotene after 1- to 4-week treatment with Lumenato. After 12 weeks of using the supplement, the score of different skin parameters was reported to significantly improve (p < 0.001). Improvement was recorded in skin elasticity, firmness, brightness, skin tone, reduction in dark spots and periorbital dark circles, skin hydration, texture and fine lines and wrinkles. A significant (p < 0.001) improvement in overall skin condition after using the supplement was observed. The subjects noticed statistically significant (p < 0.001) improvement in skin elasticity, firmness, brightness, skin tone, reduction in dark spots and periorbital dark circles, skin hydration, texture and fine lines and wrinkles after 12 weeks of using the supplement. The overall skin condition also exhibited a significant improvement (p < 0.001). Self-assessed improvement of the face was identified at the first time point (4 weeks) and improved significantly (p < 0.001) for the 12 weeks of use. Interestingly, these improvements persisted even after treatment was stopped. CONCLUSION: Based on the confines and conditions of this study, the use of oral supplement containing a mix of tomato carotenoids significantly increased plasma levels of phytoene, phytofluene, and zeta-carotene, and continuous use resulted in improved facial skin attributes which were palpable by the consumers and continued even after treatment was stopped. | zeta Carotene |
The rapidly evolving stem cell field puts much stress on developing educational resources. The ISSCR Education Committee has created a flexible stem cell syllabus rooted in core concepts to facilitate stem cell literacy. The free syllabus will be updated regularly to maintain accuracy and relevance. | Educational Status |
Corneal transparency depends on the precise organization of the stromal extracellular matrix. The morphology of the extracellular matrix of the embryonic and adult avian secondary posterior cornea was studied in glutaraldehyde-fixed, quick-frozen, deep-etched replicas with the electron microscope. Although the collagen fibrils changed from a loose network to a more ordered parallel lamellar arrangement during development, their mean diameter remained constant between 30.3 and 31.2 nm. Besides collagen fibrils, other extracellular matrix components were observed: (i) straight or Y-shaped cross-bridging interfibrillar 8-10 nm filaments with 18-22 nm globules; (ii) relatively loose networks of 10-20 nm beaded filaments, with a mean periodicity of 107 nm, often running perpendicular to the collagen fibrils and adhering to the plasma membrane of stromal cells at early developmental stages; (iii) straight or curved 6-12 nm strands forming sheets within the stromal matrix that progressively disappeared, whereas similar structures persisted at the Descemet's membrane-stroma interface; (iv) dense networks of filaments with 6-8 nm filaments, sometimes polygonally arranged, and a substructure of 2-3 nm filaments with globular domains, which progressively disappeared with maturation but remained at the Descemet's membrane-stroma interface; (v) polygonal networks of 9-10 nm filaments with globular domains adherent to the surface of cell plasma membranes at early developmental stages. The temporal expression of deep-etched supramolecular structural assemblies is compatible with that of the so-called 'interstitial basement membrane components' previously described. The quick-freeze and deep-etching method can reveal important aspects of the in situ organization of the corneal extracellular matrix. | Corneal Stroma |
Tinea universalis is a condition when most of the anatomical sites of body are involved due to dermatophyte infection both in immunocompetent and immunocompromised individuals. Here we present a case of tinea universalis due to Trichophyton indotineae (T. indotineae) from India. This species has emerged recently. Earlier, it has been reported as Trichophyton mentagrophytes (T. mentagrophytes) and Trichophyton interdigitale (T. interdigitale). T. indotineae has been associated with outbreaks and epidemics of chronic, recalcitrant, and nonresponsive to terbinafine, in India and several other countries. The patient was prescribed Itraconazole (200 mg/day), Luliconazole cream topically and antihistamine at night, with marked improvement clinically. Easy availability and misuse of corticosteroids cream, as over-the-counter drug, should be discouraged. | Tinea |
OBJECTIVE: Pediatric sleep-disordered breathing (SDB) has a disproportionately high prevalence in children who were preterm infants (preterm children) and is associated with behavioral comorbidity. Exposure to intermittent hypoxemia and sleep disruption may contribute to cognitive impairment. We quantified the association of SDB with cognition and achievement and determined whether preterm children are at a differentially increased risk for SDB-related impairments. DESIGN: Cross-sectional analyses. SETTING: Urban community. PARTICIPANTS: Eight hundred thirty-five children, aged 8 to 11 years.Intervention(s) None. MAIN OUTCOME MEASURES: Scores on the Peabody Picture Vocabulary Test-Revised, Kaufman Assessment Battery for Children, and Continuous Performance Test. RESULTS: One hundred sixty-four children had SDB. In unadjusted analyses, children with SDB had poorer scores on almost all tests of cognition and achievement. Group differences were attenuated after adjusting for socioeconomic status; in these analyses, children with SDB scored lower on the Peabody Picture Vocabulary Test-Revised (mean +/- SE score, 100.5 +/- 1.4 vs 103.6 +/- 0.7; P = .04), and the Kaufman Assessment Battery for Children riddles and triangles subscales. Associations were stronger in preterm than in full-term children. Of the sleep measures, snoring history was most strongly correlated with indices of cognition and achievement. CONCLUSIONS: Although moderate group differences were observed for almost all cognitive measures, an attenuation of effects was observed once socioeconomic status was considered. The deficits in selective measures of academic abilities, language comprehension, and planning and organizational skills suggest a negative impact of SDB on achievement and cognition. Stronger associations in preterm children suggest the importance of screening for snoring, a good predictor of cognitive function in this population. | Underachievement |
Reproductive success in mice depends on sexually dimorphic major urinary proteins (Mup) that facilitate interactions between females and males. Deletion of cystathionine beta-synthase (Cbs) gene, a metabolic gene important for homeostasis of one-carbon metabolism, impairs reproduction by causing female infertility in mice. Here, we examined Mup biogenesis and sexual signaling in Cbs(-/-) versus Cbs(+/-) mice. We found significantly reduced levels of total urinary Mup protein in male and female Cbs(-/-) versus Cbs(+/-) mice. SDS-PAGE/Western blot, ESI-MS, and RT-qPCR analyses of the liver, plasma, and urinary proteins identified a male-specific Mup20 in Cbs(-/-) , but not in Cbs(+/-) females. The 18 893 Da Mup20 became the most abundant in urine of Cbs(-/-) females and males. Effects of Cbs genotype on 18 645 Da, 18 693 Da, and 18 709 Da Mup species abundance were Mup- and sex-specific. Cbs genotype-dependent changes in hepatic Mups and Mup20 expression were similar at the protein and mRNA level. Changes in Mups, but not in Mup20, can be explained by downregulation of hepatic Zhx2 and Ghr receptors in Cbs(-/-) mice. Behavioral testing showed that Cbs(+/-) females ignored Cbs(-/-) male urine but were attracted to Cbs(+/-) male urine. Cbs(+/-) males ignored urine of Cbs(-/-) males but countermarked urine of other Cbs(+/-) males and were attracted to urines of Cbs(-/-) as well as Cbs(+/-) females. Cbs(-/-) males did not countermark urine of Cbs(+/-) males but were attracted to urines of Cbs(+/-) females. Taken together, these findings show that Cbs, a metabolic gene, interacts with the processes involved in Mup biogenesis that are essential for the maintenance of sexual dimorphism and signaling and suggest that dysregulation of these interactions impairs reproductive fitness in mice. | Cystathionine beta-Synthase |
At present, the inability to meaningfully and reliably conduct toxicological testing on human skeletal material represents a significant gap in forensic practice, especially in a time when the U.S. has declared opioid use a public health emergency and chemical weapon use in both mass and isolated attacks is prevalent in international news. In recent years, an increasing number of case studies and experiments have been published in an attempt to fill this knowledge gap. These papers are reviewed, and their valuable and pertinent findings discussed. However, the lack of an established model for the incorporation of drugs of forensic interest into bone has limited interpretation of results and delayed adoption of skeletal toxicology methods into accepted forensic practice. A model for the in vivo incorporation of drugs of forensic interest into bone tissue is proposed herein. This model is derived from known pathways for in vivo incorporation of compounds and analytes not of traditional forensic interest into bone tissue and is based on principles of ionic exchange, adsorption, and substitution. Testing and understanding these pathways may better guide skeletal toxicological experimentation, resulting in methods more tailored to human bone as a unique, largely inorganic matrix, as well as in increased interpretability of results. Further, the proposed model suggests possible novel applications for the field of skeletal toxicology on the humanitarian stage. Indeed, based on their chemical properties, chemical weapon nerve agents should be investigated as xenobiotics that may incorporate into the human skeleton at relatively elevated levels. If nerve agents can be isolated from skeletal remains, the field of skeletal toxicology may be able to offer important contributions to human rights investigations of mass graves. | Nerve Agents |
OBJECTIVE: Echinococcus granulosus contains a complex of different strains that represent diversity in the pattern of the life cycle and also their host types. So far 10 genotypes of this parasite have been identified, using molecular methods. The current study aimed to evaluate and compare the genotypic diversity of E. granulosus metacestodes from livestock of Turkey and Iran. METHODS: A total of 90 livestock liver and lung organs infected with hydatid cyst from industrial slaughterhouses of Bonab Province in the East Azerbaijan Province in Iran (60 samples, including 30 sheep and 30 cattle) and Van Province in Turkey (30 samples, including 15 sheep and 15 cattle) were collected. DNA was extracted from the protoscolices or germinal layers and polymerase chain reaction (PCR) were utilized, targeting the partial mitochondrial cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase 1 (nad1) genes. PCR products were isolated from the electrophoresis gels and sequenced. The sequences were compared with each other, as well as with those related available sequences in the GenBank, using the BioEdit software and the BLAST algorithm. Finally, the phylogenetic trees were constructed by comparing sequences of cox1 and nad1 fragments, using the MEGA7 software and the maximum likelihood method. RESULTS: All samples sequenced from Iran corresponded to the genotype G1 (100%). Among the samples from Turkey, 15 samples (78.9%) were identified as G1 while only one sample (5.3%) corresponded to the genotype G3 and 3 isolates (15.8%) were defined as genotypes G1/G3. Five distinct haplotypes were determined within the examined isolates from sheep and cattle in both countries and all isolates clustered in one group. Phylogenetic analysis revealed that the intra-species genetic variations were 0.0-0.6% and 0.0-1.4% for cox1 and nad1, respectively. CONCLUSION: The dominant genotype of E. granulosus sensu stricto of livestock in both countries was the G1 (sheep strain) genotype. Our findings indicate that the sheep-dog cycle is the leading cycle of E. granulosus in these two areas. Hence, adopting regional common policies and bilateral cooperation helps to control the disease in livestock as well as in human in these two regions. Further study is required to compare the genetic diversity of human isolates of E. granulosus in these two countries. | Echinococcus granulosus |
In this work, the molecular and phenotypic antimicrobial resistance and clonal diversity of 10 linezolid-resistant Staphylococcus spp. isolates were investigated. The 7 Staphylococcus haemolyticus isolates presented Staphylococcal cassete chromosome mec (SCCmec) V and belonged to the same pulsed-field gel electrophoresis pulsotype. Their MICs for oxacillin, vancomycin, and linezolid were >/= 256 mug/mL, 1-4 mug/mL, and 8-16 mug/mL, respectively. The 3 S. hominis presented MIC values 32 to >256 mug/mL, 2-4 mug/mL, and 12-24 mug/mL, and all carried the nontypeable SCCmec (ccr1 + mecA class) and belonged to 2 different genotypes. The cfr gene was not found, but the mutation G2603T was detected in S. haemolyticus and C2190T and G2603T in Staphylococcus hominis in 23S rRNA. This study demonstrates the spread of a linezolid-resistant S. haemolyticus genotype and, for the first time, describes the mutation C2190T among S. hominis isolates with a double mutation in Brazil. | Staphylococcus haemolyticus |
Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489). | Chalcones |
Fever of unknown origin (FUO) is defined as a temperature elevation of 101 degrees F (38.3 degrees C) or higher for 3 weeks or longer, the cause of which is not diagnosed after 1 week of intensive in-hospital investigation. This article discusses the causes, diagnosis, and treatment of FUOs. | Fever of Unknown Origin |
Up to 6% of men who have undergone vasectomy will ultimately elect for reversal in the form of vasovasostomy or vasoepididymostomy for various reasons. Vasovasostomy performed to regain fertility is a technique that has undergone numerous advances during the last century, including the use of microsurgical equipment and principles to construct a meticulous anastomosis. It is important during vasovasostomy to ensure good blood supply to the anastomosis as well as to build as a tension-free anastomosis. Visual inspection to ensure healthy mucosa and inner muscularis as well as atraumatic handling of tissues is helpful. With vasovasostomy, it is essential to create a watertight anastomosis to prevent secondary scar formation. The microdot technique of vasovasostomy allows for markedly discrepant lumens to be brought together more precisely. Thereby, the planning is separated from suture placement, which prevents dog-ears and avoids subsequent leaks. In the age of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), it becomes even more important to clarify outcomes after vasectomy reversals, as patients now have a choice between surgical sperm retrieval coupled with IVF/ICSI versus vasectomy reversal. Little data on long-term outcomes for vasectomy reversals exist. Therefore, further research in this field needs to evaluate the rate of late failures and the predictors of late failures. | Vasovasostomy |
Routine examinations during chemotherapy containing anthracyclines evaluate heart function before treatment and monitor cardiotoxic effects during and after therapy. A number of methods are useful in cardiac assessment, including electrocardiography, radiology techniques (RTG, CT, MRI,PET-CT, PET-MRI), echocardiography, radioisotope imaging techniques (scintigraphy, MUGA,PET), and ultra-structure evaluation in biopsy samples. Nevertheless, there is a continuous need for new methods to predict future damage at the initial stages of cardiac changes. In recent years the therapeutic usefulness of biochemical blood parameters in anthracycline-treated patients has been assessed. The levels of cardiac troponins (cTnI, cTnT), natriuretic peptides (ANP, BNP), and endothelin 1 have been included in the studies. Heart-type fatty acid binding protein (H-FABP) is another promising factor showing cardiomyocytic impairment. However, the clinical use of biochemical parameters in diagnosing anthracycline-related cardiotoxicity is still a controversial issue. | Cardiotoxins |
Protein affinity is of importance for porphyrins in their application in photodynamic therapy (PDT). A new Phenol Red-modified porphyrin (R-TPP) was designed and synthesized to fully take advantage of the binding character of Phenol Red towards protein. Detailed comparisons of absorption spectra, fluorescence spectra, n-octanol/water partition coefficients, (1)O(2) quantum yields, as well as protein photocleaving abilities between R-TPP and its parent porphyrin Br-TPP clearly demonstrate the benefits stemming from the modification of Phenol Red. On one hand, the presence of Phenol Red moiety greatly enhances the binding affinity of R-TPP towards model proteins (bovine serum albumin and hen egg lysozyme), and therefore improves the availability of (1)O(2). On the other hand, the presence of Phenol Red moiety provides R-TPP with amphiphilic character, and therefore restricts aggregation and favors the generation of (1)O(2). As a result, R-TPP photocleaves proteins efficiently, showing promising application potential in PDT. | Phenolsulfonphthalein |
A prospective study of 60 patients with the temporomandibular pain and dysfunction syndrome (TMPDS) was done using the General Health Questionnaire, the Crown-Crisp Experiential Index, and the Parental Bonding Instrument. Three months after an initial visit 59 patients were reassessed: 18 patients were completely better or improved a lot, 27 were improved a little, and 14 were the same or worse. Patients' outcomes were not related to the severity or duration of symptoms at the initial presentation. Thirty-five percent of the patients had not received any therapy in the 3-month interval. The outcomes of these patients were not different from the outcomes of patients who had received treatment. A significant relationship was found between initial psychological test scores and outcome (multivariate F = 3.80, P less than 0.05). This relationship was curvilinear: the group with the worst outcomes scored highest, that with the best outcomes scored in the middle, and that with intermediate outcomes scored lowest. These results imply that mild psychological distress may facilitate a successful outcome, whereas either excessive psychological disturbance or minimal psychological complaint is associated with poor results." | Temporomandibular Joint Dysfunction Syndrome |
Regulation of the stability and the quality of mitochondrial RNA is essential for the maintenance of mitochondrial and cellular functions in eukaryotes. We have previously reported that the eukaryotic poly(A)-specific ribonuclease (PARN) and the prokaryotic poly(A) polymerase encoded by AHG2 and AGS1, respectively, coordinately regulate the poly(A) status and the stability of mitochondrial mRNA in Arabidopsis. Mitochondrial function of PARN has not been reported in any other eukaryotes. To know how much this PARN-based mitochondrial mRNA regulation is conserved among plants, we studied the AHG2 and AGS1 counterparts of the liverwort, Marchantia polymorpha, a member of basal land plant lineage. We found that M. polymorpha has one ortholog each for AHG2 and AGS1, named MpAHG2 and MpAGS1, respectively. Their Citrine-fused proteins were detected in mitochondria of the liverwort. Molecular genetic analysis showed that MpAHG2 is essential and functionally interacts with MpAGS1 as observed in Arabidopsis. A recombinant MpAHG2 protein had a deadenylase activity in vitro. Overexpression of MpAGS1 and the reduced expression of MpAHG2 caused an accumulation of polyadenylated Mpcox1 mRNA. Furthermore, MpAHG2 suppressed Arabidopsis ahg2-1 mutant phenotype. These results suggest that the PARN-based mitochondrial mRNA regulatory system is conserved in land plants. | Marchantia |
Abnormal uterine bleeding in women is a common cause for gynecologic consultation. Physicians must maintain a low threshold for endometrial assessment in abnormal uterine bleeding. Accurately determining the etiology of the bleeding permits appropriate treatment, minimizes unnecessary delays in therapy, and prevents needless worry in women. There are few national consensus guidelines, best practice guidelines, or treatment algorithms that provide gynecologists with scrupulous data to make concise decisions for the utilization of technology such as endometrial biopsy, transvaginal ultrasound, saline infusion sonography, or hysteroscopy in the evaluation of menstrual aberrations. Using technology that has a high sensitivity to detect a disease allows a physician to make concise decisions for proceeding with minimally invasive procedures or reliance on medical therapies that will probably be effective. | Metrorrhagia |
The recent widespread adoption of compact fluorescent lamps (CFL) has increased their importance as a source of environmental Hg. Stable isotope analysis can identify the sources of environmental Hg, but the isotopic composition of Hg from CFL is not yet known. Results from analyses of CFL with a range of hours of use show that the Hg they contain is isotopically fractionated in a unique pattern during normal CFL operation. This fractionation is large by comparison to other known fractionating processes for Hg and has a distinctive, mass-independent signature, such that CFL Hg could be uniquely identified from other sources. The fractionation process described here may also explain anomalous fractionation of Hg isotopes in precipitation. | Mercury Isotopes |
Tax credits will help reimburse employers for the added costs of hiring and training disadvantaged workers from seven target groups with especially high rates of unemployment. | Income Tax |
Toxoplasma gondii is an intracellular parasite that causes severe disease when the infection occurs during pregnancy. Adenosine is a purine nucleoside involved in numerous physiological processes; however, the role of adenosine receptors in T. gondii-induced trophoblast cell function has not been investigated until now. The goal of the present study was to evaluate the intracellular signaling pathways regulated by adenosine receptors using a HTR-8/SVneo trophoblast cell model of T. gondii infection. HTR8/SVneo human extravillous trophoblast cells were infected with or without T. gondii and then evaluated for cell morphology, intracellular proliferation of the parasite, adenosine receptor expression, TNF-alpha production and mitogen-activated protein (MAP) kinase signaling pathways triggered by adenosine A3 receptor (A3AR). HTR8/SVneo cells infected with T. gondii exhibited an altered cytoskeletal changes, an increased infection rate and reduced viability in an infection time-dependent manner. T. gondii significantly promoted increased TNF-alpha production, A3AR protein levels and p38, ERK1/2 and JNK phosphorylation compared to those observed in uninfected control cells. Moreover, the inhibition of A3AR by A3AR siRNA transfection apparently suppressed the T. gondii infection-mediated upregulation of TNF-alpha, A3AR production and MAPK activation. In addition, T. gondii-promoted TNF-alpha secretion was dramatically attenuated by pretreatment with PD098059 or SP600125. These results indicate that A3AR-mediated activation of ERK1/2 and JNK positively regulates TNF-alpha secretion in T. gondii-infected HTR8/SVneo cells. | Receptor, Adenosine A3 |
Date of birth>09/06/2004; sex: female. Pre-treatment documents>13years 4months old: 07/07/2017. Diagnosis>Skeletal class II with mandibular retrusion, normodivergent facial pattern; class II division 2. Treatment planning>bimaxillary buccal fixed appliance. Duration of active treatment>29months. Post-treatment documents>15years 6months; 20/12/2019. Post-retention documents>16years 7months old; 04/01/2021. Retention period>2years 9months and still continued. | Retrognathia |
The postoperative necrotizing sclerokeratitis is a rare condition occurring shortly after surgical procedures, mainly following cataract extractions. After several exacerbations and remissions spontaneous scleral perforation may occur. In the described case the conservative treatment/topical antibiotics, corticosteroids/failed, therefore the damaged scleral surface was covered with lyophilized dura and the condition came to a standstill. | Scleroplasty |
* We identified one RHD case caused by a new RHDV variant (GI.2) in China through HA, TEM, and genome sequencing. * This is the first study to demonstrate that GI.2 can replicate efficiently in the reproductive system. * Our evidence suggests that GI.2 might be introduced into China by contaminated rabbit semen. | Lagovirus |
BACKGROUND: Colorectal cancer (CRC) is the third most diagnosed malignancy worldwide. The global burden is expected to increase along with ongoing westernized behaviors and lifestyle. The etiology of CRC remains elusive and most likely combines environmental and genetic factors. The Kv2.1 potassium channel encoded by KCNB1 plays a collection of roles in malignancy of cancer and may be a key factor of CRC susceptibility. Our study provides baseline association between Tunisian CRC and interactions between KCNB1 variants and lifestyle factors. METHODS: A case-control study involving 300 CRC patients, and 300 controls was conducted Patients were carefully phenotyped and followed till the end of study. KCNB1 genotyping was confirmed by Sanger sequencing. Bivariate and multivariable logistic regression analyses were used to assess the clinical status, lifestyle and study polymorphisms association with CRC. RESULTS: We noted significant gender association with CRC occurrence. Moreover, CRC risk increases with high meat and fat consumption, alcohol use and physical activity (PA). Carriage of rs1051296 A/G and both rs11468831 ins/del and del/del genotypes (p < 0.001) were significantly associated with CRC risk. Analysis according to gender reveals correlation of rs1051295 A/G, rs11468831 non ins/ins (p = 0.01) with CRC susceptibility regardless of patients' gender while rs3331 T/C (p = 0.012) was associated with females. Stratification study according to malignancy site; Rectal Cancer (RC) and Colon Cancer (CC), reveals increasing RC risk by gender and high meat and fat consumption, alcohol use and PA. However, additional association with high brine consumption was noted for CC. The rs1051295 A/G (p = 0.01) was associated with RC risk. Increased CC risk was associated with carriage of rs1051295 A/G, rs11168831 (del/del) and (ins/del) genotypes. CONCLUSION: The risk of CRC increases with modifiable factors by Western influences on Tunisian lifestyle such as alcohol use, high fat consumption and possibly inadequate intake of vegetables. In addition, KCNB1 polymorphisms also markedly influence CRC susceptibility. Our study establishes key elements of a baseline characterization of clinical state, Western influenced lifestyle and KCNB1 variants associated with Tunisian CRC. | Shab Potassium Channels |
Alanine scanning mutagenesis of the HyHEL-10 paratope of the HyHEL-10/HEWL complex demonstrates that the energetically important side chains (hot spots) of both partners are in contact. A plot of deltadeltaG(HyHEL-10_mutant) vs. deltadeltaG(HEWL_mutant) for the five of six interacting side-chain hydrogen bonds is linear (Slope = 1). Only 3 of the 13 residues in the HEWL epitope contribute >4 kcal/mol to the free energy of formation of the complex when replaced by alanine, but 6 of the 12 HyHEL-10 paratope amino acids do. Double mutant cycle analysis of the single crystallographically identified salt bridge, D32H/K97, shows that there is a significant energetic penalty when either partner is replaced with a neutral side-chain amino acid, but the D32(H)N/K97M complex is as stable as the WT. The role of the disproportionately high number of Tyr residues in the CDR was evaluated by comparing the deltadeltaG values of the Tyr --> Phe vs. the corresponding Tyr --> Ala mutations. The nonpolar contacts in the light chain contribute only about one-half of the total deltadeltaG observed for the Tyr --> Ala mutation, while they are significantly more important in the heavy chain. Replacement of the N31L/K96 hydrogen bond with a salt bridge, N31D(L)/K96, destabilizes the complex by 1.4 kcal/mol. The free energy of interaction, deltadeltaG(int), obtained from double mutant cycle analysis showed that deltadeltaG(int) for any complex for which the HEWL residue probed is a major immunodeterminant is very close to the loss of free energy observed for the HyHEL-10 single mutant. Error propagation analysis of double mutant cycles shows that data of atypically high precision are required to use this method meaningfully, except where large deltadeltaG values are analyzed. | Antigen-Antibody Complex |
West Nile virus (WNV) has emerged in recent years in temperate regions of Europe and North America, presenting a threat to both public and animal health. The most serious manifestation of infection is fatal encephalitis in humans and horses, as well as mortality in certain domestic and wild birds. A recent development in the epizootiology of this mosquito-borne flavivirus was the occurrence of a severe outbreak in New York City and surrounding areas. During this outbreak, mortality was observed in humans, horses, a cat and numerous species of wild birds, particularly members of the family Corvidae (crows). The author reviews basic information and summarises recent developments in the epidemiology and epizootiology of WNV. | West Nile Fever |
As a peacetime work of Katherine S. Macphail (Glasgow, 1887- St.Andrews, 1974) MB ChB (Bachelor of Medicine and Surgery), the Anglo-Serbian Children's Hospital in Belgrade was established after World War I, and the English-Yugoslav Children's Hospital for Treatment of Osteoarticular Tuberculosis was founded in Sremska Kamenica in 1934. Situated on the Fruska Gora slope, the hospital-sanatorium was a well-equipped medical institution with an operating theatre and x-ray machine providing very advanced therapy, comparable to those in Switzerland and England: aero and heliotherapy, good quality nourishment, etc. In addition, school lessons were organized as well as several types of handwork as the work-therapy. It was a privately owned hospital but almost all the children were treated free of cost. The age for admission was up to 14. During the period from 1934 to 1937, around 458 children underwent hospital treatment, most of them with successful results. During the war years the Sanatorium was closed but after the war it was reactivated. In 1948 by the act of final nationalization of all medical institutions in the communist Yugoslavia, the hospital was transformed into a ward of orthopedic surgery under the supervision of the referent departments in Belgrade and Novi Sad. Today, hospital is out of work and deprived of its humanitarian mission. The building is neglected and in ruins although it has been proclaimed the national treasure by the Regional Institute for Protection of Monuments of Culture. | Hospitals, Chronic Disease |
BACKGROUND AND OBJECTIVE: In Spain, as in other Mediterranean regions the most common beta-thalassemia mutations are due to point mutations in gene regions that are critical for production of mRNA, such as [IVS-I-nt1 (G-->A), IVS-I-nt6 (T-->C), IVS-I-nt110 (G-->A)] which interrupt normal RNA processing or nonsense mutations [CD39 (C-->T)] which interrupt the translation of mRNA. The frameshift mutation CD8/9 (+G) is a very common allele in Asian Indians but is rare in the Mediterranean regions in which isolated alleles with this mutation have been found in Israel, Greece, Portugal and Turkey. DESIGN AND METHODS: We performed a molecular analysis of 175 chromosomes corresponding to 233 beta-thalassemia patients (221 heterozygous, 10 homozygous and 2 compound heterozygous) who belong to 169 Spanish families. The study of beta-thalassemia was made by PCR-ARMS, the alpha genes by Southern blot, the phenotype of Hb Lepore by enzymatic amplification and the presence of -158 gamma G C-->T mutation by PCR and digestion with the restriction enzyme XmnL. RESULTS: Twenty of these 233 patients showed the beta-thalassemia mutation CD8/9 (+G) (17 were heterozygous, 2 homozygous and in one patient the mutation was associated with a structural variant Hb Lepore Boston). INTERPRETATION AND CONCLUSIONS: These data reveal the heterogeneity of beta-thalassemia in Spain and the relatively high frequency (8.6%) of the frameshift mutation CD8/9 (+G). It is surprising that homozygotes for beta zero-thalassemia due to this mutation with very high Hb F values (around 90%) present a phenotype of intermediate thalassemia. | CD8 Antigens |
ZNF384-related fusion genes are associated with a distinct subgroup of B-cell precursor acute lymphoblastic leukemias in childhood, with a frequency of approximately 3-4%. We previously identified a novel EP300-ZNF384 fusion gene. Patients with the ZNF384-related fusion gene exhibit a hematopoietic stem cell (HSC) gene expression signature and characteristic immunophenotype with negative or low expression of CD10 and aberrant expression of myeloid antigens, such as CD33 and CD13. However, the molecular basis of this pathogenesis remains completely unknown. In the present study, we examined the biological effects of EP300-ZNF384 expression induced by retrovirus-mediated gene transduction in an REH B-cell precursor acute lymphoblastic leukemia cell line, and observed the acquisition of the HSC gene expression signature and an up-regulation of GATA3 gene expression, as assessed by microarray analysis. In contrast, the gene expression profile induced by wild-type ZNF384 in REH cells was significantly different from that by EP300-ZNF384 expression. Together with the results of reporter assays, which revealed the enhancement of GATA3-promoter activity by EP300-ZNF384 expression, these findings suggest that EP300-ZNF384 mediates GATA3 gene expression and may be involved in the acquisition of the HSC gene expression signature and characteristic immunophenotype in B-cell precursor acute lymphoblastic leukemia cells. | Gene Fusion |
In vitro histamine response in rat and guinea pig uterine strips was similar to the one observed with zoapatle aqueous crude extract (ZACE). The relaxing effect elicited by ZACE/tomentosa on the in vitro rat uterine strips was not mediated by activation of H-2 histamine receptors; moreover, the increase on uterine contractility elicited by ZACE/tomentosa on the in vitro guinea pig uterine strip was not mediated through the activation of H-1 histamine receptors. | Montanoa |
BACKGROUND: African yam bean (Sphenostylis stenocarpa) is an underutilized crop that has the potential to contribute to sustainable food security. In October 2021, more than 90% African Yam Bean (AYB) plants showed typical virus symptoms of mosaic and necrosis in the grain legumes field of the Institute of Agricultural Research and Training (IAR&T), Nigeria. METHODS AND RESULTS: Subsequently, leaf samples were collected and tested by ELISA and PCR to identify the virus species. Anti-BCMV and anti-potyvirus antibodies both gave positive results when symptomatic leaves were tested, and PCR using primers designed to the coat protein gene of BCMV amplified a band of the expected size (469 bp). The sequence of the PCR product was deposited in GenBank with the accession No. OL763314. The nucleotide sequence of the coat protein gene had 99% identity with BCMV isolate TN2 (KY044818). The identities of the nucleotide and amino acid sequence of the partial CP gene of the isolated virus relative to those of other potyviruses were 82.96-99.12% and 87.33-100%,, respectively. Phylogenetic analyses of the partial CP-nucleotide sequences grouped the isolate from this study (BCMV-IART-AYB) and BCMV-TN2 in the same cluster with other BCMV strains of the peanut stripe (PSt) and the blackeye cowpea (BlC) strains. CONCLUSIONS: In this study, we identified Bean commom mosaic virus (BCMV) infecting AYB for the first time in Nigeria and show that it has high nucleotide and amino acid identity with an Isolate of cowpea-infecting BCMV in India and China respectively than isolate in Nigeria. | Sphenostylis |
The PSORS4 genetic risk factor for psoriasis is a deletion of two late cornified envelope (LCE) genes (LCE3C_LCE3Bdel) in a cluster of five LCE3 genes with a proposed role in skin repair. We previously showed that 1,25-dihydroxyvitamin D3 (1,25D) modestly upregulates transcripts from all five LCE3 genes as monitored by real time PCR in primary human keratinocytes. Herein we report that cyanidin, a plant-derived compound with anti-inflammatory/anti-oxidant properties, upregulates expression of all five LCE3 genes in cultures of differentiating primary human keratinocytes to a greater extent that does 1,25D. This action of cyanidin is dependent on the differentiation state of the keratinocytes, with a stronger effect after the cells have been incubated with 1.2mM calcium for 24h. Competition displacement assays using radiolabeled 1,25D revealed that cyanidin directly competes as a ligand for vitamin D receptor (VDR) binding with an estimated IC50 of 500muM. However, 20muM cyanidin is sufficient to upregulate LCE3 genes. The 25-fold discrepancy between the cyanidin concentration required for upregulating LCE3 genes in intact keratinocytes vs. that required for direct binding to VDR in vitro suggests that cyanidin may be: (a) metabolized to a more active VDR ligand in keratinocytes and/or (b) functioning via a non-VDR mediated mechanism. The fact that cyanidin is the most potent upregulator of global LCE3 gene expression reported to date suggests that this or related compounds may have potential in psoriasis therapy." | Cornified Envelope Proline-Rich Proteins |
Metastasis is the primary cause of death in cancer patients. However, the molecular mechanism of the metastatic process is poorly understood because it involves multiple steps with a high degree of complexity. A critical step for successful establishment of secondary colonization is the hematogenous dissemination of malignant cells. During this process, the attachment of cancer cells to the endothelial cells on microvasculature is considered to be an essential step and many adhesion molecules as well as chemokines have been found to be involved in this process. This interaction of cancer-endothelial cell is considered not only to determine the physical site of metastasis, but also to provide the necessary anchorage to facilitate tumor cell extravasation. However, recent evidence indicates that this interaction also serves as a host defense mechanism and hinders the process of metastasis. The tumor metastases suppressor gene, KAI1, has been known to block metastatic process without affecting the primary tumor growth, and this protein has been found to be able to bind to the chemokine receptor, Duffy antigen receptor for chemokines (DARC), which is expressed on endothelial cells. Importantly, this interaction markedly induces senescence of tumor cells. This novel finding is not only significant in the context of molecular dissection of metastatic process but also in the therapeutic implication to develop drugs inhibiting metastasis. | Kangai-1 Protein |
BACKGROUND: Prasinophytes are widespread marine green algae that are related to plants. Cellular abundance of the prasinophyte Micromonas has reportedly increased in the Arctic due to climate-induced changes. Thus, studies of these unicellular eukaryotes are important for marine ecology and for understanding Viridiplantae evolution and diversification. RESULTS: We generated evidence-based Micromonas gene models using proteomics and RNA-Seq to improve prasinophyte genomic resources. First, sequences of four chromosomes in the 22 Mb Micromonas pusilla (CCMP1545) genome were finished. Comparison with the finished 21 Mb genome of Micromonas commoda (RCC299; named herein) shows they share </=8,141 of ~10,000 protein-encoding genes, depending on the analysis method. Unlike RCC299 and other sequenced eukaryotes, CCMP1545 has two abundant repetitive intron types and a high percent (26 %) GC splice donors. Micromonas has more genus-specific protein families (19 %) than other genome sequenced prasinophytes (11 %). Comparative analyses using predicted proteomes from other prasinophytes reveal proteins likely related to scale formation and ancestral photosynthesis. Our studies also indicate that peptidoglycan (PG) biosynthesis enzymes have been lost in multiple independent events in select prasinophytes and plants. However, CCMP1545, polar Micromonas CCMP2099 and prasinophytes from other classes retain the entire PG pathway, like moss and glaucophyte algae. Surprisingly, multiple vascular plants also have the PG pathway, except the Penicillin-Binding Protein, and share a unique bi-domain protein potentially associated with the pathway. Alongside Micromonas experiments using antibiotics that halt bacterial PG biosynthesis, the findings highlight unrecognized phylogenetic complexity in PG-pathway retention and implicate a role in chloroplast structure or division in several extant Viridiplantae lineages. CONCLUSIONS: Extensive differences in gene loss and architecture between related prasinophytes underscore their divergence. PG biosynthesis genes from the cyanobacterial endosymbiont that became the plastid, have been selectively retained in multiple plants and algae, implying a biological function. Our studies provide robust genomic resources for emerging model algae, advancing knowledge of marine phytoplankton and plant evolution. | RNA, Algal |
The calcium requirements of boys and girls during adolescence have largely been based on balance studies, including more recently the use of stable nuclides. Bone measurements by dual energy X-ray absorptiometry (DXA) and similar instruments have provided an end-point by which to assess skeletal development, either of the entire skeleton or of specific bones, in relation to the consumption of calcium and other nutrients and to physical activity. Several cross-sectional studies, using measurements of bone mineral density (BMD) and bone mineral content (BMC), suggest that optimal calcium intakes for female adolescents may be somewhat lower than published as the Adequate Intakes (AIs) by the Institute of Medicine in 1997, but they may be somewhat higher for adolescent males. These results suggest that gender should be considered in establishing recommendations for calcium. In addition, other studies have provided evidence that prepubertal and postpubertal skeletal growth of males and females is enhanced by regular physical activities and that the optimal attainment of BMC and BMD by females by late adolescence may not be dependent on such a high calcium intake as previously thought, although males may need at least the recommended amount. Therefore, physical activity should also be considered in establishing recommendations for calcium. In summary, two lines of evidence suggest that more extensive information on diet and lifestyle should be considered in the future for making more specific recommendations on calcium intakes for optimal skeletal development for prepubertal and postpubertal boys and girls. | Calcium, Dietary |
Natural landscapes are both fragmented and heterogeneous, affecting the distribution of organisms, and their interactions. While predation in homogeneous environments increases the probability of population extinction, fragmentation/heterogeneity promotes coexistence and enhances community stability as shown by experimentation with animals and microorganisms, and supported by theory. Patch connectivity can modulate such effects but how microbial predatory interactions are affected by water-driven connectivity is unknown. In soil, patch habitability by microorganisms, and their connectivity depend upon the water saturation degree (SD). Here, using the obligate bacterial predator Bdellovibrio bacteriovorus, and a Burkholderia prey, we show that soil spatial heterogeneity profoundly affects predatory dynamics, enhancing long-term co-existence of predator and prey in a SD-threshold dependent-manner. However, as patches and connectors cannot be distinguished in these soil matrices, metapopulations cannot be invoked to explain the dynamics of increased persistence. Using a set of experiments combined with statistical and physical models we demonstrate and quantify how under full connectivity, predation is independent of water content but depends on soil microstructure characteristics. In contrast, the SD below which predation is largely impaired corresponds to a threshold below which the water network collapses and water connectivity breaks down, preventing the bacteria to move within the soil matrix. | Bdellovibrio bacteriovorus |
Physical activity, particularly walking, is commonly used for the treatment of diseases such as low back pain. In this study, the effects of walking wearing the new ToneFit Reha training belt (TFR) were compared to both Nordic walking and regular walking. The TFR is intended to intensify the effects of walking through the integration of two adjustable resistance handles. Ten patients with low back pain performed regular walking, Nordic walking, and walking with the TFR in a movement laboratory. The kinematics of the trunk, upper extremities, and lower extremities were measured, and the activity of the trunk and upper extremity muscles recorded. Data were analyzed by repeated-measures ANOVA and paired t-test. Kinematics indicated that walking with the TFR introduces instability that was mitigated by a delayed peak trunk rotation (peak at 63.3% gait cycle, vs. 52.8% in walking (p = .001) and 51.0% in NW (p = .007)). Upper extremity kinematics (constrained elbow flexion, high peak shoulder abduction) showed movement patterns that need to be considered when training over a longer period. Increased muscle activity was observed especially for upper extremity muscles, when training with TFR. Overall, walking with the TFR was found to be a suitable therapy for use in a rehabilitation setting. | Nordic Walking |
Flumazenil is a central antagonist of the sedative effects of benzodiazepines. It has been used to reverse benzodiazepine effects in conscious sedation, general anesthesia, and overdose with restoration of alertness and psychomotor function within minutes of administration. Seizures have followed the use of flumazenil. Overdose patients who have co-ingested cyclic antidepressants are especially at risk for this complication. Flumazenil is administered intravenously in small, incremental doses. | Flumazenil |
BACKGROUND: Miosis occurs following exposure to toxins that decrease the sympathomimetic tone, increase the cholinergic tone, or exert sedative-hypnotic effects, but has not been reported in insulin poisoning. CASE REPORT: A 64-year- old woman without co-morbidities was found unconscious next to an empty insulin pen. Her Glasgow Coma Scale was 3 with absent reflexes, bilateral reactive miosis, and injection marks across the abdominal wall. The patient was endotracheally intubated, mechanically ventilated, and transferred to this hospital. At admission, the blood glucose level was 34 mg/dL. Glasgow Coma Scale remained at 3, with persistent bilateral reactive miosis. The toxicology screening was negative for ethanol, barbiturates, tricyclic antidepressants, phenothiazines, amphetamines, cannabinoids, salicylates, acetaminophen, and cocaine. Cranial computed tomography with angiography and magnetic resonance imaging (MRI) did not show any structural brain lesions. Intravenous glucose was continued at 6-14 g/h for 3 days. On repeated neurological examinations, the patient remained deeply comatose, with partial loss of cranial nerve function. Bilateral reactive miosis persisted for 4 days. From day 5 on, the patient awoke progressively. At discharge, the patient was fully alert and orientated, without a focal neurological deficit. CONCLUSIONS: Prolonged bilateral reactive miosis can be a clinical symptom accompanying metabolic encephalopathy in severe insulin poisoning. Functional impairment of the pons due to relative hypoperfusion during hypoglycemia may serve as a reasonable pathophysiologic explanation for this phenomenon. | Insulin Coma |
Lewy bodies (LBs) are the pathological hallmarks of degenerating neurons in the brains of patients with Parkinson's disease and diffuse Lewy body disease. We developed a novel purification procedure for LBs using sucrose density separation followed by fluorescence-activated particle sorting, and we raised > 15 monoclonal antibodies to LBs purified from diffuse Lewy body disease brains. The monoclonal antibody that stained the largest number of LBs most intensely did not recognize ubiquitin in free or monoubiquitinated forms nor the ubiquitin conjugating enzymes, but it did react with polyubiquitin chains as well as with high molecular weight polyubiquitinated LB-derived proteins. Thus, these results suggest that LBs contain polyubiquitin chains. Although polyubiquitination of LB proteins may trigger ubiquitin-proteasome proteolytic pathways, the incomplete activation of these pathways could play a mechanistic role in the formation of LBs in neurodegenerative diseases. | Lewy Bodies |
Ehrlichiae are obligately intracellular bacteria that reside and replicate in phagocytes by circumventing host cell defenses and modulating cellular processes, including host cell gene transcription. However, the mechanisms by which ehrlichiae influence host gene transcription have largely remained undetermined. Numerous ankyrin and tandem repeat-containing proteins associated with host-pathogen interactions have been identified in Ehrlichia species, but their roles in pathobiology are unknown. In this study, we determined by confocal immunofluorescence microscopy and by immunodetection in purified nuclear extracts that the ankyrin repeat-containing protein p200 is translocated to the nuclei of Ehrlichia-infected monocytes. Chromatin immunoprecipitation (ChIP) with DNA sequencing revealed an Ehrlichia chaffeensis p200 interaction located within host promoter and intronic Alu-Sx elements, the most abundant repetitive elements in the human genome. A specific adenine-rich (mid-A-stretch) motif within Alu-Sx elements was identified using electrophoretic mobility shift and NoShift assays. Whole-genome analysis with ChIP and DNA microarray analysis (ChIP-chip) determined that genes (n = 456) with promoter Alu elements primarily related to transcription, apoptosis, ATPase activity, and structural proteins associated with the nucleus and membrane-bound organelles were the primary targets of p200. Several p200 target genes (encoding tumor necrosis factor alpha, Stat1, and CD48) associated with ehrlichial pathobiology were strongly upregulated during infection, as determined by quantitative PCR. This is the first study to identify a nuclear translocation of bacterially encoded protein by E. chaffeensis and to identify a specific binding motif and genes that are primary targets of a novel molecular strategy to reprogram host cell gene expression to promote survival of the pathogen. | Ehrlichia chaffeensis |
In Canada, responsibility for corrections is divided between federal, provincial and territorial governments, with nurses being the largest group of healthcare professionals working in correctional institutions (penitentiaries, jails, prisons, correctional centres and secure correctional treatment centres) across the country. Correctional institutions are among the most challenging workplace settings for nurses, as they face competing tensions between the provision of quality care and strict security requirements for safety. They also experience unique workforce issues with high reports of burnout and emotional exhaustion. Nursing leadership at all levels of the correctional system is critical in creating work environments that optimize workplace well-being and minimize burnout. The purpose of this paper is to discuss the role of nursing leadership in facilitating and enabling a healthy workforce in corrections. Minimal research has examined leadership and healthy work environments in correctional institutions. Several authors have, however, discussed transformational leadership as a strategy to positively influence correctional nursing practice. In this article, we expand on this previous work to describe the full range leadership model and how it can be used to form the foundation of effective leadership and support the creation of healthy work environments in the correctional context. | Health Workforce |
Anderson-Fabry Disease (AFD) is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficient or absent activity of the lysosomal enzyme, alpha-galactosidase A, resulting in the progressive multisystem lysosomal accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Among the wide spectrum of clinical signs and symptoms and the life-threatening complications of Fabry disease, renal failure causes significant morbidity and mortality. Various evidence shows that the accumulation of Gb3 in different renal cells is present since the first years of life, many years and usually decades before manifest symptoms and signs of renal involvement. Early renal damage can be demonstrated by clinical signs as microalbuminuria and proteinuria, developing as early as in the second decade of life. A decline in GFR is uncommon at paediatric ages but may be seen as early as adolescence. Renal biopsy is rarely used in paediatric patients with Fabry disease although evidence shows that it may be considered a valid tool for the diagnosis of early and potentially reversible nephropathy, as well as for the evaluation of the effectiveness of enzyme replacement therapy (ERT). Although there is consensus in considering the early initiation of ERT as the only tool able to prevent the progression of nephropathy, the issue on the correct timing for the onset of ERT in pediatric age remains open in the management of this chronic and progressive disease. | Trihexosylceramides |
OBJECTIVE: Our objective was to review recent drug and medical device recalls, categorize recall types based on the free text descriptions posted within the recall announcements, and conduct exploratory analyses for researchers interested in pharmaceutical supply chain challenges. METHODS: A cross-sectional study of all current recalls, market withdrawals, and safety alerts published by the United States Food and Drug Administration pertaining to drugs was conducted. A manual review of all the recalls was also conducted to extract additional information including company details, recall type (labeling or quality), and location of failure in the pharmaceutical supply chain (manufacturing or distribution). Descriptive statistics and exploratory bivariate analyses were conducted to test any potential differences between drug and device recalls. RESULTS: Most recalls issued between January 2017 and September 2019 were pharmaceutical drug recalls (85.2%), while 34 (14.8%) medical device recalls were issued for the same period. For drug recalls, 85.1% (166/195) were because of quality, while 14.9% (29/195) were because of labeling issues. Of the quality issues for drug recalls, lack of sterility was the most frequent issue (139/166, 83.7%). There was no difference between drug or device recalls based on recall type (P = 0.16), top 20 pharmaceutical company (P = 0.62), or location of the supply chain failure (P = 0.20). CONCLUSIONS: This study provides a process to categorize and evaluate drug and device recalls by recall type and location of the supply chain. By categorizing the free text provided in public recall data it would be easier to monitor trends over time." | Product Recalls and Withdrawals |
BACKGROUND: The aim of the present study was to investigate the indications, clinical utility, feasibility and safety of double-balloon enteroscopy (DBE) in the diagnosis and management of small intestinal diseases in pediatric patients. METHODS: This is a retrospective analysis of pediatric patients younger than 18 years referred to Shanghai Rui Jin Hospital from May 2003 to June 2008 for investigation of suspected small bowel disorders. Demographic, clinical, procedural and outcome data were collected for analysis. RESULTS: A total of 35 DBE were carried out in 30 children with a mean age of 13 years. Indications for DBE were obscure gastrointestinal (GI) bleeding (n = 22), chronic abdominal pain (n = 4), chronic diarrhea (n = 3), and incomplete small bowel obstruction (n = 1). DBE evidenced pathological findings in 29 patients (96.7%). DBE altered management in 90% of patients with positive findings. Follow up was obtained on all patients with a mean (range) of 40 months (14-75 months). The procedure was successful in all patients and there were no serious complications related to sedation. CONCLUSION: DBE is feasible and safe and has a high diagnostic yield and therapeutic impact on the diagnosis and management of small bowel disorders in selected pediatric patients. | Balloon Enteroscopy |
BACKGROUND: Listeriosis may cause severe disease in fetuses and neonates. The outcomes of critically ill neonates with early-onset listeriosis requiring extracorporeal membrane oxygenation (ECMO) from 1975 to 1991 have been reported. OBJECTIVE: To update the characteristics and outcomes of neonates with listeriosis supported by ECMO. STUDY DESIGN: Retrospective study of neonates with culture-proven listeriosis reported to the Extracorporeal Life Support Organization Registry between 1991 and 2017. Comparisons were made between this cohort and the case series from 1975-1991. RESULTS: Twenty-two neonates had culture-proven Listeria monocytogenes infection and required ECMO support. Eight-six percent survived to discharge, compared with 67% in the previous cohort (p = 0.2). The median ECMO duration was 131 h, compared with 209 h in the previous cohort (p = 0.1). Nonsurvivors had a significantly lower pre-ECMO pH (6.91 vs 7.31, p = 0.0006). CONCLUSION: The survival of neonates with listeriosis supported with ECMO is high, supporting the use of ECMO as rescue therapy for this condition. | Listeriosis |
Sensory deprivation sheds light on cortical plasticity mechanisms, but recovery of lost brain function may bear the greatest clinical relevance. Ramoa and colleagues now find that binocular recovery from monocular occlusion can be extraordinarily rapid, independent of protein synthesis, and precise. Reactivation of latent connections may then reverse amblyopia. | Sensory Deprivation |
OBJECTIVES: To improve programs aimed to enhance medical student resiliency, we examined both medical student and faculty advisor perspectives on resiliency-building in an Asian medical school. METHODS: In two separate focus groups, a convenience sample of 8 MD-PhD students and 8 faculty advisors were asked to identify strategies for enhancing resilience. Using thematic analysis, two researchers independently examined discussion transcripts and field notes and determined themes through a consensus process. They then compared the themes to discern similarities and differences between these groups. RESULTS: Themes from the student suggestions for increasing resilience included Perspective changes with time and experience", "Defining effective advisors," and "Individual paths to resiliency". Faculty-identified themes were "Structured activities to change student perspectives," "Structured teaching of coping strategies", and "Institution-wide social support". Students described themselves as individuals building their own resilience path and preferred advisors who were not also evaluators. Faculty, however, suggested systematic, structural ways to increase resilience. CONCLUSIONS: Students and advisors identified some common, and many distinct strategies for enhancing medical student resilience. Student/advisor discrepancies may exemplify a cultural shift in Singapore's medical education climate, where students value increased individualism and autonomy in their education. As medical schools create interventions to enhance resilience and combat potential student burnout, they should consider individually-tailored as well as system-wide programs to best meet the needs of their students and faculty." | Faculty, Medical |
This article is a retrospective look at the changes in hospital libraries from 1970 to 2014 based on the author's experience and a survey of the literature related to hospital libraries indexed in PubMed from 1970 to the present. New roles for librarians and methods for conveying the value of libraries to administrators are described. | Libraries, Hospital |
PURPOSE: Pay tribute to Christiane Ferradini and highlight the importance of her work as a scientist. CONCLUSIONS: Christiane Ferradini was born in 1924 in the south of France. She graduated from the Paul Sabatier University in Toulouse, France. In 1947, she joined the Curie Laboratory of the Radium Institute (which was then under the leadership of Madame Irene Joliot-Curie) to pursue her doctoral research. After her defence in 1955, she commenced her journey dedicated to the advancement of science. She became an exceptional teacher. She led a research group that contributed, through many fruitful collaborations, to the opening of a new chapter in radiation biology and medicine. Together they shed light on free radical formation and their reactions with biomolecules. Christiane published a total of 190 scientific articles and 9 books. She died in 2002. | Radiobiology |
The evidence on the relationship between dietary mineral supply and bone development in children has been extensively reviewed. Data from children and primates suggest that overt deficiencies of Ca, P and Zn are likely to produce rickets and growth retardation, while the effects of Mg deficiency on human bone are unknown. The manifestations of marginal deficiencies are little understood. The biological needs for Ca, P, Mg and Zn in childhood have been calculated based on mineral deposition rates, using published values for the mineral content of the human body, and on obligatory endogenous losses. As a rough guide, the estimated biological requirements for the Ca, P, Mg and Zn can be taken as 200, 100, 4 and 1 mg/d respectively. A comparison of measured daily intakes of children in developing countries with biological requirements was made. This revealed that P and Mg intakes were many times higher than estimated needs. Ca intakes at all ages were found to be close to the biological requirement for children in many Third World societies, before any allowance for possible poor absorption. Zn intakes approach estimated needs in breast-fed infants, particularly during weaning, but are 4-5 times higher in older children. Poor absorption from phytate-rich diets could affect Zn supply. Supplementation studies indicate that raising Zn intakes can increase height gains in certain vulnerable groups, such as infant and adolescent boys. In conclusion, the evidence suggests that inadequate dietary intakes of Ca and Zn may contribute to linear growth retardation in children of developing countries but more research is needed. | Infant Nutrition Disorders |
A severe fungal infection affecting the head and lateral line system was diagnosed in 7 captive scalloped hammerhead sharks Sphyrna lewini in an aquarium in Thailand. Extensive and severe necrotizing cellulitis was consistently observed microscopically along the cephalic and lateral line canals in conjunction with positive fungal cultures for Fusarium sp. Molecular phylogenetic analysis was performed from 3 isolates based on the nucleotide sequences containing internally transcribed spacer (ITS) and a portion of 5.8S and 28S rDNA. The fungus was highly homologous (100%) and closely related to F. solani species complex 2 (FSSC 2), which belongs to Clade 3 of the FSSC. Our results illustrate the histopathological findings and expand upon our knowledge of the prevalence of invasive fusariosis in the head and lateral line system of hammerhead sharks. | Lateral Line System |
We report here the characterization of the first mammalian-like purine nucleoside phosphorylase from the hyperthermophilic archaeon Pyrococcus furiosus (PfPNP). The gene PF0853 encoding PfPNP was cloned and expressed in Escherichia coli and the recombinant protein was purified to homogeneity. PfPNP is a homohexamer of 180 kDa which shows a much higher similarity with 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) than with purine nucleoside phosphorylase (PNP) family members. Like human PNP, PfPNP shows an absolute specificity for inosine and guanosine. PfPNP shares 50% identity with MTAP from P. furiosus (PfMTAP). The alignment of the protein sequences of PfPNP and PfMTAP indicates that only four residue changes are able to switch the specificity of PfPNP from a 6-oxo to a 6-amino purine nucleoside phosphorylase still maintaining the same overall active site organization. PfPNP is highly thermophilic with an optimum temperature of 120 degrees C and is characterized by extreme thermodynamic stability (T(m), 110 degrees C that increases to 120 degrees C in the presence of 100 mm phosphate), kinetic stability (100% residual activity after 4 h incubation at 100 degrees C), and remarkable SDS-resistance. Limited proteolysis indicated that the only proteolytic cleavage site is localized in the C-terminal region and that the C-terminal peptide is not necessary for the integrity of the active site. By integrating biochemical methodologies with mass spectrometry we assigned three pairs of intrasubunit disulfide bridges that play a role in the stability of the enzyme against thermal inactivation. The characterization of the thermal properties of the C254S/C256S mutant suggests that the CXC motif in the C-terminal region may also account for the extreme enzyme thermostability." | Purine-Nucleoside Phosphorylase |
Stimulation of primary human T lymphocytes results in up-regulation of cyclin T1 expression, which correlates with phosphorylation of the C-terminal domain of RNA polymerase II (RNAP II). Up-regulation of cyclin T1 and concomitant stabilization of cyclin-dependent kinase 9 (CDK9) may facilitate productive replication of HIV in activated T cells. We report that treatment of PBLs with two mitogens, PHA and PMA, results in accumulation of cyclin T1 via distinct mechanisms. PHA induces accumulation of cyclin T1 mRNA and protein, which results from cyclin T1 mRNA stabilization, without significant change in cyclin T1 promoter activity. Cyclin T1 mRNA stabilization requires the activation of both calcineurin and JNK because inhibition of either precludes cyclin T1 accumulation. In contrast, PMA induces cyclin T1 protein up-regulation by stabilizing cyclin T1 protein, apparently independently of the proteasome and without accumulation of cyclin T1 mRNA. This process is dependent on Ca2+-independent protein kinase C activity but does not require ERK1/2 activation. We also found that PHA and anti-CD3 Abs induce the expression of both the cyclin/CDK complexes involved in RNAP II C-terminal domain phosphorylation and the G1-S cyclins controlling cell cycle progression. In contrast, PMA alone is a poor inducer of the expression of G1-S cyclins but often as potent as PHA in inducing RNAP II cyclin/CDK complexes. These findings suggest coordination in the expression and activation of RNAP II kinases by pathways that independently stimulate gene expression but are insufficient to induce S phase entry in primary T cells. | Cyclin T |
BACKGROUND: There are a number of dietary components that may prove useful in the prevention and treatment of cancer. In some cultures, fenugreek seeds are used to treat cancer. The current study focuses on the anticancer properties and proteomic profiles of fenugreek seeds, and is prompted by the clinical profile of a case of primary CNS T cell lymphoma that responded to fenugreek treatment and resulted in tumor regression. METHOD: Various normal and cancer cell lines were exposed to fenugreek extract at differing concentrations (100 mug/ml, 200 mug/ml and 300 mug/ml) and at different time points (0, 24, 48, 72 and 96 hrs). Protein fingerprints of fenugreek grain/seed types, obtained from four different geographical regions, were analyzed by proteomic expression profiles. RESULTS: We observed selective cytotoxic effects of fenugreek extract in vitro to a panel of cancer cell lines, including T-cell lymphoma. Additionally, the cluster analysis of proteomics data showed that the protein profile of the particular fenugreek used by the patient is significantly different from three other regional subtypes of fenugreek extract. CONCLUSION: The in vitro effect of fenugreek as a substance with significant cytotoxicity to cancer cells points to the potential usefulness of fenugreek in the prevention and treatment of cancer. | Trigonella |
Rilmenidine is an antihypertensive agent acting at the imidazoline receptor that may have both central effects in the ventral lateral medulla and direct effects on the kidney to alter Na+ excretion. The present experiments examined whether rilmenidine induces a leftward shift or change in the slope of the pressure-natriuresis curve in the spontaneously hypertensive rat (SHR). A single oral gavage dose indicated that 3 and 10 mg/kg rilmenidine significantly lowers arterial pressure at 4-12 h after administration by oral gavage. The effect of rilmenidine on pressure-natriuresis was studied using twice daily doses of 1 and 3 mg/kg for control and treated SHR drinking tap water or 1% NaCl for 3 days. Na+ excretion was measured over 24 h, and mean arterial pressure was measured 6-8 h after the morning dose of rilmenidine. The results indicate that 1 mg/kg had no effect, while the pressure-natriuresis relationship for the rats receiving the 3 mg/kg dose was shifted to the left and was not significantly different from the vertical slope of the untreated SHR. This experiment also suggested that rilmenidine may attenuate the salt preference of the rats. This was confirmed in an additional series of experiments in which the rats had access to both tap water and 1% NaCl. Thus, rilmenidine shifts the pressure-natriuresis relationship to the left and reduces salt preference in SHR. | Rilmenidine |
Leishmaniasis is an important disease that affects 12 million people in 88 countries, with 2 million new cases every year. Leishmania amazonensis is an important agent in Brazil, leading to clinical forms varying from localized (LCL) to diffuse cutaneous leishmaniasis (DCL). One interesting issue rarely analyzed is how host immune response affects Leishmania phenotype and virulence. Aiming to study the effect of host immune system on Leishmania proteins we compared proteomes of amastigotes isolated from BALB/c and BALB/c nude mice. The athymic nude mice may resemble patients with diffuse cutaneous leishmaniasis, considered T-cell hyposensitive or anergic to Leishmania's antigens. This work is the first to compare modifications in amastigotes' proteomes driven by host immune response. Among the 44 differentially expressed spots, there were proteins related to oxidative/nitrosative stress and proteases. Some correspond to known Leishmania virulence factors such as OPB and tryparedoxin peroxidase. Specific isoforms of these two proteins were increased in parasites from nude mice, suggesting that T cells probably restrain their posttranslational modifications in BALB/c mice. On the other hand, an isoform of HSP70 was increased in amastigotes from BALB/c mice. We believe our study may allow identification of potential virulence factors and ways of regulating their expression." | Leishmaniasis, Diffuse Cutaneous |
BACKGROUND: Syringomyelia is a progressive cerebrospinal fluid disorder that can lead to irreversible spinal cord injury. To date, the optimal management of syringomyelic cavities remains controversial. Multiple studies have emphasized the importance of the craniocervical decompression or shunting procedures; however, except for syrinx related to Chiari malformation, nearly one-half of patients need to undergo reoperation. The purpose of the present study was to describe a simple and efficient surgical technique and to report the long-term radioclinical outcomes. MATERIAL AND METHODS: We report a series of 17 consecutive patients (10 male, 7 female) with symptomatic syringomyelia treated by myringotomy tube between January 1999 and January 2014. The mean follow-up was 43.6 months (5-118). For each case, a laminectomy was carried out at the level of the most expanded part of the syrinx. The myringotomy tube was then placed through a puncture myelotomy. RESULTS: Clinical examination showed disappearance of symptoms in 3 cases, a significant improvement in 8 cases, stabilization in 5 patients, and continuation of neurologic deterioration in 1 case. Thus, favorable long-term outcomes were observed in two-thirds of patients. No permanent postoperative complication was reported. The postoperative imaging showed complete or almost complete disappearance of the syrinx in 11 cases and a reduction over 80% in 4 cases. In 2 cases, the cavity remained stable. Moreover, just 2 patients had to undergo reoperation with the placement of a syringoperitoneal shunt. CONCLUSION: A myringotomy tube is a simple surgical technique that seems to be an efficient and safe treatment for syringomyelic cavities. | Cerebrospinal Fluid Shunts |
Selective sustained attention (SSA) is crucial for higher order cognition. Factors promoting SSA are described as exogenous or endogenous. However, there is little research specifying how these factors interact during development, due largely to the paucity of developmentally appropriate paradigms. We report findings from a novel paradigm designed to investigate SSA in preschoolers. The findings indicate that this task (a) has good psychometric and parametric properties and (b) allows investigation of exogenous and endogenous factors within the same task, making it possible to attribute changes in performance to different mechanisms of attentional control rather than to differences in engagement in different tasks. | Aptitude Tests |
BACKGROUND: The development of risk prediction models is of increasing importance in medical research - their use in practice, however, is rare. Among other reasons this might be due to the fact that thorough validation is often lacking. This study focuses on two Bayesian approaches of how to validate a prediction rule for the diagnosis of pneumonia, and compares them with established validation methods. METHODS: Expert knowledge was used to derive a risk prediction model for pneumonia. Data on more than 600 patients presenting with cough and fever at a general practitioner's practice in Switzerland were collected in order to validate the expert model and to examine the predictive performance of it. Additionally, four modifications of the original model including shrinkage of the regression coefficients, and two Bayesian approaches with the expert model used as prior mean and different weights for the prior covariance matrix were fitted. We quantify the predictive performance of the different methods with respect to calibration and discrimination, using cross-validation. RESULTS: The predictive performance of the unshrinked regression coefficients was poor when applied to the Swiss cohort. Shrinkage improved the results, but a Bayesian model formulation with unspecified weight of the informative prior lead to large AUC and small Brier score, naive and after cross-validation. The advantage of this approach is the flexibility in case of a prior-data conflict. CONCLUSIONS: Published risk prediction rules in clinical research need to be validated externally before they can be used in new settings. We propose to use a Bayesian model formulation with the original risk prediction rule as prior. The posterior means of the coefficients, given the validation data showed best predictive performance with respect to cross-validated calibration and discriminative ability. | Epidemiologic Methods |
BACKGROUND: This systematic review assesses the effect of methods commonly used to manage the pulp in cases of deep caries lesions, and the extent the pulp chamber remains uninfected and does not cause pulpal or periapical inflammatory lesions and associated tooth-ache over time. STUDY DESIGN: An electronic literature search included the databases PubMed, EMBASE, The Cochrane Central Register of Controlled Trials and Cochrane Reviews from January 1950 to March 2013. In addition, hand searches were carried out. Two reviewers independently evaluated abstracts and full-text articles. An article was read in full if at least one of the two reviewers considered the abstract potentially relevant. Altogether, 161 articles were read in full text. Of these, 24 studies fulfilled established inclusion criteria. Based on studies of at least moderate quality, the quality of evidence of each procedure was rated in four levels according to GRADE. RESULTS: No study reached the high quality level. Twelve were of moderate quality. The overall evidence was insufficient to assess which of indirect pulp capping, stepwise excavation, direct excavation and pulp capping/partial pulpotomy, pulpotomy or pulpectomy is the most effective treatment approach for teeth with deep caries. CONCLUSIONS: Because of the lack of good studies it is not possible to determine whether an injured pulp by deep caries can be maintained or whether it should be removed and replaced with a root canal filling. Both randomized studies and prospective observational studies are needed to investigate whether a pulp exposed to deep caries is best treated by measures intended to preserve it or by pulpectomy and root filling." | Dental Atraumatic Restorative Treatment |
BACKGROUND: Port-wine stains (PWS) are capillary malformations, typically located in the dermis of the head and neck, affecting 0.3% of the population. Current theories suggest that port-wine stains are caused by somatic mutations that disrupt vascular development. OBJECTIVES: Understanding PWS genetic determinants could provide insight into new treatments. METHODS: Our study used a custom next generation sequencing (NGS) panel and digital polymerase chain reaction to investigate genetic variants in 12 individuals with isolated port-wine stains. Importantly, affected and healthy skin tissue from the same individual were compared. A subtractive correction method was developed to eliminate background noise from NGS data. This allowed the detection of a very low level of mosaicism. RESULTS: A novel somatic variant GNAQ, c.547C>G, p.Arg183Gly was found in one case with 4% allele frequency. The previously reported GNAQ c.548G>A, p.Arg183Gln was confirmed in 9 of 12 cases with an allele frequency ranging from 1.73 to 7.42%. Digital polymerase chain reaction confirmed novel variants detected by next generation sequencing. Two novel somatic variants were also found in RASA1, although neither was predicted to be deleterious. CONCLUSIONS: This is the second largest study on isolated, non-syndromic PWS. Our data suggest that GNAQ is the main genetic determinant in this condition. Moreover, isolated port-wine stains are distinct from capillary malformations seen in RASA1 disorders, which will be helpful in clinical evaluation." | p120 GTPase Activating Protein |
Despite the increasing success of lung transplantation as the mainstay therapeutic modality for end-stage lung disease, the 1-year survival rate after lung transplantation remains 80% and primary graft dysfunction (PGD) accounts for 30% of mortality. Ischemia-reperfusion injury has been identified as one of the main causes of PGD, and thus significant efforts have been made to optimize the methods for lung preservation in an attempt to minimize lung injury during the period of ischemia. The composition of the lung preservation solution used in the pulmonary artery flush has been considered to be the key to successful lung preservation, and many lung transplant programs have been shifting the use of the preservation solution from the intracellular fluid type to the extracellular fluid type because of preferable posttransplant lung function with the latter. This review summarizes the experimental and clinical studies on lung preservation, particularly focusing attention on the preservation solution being employed for clinical lung transplantation. | Organ Preservation Solutions |
BACKGROUND: Concomitant asymptomatic striatocapsular slit-like hemorrhage (SSH) is occasionally found in patients of spontaneous intracerebral hemorrhage (ICH), but was seldomly described in the literature. In this study, we described the clinico-radiological features of asymptomatic SSH in ICH patients with hypertensive microangiopathy. METHODS AND RESULTS: 246 patients with strictly deep or mixed deep and lobar ICH/microbleeds were included. SSH was defined as hypointense lesions involving the lateral aspect of lentiform nucleus or external capsule in slit shape (>1.5 cm) on susceptibility-weighted imaging without history of associated symptoms. Demographics and neuroimaging markers were compared between patients with SSH and those without. Patients with SSH (n=24, 10%) and without SSH had comparable age (62.0 +/- 12.6 vs. 62.3 +/- 13.5, pâ¯=â¯0.912) and vascular risk factor profiles including the diagnosis of chronic hypertension, diabetes, and dyslipidemia (all p>0.05). SSH was associated with more common lobar microbleeds (79.2% vs 48.2%, pâ¯=â¯0.005), lacunes (75% vs. 41.4%, pâ¯=â¯0.002) and higher white matter hyperintensity (WMH) volumes (24.1 [10.4-46.3] vs. 13.9 [7.0-24.8] mL, pâ¯=â¯0.012) on MRI, as well as more frequent left ventricular hypertrophy (LVH) (50.0% vs. 20.5%, pâ¯=â¯0.004) and albuminuria (41.7% vs. 19.4%, pâ¯=â¯0.018). In multivariable analyses, SSH remains independently associated with LVH (pâ¯=â¯0.017) and albuminuria (p = 0.032) after adjustment for age, sex, microbleed, lacune and WMH volume. CONCLUSIONS: Asymptomatic SSH is associated with more severe cerebral small vessel disease-related change on brain MRI, and hypertensive cardiac and renal injury, suggesting a more advanced stage of chronic hypertension. | External Capsule |
Necrobiosis lipoidica diabeticorum is an unusual dermatologic condition with a characteristic clinical appearance and a clear association with diabetes mellitus. There is currently no treatment that reverses the atrophic changes associated with this lesion. We have carried out a clinicopathologic study on 15 subjects and, in addition, have reviewed 10 further biopsy specimens of necrobiosis lipoidica diabeticorum. We found a frequent association of necrobiosis lipoidica diabeticorum with other chronic complications of diabetes mellitus, including limited joint mobility. It is possible that nonenzymatic glucosylation or other changes in collagen may be important in the etiology of necrobiosis lipoidica diabeticorum and the limited joint mobility. We confirmed that cutaneous anesthesia is usually present in the necrobiosis lipoidica diabeticorum lesions. With the use of an antibody to S100 protein and an immunohistochemical method, there was an apparent decreased number of nerves in the skin lesions. We suggest that sensory loss results from local destruction of cutaneous nerves by the inflammatory process. Finally, in six elliptical biopsies extending into clinically normal skin, we demonstrated that the inflammatory infiltrate of necrobiosis lipoidica diabeticorum extended from the lesion into apparently normal skin surrounding clinically active lesions. Thus, intradermal steroids might be administered to perilesional areas surrounding active lesions in the hope of halting progression. | Necrobiosis Lipoidica |
Reverse triiodothyronine (rT3) was measured in cord serum from 5 infants with congenital hypothyroidism and compared with normal values in 70 euthyroid control infants. The mean (and SEM) value in the affected infants (135 +/- 12 ng/dl) was significantly lower than that in the control population (270 +/- 9 ng/dl). However, the large overlap in range of concentrations in affected and control infants indicates that newborn screening based on the determination of rT3 in cord blood specimens offers no advantage over present screening methods. | Triiodothyronine, Reverse |
Nucleolus organizer regions (NORs) are chromosomal loci where hundreds of rRNA genes are clustered. Despite being nearly identical in sequence, specific rRNA genes are selected for silencing during development via choice mechanism(s) that remain unclear. In Arabidopsis thaliana, rRNA gene subtypes that are silenced during development were recently mapped to the NOR on chromosome 2, NOR2, whereas active rRNA genes map to NOR4, on chromosome 4. In a mutant line deficient for ATXR5 or ATXR6-dependent histone H3 lysine 27 (H3K27) monomethylation, we show that millions of base pairs of chromosome 4, including the telomere, TEL4N, and much of NOR4, have been converted to the corresponding sequences of chromosome 2. This genomic change places rRNA genes of NOR2, which are normally silenced, at the position on chromosome 4 where active rRNA genes are normally located. At their new location, NOR2-derived rRNA genes escape silencing, independent of the atxr mutations, indicating that selective rRNA gene silencing is chromosome 2-specific. The chromosome 2 position effect is not explained by the NOR2-associated telomere, TEL2N, which remains linked to the translocated NOR, implicating centromere-proximal sequences in silencing. | Chromosomal Position Effects |
RATIONALE: Endocarditis with Abiotrophia defectiva represents 4.3% to 6% of all streptococcal endocarditis. The article presents diagnosis issues and the complexity of the treatment. PATIENT CONCERNS: We present the case of a female white patient, aged 26 years, who developed infectious endocarditis caused by A defectiva, in the last trimester of pregnancy, a biofilm-related infection associated with the presence of fixed braces. DIAGNOSES: The diagnosis of infectious endocarditis was confirmed by the cardiac ultrasound examination that revealed a voluminous vegetation on the mitral valve, and acute mitral regurgitation caused by chordae tendinae rupture, and also by isolating Abiotrophia defectiva from two positive blood cultures. INTERVENTIONS: The decision to undergo surgical intervention was taken, and a mitral valve replacement was performed. Surgical intervention that was associated with board-spectrum antibiotic therapy. OUTCOMES: A defectiva, remains a rare cause of infective endocarditis, with a reserved prognosis that is motivated by the extensive valvular lesions and the risk of embolism. LESSONS: The use of antibiotics administered in association, in the management of infective endocarditis, is mandatory. | Abiotrophia |
Branched-chain polyamine (BCPA) synthase (BpsA), encoded by the bpsA gene, is responsible for the biosynthesis of BCPA in the hyperthermophilic archaeon Thermococcus kodakarensis, which produces N(4)-bis(aminopropyl)spermidine and spermidine. Here, next-generation DNA sequencing and liquid chromatography-mass spectrometry (LC-MS) were used to perform transcriptomic and proteomic analyses of a T. kodakarensis strain (DBP1) lacking bpsA. Subsequently, the contributions of BCPA to gene transcription (or transcript stabilization) and translation (or protein stabilization) were analyzed. Compared with those in the wild-type strain (KU216) cultivated at 90 degrees C, the transcript levels of 424 and 21 genes were up- and downregulated in the DBP1 strain, respectively. The expression levels of 12 frequently-used tRNAs were lower in DBP1 cells than KU216 cells, suggesting that BCPA affects translation efficiency in T. kodakarensis. LC-MS analyses of cells grown at 90 degrees C detected 50 proteins in KU216 cells only, 109 proteins in DBP1 cells only, and 499 proteins in both strains. Notably, the transcript levels of some genes did not correlate with those of the proteins. RNA-seq and RT-qPCR analyses of ten proteins that were detected in KU216 cells only, including three flagellin-related proteins (FlaB2-4) and cytosolic NiFe-hydrogenase subunit alpha (HyhL), revealed that the corresponding transcripts were expressed at higher levels in DBP1 cells than KU216 cells. Electron microscopy analyses showed that flagella formation was disrupted in DBP1 cells at 90 degrees C, and western blotting confirmed that HyhL expression was eliminated in the DBP1 strain. These results suggest that BCPA plays a regulatory role in gene expression in T. kodakarensis. | Thermococcus |
OBJECTIVE: To describe the physiology of air leak in bronchopleural fistula in mechanically ventilated patients and how understanding of its physiology drives management of positive-pressure ventilation. To provide guidance of lung isolation, mechanical ventilator, pleural catheter, and endobronchial strategies for the management of bronchopleural fistula on mechanical ventilation. DATA SOURCES: Online search of PubMed and manual review of articles (laboratory and patient studies) was performed. STUDY SELECTION: Articles relevant to bronchopleural fistula, mechanical ventilation in patients with bronchopleural fistula, independent lung ventilation, high-flow ventilatory modes, physiology of persistent air leak, extracorporeal membrane oxygenation, fluid dynamics of bronchopleural fistula airflow, and intrapleural catheter management were selected. Randomized trials, observational studies, case reports, and physiologic studies were included. DATA EXTRACTION: Data from selected studies were qualitatively evaluated for this review. We included data illustrating the physiology of driving pressure across a bronchopleural fistula as well as data, largely from case reports, demonstrating management and outcomes with various ventilator modes, intrapleural catheter techniques, endoscopic placement of occlusion and valve devices, and extracorporeal membrane oxygenation. Themes related to managing persistent air leak with mechanical ventilation were reviewed and extracted. DATA SYNTHESIS: In case reports that demonstrate different approaches to managing patients with bronchopleural fistula requiring mechanical ventilation, common themes emerge. Strategies aimed at decreasing peak inspiratory pressure, using lower tidal volumes, lowering positive end-expiratory pressure, decreasing the inspiratory time, and decreasing the respiratory rate, while minimizing negative intrapleural pressure decreases airflow across the bronchopleural fistula. CONCLUSIONS: Mechanical ventilation and intrapleural catheter management must be individualized and aimed at reducing air leak. Clinicians should emphasize reducing peak inspiratory pressures, reducing positive end-expiratory pressure, and limiting negative intrapleural pressure. In refractory cases, clinicians can consider lung isolation, independent lung ventilation, or extracorporeal membrane oxygenation in appropriate patients as well as definitive management with advanced bronchoscopic placement of valves or occlusion devices. | Bronchial Fistula |
This study evaluated the dietary uptake kinetics and sublethal toxicity of p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE) in Antarctic krill. The uptake rate constant (characterised by the seawater volume stripped of contaminant sorbed to algae) of 200 +/- 0.32 mL g(-1) wet weight h(-1), average absorption efficiency of 86 +/- 13% and very low elimination rate constant of 5 x 10(-6) +/- 0.0031 h(-1) demonstrate the importance of feeding for p,p'-DDE bioaccumulation in Antarctic krill. Faecal egestion of unabsorbed p,p'-DDE of 8.1 +/- 2.7% indicates that this pathway contributes considerably to p,p'-DDE sinking fluxes. A median internal effective concentration (IEC50) of 15 mmol/kg lipid weight for complete immobility indicates baseline toxicity and that Antarctic krill exhibit comparable toxicological sensitivity as temperate species under similar 10 d exposure conditions. These findings support the critical body residue approach and provide insight to the role of Antarctic krill in the biogeochemical cycling of p,p'-DDE in the Southern Ocean." | Dichlorodiphenyl Dichloroethylene |
Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-beta receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondrial reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis." | Endothelin B Receptor Antagonists |
Hepatic stellate cells (HSC) play a critical role in the development and maintenance of liver fibrosis. HSC are lipocytes that displayed the capacity to develop into myofibroblast-like cells. Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) regulate the concentration of extracellular nucleotides, signaling molecules that play a role in the pathogenesis of hepatic fibrosis. In the present study, we identified and compared the expressions of E-NTPDase family members in two different phenotypes of the mouse hepatic stellate cell line (GRX) and evaluated the nucleotide hydrolysis by these cells. We show that both phenotypes of GRX cell line expressed NTPDase 3 and 5. However, only activated cells expressed NTPDase 6. In quiescent-like cells, the hydrolysis of triphosphonucleosides was significantly higher, and was related to an increase in Entpd3 mRNA expression. The diphosphonucleosides were hydrolyzed at a similar rate by two phenotypes of GRX cells. We suggest that up-regulation of Entpd3 mRNA expression modulates the extracellular concentration of nucleotides/nucleosides and affect P2-receptor signaling differently in quiescent-like cells and may play a role in the regulation of HSC functions. | Pyrophosphatases |
OBJECTIVE: In the recent time, endoradionuclide therapy for metastatic castration-resistant prostate carcinoma employing (177)Lu-PSMA-617 has yielded encouraging results and several clinical trials with the agent are currently ongoing. Routine preparation of (177)Lu-PSMA-617 patient doses can be made simpler and convenient, if the ingredients essential for radiolabeling are made available in a ready-to-use lyophilized form. METHODS: PSMA-617 freeze-dried kit was formulated and used for the preparation of (177)Lu-PSMA-617 clinical dose with high radiochemical purity using low/medium specific activity (177)Lu. Detailed radiochemical studies were performed to determine the maximum activity and volume of (177)LuCl(3), which can be added in the kit for the formulation of (177)Lu-PSMA-617. Studies were also performed to determine the shelf life of the kit to ensure its long-term usage. Studies were performed in buffer as well as human serum medium to determine the stability of the (177)Lu-PSMA-617 complex after storing in respective media up to 7 days postpreparation. About ten patient doses of (177)Lu-PSMA-617 were administered, and posttherapy scans were acquired. RESULTS: The formulated freeze-dried kit of PSMA-617 could be radiolabeled with an average percentage radiochemical purity > 98.53 +/- 0.38. The freeze-dried kit was found suitable for tolerating up to 0.5 mL of (177)LuCl(3) (in 0.01 N HCl) and specific activity of 555 MBq/mug (15 mCi/mug) for the preparation of the patient dose of (177)Lu-PSMA-617. The (177)Lu-PSMA-617 complex prepared using the freeze-dried kit of PSMA-617 was observed to maintain % radiochemical purity (RCP) of 96.74 +/- 0.87 and 94.81 +/- 2.66, respectively, even after storing up to 7 days in buffer and human serum, respectively. (177)Lu-PSMA-617 prepared using the in-house formulated freeze-dried kit of PSMA-617 exhibited accumulation in metastatic lesions picked up in a pretherapy PET scan. Reduction in number as well as size of lesions was observed in posttherapy scans acquired after two months of administering the first therapeutic dose of (177)Lu-PSMA-617. CONCLUSIONS: The freeze-dried kit of PSMA-617 could be used for the preparation of (177)Lu-PSMA-617 with high radiochemical purity (>98%) in a reproducible manner. (177)Lu-PSMA-617 prepared using the developed kit was successfully evaluated in patients suffering from metastatic prostate cancer. | Nuclear Pharmacy |
Invasive fusariosis (IF) is associated with severe neutropenia in patients with concurrent hematologic conditions. We conducted a retrospective observational study to characterize the epidemiology of IF in 18 Spanish hospitals during 2000-2015. In that time, the frequency of IF in nonneutropenic patients increased from 0.08 cases per 100,000 admissions in 2000-2009 to 0.22 cases per 100,000 admissions in 2010-2015. Nonneutropenic IF patients often had nonhematologic conditions, such as chronic cardiac or lung disease, rheumatoid arthritis, history of solid organ transplantation, or localized fusariosis. The 90-day death rate among nonneutropenic patients (28.6%) and patients with resolved neutropenia (38.1%) was similar. However, the death rate among patients with persistent neutropenia (91.3%) was significantly higher. We used a multivariate Cox regression analysis to characterize risk factors for death: persistent neutropenia was the only risk factor for death, regardless of antifungal therapy. | Hyalohyphomycosis |
Gastric inhibitory polypeptide (GIP) is a physiological gut peptide secreted from the intestinal K-cells with well documented insulin-releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex and brain, suggesting that it may have other functions. The presence of functional GIP receptors on adipocytes and the key role played by GIP in lipid metabolism and fat deposition suggest a possible beneficial effect of compromised GIP action in obesity and insulin resistance. Several key observations in animal models of obesity-related diabetes with chemically or genetically mediated biological GIP deficiency support this concept. Thus, obese diabetic animals with compromised GIP action due to peptide-based GIP receptor antagonists, small molecular weight GIP receptor antagonists, vaccination against GIP, genetic knockout of GIP receptor or targeted K-cell destruction are protected against obesity and associated metabolic disturbances. In addition, by causing preferential oxidation of fat, blockade of GIP signalling clears triacylglycerol deposits from liver and muscle, thereby restoring mechanisms for suppression of hepatic glucose output and improving insulin sensitivity. Emerging evidence also suggests that rapid cure of diabetes in grossly obese patients undergoing bypass surgery is mediated, in part, by surgical removal of GIP-secreting K-cells in the upper small intestine." | Gastric Inhibitory Polypeptide |
Substituted allylic amines and their derivatives are key structural motifs of many drug molecules and natural products. A general, mild, and practical palladium-catalyzed gamma-arylation of tertiary allylic amines, one of the most challenging Heck arylation substrates, has been developed. The gamma-arylation products were obtained in excellent regio- and stereoselectivity. Moreover, novel and potent adenylyl cyclase inhibitors with the potential for treating neuropathic and inflammatory pain have been identified from the gamma-arylation products. | Adenylyl Cyclase Inhibitors |
Objectives The present study was designed to investigate the effectiveness of trihexyphenidyl, a central anticholinergic drug, in preventing the post-traumatic stress disorder (PTSD) symptoms in a mouse model. Methods Mice were subjected to underwater trauma stress for 30 s on day 1 followed by three situational reminders (3rd, 7th and 14th day). Thereafter, the behavioral alterations including freezing behavior were noted on 21st day. The serum corticosterone levels were measured as a biochemical marker of trauma. Elevated plus maze test was done on day 1 and day 2 to assess the memory formation following exposure to trauma. Results Trauma and situational reminders were associated with a significant development of behavioral changes and freezing behavior on the 21st day. Moreover, there was also a significant decrease in the serum corticosterone levels. A single administration of trihexyphenidyl (2 and 5 mg/kg) significantly restored trauma associated-behavioral changes and serum corticosterone levels. Moreover, it significantly increased the transfer latency time on day 2 following stress exposure in comparison to normal mice suggesting the inhibition of memory formation during trauma exposure. Trihexyphenidyl also led to significant reduction in freezing behavior in response to situational reminders again suggesting the inhibition of formation of aversive fear memory. Conclusion The blockade of central muscarinic receptors may block the formation of aversive memory during the traumatic event, which may be manifested in form of decreased contextual fear response during situational reminders. Central anticholinergic agents may be potentially useful as prophylactic agents in preventing the development of PTSD symptoms. | Elevated Plus Maze Test |
A novel analytical method is proposed for rapid simultaneous determination of five 4-hydroxycoumarin rodenticides in animal liver tissues by eluent generator reagent free ion chromatography (RFIC) with fluorescence detection. Rodenticides were initially extracted from homogenized animal liver tissues with ethyl acetate and the extracts subjected to a solid-phase extraction process using Oasis HLB cartridges. The IC separation was carried out on an IonPac AS11 analytical column (250 mm x 4.0 mm) using gradient KOH containing 10% acetonitrile as organic modifier at a constant flow rate of 1.0 mL/min. The analytes were detected by fluorescence at an excitation wavelength of 270 nm and an emission wavelength of 380 nm. The average recoveries of the objective compounds spiked in animal liver tissues were between 81% and 98%. The limits of quantification (LOQs) were 0.004-0.010 mg/kg for them. Within-day and day-to-day relative standard deviations (RSD) were less than 8.5% and 9.7%, respectively. It was confirmed that this method could be used in a toxicological analysis. | Rodenticides |
Although arthrodesis of an arthritic proximal interphalangeal joint provides excellent relief of pain, it does so at the expense of mobility. Silicone rubber implant arthroplasty also provides predictable relief of pain and approximately 60 degrees of motion. Insertion of the implant through a dorsal extensor-splitting approach is preferred when a tendon reconstruction is necessary, as in cases of boutonniere deformity. If tendon reconstruction is not necessary, the lateral approach is an excellent alternative because it does not disturb the extensor mechanism and therefore permits earlier rehabilitation exercises. The following article outlines the dorsal and lateral techniques and postoperative rehabilitation of silicone rubber arthroplasty. | Joint Prosthesis |
Twenty-five percent of ischemic strokes are lacunar in type, but the cause remains unclear. Pathological descriptions of lacunar lesions are available but have not been systematically assessed. We therefore systematically summarized studies describing lacunar lesions by extracting data on the number of patients and lesions, clinical details, pathological methods, brain regions and/or vessels examined, and both parenchymal and vascular findings. Among 39 papers describing >4000 lesions (>50% from one study), 15 papers examined patients with a clinical lacunar syndrome. Terminology varied, many studies only reported macroscopic pathology and many lesions were cavitated (ie, old). Aside from symptomatic lesions occurring more often in the internal capsule or caudate nucleus, we found no other differences between symptomatic and asymptomatic patients. Perivascular edema and thickening, inflammation and disintegration of the arteriolar wall were common, whereas vessel occlusion was rare. The causal mechanisms of lacunar stroke remain poorly defined because of methodological inconsistencies and challenges. Standardised pathological definitions based on well-characterized post-mortem derived material supported by detailed clinical and imaging data are needed. | Thrombotic Stroke |
Thromboangiitis obliterans, or Buerger's disease, is a non-atherosclerotic, segmental, inflammatory disease affecting the small- and medium-sized vessels of the distal extremities. Other than discontinuation of tobacco, there is no standard-of-care treatment. Although two randomized trials have demonstrated a role for intravenous iloprost, no oral drug has yet been demonstrated to be effective in treating thromboangiitis obliterans. We present the first three reported cases of thromboangiitis obliterans successfully treated with phosphodiesterase type 5 inhibitors, followed by a discussion of the rationale for the use of these agents in thromboangiitis obliterans. | Thromboangiitis Obliterans |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.