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In modern hematology, research on hematopoiesis and blood cells in vertebrates, such as birds, reptiles, amphibians, and fish, is lagging. This is because there are many experimental constraints when selecting subjects other than humans and mice as research subjects. Currently, the availability of flow cytometry to count classified nucleated blood cells and utilization of whole genome information have led to novel findings. For example, in case of amphibian hematopoiesis studies, megakaryocytes have been found to be present in African clawed frogs (Xenopus laevis), which do not have platelets but have circulating nucleated thrombocytes. Moreover, we shed light on several mysteries, such as the C-terminal region in human TPO molecules not being found in birds, amphibians, and fish TPO molecules and the functional universalities of mutant CALR-MPL binding and EPO-EphB4 binding, in conjunction with comparative hematology. | Histology, Comparative |
As an approach to an analysis of the biosynthesis of the aminoglycoside antibiotic butirosin (But), we investigated the chromosomal regions flanking the ButR gene (aphA4/butA) of Bacillus circulans NRRL-B3312, and have identified, by nucleotide sequence analysis, a large open reading frame (ORF; ButB) upstream from the ButR gene. Hybridization was detected between butB and chromosomal DNA from other Bacillaceae that produce But-like compounds (but not from non-producers). Interruption of this sequence by insertion of an erythromycin-resistance-encoding gene (erm) at either of two distinct sites eliminated the production (biosynthesis or export) of But, thus indicating a role for butB in antibiotic production. Gene butB is transcribed in the same direction as butA and encodes a protein of 1616 amino acid (aa) residues with a 30-aa N-terminal signal peptide. Comparison of the sequence for the translation product (ButB) with the aa compositions and sequences of known bacterial surface proteins, such as S-layer proteins, suggests that this protein is cell-wall associated. It is proposed that ButB plays a role in the export of But from the producing organism. | Butirosin Sulfate |
In the context of the origin of life, phyllosilicate surfaces might favor the adsorption, concentration and reactivity of otherwise diluted prebiotic molecules. The primitive oceanic seafloor was certainly rich in Fe-Mg-rich phyllosilicates. The salinity of the primitive seawater remains largely unknown. Values ranging from 1 to 15 times modern salinity have been proposed and the salt composition of the primitive ocean also remains elusive although it may have played a role in the interactions between nucleotides and mineral surfaces. Therefore we studied the adsorption of 5'-monophosphate deoxyguanosine (dGMP) as a model nucleotide onto a Fe-rich swelling clay, i.e. nontronite, and an Al-rich phyllosilicate, i.e. pyrophyllite, for comparison. Experiments were carried out at atmospheric pressure, 25 degrees C and natural pH, with a series of salts NaCl, MgCl(2), CaCl(2), MgSO(4), NaH(2)PO(4) and LaCl(3) in order to evaluate the effect of cations and anions on dGMP adsorption. The present study shows that nucleotides are adsorbed on both phyllosilicates via a ligand exchange mechanism. The phosphate group of the nucleotide is adsorbed on the lateral metal hydroxyls of the broken edges of phyllosilicates. The presence of divalent cations or molecular anions, such as phosphate or sulfate, tends to inhibit this interaction on mineral surfaces. However, in the presence of divalent cations, cationic bridging on the basal surfaces of the swelling clay also occurs and could induce a higher retention capacity of the swelling clays compared to non-swelling phyllosilicates in primitive and modern natural environments. | Deoxyguanine Nucleotides |
PURPOSE: To help guide treatment strategies and create insight into functional outcomes in patients with Giant herniated thoracic discs (GHTD), which are defined as occupying more than 40% of spinal canal. METHODS: Authors did a retrospective analysis of prospective cohort of 33 cases of GHTD, using clinical letters, notes, and telephonic questionnaires to determine their pre and postoperative functional status, surgical details, and complication rates. 16 males and 17 females operated between 2006 and 2014 were included in the study. A total of 23 patients underwent thoracotomy, 9 costotransversectomy, and 2 transpedicular approaches for excision of thoracic discs. Neuromonitoring was used in seven patients. RESULTS: Frankel grade improved by 1 in 13 patients and by 2 in 1 patient. One patient of T11/12 GHTD with neurogenic claudication recovered completely, taking the overall improvement rate to 45.5%. It remained static in 15 patients (45.5%) and deteriorated by 1 in 3 patients (9%). By mJOA scoring too, the outcome was favorable in majority (84.4%) of patients. There were three intraoperative complications (9%), which included two incidental durotomies and one massive blood loss. Late postoperative complications were seen in 12(39%) patients. They included intercostal neuralgia, mechanical pain around costotransversectomy, progressive thoracic paraplegia due to spinal cord herniation and residual disc fragments, reactive pleural effusion, CSF fistula induced pleural effusion, and infective discitis. CONCLUSIONS: Surgery for giant herniated thoracic disc has favorable outcome in majority (91%) of patients. However, significant approach-related complications are to be anticipated in patients undergoing thoracotomies, most of them being manageable. Author recommends costotransversectomy, only in paracentral discs with smaller percentage canal stenosis. | Diskectomy |
The kisspeptin system is a central modulator of the hypothalamic-pituitary-gonadal axis in vertebrates. Its existence outside the vertebrate lineage remains largely unknown. Here, we report the identification and characterization of the kisspeptin system in the sea cucumber Apostichopus japonicus. The gene encoding the kisspeptin precursor generates two mature neuropeptides, AjKiss1a and AjKiss1b. The receptors for these neuropeptides, AjKissR1 and AjKissR2, are strongly activated by synthetic A. japonicus and vertebrate kisspeptins, triggering a rapid intracellular mobilization of Ca(2+), followed by receptor internalization. AjKissR1 and AjKissR2 share similar intracellular signaling pathways via G(alphaq)/PLC/PKC/MAPK cascade, when activated by C-terminal decapeptide. The A. japonicus kisspeptin system functions in multiple tissues that are closely related to seasonal reproduction and metabolism. Overall, our findings uncover for the first time the existence and function of the kisspeptin system in a non-chordate species and provide new evidence to support the ancient origin of intracellular signaling and physiological functions that are mediated by this molecular system. | Kisspeptins |
The biological diagnosis of polycystic ovary syndrome (PCO) remains questionable, and a single immunological hLH (ihLH) determination can be misleading. In order better to characterize these patients, we studied hLH pulsatility every 10 min for 4h using a radioimmunoassay and then compared the results with others we obtained with a biological method. Radioimmunological and biological profiles were similar in patients with PCO and in controls. We also studied pulsatility characteristics - frequency and amplitude - and calculated the area under the curve (AUC). There was no significant increase in frequency in our 10 patients with PCO but, as in other studies, increased amplitude of hLH pulses was observed. The most discriminating parameter was the AUC. For practical purposes, we propose that hLH in patients with PCO could be assessed efficiently by taking four samples every 10 min, with computerized calculation of the AUC. | Luteinizing Hormone |
This paper aimed to study the chemical constituents from the root bark of Schisandra sphenanthera. Silica, Sephadex LH-20 and RP-HPLC were used to separate and purify the 80% ethanol extract of S. sphenanthera. Eleven compounds were identified by ~1H-NMR, ~(13)C-NMR, ESI-MS, etc., which were 2-[2-hydroxy-5-(3-hydroxypropyl)-3-methoxyphenyl]-propane-1,3-diol(1), threo-7-methoxyguaiacylglycerol(2),4-O-(2-hydroxy-1-hydroxymethylethyl)-dihydroconiferylalcohol(3), morusin(4), sanggenol A(5), sanggenon I(6), sanggenon N(7), leachianone G(8),(+)-catechin(9), epicatechin(10), and 7,4'-dimethoxyisoflavone(11). Among them, compound 1 was a new compound, and compounds 2-9 were isolated from S. sphenanthera for the first time. Compounds 2-11 were subjected to cell viability assay, and the results revealed that compounds 4 and 5 had potential cytotoxicity, and compound 4 also had potential antiviral activity. | Schisandra |
Two new alkaloids, 2-demethyl-oxypalmatine (1) and 5-ethoxycarbonylsinoracutine (2), were isolated from the rhizomes of Sinomenium acutum, along with thirty-four known compounds. Cytotoxicity of the isolated compounds was examined for the MCF-7, H460, HT-29, and CEM human cancer cell lines. Dauriporphine (16), 6-O-demethylmenisporphine (17), bianfugecine (18), menisporphine (19), and 6-O-demethyldauriporphine (20) showed differential effects in their cytotoxic activity on the target cancer cell lines. Significant angiogenesis inhibitions of 16 and 19 were also observed. | Sinomenium |
If (a revision of) a conventional endodontic treatment is not possible or not successful, apical endodontic surgery can be indicated. The contemporary indications, the better retrograde preparation techniques with ultrasonic retro-tips, and the better visualisation of the operation area with an operation microscope can lead to higher success percentages. Moreover, the current developments in the field of compatible filling materials are promising. Also the application of lasers is promising, but has still to prove its clinical usefulness. | Retrograde Obturation |
A new study finds that 11.8% of men with metastatic prostate cancer carry mutations in DNA repair genes. The mutations were more than five times as prevalent in men with metastatic disease as in men with localized prostate cancer. Although relatives of the men weren't more likely to have prostate cancer, they were more likely to have breast, ovarian, and other cancers. | Checkpoint Kinase 2 |
OBJECTIVE: To review the outcomes of patients who underwent autologous oocyte thaw after planned oocyte cryopreservation. DESIGN: Retrospective cohort study. SETTING: Large urban university-affiliated fertility center. PATIENT(S): All patients who underwent >/=1 autologous oocyte thaw before December 31, 2020. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was the final live birth rate (FLBR) per patient, and only patients who had a live birth (LB) or consumed all remaining inventory (cryopreserved oocytes and resultant euploid/untested/no result embryos) were included. The secondary outcomes were laboratory outcomes and LB rates per transfer. RESULT(S): A total of 543 patients underwent 800 oocyte cryopreservations, 605 thaws, and 436 transfers. The median age at the first cryopreservation was 38.3 years. The median time between the first cryopreservation and thaw was 4.2 years. The median numbers of oocytes and metaphase II oocytes (M2s) thawed per patient were 14 and 12, respectively. Overall survival of all thawed oocytes was 79%. Of all patients, 61% underwent >/=1 transfer. Among euploid (n = 262) and nonbiopsied (n = 158) transfers, the LB rates per transfer were 55% and 31%, respectively. The FLBR per patient was 39%. Age at cryopreservation and the number of M2s thawed were predictive of LB; the FLBR per patient was >50% for patients aged <38 years at cryopreservation or who thawed >/=20 M2s. A total of 173 patients (32%) have remaining inventory. CONCLUSION(S): Autologous oocyte thaw resulted in a 39% FLBR per patient, which is comparable with age-matched in vitro fertilization outcomes. Studies with larger cohorts are necessary. | Fertilization in Vitro |
Mass spectrometry has been frequently applied to monitor the O(2) and CO(2) content in the off-gas of animal cell culture fermentations. In contrast to classical mass spectrometry the proton transfer reaction mass spectrometry (PTR-MS) provides additional information of volatile organic compounds by application of a soft ionization technology. Hence, the spectra show less fragments and can more accurately assigned to particular compounds. In order to discriminate between compounds of non-metabolic and metabolic origin cell free experiments and fed-batch cultivations with a recombinant CHO cell line were conducted. As a result, in total eight volatiles showing high relevance to individual cultivation or cultivation conditions could be identified. Among the detected compounds methanethiol, with a mass-to-charge ratio of 49, qualifies as a key candidate in process monitoring due to its strong connectivity to lactate formation. Moreover, the versatile and complex data sets acquired by PTR MS provide a valuable resource for statistical modeling to predict non direct measurable parameters. Hence, partial least square regression was applied to the complete spectra of volatiles measured and important cell culture parameters such as viable cell density estimated (R(2) = 0.86). As a whole, the results of this study clearly show that PTR-MS provides a powerful tool to improve bioprocess-monitoring for mammalian cell culture. Thus, specific volatiles emitted by cells and measured online by the PTR-MS and complex variables gained through statistical modeling will contribute to a deeper process understanding in the future and open promising perspectives to bioprocess control. | Lactic Acid |
Bovine Factor X is isolated in two chromatographically separable forms, Factor X1 and Factor X2. Whereas only a single form of Factor Xa, the active protease, exists, the activation peptides also exist as two chromatographically distinct species. These peptides have been shown to differ at a tyrosyl residue by ultraviolet spectrophotometry, and in their composition after alkaline hydrolysis. On the basis of the spectral properties, and elution position of the modified tyrosine on Dowex 1 columns and on an amino acid analyzer, it has been concluded that Factor X2 contains a tyrosyl-O-SO4 residue at position 18 in the activation peptide whereas Factor X1 contains only tyrosine. Alternative explanations such as differences in carbohydrate composition, differences in phosphate content, or differences in the number of gamma-carboxyglutamic acid residues were demonstrated to be unrelated to the difference in chromatographic behavior between bovine Factors X1 and X2. | Factor X |
Complementary advances in medical imaging, vascular biology and biomechanics promise to enable computational modelling of abdominal aortic aneurysms to play increasingly important roles in clinical decision processes. Using a finite-element-based growth and remodelling model of evolving aneurysm geometry and material properties, we show that regional variations in material anisotropy, stiffness and wall thickness should be expected to arise naturally and thus should be included in analyses of aneurysmal enlargement or wall stress. In addition, by initiating the model from best-fit material parameters estimated for non-aneurysmal aortas from different subjects, we show that the initial state of the aorta may influence strongly the subsequent rate of enlargement, wall thickness, mechanical behaviour and thus stress in the lesion. We submit, therefore, that clinically reliable modelling of the enlargement and overall rupture-potential of aneurysms may require both a better understanding of the mechanobiological processes that govern the evolution of these lesions and new methods of determining the patient-specific state of the pre-aneurysmal aorta (or correlation to currently unaffected portions thereof) through knowledge of demographics, comorbidities, lifestyle, genetics and future non-invasive or minimally invasive tests. | Aorta, Abdominal |
BACKGROUND: This study compares effectiveness of two commercially available signals, Pulsed Electromagnetic Field (PEMF) and Combined Magnetic Field (CMF) clinical signals, to stimulate bone healing in rabbit tibial osteotomies. METHODS: One millimeter osteotomies in New Zealand White rabbits, stabilized with external fixators, were exposed daily to either signal for 30 minutes, three or six hours. Osteotomized sham controls received no signal exposure. Analyses of torsional strength, periosteal callus area and fracture healing stage demonstrated dose responses to increasing daily exposures to both signals. RESULTS: By 14 days torsional strength increased over shams in the three and six hour-treated groups, significant only for the six hour groups (p<0.05). By 21 days both three and six hour-treated groups were significantly stronger than shams (p<0.05, p<0.005) and the PEMF 30 minute treated group also showed significance (p<0.05). PEMF versus CMF-treated groups were not different at any exposure time. CONCLUSIONS: Both CMF and PEMF signals were most effective in this model when used for six hours per day. CLINICAL RELEVANCE: In this model we demonstrate that though both PEMF and CMF are bioactive" and promote healing at shorter and longer exposure dosages, there exists an "optimal" threshold effect of 6 hours/day electromagnetic wave stimulation for bone healing." | Magnetic Field Therapy |
BACKGROUND: In the present study, the effects of extracorporeal cardiac shock waves combined with different concentrations of sulfur hexafluoride ultrasound microbubbles on myocardial ultrastructure in rats were observed. METHODS: Thirty-six rats were randomly divided into 6 groups: control group (N), extracorporeal cardiac shock wave group, and combined group, i.e., extracorporeal cardiac shock wave combined with different concentrations of sulfur hexafluoride microbubble (0.225 mL/kg/min, 0.45 mL/kg/min, 0.9 mL/kg/min, 1.8 mL/kg/min). The combination of extracorporeal cardiac shock wave combined with sulfur hexafluoride microbubbles of different concentrations had no significant effect on hemodynamic indexes and left ventricular function in rats. RESULTS: There were significant differences in cardiac troponin I (cTnI) and nitricoxide among different groups. Histopathology showed that inflammatory cells infiltrated in the shock wave+microbubble 0.9 and shock wave+microbubble 1.8 groups. The myocardial ultrastructural injury score of shock wave+microbubble1.8 group was significantly higher than that of the N group, shock wave group, shock wave+microbubble 0.225 group, and shock wave+microbubble 0.45 group. The score of shock wave+microbubble 0.9 group was higher than that of the control group (P=.009). Western blot results showed that the expression of vascular endothelial growth factor and endothelial nitricoxide synthase (eNOS) protein in the rats treated with extracorporeal cardiac shock wave combined with sulfur hexafluoride microbubbles of different concentrations was higher than that in the N group and shock wave group, with shock wave+microbubble 0.45 group having the strongest expression. CONCLUSION: Myocardial ultrastructure damage occurs when high concentrations of sulfur hexafluoride microbubbles are present, but a proper concentration of sulfur hexafluoride microbubbles could promote the cavitation effect of extracorporeal cardiac shock waves. Thus combination therapy may become a new paradigm in coronary heart disease, especially contributing to the treatment of refractory angina. Combination therapy may change coronary heart disease treatment, especially for refractory angina. | Sulfur Hexafluoride |
In the owl monkey, microelectrode mapping of Brodmann's area 19 indicates that this region contains part or all of at least 5 separate representations of the visual field, each of which adjoins the anterior border of V II and collectively are termed the third tier of cortical visual areas (V I is the first tier; V II is the second tier). Described in detail in this report is one of the third tier areas which is located on the dorsal surface and the adjacent medial wall of the occipital lobe and corresponds to a densely myelinated zone of cortex. In this dorsomedial area (DM), the representation of the horizontal meridian is partially split, and thus, like V II (see ref. 4) and the dorsolateral crescent5, DM is a second order transformation of the visual hemifield. In one abnormal owl monkey, a portion of the upper quadrant was represented twice in DM. This abnormal case may provide some clues as to how the normal pattern of visuotopic organization is established in the developing brain. | Aotus trivirgatus |
The prevalence of vector-borne parasitic diseases is widely influenced by biological and ecological factors. Environmental conditions such as temperature and precipitation can have a marked effect on haemosporidian parasites (Plasmodium spp.) that cause malaria and those that cause other malaria-like diseases in birds. However, there have been few long-term studies monitoring haemosporidian infections in birds in northern latitudes, where weather conditions can be highly variable and the effects of climate change are becoming more pronounced. We used molecular methods to screen more than 2,000 blood samples collected from black-capped chickadees (Poecile atricapillus), a resident passerine bird. Samples were collected over a 10 year period, mostly during the non-breeding season, at seven sites in Alaska, USA. We tested for associations between Plasmodium prevalence and local environmental conditions including temperature, precipitation, site, year and season. We also evaluated the relationship between parasite prevalence and individual host factors of age, sex and presence or absence of avian keratin disorder. This disease, which causes accelerated keratin growth in the beak, provided a natural study system in which to test the interaction between disease state and malaria prevalence. Prevalence of Plasmodium infection varied by year, site, age and individual disease status but there was no support for an effect of sex or seasonal period. Significantly, birds with avian keratin disorder were 2.6 times more likely to be infected by Plasmodium than birds without the disorder. Interannual variation in the prevalence of Plasmodium infection at different sites was positively correlated with summer temperatures at the local but not statewide scale. Sequence analysis of the parasite cytochrome b gene revealed a single Plasmodium spp. lineage, P43. Our results demonstrate associations between prevalence of avian malaria and a variety of biological and ecological factors. These results also provide important baseline data that will be informative for predicting future changes in Plasmodium prevalence in the subarctic. | Malaria, Avian |
The organ distribution of a colloidal plasma substitute on the basis of oxypolygelatin (Gelifundol S) has been determined in chimpanzees with radioactively tagged material. The radioactivity was distributed uniformly in the whole body and after 24 h it was nearly completely excreted. As liver, spleen, heart, lungs and kidneys were not depicted radiographically in contrast to the body background, it can be concluded that ther e is no preference for the colloid to be stored in any of these organs. Only in the bladder a transiently higher radioactivity could be measured. The urine was collected fo 7 d and contained 91.5% of the colloid originally infused. | Plasma Substitutes |
Advances in digital technology have vastly increased the speed and content of information transfer. Equine practitioners of the future should be in contact with their office and other information resources at all times through an array of digital networks. Patients and practitioners alike should benefit from better information access. | Practice Management |
As sugar-modified oligodeoxyribonucleotides, L-homooligomers (L-dA12 and L-dT12) and a L/D-alternative oligomer ((L-dA-D-dA)6) were synthesized. These oligomers were quite resistant towards phosphodiesterase degradations. L-dA12 formed complexes with poly(dT) and poly(U) at 0 degree C with different stabilities, on the other hand L-dT12 did not show obvious hypochromicities after mixing with complementary natural homopolymers. An alternative sequence, (L-dA-D-dA)6, interacted with both type homopolymers and stabilities of the complexes increased compared to that of L-dA12. | Oligodeoxyribonucleotides |
Methods for characterizing the higher-order structure of protein therapeutics are in great demand for establishing consistency in drug manufacturing, for detecting drug product variations resulting from modifications in the manufacturing process, and for comparing a biosimilar to an innovator reference product. In principle, solution NMR can provide a robust approach for characterization of the conformation(s) of protein therapeutics in formulation at atomic resolution. However, molecular weight limitations and the perceived need for stable isotope labeling have to date limited its practical applications in the biopharmaceutical industry. Advances in NMR magnet and console technologies, cryogenically cooled probes, and new rapid acquisition methodologies, particularly selective optimized flip-angle short transient pulse schemes and nonuniform sampling, have greatly ameliorated these limitations. Here, we describe experimental methods for the collection and analysis of 2D (1)H(N)-(15)N-amide- and (1)H-(13)C-methyl-correlated spectra applied to protein drug products at natural isotopic abundance, including representatives from the rapidly growing class of monoclonal antibody (mAb) therapeutics. Practical aspects of experimental setup and data acquisition for both standard and rapid acquisition NMR techniques are described. Furthermore, strategies for the statistical comparison of 2D (1)H(N)-(15)N-amide- and (1)H-(13)C-methyl-correlated spectra are detailed. | Nitrogen Radioisotopes |
Reflective functioning or mentalizing is the capacity to interpret both the self and others in terms of internal mental states such as feelings, wishes, goals, desires, and attitudes. This paper is part of a series of papers outlining the development and psychometric features of a new self-report measure, the Reflective Functioning Questionnaire (RFQ), designed to provide an easy to administer self-report measure of mentalizing. We describe the development and initial validation of the RFQ in three studies. Study 1 focuses on the development of the RFQ, its factor structure and construct validity in a sample of patients with Borderline Personality Disorder (BPD) and Eating Disorder (ED) (n = 108) and normal controls (n = 295). Study 2 aims to replicate these findings in a fresh sample of 129 patients with personality disorder and 281 normal controls. Study 3 addresses the relationship between the RFQ, parental reflective functioning and infant attachment status as assessed with the Strange Situation Procedure (SSP) in a sample of 136 community mothers and their infants. In both Study 1 and 2, confirmatory factor analyses yielded two factors assessing Certainty (RFQ_C) and Uncertainty (RFQ_U) about the mental states of self and others. These two factors were relatively distinct, invariant across clinical and non-clinical samples, had satisfactory internal consistency and test-retest stability, and were largely unrelated to demographic features. The scales discriminated between patients and controls, and were significantly and in theoretically predicted ways correlated with measures of empathy, mindfulness and perspective-taking, and with both self-reported and clinician-reported measures of borderline personality features and other indices of maladaptive personality functioning. Furthermore, the RFQ scales were associated with levels of parental reflective functioning, which in turn predicted infant attachment status in the SSP. Overall, this study lends preliminary support for the RFQ as a screening measure of reflective functioning. Further research is needed, however, to investigate in more detail the psychometric qualities of the RFQ. | Theory of Mind |
ETHNOPHARMACOLOGICAL RELEVANCE: Ethnoveterinary medicine (EVM) practices remain a common feature of South African animal husbandry, particularly in rural livestock healthcare. This review provides an update of research undertaken on South African EVM from 2009 until 2019. AIM OF THE STUDY: This review collates information and investigates trends in the increasing field of EVM research in South Africa over the last decade. MATERIALS AND METHODS: A literature search was conducted using available databases including ScienceDirect, PubMed, Scopus and Google Scholar. Dissertations, theses, books and technical reports were also searched. RESULTS: In the past decade, ethnoveterinary surveys conducted in South Africa report the use of 139 plants from 50 families used against 21 animal diseases and conditions. Leaves, roots and bark have remained popular plant parts used for EVM. In terms of livestock species reported, the major focus was on cattle, goats and poultry. Only four of the nine provinces in the country have been surveyed. CONCLUSIONS: Relatively few publications reporting on ethnoveterinary surveys have originated from South Africa. These papers refer to many plants used for a variety of commonly encountered animal diseases and afflictions. With reference to recently published guidelines on conducting ethnobotanical surveys, several recommendations can be made to improve the robustness of surveys documenting the use of plants for EVM in South Africa. | Medicine, African Traditional |
Viruses show noticeable evolution to adapt and reproduce within their hosts. Theoretically, patterns and factors that affect the codon usage of viruses should reflect evolutionary changes that allow them to optimize their codon usage to their hosts. Some software tools can analyze the codon usage of organisms; however, their performance has room for improvement, as these tools do not focus on examining the codon usage co-adaptation between viruses and their hosts. This paper describes the vhcub R package, which is a crucial tool used to analyze the co-adaptation of codon usage between a virus and its host, with several implementations of indices and plots. The tool is available from: https://cran.r-project.org/web/packages/vhcub/. | Codon Usage |
Details of the design and construction of removable and simple fixed appliances are presented. Equipment, instruments, and supplies are listed. Welding, soldering, banding and bonding are illustrated. Finally, step-by-step descriptions are given of first aid measures for the repair of fixed appliances applicable to the general practice situation. | Dental Soldering |
Ionotropic gamma-aminobutyric acid (GABA) receptors (iGABARs) are validated targets of drugs and insecticides. Our previous studies showed that the competitive antagonists of insect iGABARs exhibit insecticidal activities and that the 3-isothiazolol scaffold is used as a lead for developing novel iGABAR antagonists. Here, we designed a novel series of 4-aryl-5-(4-pyridinyl)-3-isothiazolol (4-API) analogs that have various aromatic substituents at the 4-position. Two-electrode voltage clamp experiments showed that all synthesized 4-APIs exhibited antagonistic activity against Musca domestica and Spodoptera litura iGABARs (RDL) expressed in oocytes of Xenopus laevis at 100 muM. Of the 4-APIs, the 4-(1,1'-biphenylyl) analog was the most potent antagonist with IC(50)s of 7.1 and 9.9 muM against M. domestica and S. litura RDL receptors, respectively. This analog also showed a certain insecticidal activity against S. litura larvae, with >75% mortality at 100 mug/g diet. Molecular docking studies with a M. domestica iGABAR model indicated that the pi-pi stacking interactions formed between the pyridinyl ring and Y252 and between the 4-substituted aromatic group and Y107 might be important for antagonism by the 4-(1,1'-biphenylyl) analog. Our studies provide important information for designing novel iGABAR antagonists and suggest that the 4-APIs acting on iGABARs are promising insecticide leads for further studies. | GABA Antagonists |
A case of disseminated cryptococcus infection in an immunocompetent host is described. The present case attests to the importance of using a cautious approach for the diagnosis of granulomatous lymphadenitis. The patient was initially misdiagnosed and treated as disseminated tuberculosis. Later the patient developed visual loss and skin lesions. Periodic Acid Schiff stained sections of lymph node biopsy and cerebrospinal fluid culture established the diagnosis. | Lymphadenitis |
The colony-stimulating factor 3 receptor (CSF3R) controls the growth of neutrophils, the most abundant type of white blood cell. In healthy neutrophils, signaling is dependent on CSF3R binding to its ligand, CSF3. A single amino acid mutation in CSF3R, T618I, instead allows for constitutive, ligand-independent cell growth and leads to a rare type of cancer called chronic neutrophilic leukemia. However, the disease mechanism is not well understood. Here, we investigated why this threonine to isoleucine substitution is the predominant mutation in chronic neutrophilic leukemia and how it leads to uncontrolled neutrophil growth. Using protein domain mapping, we demonstrated that the single CSF3R domain containing residue 618 is sufficient for ligand-independent activity. We then applied an unbiased mutational screening strategy focused on this domain and found that activating mutations are enriched at sites normally occupied by asparagine, threonine, and serine residues-the three amino acids which are commonly glycosylated. We confirmed glycosylation at multiple CSF3R residues by mass spectrometry, including the presence of GalNAc and Gal-GalNAc glycans at WT threonine 618. Using the same approach applied to other cell surface receptors, we identified an activating mutation, S489F, in the interleukin-31 receptor alpha chain. Combined, these results suggest a role for glycosylated hotspot residues in regulating receptor signaling, mutation of which can lead to ligand-independent, uncontrolled activity and human disease." | Leukemia, Neutrophilic, Chronic |
Phenanthroindolizidines are naturally occurring alkaloids mainly isolated from different species of Asclepiadaceae. These alkaloids are characterized by an excellent anticancer activity against a very wide range of cancerous cell lines including those who are multi drug resistant. Nevertheless, phenanthroindolizidines are associated with sever neurotoxicity that prevented any candidate from this family to pass the clinical trials. A number of boron-based analogues of (R)-6-O-desmethylantofine have been synthesised. Their physochemical properties were evaluated, same as their in-vitro antiproliferative activity. The pinacol boronate ester derivative (3) showed interesting cytotoxicity against a panel of cancerous cell lines attested by a cancer cell growth-inhibitory potency (GI(50)) as low as 30 nM. | Boronic Acids |
Iron (Fe) deficiency is a major plant nutritional disorder in many parts of the world, particularly in areas with saline soils. Among the numerous root-associated microbes that are beneficial for plant nutrient uptake, Trichoderma spp. are the most effective rhizosphere fungi for enhancing plant growth and plant resistance to biotic and abiotic stresses. To investigate the potential mechanisms of action of Trichoderma on insoluble Fe in the soil, which is difficult for plants to absorb and utilize, a high siderophore-producing strain of Trichoderma T6, was isolated from the rhizosphere of cucumber plants. The strain was identified as T. asperellum based on the morphological features and molecular phylogenetic analyses. Applying strain T6 to sterile soil could increase soil levels of Fe(2+) and siderophores, as well as increase Fe(2+) and Fe(3+)-chelate reductase (FCR) activity in cucumber tissues. Purified siderophore eluent (PSE) increased plant growth, thus confirming its role in plant growth promotion. Moreover, extracellular Fe(3+) reducing activity and three kinds of organic acids were detected in the culture filtrate of strain T6. These results indicate that strain T6 influences plant Fe absorption in several ways. Siderophore-based Fe chelation is effective in providing Fe to plants, organic acids, and Fe(3+) reducing enzymes may participate in the solubilization and reduction of insoluble Fe(3+) to Fe(2+). | Cucumis |
The evolution of the brain in mammals has been accompanied by a reorganization of the brain as a result of differential growth of certain brain regions. Consequently, the geometry of the brain, and especially the size and shape of the cerebral cortex, has changed notably during evolution. Comparative studies of the cerebral cortex suggest that there are general architectural principles governing its growth and evolutionary development and that the primate neocortex is uniformly organized and composed of neural processing units. We are beginning to understand the geometric, biophysical, and energy constraints that have governed the evolution of these neuronal networks. In this review, some of the design principles and operational modes will be explored that underlie the information processing capacity of the cerebral cortex in primates, and it will be argued that with the evolution of the human brain we have nearly reached the limits of biological intelligence. | Nerve Net |
Opponents of the provision of therapeutic, healthy limb amputation in Body Integrity Identity Disorder cases argue that such surgeries stand in contrast to the goal of medical practice - that of health restoration and maintenance. This paper refutes such a conclusion via an appeal to the nuanced and reflective model of health proposed by Georges Canguilhem. The paper examines the conceptual entanglement of the statistically common with the normatively desirable, arguing that a healthy body can take multiple forms, including that of an amputee, provided that such a form enables the continuing ability to initiate new norms of existence. It concludes that the practice of healthy limb amputation in cases of Body Integrity Identity Disorder is not only compatible with the goal of medicine but is potentially the only method of achieving this goal in the face of a complex and often mischaracterized disorder." | Body Integrity Identity Disorder |
CX(3)CL1, or fractalkine, the unique member of the CX(3)C chemokine family, exists as a transmembrane glycoprotein, as well as in soluble form, each mediating different biological activities, and is constitutively expressed in many hematopoietic and nonhematopoietic tissues. CX(3)CR1, the CX(3)CL1 exclusive receptor, is a classical GPCR, expressed on NK cells, CD14(+) monocytes, and some subpopulation of T cells, B cells, and mast cells. A recent paper by our group has demonstrated for the first time that highly purified human B cells from tonsil and peripheral blood expressed CX(3)CR1 at mRNA and protein levels. In particular, tonsil naive, GC, and memory B cells expressed CX(3)CR1, but only GC centrocytes were attracted by soluble CX(3)CL1, which with its receptor, are also involved in the pathogenesis of several inflammatory disorders, as well as of cancer. Previous studies have shown that CX(3)CR1 is up-regulated in different types of B cell lymphoma, as well as in B-CLL. Recently, we have demonstrated that the CX(3)CL1/CX(3)CR1 axis is involved in the interaction of B-CLL cells with their microenvironment. Taken together, our data delineate a novel role for the CX(3)CL1/CX(3)CR1 complex in the biology of normal B cells and B-CLL cells. These topics are the subject of this review article. | Chemokine CX3CL1 |
Human RON (Recepteur d'Origine Nantais) receptor tyrosine kinase is a cell surface receptor for Macrophage Stimulating Protein (MSP). RON mediates signal transduction pathways that regulate cell adhesion, invasion, motility and apoptosis processes. Elevated levels of RON and its alternatively spliced variants are implicated in the progression and metastasis of tumor cells. The binding of MSP alpha/beta heterodimer to the extracellular region of RON receptor induces receptor dimerization and activation by autophosphorylation of the intracellular kinase domains. The ectodomain of RON, containing the ligand recognition and dimerization domains, is composed of a semaphorin (Sema), Plexins-Semaphorins-Integrins domain (PSI), and four Immunoglobulins-Plexins-Transcription factor (IPT) domains. High affinity association between MSP and RON is mediated by the interaction between MSP beta-chain and RON Sema, although RON activation requires intact RON and MSP proteins. Here, we report the structure of RON Sema-PSI domains at 1.85 A resolution. RON Sema domain adopts a seven-bladed beta-propeller fold, followed by disulfide bond rich, cysteine-knot PSI motif. Comparison with the homologous Met receptor tyrosine kinase reveals that RON Sema-PSI contains distinguishing secondary structural features. These define the receptors' exclusive selectivity towards their respective ligands, RON for MSP and Met for HGF. The RON Sema-PSI crystal packing generates a homodimer with interface formed by the Sema domain. Mapping of the dimer interface using the RON homology to Met, MSP homology to Hepatocyte Growth Factor (HGF), and the structure of the Met/HGF complex shows the dimer interface overlapping with the putative MSPbeta binding site. The crystallographically determined RON Sema-PSI homodimer may represent the dimer assembly that occurs during ligand-independent receptor activation and/or the inhibition of the constitutive activity of RONDelta160 splice variant by the soluble RON splice variant, RONDelta85." | Receptor Protein-Tyrosine Kinases |
The rising acuity of hospitalized patients requires that critical care nurses maintain a high level of clinical expertise. Expert skill levels (critical thinking, technical skills, and interpersonal skills) of clinicians improve patient outcomes that translates into savings for the institution through shorter length of stay and decreased frequency of re-admissions. The authors outline the steps to follow in developing a theory-based career advancement plan that encourages and rewards clinical competence. | Employee Incentive Plans |
BACKGROUND: Despite declines in deaths from rheumatic heart disease (RHD) in Africa over the past 30 years, it remains a major cause of cardiovascular morbidity and mortality on the continent. We present an investment case for interventions to prevent and manage RHD in the African Union (AU). METHODS: We created a cohort state-transition model to estimate key outcomes in the disease process, including cases of pharyngitis from group A streptococcus, episodes of acute rheumatic fever (ARF), cases of RHD, heart failure, and deaths. With this model, we estimated the impact of scaling up interventions using estimates of effect sizes from published studies. We estimated the cost to scale up coverage of interventions and summarised the benefits by monetising health gains estimated in the model using a full income approach. Costs and benefits were compared using the benefit-cost ratio and the net benefits with discounted costs and benefits. FINDINGS: Operationally achievable levels of scale-up of interventions along the disease spectrum, including primary prevention, secondary prevention, platforms for management of heart failure, and heart valve surgery could avert 74 000 (UI 50 000-104 000) deaths from RHD and ARF from 2021 to 2030 in the AU, reaching a 30.7% (21.6-39.0) reduction in the age-standardised death rate from RHD in 2030, compared with no increase in coverage of interventions. The estimated benefit-cost ratio for plausible scale-up of secondary prevention and secondary and tertiary care interventions was 4.7 (2.9-6.3) with a net benefit of $2.8 billion (1.6-3.9; 2019 US$) through 2030. The estimated benefit-cost ratio for primary prevention scale-up was low to 2030 (0.2, <0.1-0.4), increasing with delayed benefits accrued to 2090. The benefit-cost dynamics of primary prevention were sensitive to the costs of different delivery approaches, uncertain epidemiological parameters regarding group A streptococcal pharyngitis and ARF, assumptions about long-term demographic and economic trends, and discounting. INTERPRETATION: Increased coverage of interventions to control and manage RHD could accelerate progress towards eradication in AU member states. Gaps in local epidemiological data and particular components of the disease process create uncertainty around the level of benefits. In the short term, costs of secondary prevention and secondary and tertiary care for RHD are lower than for primary prevention, and benefits accrue earlier. FUNDING: World Heart Federation, Leona M and Harry B Helmsley Charitable Trust, and American Heart Association. | African Union |
1. In the present study, we investigated the effects of the inducible nitric oxide (iNOS) inhibitors S-methylisothiourea (SMT) and l-N(6)-(1-iminoethyl)-lysine (l-Nil) on endotoxin-induced acute lung injury (ALI), as well as the associated physiological, biomedical and pathological changes, in anaesthetized Sprague-Dawley rats and in rat isolated perfused lungs. 2. Endotoxaemia was induced by an intravenous (i.v.) infusion of lipopolysaccharide (LPS; Escherichia coli 10 mg/kg). Lipopolysaccharide produced systemic hypotension and tachycardia. It also increased the lung weight/bodyweight ratio, lung weight gain, exhaled nitric oxide (NO), the protein concentration in bronchoalveolar lavage and microvascular permeability. 3. Following infusion of LPS, plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-1beta) were markedly elevated. Pathological examination revealed severe pulmonary oedema and inflammatory cell infiltration. Pretreatment with SMT (3 mg/kg, i.v.) or l-Nil (3 mg/kg, i.v.) significantly attenuated the LPS-induced changes and ALI. 4. The results suggest that the inflammatory responses and ALI following infusion of LPS are due to the production of NO, free radicals and pro-inflammatory cytokines through the iNOS system. Inhibition of iNOS is effective in mitigating the endotoxaemic changes and lung pathology. Inhibitors of iNOS may be potential therapeutic agents for clinical application in patients with acute respiratory distress syndrome. | Isothiuronium |
PsbO-D158 is a highly conserved residue of the PsbO protein in photosystem II (PSII), and participates in one of the hydrogen-bonding networks connecting the manganese cluster with the lumenal surface. In order to examine the role of PsbO-D158, we mutated it to E, N or K in Thermosynechococcus vulcanus and characterized photosynthetic properties of the mutants obtained. The growth rates of these three mutants were similar to that of the wild type, whereas the oxygen-evolving activity of the three mutant cells decreased to 60-64% of the wild type. Fluorescence kinetics showed that the mutations did not affect the electron transfer from Q(A) to Q(B), but slightly affected the donor side of PSII. Moreover, all of the three mutant cells were more sensitive to high light and became slower to recover from photoinhibition. In the isolated thylakoid membranes from the three mutants, the PsbU subunit was lost and the oxygen-evolving activity was reduced to a lower level compared to that in the respective cells. PSII complexes isolated from these mutants showed no oxygen-evolving activity, which was found to be due to large or complete loss of PsbO, PsbV and PsbU during the process of purification. Moreover, PSII cores purified from the three mutants contained Psb27, an assembly co-factor of PSII. These results suggest that PsbO-D158 is required for the proper binding of the three extrinsic proteins to PSII and plays an important role in maintaining the optimal oxygen-evolving activity, and its mutation caused incomplete assembly of the PSII complex. | Thermosynechococcus |
INTRODUCTION: Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting beta(2)-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 microg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA). METHODS: A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV(1)), post-dose peak FEV(1), and St. George's Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12-24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. RESULTS: Eighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario. CONCLUSION: This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available. | Formoterol Fumarate |
The beta-carboline compounds norharman and harman exhibit neuroactive activity in the human body. Chicory coffee has proved to be a source of beta-carboline compounds. This study assessed the norharman and harman contents of traditional and novel raw materials for the production of chicory coffee, as well as in samples of chicory coffee with novel additives. The highest content of the beta-carbolines among the traditional raw materials was recorded in roasted sugar beet (2.26 mug/g), while roasting the chicory caused a 25-fold increase in the content of norharman in this raw material (from 0.05 to 1.25 mug/g). In novel raw materials not subjected to the action of high temperature, beta-carboline was not detected. Among the roasted novel raw materials, the highest contents of harman and norharman were found in artichokes. High harman levels were also recorded in roasted chokeberry. | Harmine |
OBJECTIVE: The aim of this study was to examine emotional recognition (prosodic and visual) in anorexia nervosa. METHODS: Thirty people with anorexia nervosa and a comparison group of 30 healthy women were tested with facial and vocal stimuli that expressed specific emotions and they were given a neutral task. RESULTS: The group of women with anorexia nervosa was poor at emotional recognition. This was most marked for negative emotions in faces and for both positive and negative emotions in voices. This decreased ability to recognize negative affect in faces remained even after adjustment for confounding variables such as age, education, and depression. DISCUSSION: People with anorexia nervosa have difficulty recognizing emotions from facial expression and vocal tone. This may contribute to poor interpersonal communication and a lack of empathy, both of which are associated with anorexia nervosa patients. | Perceptual Disorders |
The triad of obesity, hypoventilation and inordinate hypersomnolence characterizes the obesity-hypoventilation syndrome. The reasons for daytime hypoventilation appear related to decreased chemical drives to breathe combined with the added physical impediment of extreme obesity. When the physiology of sleep was investigated in patients with this syndrome, intermittent nocturnal obstructive apneas were documented that produced blood gas abnormalities, arrhythmias and serious elevations of both pulmonary and systemic pressures. The obstructive apneas are due to intermittent loss of muscle tone of the tongue resulting in its prolapse against the posterior pharynx. The special importance of the obesity-hypoventilation syndrome lies in its being an example of a disorder of sleep and breathing that can appear in widely different clinical settings. Therapeutic measures include weight loss, progestational agents or permanent tracheostomy. | Hypoventilation |
A 66-year-old man with diabetes developed acute renal failure after ingestion of Amanita pseudoporphyria Hongo. Laboratory data showed acute nonoliguric renal failure. A renal biopsy showed acute tubular necrosis with glomerular minor abnormalities. He received hemodialysis treatment for 3 weeks and his renal function normalized 2 months after admission. We discuss the differences in acute renal failure caused by possible toxins of Amanita pseudoporphyria Hongo from that caused by other poisonous mushrooms." | Kidney Tubular Necrosis, Acute |
Seroconversion rates to measles, mumps and rubella (MMR) in children given MMR vaccine at 9, 12 and 15 months of age were assessed so as to recommend the optimum age for vaccination. A total of 164 infants were recruited, of whom 123 completed the study. Sera were tested pre-immunization and 4 wk after MMR vaccine, for the presence and titres of antibodies by the haemagglutination inhibition (HI) test and by enzyme-linked immunosorbant assay (ELISA). The pre-immunization results showed that levels of maternal antibody detectable by HI had disappeared by 9 months in all infants in the case of measles, but not in the case of mumps or rubella. Evidence for subclinical infection with the three viruses was found in 19 to 31 per cent of infants by 15 months of age. The responses to measles antigen by both HI test and ELISA were better (> 95%) at 12 or 15 months than at 9 months (80%). Vaccine failure was low at 12 or 15 months. The response to mumps antigen by HI antigen was also higher (92%) at 12 months than at 9 months (75%). Vaccine failure was less frequent at 12 months than at 9 months. The ELISA was found to be unreliable for mumps virus antibody testing. Rubella vaccine evoked good seroresponse (> 92%) at 9, 12 and 15 months, both by HI test and ELISA. Thus a better response to the MMR vaccine was obtained at or after 12 months of age than earlier. Hence, a dose of MMR may be given optimally at 12 months for children not previously immunized with measles vaccine. For those already given measles vaccine, the MMR may be given at 12 or 15 months. | Mumps Vaccine |
Cronobacter spp. (Enterobacter sakazakii) are important foodborne pathogens. Infections with this pathogen can lead to neonatal meningitis, necrotizing enterocolitis, and bacteremia. This study examined Cronobacter spp. contamination in commercial powdered infant formulas (PIFs) and follow-up formulas (FUFs) in China. Forty-nine of 399 samples were contaminated with Cronobacter spp. and 10.2% of the isolates were resistant to cefotaxime; in contrast, all of the tested isolates were susceptible to amikacin, amoxicillin/clavulanic acid, cefepime, ciprofloxacin, imipenem, and meropenem. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) analyses produced a total of 16 PFGE banding patterns and 11 sequence types (STs), including 7 novel STs. In summary, the rates at which Cronobacter spp. were isolated from commercial PIF and FUF samples in China were relatively high, and the isolated strains exhibited high susceptibility in vitro to most antibiotics. The PFGE method exhibited higher typing capability than the MLST method, and molecular typing results revealed that the contamination of PIF and FUF with Cronobacter spp. in China may be mainly due to the addition of contaminated materials. Thus, the development of more effective control strategies during the manufacturing process is needed. | Cronobacter |
BACKGROUND: Sex differences in personality are believed to be comparatively small. However, research in this area has suffered from significant methodological limitations. We advance a set of guidelines for overcoming those limitations: (a) measure personality with a higher resolution than that afforded by the Big Five; (b) estimate sex differences on latent factors; and (c) assess global sex differences with multivariate effect sizes. We then apply these guidelines to a large, representative adult sample, and obtain what is presently the best estimate of global sex differences in personality. METHODOLOGY/PRINCIPAL FINDINGS: Personality measures were obtained from a large US sample (N = 10,261) with the 16PF Questionnaire. Multigroup latent variable modeling was used to estimate sex differences on individual personality dimensions, which were then aggregated to yield a multivariate effect size (Mahalanobis D). We found a global effect size D = 2.71, corresponding to an overlap of only 10% between the male and female distributions. Even excluding the factor showing the largest univariate ES, the global effect size was D = 1.71 (24% overlap). These are extremely large differences by psychological standards. SIGNIFICANCE: The idea that there are only minor differences between the personality profiles of males and females should be rejected as based on inadequate methodology. | Venus |
During the current pandemic of COVID-19, the authors observed that during screening test for SARS-CoV-2 targeting the E-gene by qRT-PCR, few nasopharyngeal/oropharyngeal samples showed amplification signals at late cycle threshold (C(T)-value)â¯>â¯35 despite being negative for other confirmatory target genes. Thirty such samples (taken as cases) showing detectable C(T) of > 35 cycle in E-gene which were negative for other target genes of SARS-CoV-2 and 30 samples with undetectable fluorescence in E-gene were taken as controls for investigation. An in-vitro diagnostic approved commercial qRT-PCR multiplex kit detecting 33 respiratory pathogens which can also detect Haemophilus influenzae was used for screening the samples. It was observed that out of the 30 samples showing detectable C(T)> 35 in E-gene, 11 samples were positive for Haemophilus influenzae whereas in the controls only three samples were positive for H. influenzae (p-value: 0.03) which was statistically significant. Further, the probes and primers were screened against H. influenzae for matches in the genome. It was observed that all primers and probes for the E-gene of SARS-CoV-2 had over 13 bp long sequences matching 100% with multiple sites across the H. influenzae genome. This qRT-PCR primer & probes are being used extensively across India, and laboratories using them should be aware of the cross-reactivity of primers & probes with the H. influenzae genome. Further, the authors observed that 95.9% (5415/5642) of COVID-19 positive cases detected in their laboratory were asymptomatic at the time of collection of samples. This warrants further investigations. | Coronavirus Envelope Proteins |
Evidence has accumulated concerning the medicinal application of Nelumbo nucifera in the treatment of various diseases. Neferine, an alkaloid from N. nucifera was found to exert cytotoxicity on liver cancer cells HepG2 in a dose-dependent manner. We evaluated its anticancer potential by studying its effect on mitochondrial membrane potential, intracellular calcium levels [Ca(2+)](i), cell membrane integrity, apoptotic body formation and DNA fragmentation in cultured HepG2 cells. The reactive oxygen species level has been increased upon neferine treatment with concomitant decrease in reduced glutathione. Our data further indicate reduction of DeltapsiM and increased [Ca(2+)](i) during apoptosis induction by neferine with increased expression of apoptotic proteins such as Bax, Bad, cleaved forms of caspase 3, caspase 9 and PARP, with the downregulation of anti-apoptotic protein Bcl2 in HepG2 cells. Moreover, the expressions of tumour suppressor proteins p53 and PTEN were upregulated along with the downregulation of P-Akt. In addition, expression levels of TNF-alpha, p38 and ERK1/2 MAP kinases were increased upon neferine treatment. These results imply that mitochondrial-mediated ROS generation induced by neferine leads to caspase-dependent apoptosis in HepG2 cells. | Nelumbonaceae |
Biomonitoring of human exposure to estrogens most frequently focuses on environmental and dietary estrogens, and infrequently includes measures of exposure to potent endogenous estrogens present in serum. Pregnancy is a developmentally sensitive period during which added" serum estrogenicity exceeding normal intra-individual daily variability may be of particular relevance. We made repeated measurements of serum concentrations of estrone (E1), estradiol (E2), estriol (E3), estetrol (E4), daidzein (DDZ), genistein (GEN) and bisphenol A (BPA) in thirty pregnant women using ultra-performance liquid chromatography coupled with tandem mass spectrometry detection (UPLC-MS/MS) and electrospray ionization (ESI). Serum E1, E2, and E3 concentrations varied significantly (coefficients of variation 9-10%) with broad ranges across the cohort: 1.61-85.1â¯nM, 9.09-69.7â¯nM, and 1.5-36.3â¯nM respectively. BPA (undetected, estimated from total exposure), DDZ and GEN concentrations were 1-5 orders of magnitude lower. The 24-h urinary elimination profiles of endogenous estrogens were each strongly correlated with their corresponding serum concentrations (Pearson's Correlation Coefficients of 0.83 (E1), 0.84 (E2) and 0.94 (E3)). A multivariate regression analysis produced equations for estimating serum concentrations of E1, E2, E3, E4, GEN and DDZ from urinary elimination rates and gestation period, an important step towards non-invasive biomonitoring for assessment of "added" estrogenicity during pregnancy." | Estrogens |
INTRODUCTION: Current classifications of psychotropic drugs, developed in the 1960s, are based on beliefs about clinical effectiveness. This article evaluates the scientific validity of current drug terms and possible alternative classifications. METHODS: A historical, conceptual, and empirical review of the psychopharmacology literature is provided. Consistency of classification is examined by 3 major categories: chemical structure, pharmacodynamic mechanism, and clinical efficacy. RESULTS: Current drug terms based on clinical effectiveness are not valid scientifically, either claiming efficacy which is disproven or ignoring other areas of clinical efficacy. Hence, clinical efficacy is not a consistent and scientifically valid way of classifying psychotropic drugs. Chemical structures are also heterogeneous for drugs with similar clinical efficacy. The most consistent way to define drug classes is pharmacodynamic mechanism. Specific drug groups identified are: monoamine agonists (antidepressants" and "stimulants"), dopamine blockers ("antipsychotics"), second messenger modifiers ("mood stabilizers), and gabaergic agonists ("anxiolytics" or "hypnotics"). CONCLUSIONS: Consistent with a recent proposal of psychopharmacology organizations, this article proposes a new nomenclature based mainly on biological pharmacodynamic mechanisms. Specific terms that are scientifically valid and clinically practical are suggested. It is hoped that this new language would allow for more meaningful and accurate communication between clinicians and patients." | Psychotropic Drugs |
Since the publication of the sequence of the genome of Plasmodium falciparum, the major causative agent of human malaria, many post-genomic studies have been completed. Invaluably, these data can now be analysed comparatively owing to the availability of a significant amount of genome-sequence data from several closely related model species of Plasmodium and accompanying global proteome and transcriptome studies. This review summarizes our current knowledge and how this has already been--and will continue to be--exploited in the search for vaccines and drugs against this most significant infectious disease of the tropics. | Haemosporida |
Grapevine viruses are found throughout the viticultural world and have detrimental effects on vine productivity and grape and wine quality. This report provides a comprehensive and up-to-date review on grapevine viruses in Australia with a focus on Shiraz Disease" (SD) and its two major associated viruses, grapevine virus A (GVA) and grapevine leafroll-associated virus 3 (GLRaV-3). Sensitive grapevine cultivars like Shiraz infected with GVA alone or with a co-infection of a leafroll virus, primarily GLRaV-3, show symptoms of SD leading to significant yield and quality reductions in Australia and in South Africa. Symptom descriptors for SD will be outlined and a phylogenetic tree will be presented indicating the SD-associated isolates of GVA in both countries belong to the same clade. Virus transmission, which occurs through infected propagation material, grafting, and naturally vectored by mealybugs and scale insects, will be discussed. Laboratory and field-based indexing will also be discussed along with management strategies including rogueing and replanting certified stock that decrease the incidence and spread of SD. Finally, we present several cases of SD incidence in South Australian vineyards and their effects on vine productivity. We conclude by offering strategies for virus detection and management that can be adopted by viticulturists. Novel technologies such as high throughput sequencing and remote sensing for virus detection will be outlined." | Closteroviridae |
Pompe disease is an autosomal recessive lysosomal storage disease caused by pathogenic variants in GAA, which encodes an enzyme integral to glycogen catabolism, acid alpha-glucosidase. Disease-relevant cell lines are necessary to evaluate the efficacy of genotype-specific therapies. Dermal fibroblasts from two patients presenting clinically with Pompe disease were reprogrammed to induced pluripotent stem cells using the Sendai viral method. One patient is compound heterozygous for the c.258dupC (p.N87QfsX9) frameshift mutation and the c.2227C>T (p.Q743X) nonsense mutation. The other patient harbors the c.-32-13T>G splice variant and the c.1826dupA (p.Y609X) frameshift mutation in compound heterozygosity." | Glycogen Storage Disease Type II |
Primary faecal incontinence (encopresis) in children is usually treated with laxative medication and a behaviour modification programme aimed at promoting regular toileting, but the effectiveness of laxatives has never been adequately investigated. 169 children with encopresis and evidence of stool on plain abdominal radiograph were randomly allocated to receive multimodal (MM) therapy (laxatives plus behaviour modification; n = 83) or behaviour modification alone (BM; n = 86). Mean (SD) follow-up was 55.1 (27.0) weeks and 56.7 (32.0) weeks, respectively. By 12 months' follow-up 42 (51%) of the MM group and 31 (36%) of the BM group (p = 0.079) had achieved remission (at least one 4 week period with no soiling episodes) and 52 (63%) vs 37 (43%) (p = 0.016) had achieved at least partial remission (soiling no more than once a week). MM subjects achieved remission significantly sooner than BM subjects, and the difference in the Kaplan-Meier remission curves was most striking in the first 30 weeks of follow-up (p = 0.012). The patterns of compliance with toileting in the treatment groups were almost identical, although about 1 in 8 children overall did not comply with the sitting programme. After exclusion of the 24 poor compliers, there was no significant difference between BM and MM groups. This study shows a clear advantage overall for the use of laxative medication, although the benefit may not be as great for children who are able to maintain regular toileting. | Encopresis |
Congenital erythropoietic porphyria (CEP) is an inherited disease due to a deficiency in the uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme pathway. It is characterized by accumulation of uroporphyrin I in the bone marrow, peripheral blood, and other organs. The onset of most cases occurs in infancy and the main symptoms are cutaneous photosensitivity and hemolysis. For severe transfusion-dependent cases, when allogeneic cell transplantation cannot be performed, autografting of genetically modified primitive/stem cells is the only alternative. In the present study, efficient mobilization of peripheral blood primitive CD34(+) cells was performed on a young adult CEP patient. Retroviral transduction of this cell population with the therapeutic human UROS (hUS) gene resulted in both enzymatic and metabolic correction of CD34(+)-derived cells, as demonstrated by the increase in UROS activity and by a 53% drop in porphyrin accumulation. A 10-24% gene transfer efficiency was achieved in the most primitive cells, as demonstrated by the expression of enhanced green fluorescent protein (EGFP) in long-term culture-initiating cells (LTC-IC). Furthermore, gene expression remained stable during in vitro erythroid differentiation. Therefore, these results are promising for the future treatment of CEP patients by gene therapy." | Uroporphyrinogen III Synthetase |
OBJECTIVE: To evaluate the effects of levomilnacipran extended-release (ER) on suicidal ideation and behavior in adults with major depressive disorder (MDD). METHODS: Post hoc analyses were conducted in patients from 4 randomized, double-blind, placebo-controlled trials and a long-term, open-label extension study of levomilnacipran ER (40-120 mg/d) in adults with MDD. Analyses included incidence of suicide-related treatment-emergent adverse events (TEAEs); incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation (score=1-5) and behavior (score=6-10); percent of patients who shifted from no C-SSRS suicidal ideation/behavior at baseline to suicidal ideation during treatment (worsened from score=0 to score=1-5), or vice-versa (improved from score=1-5 to score=0). RESULTS: Suicide-related TEAEs occurred in<1% of patients in the levomilnacipran ER studies. The incidence of C-SSRS suicidal ideation was 22.2%, 23.9%, and 21.7% for placebo, short-term levomilnacipran ER, and long-term levomilnacipran ER, respectively; C-SSRS suicidal behavior was<1% in all of these groups. In the short-term studies, the percentage of patients with C-SSRS shifts were as follows: worsening from score=0 to score=1-5 (placebo, 8.6%; levomilnacipran ER, 11.0%); improvement from score=1-5 to score=0 (placebo, 24.0%; levomilnacipran ER, 27.7%). CONCLUSION: In adult MDD patients, the incidence of suicidal ideation and behavior was similar between placebo and short-term levomilnacipran ER as indicated by TEAE reports and C-SSRS scores. Worsening in C-SSRS scores was also similar between placebo and levomilnacipran ER. There was no indication of increased suicidality during longer courses of continued therapy. Together, these findings suggest that this medication is not associated with increased risks of suicidal ideation or behavior. | Levomilnacipran |
Camptothecin (CPT) and its derivatives from Camptotheca acuminata have antitumor effects as a DNA topoisomerase I inhibitor. Previous studies have shown that application of exogenous abscisic acid (ABA) significantly promoted the accumulation level of CPT and induced the expression of CPT biosynthetic genes, which revealed that ABA signaling is effectively involved in regulating CPT biosynthesis in C. acuminata. In this study, an ABA transporter, CaABAT, which encodes a plasma membrane protein belonging to the ABCG subfamily, was identified in C. acuminata, and its ABA import activity was confirmed by transport assay in yeast cells. Real-time PCR analysis showed that CaABAT was predominately expressed in C. acuminata leaves and its expression could be significantly upregulated by exogenous ABA treatment. Silencing of CaABAT down-regulated the expression of ABA response genes, which indicated that translocation of ABA by CaABAT should initiate changes in plant physiological status in response to ABA signaling, thus leading to decreased expression of CPT biosynthesis pathway genes and low accumulation levels of CPT in C. acuminata. | Nyssaceae |
This study reports on the development of a reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific detection of turkey coronavirus (TCoV). Of the several sets of primers tested, 1 set of primers derived from the P gene and 2 sets derived from the N gene of TCoV could amplify the TCoV genome in the infected samples. The RT-PCR was sensitive and specific for TCoV and did not amplify other avian RNA and DNA viruses tested except the infectious bronchitis virus (IBV). To overcome the problem of IBV amplification, a set of separate primers was designed from the spike protein gene of IBV. The RT-PCR under the same conditions as above could effectively differentiate between TCoV and IBV. The closely related bovine coronavirus and transmissible gastroenteritis virus of pigs were differentiated from TCoV using the same RT-PCR with slight modifications. The results of RT-PCR correlated well with the results of the immunofluorescent test for the same samples tested at the Purdue University Animal Disease Laboratory, West Lafayette, Indiana. The nucleotide sequence and projected amino acid sequence comparison of the P gene of different isolates of TCoV from 5 different states in the United States revealed a close association among the different isolates of TCoV. | Coronavirus, Turkey |
The combined effects of ethanol (EtOH) and cigarette smoke (CS) on hepatic and pulmonary monooxygenase (MO) activities (aniline 4-hydroxylase (AH), aminopyrine N-demethylase (AMND), 7-ethoxyresorufin O-deethylase (EROD), p-nitroanisole O-demethylase (p-NAOD)), lipid peroxidation (LP) and reduced glutathione (GSH) levels and glutathione S-transferase (GST) activities toward several substrates (l-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (ENPP)) were determined and compared with those of EtOH or CS alone in rats. When the male adult rats (225-275 g) were treated with 10% EtOH (v/v) in their drinking for 21 days AH, AMND and EROD activities and LP and GSH levels increased significantly whereas GST activity for EAA decreased significantly in liver as compared to controls. EtOH did not change the hepatic p-NAOD and GST activities toward CDNB, DCNB and ENPP. In lung, EtOH increased GST activities toward CDNB and ENPP and LP level but decreased GST activity toward DCNB, significantly. No alterations were noted in pulmonary MO activities and GST activity toward EAA and GSH level by EtOH treatment. When the animals were exposed to CS five times a day, with 1 h intervals, for 3 days in a chamber where smoke and fresh air lead alternatively, AMND, EROD and p-NAOD activities, GST activity toward EAA and GSH level increased but LP level and GST activity for ENPP decreased significantly in liver. CS did not alter the hepatic AH and GST activities toward CDNB and DCNB. In lung, CS increased AH, EROD and p-NAOD activities and LP and GSH levels and decreased all the GST activities studied significantly. CS had no influence on pulmonary AMND activity. For the combined treatment, the animals were treated with 10% EtOH (v/v) in their drinking water for 21 days and during the last 3 days they were exposed to CS five times a day, with 1 h intervals, in a chamber where smoke and fresh air lead alternatively. In these animals, augmentation of elevations were noted in AH and p-NAOD activities and LP and GSH levels but not in EROD and AMND activities in liver. Combined treatment significantly decreased GST activity toward CDNB, ameliorated the alteration caused by either EtOH or CS treatment alone on GST activity toward EAA and potentiated the depression of GST activity toward ENPP to a greater degree. No change was observed in GST activity toward DCNB. In lung, combined treatment potentiated the elevations of AMND and p-NAOD activities and LP level and not those of AH and EROD activities. GST activities toward CDNB, DCNB and ENPP were highly elevated by the combined treatment. No changes were observed in pulmonary GSH level and GST activity for EAA by the combined treatment. These results reveal that the regulations of the hepatic and pulmonary MO and GST are differentially influenced by EtOH, CS and the combined treatment." | Oxidoreductases, O-Demethylating |
The respiratory tract is continually exposed to various insults that are a permanent threat to the maintenance of lung homeostasis. Repair of the parenchyma structure, particularly of the alveolar epithelium, requires complex cellular strategies. Among the molecular components that play an important role in these processes are the surfactant proteins (SPs), particularly SP-A. The present review examines current evidence regarding the role of SP-A in lung host defence mechanisms through its implication in innate/adaptive immunity of the lung and epithelium integrity and repair. New information on SP-A deficiency in various forms of pulmonary diseases could help define therapeutic strategies aimed at restoring functional SP-A within the alveolar structure." | Pulmonary Surfactant-Associated Protein A |
BACKGROUND: Bosworth described an unusual fracture-dislocation of the ankle with fixed posterior fracture-dislocation of the fibula. Previous epidemiological data on the prevalence and characteristics of patients with Bosworth ankle fractures have been limited. Bosworth fracture-dislocations are often missed in patients with ankle fractures. We investigated the outcomes of missed diagnosis and the prevalence of Bosworth fracture-dislocation in patients with ankle fractures. METHODS: We conducted a retrospective analysis of inpatients aged 15 years and older with an ankle fracture, who underwent surgery between 2007 and 2016 in 4 Korean hospitals. The patient demographics, risk factors, fracture characteristics, treatment data, outcomes, and complications were analyzed. RESULTS: We reviewed 3405 hospital admissions for ankle fractures. During the study period, Bosworth fracture-dislocations were diagnosed in 51 cases. The prevalence of Bosworth fracture-dislocations (n=51) was 1.62% among patients with ankle fractures who were enrolled in this study (n=3140). Emergency surgery was performed within 24h of injury in 36 cases (group A) and delayed surgery was performed in 15 cases (group B). The mean patient age at admission was 35.97 (standard deviation [SD], 1.643) years in group A and 34.33 (SD, 2.296) years in group B. Men were more commonly affected than women, with a 32:19 ratio. Most of the patients with Bosworth fracture-dislocations were young adults with high-energy trauma. The most frequent mechanism of trauma was falling down stairs (n=27, 52.94%), followed by traffic accidents. Patient outcomes were significantly better in group A than in group B. CONCLUSION: The prevalence of Bosworth fracture-dislocations was higher than expected. If unrecognized, it can result in inappropriate treatment and permanent disability. With accurate diagnosis and prompt treatment, excellent results can usually be obtained. LEVEL OF CLINICAL SIGNIFICANCE: 4. | Missed Diagnosis |
PURPOSE: To report a case of bull's eye maculopathy associated with mutations in RDS/PRPH2 and ROM-1 genes. METHODS: We present a case report of a patient with a characteristic maculopathy and describe the multimodal retinal imaging findings including spectral domain optical coherence tomography and fundus autofluorescence and full-field electrophysiology. The results of genetic testing are also reported. RESULTS: A 60-year-old woman presented with decreased vision and a remarkable bull's eye maculopathy with retinal examination. Fundus autofluorescence illustrated a striking pattern of speckled hyperautofluorescence and hypoautofluorescence that highlighted the bull's eye maculopathy in each eye and guided genetic testing, which confirmed a mutation of the RDS/PRPH2 gene and a novel mutation of the ROM-1 gene. CONCLUSION: Multimodal imaging including fundus autofluorescence may guide genetic testing in patients with a characteristic maculopathy. RDS/PRPH2 genetic mutation can be associated with a bull's eye maculopathy with a signature fundus autofluorescence presentation. | Tetraspanins |
KRAS mutations are causally linked to protumor inflammation and are identified as driving factors in tumorigenesis. Here, using multiomics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS-mutant iCCA. In KRAS-mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant antitumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS-mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in patients with KRAS-mutant iCCA were significantly associated with superior response to anti-PD-1 immunotherapy. SIGNIFICANCE: This work describes a novel inflammatory checkpoint mediated by IL1RN alternative splicing variants that may serve as a promising basis to develop therapeutic options for KRAS-mutant iCCA and other cancers. This article is featured in Selected Articles from This Issue, p. 2109." | Interleukin 1 Receptor Antagonist Protein |
Bordetella parapertussis is one of the bacteria that causes whooping cough. However, little attention has been paid to this bacterium because it causes a milder illness than Bordetella pertussis and the rate of detection is low, even though research suggests that pertussis vaccines have limited efficacy against B. parapertussis infection. However, recent studies have revealed high rates of detection in patients with whooping cough in some field studies. In this review, the relevant studies of B. parapertussis are summarized and it is demonstrated that it is now necessary to pay greater attention to infections by this bacterium. | Bordetella parapertussis |
We report a serial case study of 20 patients presenting scrotal contusions and for whom an emergency scrotal ultrasonography was performed. This investigation is not a luxury. It was a useful confirmation diagnostic tool for hematocele in 1/3 of cases (7/20) as well as for the detection of associated epididymal and or testicular lesions. In 2/3 of cases (13/20) it detected lesions unsuspected by clinical examination so that a therapeutic decision was taken promptly. Scrotal echography is therefore a useful emergency tool not for major trauma where the surgical decision is evident, but for apparently benign trauma where the clinical examination is currently deficient and needs provided a trained ultrasonography operator is available. | Hematocele |
Natural killer (NK) activity against tumour and virus-infected target cells is shown by a subpopulation of peripheral blood mononuclear leukocytes with the morphological features of large granular lymphocytes (LGL). The lineage of human LGL is still controversial, as they display surface markers of both T lymphocytes and myelomonocytic cells. LGL have recently been reported to produce lymphokines such as interleukin-2 (IL-2) and alpha- as well as gamma-interferons, functions associated mainly with T cells. To determine whether cytokines associated with other cell lineages are also produced by LGL, we examined whether they might produce a myelomonocyte -associated cytokine such as interleukin-1 (IL-1). IL-1 is a 12-18,000 molecular weight (MW) lymphokine produced by a variety of cell types such as monocytes, keratinocytes and a human dendritic cell line, which plays a crucial role in immunoregulation and inflammation. Moreover, IL-1 has recently been reported to act synergistically with IL-2 and interferons in boosting LGL-mediated NK activity. We now show that a subset of highly purified human LGL with NK activity can be stimulated to secrete a soluble factor with the biochemical and biological characteristics of human IL-1. | Centrifugation, Zonal |
To assess the relationship between LGBTQ status and (1) current, recent, and lifetime experiences of housing instability, (2) risk of housing instability due to fears of interpersonal violence, and (3) perceived housing challenges, this study examined online survey data from individuals with a household income <$35,000 (N = 1,270). Analyses compared LGBTQ and cisgender heterosexual respondents using chi-square tests and logistic regression. Over their lifetime, LGBTQ respondents had increased odds of sleeping outdoors (adjusted odds ratios [AOR] = 1.580) or in a car (AOR = 1.465) because they had nowhere else to stay. They also had increased odds of reporting housing challenges related to violence from family/friends (AOR = 3.278), substance abuse (AOR = 3.063), and mental health (AOR = 2.048). Interventions serving LGBTQ adults should prioritize safety concerns and consider providing services to both individuals and families. In addition, providers should increase sensitivity toward issues of sexual orientation and gender identity and the unique needs of LGBTQ adults. | Housing Instability |
A case of multiple bilateral dens invaginatus in the maxillary incisor teeth and an impacted cuspid has been presented. The impacted cuspid was removed surgically. | Dens in Dente |
Fiolle reported the first description of a carpal boss". The "hump" is cosmetically disturbing and sometimes painful. It has to be distinguished from a ganglion. A lateral X-Ray with 30 degrees of supination reveals a spur or a styloid bone (12.5%). In a series of 44 patients, treated over a period of 7 years, 21 needed operation for pain or a complication of previous surgery. The technique described by Cuono and Watson was successfully used without recurrence of deformity but in 2 cases some pain remained during strenuous efforts." | Exostoses |
Methanosarcina acetivorans, considered a strict anaerobic archaeon, was cultured in the presence of 0.4-1% O2 (atmospheric) for at least 6 months to generate air-adapted cells; further, the biochemical mechanisms developed to deal with O2 were characterized. Methane production and protein content, as indicators of cell growth, did not change in air-adapted cells respect to cells cultured under anoxia (control cells). In contrast, growth and methane production significantly decreased in control cells exposed for the first time to O2. Production of reactive oxygen species was 50 times lower in air-adapted cells versus control cells, suggesting enhanced anti-oxidant mechanisms that attenuated the O2 toxicity. In this regard, (i) the transcripts and activities of superoxide dismutase, catalase and peroxidase significantly increased; and (ii) the thiol-molecules (cysteine + coenzyme M-SH + sulfide) and polyphosphate contents were respectively 2 and 5 times higher in air-adapted cells versus anaerobic-control cells. Long-term cultures (18 days) of air-adapted cells exposed to 2% O2 exhibited the ability to form biofilms. These data indicate that M. acetivorans develops multiple mechanisms to contend with O2 and the associated oxidative stress, as also suggested by genome analyses for some methanogens. | Methanosarcinales |
In the present era of expanding technology coexisting with economic constraint, appropriate quality control criteria to monitor laboratory performance must take into consideration not only analytic precision and medical utility, but also cost effectiveness. In this review, the effect of existing criteria on the clinical laboratory, the regulator, and the vendor is explored. Factors that contribute to excessive quality control cost are delineated. Strategies for developing a cost-effective quality control program are proposed. | Laboratories |
Effects of renal disease on the disposition kinetics of oxaprozin, a nonsteroidal antiinflammatory analgesic, were assessed in 15 subjects who were normal, renally impaired, or who had been undergoing hemodialysis. Oral dose clearance (Cloral), volume of distribution at steady-state (V88d), and elimination half-life (t 1/2) did not substantially differ among the three groups. Mean fraction unbound oxaprozin in plasma (fup) increased from 0.08% in the normal group to 0.18% and 0.28% in the two azotemic groups. Consequently, unbound drug kinetic parameters, including intrinsic clearance (Clint) and V88du of unbound drug were reduced from 2.9 l/hr/kg and 193 l/kg in normal subjects to approximately 1.6 l/hr/kg and 91 l/kg in azotemic patients. The smaller volume of distribution is consistent with a decrease in oxaprozin tissue binding in azotemia. The decreased plasma and tissue binding and lower Clint suggest that, in the treatment of azotemic patients with rheumatoid arthritis, the dose of oxaprozin should begin at 600 mg once a day. | Oxaprozin |
The green anole lizard exhibits seasonal courtship behavior that is sexually dimorphic. This courtship consists of the extension of a bright red throat fan (dewlap) associated with head-bobbing display behavior. While males extend their dewlaps in aggressive encounters as well as in courtship, females use their considerably smaller dewlaps much less frequently and mainly in agonistic encounters. In parallel, a number of components of the neuromuscular system controlling dewlap extension are greater in males than in females during the breeding season, including dewlap motoneuron soma size and muscle fiber size and number. These features do not seem to change substantially in adulthood, despite a dramatic decline in dewlap use during the nonbreeding season. We explored the morphology of this neuromuscular system in more detail in the present experiment in males and females during both the breeding and nonbreeding seasons. Fiber and whole muscle length (approximately perpendicular to the fibers) were measured. Acetylcholinesterase histochemistry was used to visualize neuromuscular junctions (NMJs), and the surface area and density of NMJs were assessed for each animal. During the breeding season, NMJ size was larger in males than in females, but NMJ density along each fiber was equivalent between the sexes. In addition, whole muscle length and that of individual muscle fibers, was larger in males than in females. However, when corrected for body size, the sex difference in muscle fiber length disappeared. In the nonbreeding season, the sexual dimorphisms were maintained, suggesting that these features do not change substantially due to differences in circulating testosterone or a difference in use across seasons. Overall, these results are consistent with the idea that enhanced NMJ size is a relatively stable feature of the dewlap muscle in adulthood that either facilitates or is a consequence of using a larger muscle to extend a bigger dewlap in males compared to females. | Neuromuscular Junction |
A three-dimensional finite element model is developed for the simulation of the sound transmission through the human auditory periphery consisting of the external ear canal, middle ear and cochlea. The cochlea is modelled as a straight duct divided into two fluid-filled scalae by the basilar membrane (BM) having an orthotropic material property with dimensional variation along its length. In particular, an active feed-forward mechanism is added into the passive cochlear model to represent the activity of the outer hair cells (OHCs). An iterative procedure is proposed for calculating the nonlinear response resulting from the active cochlea in the frequency domain. Results on the middle-ear transfer function, BM steady-state frequency response and intracochlear pressure are derived. A good match of the model predictions with experimental data from the literatures demonstrates the validity of the ear model for simulating sound pressure gain of middle ear, frequency to place map, cochlear sensitivity and compressive output for large intensity input. The current model featuring an active cochlea is able to correlate directly the sound stimulus in the ear canal with the vibration of BM and provides a tool to explore the mechanisms by which sound pressure in the ear canal is converted to a stimulus for the OHCs. | Ear Canal |
Artemether oily injection is recommended for the treatment of severe malaria by the intramuscular route. The major limitations of the artemisinin combination therapy are erratic absorption from the injection site and high dosing frequency due to a very short elimination half-life of the drug. Advanced drug delivery systems have shown significant improvement in the current malaria therapy; the desired drug concentration within infected erythrocytes is yet the major challenge. Recently, we have reported the fabrication of artemether-loaded polymeric nanorods for intravenous malaria therapy which was found to be biocompatible with THP-1 monocytes and rat erythrocytes. The objective of the present study was the evaluation of pharmacokinetics, biodistribution, and antimalarial efficacy of artemether-loaded polymeric nanorods. Scanning electron microscopy and confocal microscopy studies revealed that both nanospheres and nanorods were adsorbed onto the surface of rat erythrocytes after an incubation of 10 min. After intravenous administration to rats, artemether nanorods showed higher plasma concentration and lower elimination rate of artemether when compared with nanospheres. The biodistribution studies showed that, at 30 min, the liver concentration of DiR-loaded nanospheres was higher than that of DiR-loaded nanorods after intravenous administration to BALB/c mice. The in vitro schizont inhibition study showed that both nanorods and nanospheres exhibited concentration-dependent parasitic inhibition, wherein at lower concentrations (2 ppm), nanorods were more effective than nanospheres. However, at higher concentrations, nanospheres were found to be more effective. Nanorods showed higher chemosuppression on day 5 and day 7 than nanospheres and free artemether when studied with the Plasmodium berghei mouse model. Moreover, the survival rate of P. berghei infected mice was also found to be higher after treatment with artemether nanoformulations when compared with free artemether. In conclusion, polymeric nanorods could be a promising next-generation delivery system for the treatment of malaria. | Artemether |
IMPORTANCE: There is limited evidence on the optimal strategy for liberating infants and children from invasive mechanical ventilation in the pediatric intensive care unit. OBJECTIVE: To determine if a sedation and ventilator liberation protocol intervention reduces the duration of invasive mechanical ventilation in infants and children anticipated to require prolonged mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: A pragmatic multicenter, stepped-wedge, cluster randomized clinical trial was conducted that included 17 hospital sites (18 pediatric intensive care units) in the UK sequentially randomized from usual care to the protocol intervention. From February 2018 to October 2019, 8843 critically ill infants and children anticipated to require prolonged mechanical ventilation were recruited. The last date of follow-up was November 11, 2019. INTERVENTIONS: Pediatric intensive care units provided usual care (n = 4155 infants and children) or a sedation and ventilator liberation protocol intervention (n = 4688 infants and children) that consisted of assessment of sedation level, daily screening for readiness to undertake a spontaneous breathing trial, a spontaneous breathing trial to test ventilator liberation potential, and daily rounds to review sedation and readiness screening and set patient-relevant targets. MAIN OUTCOMES AND MEASURES: The primary outcome was the duration of invasive mechanical ventilation from initiation of ventilation until the first successful extubation. The primary estimate of the treatment effect was a hazard ratio (with a 95% CI) adjusted for calendar time and cluster (hospital site) for infants and children anticipated to require prolonged mechanical ventilation. RESULTS: There were a total of 8843 infants and children (median age, 8 months [interquartile range, 1 to 46 months]; 42% were female) who completed the trial. There was a significantly shorter median time to successful extubation for the protocol intervention compared with usual care (64.8 hours vs 66.2 hours, respectively; adjusted median difference, -6.1 hours [interquartile range, -8.2 to -5.3 hours]; adjusted hazard ratio, 1.11 [95% CI, 1.02 to 1.20], P = .02). The serious adverse event of hypoxia occurred in 9 (0.2%) infants and children for the protocol intervention vs 11 (0.3%) for usual care; nonvascular device dislodgement occurred in 2 (0.04%) vs 7 (0.1%), respectively. CONCLUSIONS AND RELEVANCE: Among infants and children anticipated to require prolonged mechanical ventilation, a sedation and ventilator liberation protocol intervention compared with usual care resulted in a statistically significant reduction in time to first successful extubation. However, the clinical importance of the effect size is uncertain. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN16998143. | Duration of Therapy |
Positive-strand RNA viruses within the Picornaviridae family express an RNA-dependent RNA polymerase, 3D(pol), that is required for viral RNA replication. Structures of 3D(pol) from poliovirus, coxsackievirus, human rhinoviruses, and other picornaviruses reveal a putative template RNA entry channel on the surface of the enzyme fingers domain. Basic amino acids and tyrosine residues along this entry channel are predicted to form ionic and base stacking interactions with the viral RNA template as it enters the polymerase active site. We generated a series of alanine substitution mutations at these residues in the poliovirus polymerase and assayed their effects on template RNA binding, RNA synthesis initiation, rates of RNA elongation, elongation complex (EC) stability, and virus growth. The results show that basic residues K125, R128, and R188 are important for template RNA binding, while tyrosines Y118 and Y148 are required for efficient initiation of RNA synthesis and for EC stability. Alanine substitutions of tyrosines 118 and 148 at the tip of the 3D(pol) pinky finger drastically decreased the rate of initiation as well as EC stability, but without affecting template RNA binding or RNA elongation rates. Viable poliovirus was recovered from HeLa cells transfected with mutant RNAs; however, mutations that dramatically inhibited template RNA binding (K125A-K126A and R188A), RNA synthesis initiation (Y118A, Y148A), or EC stability (Y118A, Y148A) were not stably maintained in progeny virus. These data identify key residues within the template RNA entry channel and begin to define their distinct mechanistic roles within RNA ECs. | RNA-Dependent RNA Polymerase |
Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism, remains a common and costly condition that is associated with significant morbidity and mortality. Treatment options for initial management of DVT include unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), and fondaparinux, which is the first of a new class of pentasaccharide antithrombotic agents with anti-factor Xa activity. LMWHs are an important tool in DVT management, offering advantages over UFH such as ease of dosing, lack of need for coagulation monitoring, and reduced risk for heparin-induced thrombocytopenia (HIT). Fondaparinux is also characterized by a simple dosing regimen, no need for coagulation monitoring, and potentially a lower risk of HIT compared with LMWH. In a recent clinical trial of DVT management, efficacy and bleeding rates with fondaparinux appeared similar to those observed with LMWH. In contrast to LMWH, fondaparinux is generally given as a fixed dose across a range of patient weights rather than calculated per individual patient weight. Given the increasing economic burden of VTE, particularly due to its increased rate among the elderly, pharmacoeconomic analyses have become a particularly useful tool to aid in selecting among similarly effective and safe agents for VTE treatment. A recent cost-effective analysis demonstrated that fondaparinux use offers an attractive economic alternative to other agents for initial DVT therapy that could yield cost savings without compromising clinical outcomes or patient safety. | Fondaparinux |
The steady-state localisation of membrane proteins in the endocytic system is the result of many sorting events that occur at various points throughout the endosomal pathway. A protein that has been endocytosed from the plasma membrane or sorted at the trans-Golgi network (TGN) and transported to an endosome will ultimately be delivered to one of three destinations: the plasma membrane, the TGN or the lysosome. Where a membrane protein is trafficked to depends on the interactions between sorting motifs present in the membrane protein and the machinery that can decode these motifs. Much of the protein machinery that recognises sorting motifs is conserved from yeast to man, and in this review I will discuss this machinery and the motifs that govern endosomal protein sorting. | trans-Golgi Network |
Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in the metabolism of several biological amines such as dopamine, norepinephrine, and serotonin, which are important neurochemicals in the pathogenesis of major psychiatric illnesses. MAOA is regarded as a functional plausible susceptibility gene for psychiatric disorders, whereas previous hypothesis-driven association studies obtained controversial results, a reflection of small sample size, genetic heterogeneity, or true negative associations. In addition, MAOA is not analyzed in most of genome-wide association studies (GWAS) on psychiatric disorders, since it is located on Chromosome Xp11.3. Therefore, the effects of MAOA variants on genetic predisposition to psychiatric disorders remain obscure. To fill this gap, we collected psychiatric phenotypic (schizophrenia, bipolar disorder, and major depressive disorder) and genetic data in up to 18,824 individuals from diverse ethnic groups. We employed classical fixed (or random) effects inverse variance weighted methods to calculate summary odds ratios (OR) and 95 % confidence intervals (CI). We identified a synonymous SNP rs1137070 showing significant associations with major depressive disorder (p = 0.00067, OR = 1.263 for T allele) and schizophrenia (p = 0.0039, OR = 1.225 for T allele) as well as a broad spectrum of psychiatric phenotype (p = 0.000066, OR = 1.218 for T allele) in both males and females. The effect size was similar between different ethnic populations and different gender groups. Collectively, we confirmed that MAOA is a risk gene for psychiatric disorders, and our results provide useful information toward a better understanding of genetic mechanism involving MAOA underlying risk of complex psychiatric disorders. | Minisatellite Repeats |
Two new pregnane alkaloids, (20S)-20alpha-cinnamoylamino-3beta-dimethylamino-5-en-pregnane (1) and (20S)-20alpha-cinnamoylamino-3beta-dimethylamino-pregnane (2), and four known alkaloids (+)-(20S)-20-(dimethylamino)-3-(3'R-isopropyl)-lactam-5alpha-pregn-2-en-4-one (3), axillaridine A (4), pachysamine M (5) and 20alpha-dimethylamino-16beta-hydroxy-3beta-senecioylamino-pregn-5-ene (6) were obtained from the whole herb of Pachysandra terminalis Sieb. et Zucc. Their structures were determined by various spectral techniques and computed electronic circular dichroism (ECD) data. Compounds 1-4 were tested for cytotoxicity against three human tumor cell lines and a human umbilical vein endothelial cell (HUVEC) line. Compound 4 exhibited moderate cytotoxicity against MCF-7, U251 and A549 cells with IC(50) values of 15.01 +/- 0.47 muM, 20.13 +/- 1.34 muM and 20.04 +/- 1.16 muM, respectively; compounds 1-3 showed weak cytotoxic activity against three tumor cells. | Pachysandra |
We report a rare and unusual case of invasive Enterobius vermicularis infection in a fallopian tube. The patient was a 23-year-old Malaysian woman who presented with suprapubic pain and vaginal bleeding. A clinical diagnosis of ruptured right ovarian ectopic pregnancy was made. She underwent a laparotomy with a right salpingo-oophorectomy. Histopathological examination of the right fallopian tube showed eggs and adult remnants of E. vermicularis, and the results were confirmed using PCR and DNA sequencing. | Salpingitis |
Survivin is an inhibitor of apoptosis protein (IAP) expressed in a large number of adult malignancies. Its expression levels correlate with more aggressive disease and poor clinical outcome in many of these tumors. As its expression is restricted in normal adult differentiated tissues, it has become of great interest as both a tumor prognostic marker and as a potential biologic target for future anti-cancer therapies. Survivin expression and Survivin-based therapies have been examined in many of the more common pediatric malignancies. We present an overview of Survivin function and current research exploring its biologic and therapeutic roles in pediatric tumors." | Inhibitor of Apoptosis Proteins |
Twin anemia polycythemia sequence (TAPS) is a consequence of unequal sharing of red blood cells between monochorionic twins resulting in anemia in the donor and polycythemia in the recipient twin. Prenatally TAPS can occur spontaneously or complicate incomplete laser surgery for twin transfusion syndrome. While there may be clinical overlap with twin transfusion syndrome or selective fetal growth restriction, diagnosis relies on Doppler measurement of middle cerebral artery peak systolic velocities. Significantly discordant velocities are diagnostic, while severity staging is based on signs of cardiovascular compromise. Conservative management, fetoscopic laser coagulation, selective twin reduction, fetal blood and exchange transfusion, and delivery may be selected guided by the gestational age of diagnosis, the severity of the condition, the likelihood of success, and the patients' priorities. Prenatal curative treatment that minimizes the risk for prematurity and residual morbidity at birth is most likely to offer the greatest short-term and long-term benefits. | Polycythemia |
The aim of the study was to assess the antioxidant potential of goat's milk and whey from goat's milk fermented with selected bacteria strains from kefir grain (L. plantarum, L. fermentum, L. rhamnosus and L. acidophilus) with regard to fermented cow's milk with the same bacteria strains. The assessment of antioxidant potential was made by ABTS, DPPH, TPC and FRAP methods. The work also assessed metabolic activity of tested lactic acid bacteria using measurement of electrical impedance changes in the growing medium. The highest values describing the antioxidant potential were found for fermented milk by L. acidophilus. It was also found that the time of cooling storage causes significantly increasing the antioxidant potential of most analyzed samples. Metabolic activity of tested lactic acid bacteria was the highest for cow's milk. The course of curves for goat's milk and whey from goat's milk was similar, which confirms the differences between cow and goat milk. | Kefir |
Donor treatment with granulocyle-colony stimulating factor (G-CSF) is known to modulate immune function, characterized by the generation of regulatory myelogenous and T cell populations and Th2 differentiation. Recently, these effects have been shown to be enhanced by pegylation of the G-CSF molecule, which also improves graft-versus-leukemia (GVL) via activation of invariant natural killer (iNK) T cells. We have compared G-CSF bound to a single PEG molecule (monopeg-G-CSF) as used clinically to a G-CSF molecule bound to multiple PEG molecules (multipeg-G-CSF) in major histocompatibility complex (MHC) disparate and matched models of graft-versus-host disease (GVHD) and GVL. We demonstrate that multipeg-G-CSF induces greater levels of progenitor cell, myelogenous, and iNKT cell expansion than monopeg-G-CSF, while inducing similar protection from GVHD. Despite this, multipeg-G-CSF enhanced CTL function in vivo and improved iNKT cell-dependent leukemia clearance. Thus, GVL and GVHD can be further separated after allogeneic stem cell transplantation by mobilization with a multiple-pegylated G-CSF molecule. | Graft vs Leukemia Effect |
Over the last few decades, concepts of protein intrinsic disorder have been implicated in different biological processes. Recent studies have suggested that intrinsically disordered proteins (IDPs) provide structural plasticity and functional diversity to viral proteins that are involved in rapid replication and immune evasion in host cells. In case of Zika virus, the roles of protein intrinsic disorder in mechanisms of pathogenesis are not completely understood. In this study, we have analyzed the prevalence of intrinsic disorder in Zika virus proteome (strain MR 766). Our analyses revealed that Zika virus polyprotein is enriched with intrinsically disordered protein regions (IDPRs) and this finding is consistent with previous reports on the involvement of IDPs in shell formation and virulence of the Flaviviridae family. We found abundant IDPRs in Capsid, NS2B, NS3, NS4A, and NS5 proteins that are involved in mature particle formation and replication. In our view, the intrinsic disorder-focused analysis of ZIKV proteins could be important for the development of disorder-based drugs. | Polyproteins |
PURPOSE: To analyze the 3-dimensional intrarenal anatomy of horseshoe kidneys (HK) and kidney with complete ureteral duplication (CUD), in polyester resin endocasts of the collecting system and in patients submitted to 3D computerized tomography scan (CT-scan). MATERIALS AND METHODS: We analyzed seven 3-dimensional polyester resin endocasts of the kidney collecting system obtained from 6 fresh adult cadavers (4 with unilateral CUD and 2 with horseshoe kidney) and CT-scan reconstruction images of kidneys from 24 patients: 6 patients with HK, 8 with CUD and 10 patients without renal anomalies that were used as controls. We analyzed the spatial distribution of the calices, the infundibula diameters, the angle between the lower infundibulum and the renal pelvis (LIP) and the angle between the lower infundibulum and the inferior minor calyces (LIICA). Measurements of the width and length of the inferior infundibulum and the infundibula of the minor calyces, as well as the angles (LIP and LIICA) were made with the aid of the LibreOffice 6.3 software. The data were analyzed with the IBM(R) SPSS(R) Statistics. RESULTS: There was no statistical difference in the inferior pole measurements between the groups with anomalies and the control group, both in polyester resin endocasts and CT-scan reconstruction images for LIP. When we compared the LIP in the CT-scan between HK versus CUD (p= 0.003), and HK versus the control group (p= 0.035), we observed statistical difference. CONCLUSIONS: The knowledge of spatial anatomy of lower pole is of utmost importance during endourologic procedures in patients with kidney anomalies. In the present study we observed that horseshoe kidneys had more restrictive anatomic factors in lower pole than the complete ureteral duplication. | Fused Kidney |
OBJECTIVE: To compare the efficacy and safety of hirudin and heparin for anticoagulation during continuous renal replacement therapy (CRRT) in critically ill patients. DESIGN: Prospective, randomized controlled pilot study. SETTING: Single centre; interdisciplinary intensive care unit at a university hospital. PATIENTS: Seventeen patients receiving CRRT. INTERVENTIONS: Patients were randomly allocated to two groups. Heparin group (nine patients): continuous administration of 250 IU/h heparin; dose was adjusted in 125 IU/h steps with a targeted activated clotting time (ACT) of 180-210 s. Hirudin group (eight patients): continuous infusion of 10 micrograms/kg/h hirudin, dose was adjusted in 2 micrograms/kg/h steps with a targeted ecarin clotting time (ECT) of 80-100 s. Observation time was 96 h. MEASUREMENTS AND MAIN RESULTS: Measured filter run patency and haemofiltration efficacy did not significantly differ between the two groups. Three bleeding complications were observed in the hirudin group, none in the heparin group (P < 0.01). At the onset of bleeding, which occurred 60 or more hours after the start of therapy, only one patient was still under continuous hirudin administration but levels were either in therapeutic range or below. CONCLUSIONS: Hirudin can be used efficiently for anticoagulation in CRRT. Late bleeding complications may have been caused by possible hirudin accumulation, but this was not evident from hirudin plasma and ECT levels. Since bleeding complications were observed only in the presence of documented coagulation disorders, not only adequate drug monitoring but also the plasmatic and cellular coagulation status of the patient should be taken into consideration for adjusting hirudin dosage. | Hirudin Therapy |
Oligosaccharyltransferase (OT) catalyzes the signature reaction of the asparagine-linked glycosylation pathway, namely, the transfer of preformed glycans from the lipid-linked oligosaccharide Glc3Man9GlcNAc2-P-P-Dolichol (G3M9Gn2-LLO) to appropriate asparaginyl residues on acceptor polypeptides. We have identified a reaction, possibly catalyzed by OT, that results in the hydrolysis or transfer to water" of host LLOs in response to viral infection with release of a free G3M9Gn2 glycan. The loss of LLO ostensibly hinders N-glycosylation of viral polypeptides. This response is achieved by a novel stress-activated signaling pathway in which free mannose-6-phosphate (M6P) acts as a second-messenger. Here, we describe methods with permeabilized mammalian cells for activation of the M6P-regulated LLO hydrolysis, or transfer of glycan to water, in vitro." | Mannosephosphates |
PURPOSE: To evaluate the surgical outcome in terms of intraocular pressure (IOP) control and safety of procedure using a sutureless scleral tunnel technique in patients with uncontrolled glaucoma. MATERIALS AND METHODS: This was a prospective, consecutive, noncomparative interventional case series of patients undergoing trabeculectomy. The study was conducted on 19 eyes of 19 patients with medically uncontrolled glaucoma. All of the patients underwent sutureless scleral tunnel trabeculectomy and were followed for 6 months. Patient data such as sex, age, IOP, LogMAR visual acuity (LogMAR VA), antiglaucoma medications, intraoperative and postoperative complications, bleb morphology, and success rate were collected and statistically analyzed. RESULTS: Two patients were excluded because of defaulted follow-up. Mean age was 60.58 (+/-15.14) years, and 65% of the patients were male. Before intervention mean IOP was 29.29 (+/-8.22) mmHg, and mean number of antiglaucoma medications was 2.05 (+/-0.89). Six months after intervention, mean IOP was 15.00 (+/-3.82) mmHg (P < 0.001), mean number of antiglaucoma medications was 0.52 (+/-1.06) (P < 0.001), complete success rate was 65%, and qualified success rate was 23%. Five patients (29.4%) needed adjunctive needling bleb revision. No major intraoperative complications were encountered. Only four patients (23.5%) had microscopic hyphema and three patients (18%) had flat anterior chamber (grade I) in the immediate postoperative period that managed medically. All but four had shallow and diffuse blebs at last follow-up. CONCLUSION: It appears that sutureless scleral tunnel trabeculectomy is a safe and effective drainage procedure for treating uncontrolled glaucoma. Larger-scale study is recommended. | Trabeculectomy |
Factor V deficiency is a rare autosomal recessive coagulation disorder. We report a case with inherited factor V deficiency presenting as life-threatening recurrent hemoperitoneum, following bleeding from ruptured corpus haemorrhagicum. Prolonged prothrombin and activated partial thromboplastin times, normal thrombin time and a normal platelet count pointed towards a disorder of coagulation. Mixing studies with factor V deficient plasma and coagulation factor assay revealed markedly reduced plasma factor V clotting activity. The management included blood, plasma and tranexamic acid. Family screening revealed low factor V levels in her parents. Although her brother had significant Factor V deficiency and epistaxis, he did not need hospitalization or replacement, indicating the varied manifestation of this bleeding defect in this family. | Factor V Deficiency |
The imidazole-based H3R antagonist 2-18 with high in vitro H3R antagonist affinity, excellent in vitro selectivity profile, and high in vivo H3R antagonist potency was tested for its anticonvulsant effect in maximal electroshock (MES)-induced convulsions in mice having valproic acid (VPA) as a reference antiepileptic drug (AED). Additionally, H3R antagonist 2-18 was evaluated for its reproductive toxicity in the same animal species. The results show that acute systemic administration (intraperitoneal; i.p.) of H3R antagonist 2-18 (7.5, 15, 30, and 60 mg/kg, i.p.) significantly and dose dependently protected male as well as female mice against MES-induced convulsion. The protective action observed for H3R antagonist 2-18 in both mice sexes was comparable to that of VPA and was reversed when mice were pretreated with the selective H3R agonist (R)-alpha-methylhistamine (RAMH, 10 mg/kg, i.p.). Moreover, the results show that acute systemic administration of single (7.5, 15, 30, or 60 mg/kg, i.p.) or multiple doses (15x3 mg/kg, i.p.) of H3R antagonist 2-18 on gestation day (GD) 8 or 13 did not affect the maternal body weight of mice when compared with the control group. Furthermore, no significant differences were observed in the average number of implantations and resorptions between the control and H3R antagonist 2-18-treated group at the early stages of gestation and the organogenesis period. However, oral treatment with H3R antagonist 2-18 (15 mg/kg) on GD 8 induced a reduced number of live embryos when compared with the i.p.-treated mice. In addition, no significant changes in the fetal body and placental weights were observed after injection of H3R antagonist 2-18 with all selected doses. However, three dose groups of i.p. and oral 15 mg/kg on GD 13 significantly affected the placental weight when compared with control group. Notably, the treatment of pregnant female with the H3R antagonist 2-18 did not produce significant malformation in the fetus in both groups. In conclusion, the novel H3R antagonist 2-18 proves to be a very safe compound and displays a low incidence of malformations, demonstrating that H3R antagonist 2-18 may have a potential future therapeutic value in epilepsy. | Methylhistamines |
A highly sensitive enzyme-linked immunosorbent assay (ELISA) has been developed for tetrahydrogestrinone (THG), the new designer anabolic steroid responsible for the well-known Balco scandal announced in year 2003. Antibodies have been raised against 18a-homo-pregna-4,9,11-trien-17beta-ol-3-carboxymethyl oxime coupled to horseshoe crab hemocyanin. The hapten has been synthesized from gestrinone by controlled reduction of the triple bond of the ethinyl group at position C-17, without affecting the double bonds of the steroidal rings, followed by reaction of the keto group at C-3 with (carboxymethoxy)amine hemihydrochloride to form the oxime bond. The antisera obtained has been used in combination with 18a-homo-pregna-4,9,11-trien-17beta-ol-20-yn-3-carboxymethyl oxime, a hapten derivative of gestrinone, coupled to bovine serum albumin to establish a competitive ELISA. Under the conditions used, THG can be detected in buffer with a limit of detection (LOD) of 0.045 +/- 0.015 microg L(-1) (N = 9). The assay is very selective since other steroids assessed are not recognized. Preliminary experiments performed with human urine samples demonstrate that the assay can be applied to the analysis of these samples after a simple sample treatment method reaching a LOD of 0.25 +/- 0.14 microg L(-1). Accuracy is very good as demonstrated by the excellent correlation obtained when analyzing blind spiked urine samples (slope 0.93, R2 = 0.992). | Gestrinone |
Diffuse large B-cell lymphoma (DLBCL) is the most common hematological malignancy. Although more than half of patients with DLBCL achieve long-term remission, the majority of remaining patients succumb to the disease. As abnormal iron homeostasis is implicated in carcinogenesis and the progression of many tumors, we searched for alterations in iron metabolism in DLBCL that could be exploited to develop novel therapeutic strategies. Analysis of the iron metabolism gene expression profile of large cohorts of patients with DLBCL established the iron score (IS), a gene expression-based risk score enabling identification of patients with DLBCL with a poor outcome who might benefit from a suitable targeted therapy. In a panel of 16 DLBCL cell lines, ironomycin, a promising lysosomal iron-targeting small molecule, inhibited DLBCL cell proliferation at nanomolar concentrations compared with typical iron chelators. Ironomycin also induced significant cell growth inhibition, ferroptosis, and autophagy. Ironomycin treatment resulted in accumulation of DNA double-strand breaks, delayed progression of replication forks, and increased RPA2 phosphorylation, a marker of replication stress. Ironomycin significantly reduced the median number of viable primary DLBCL cells of patients without major toxicity for nontumor cells from the microenvironment and presented low toxicity in hematopoietic progenitors compared with conventional treatments. Significant synergistic effects were also observed by combining ironomycin with doxorubicin, BH3 mimetics, BTK inhibitors, or Syk inhibitors. Altogether, these data demonstrate that a subgroup of high-risk patients with DLBCL can be identified with the IS that can potentially benefit from targeting iron homeostasis. SIGNIFICANCE: Iron homeostasis represents a potential therapeutic target for high-risk patients with DLBCL that can be targeted with ironomycin to induce cell death and to sensitize tumor cells to conventional treatments." | Lymphoma, Large B-Cell, Diffuse |
Ten patients of nephropathic cystinosis were admitted during the period 1995-2000. Their mean age was 12 months. The signs of failure to thrive and advanced rickets were seen in all patients. Other features included polyuria, polydipsia, pathologic fractures and deafness. Laboratory findings included glucosuria, hyposthenuria, hypocalcemia, proteinuria and azotemia. Therapy with phosphocysteamine showed marked clinical improvement. | Cystaphos |
Avian astroviruses, including chicken astrovirus (CAstV), avian nephritisvirus (ANV), and goose astrovirus (GoAstV), are ubiquitous enteric RNA viruses associated with enteric disorders in avian species. Recent research has found that infection of these astroviruses usually cause visceral gout in chicken, duckling and gosling. However, the underlying mechanism remains unknown. In the current article, we review recent discoveries of genetic diversity and variation of these astroviruses, as well as pathogenesis after astrovirus infection. In addition, we discuss the relation between avian astrovirus infection and visceral gout in poultry. Our aim is to review recent discoveries about the prevention and control of the consequential visceral gout diseases in poultry, along with the attempt to reveal the possible producing process of visceral gout diseases in poultry. | Avastrovirus |
Periodic paralyses are rare diseases characterized by severe episodes of muscle weakness concomitant to variations in blood potassium levels. It is thus usual to differentiate hypokalemic, normokalemic, and hyperkalemic periodic paralysis. Except for thyrotoxic hypokalemic periodic paralysis and periodic paralyses secondary to permanent changes of blood potassium levels, all of these diseases are of genetic origin, transmitted with an autosomal-dominant mode of inheritance. Periodic paralyses are channelopathies, that is, diseases caused by mutations in genes encoding ion channels. The culprit genes encode for potassium, calcium, and sodium channels. Mutations of the potassium and calcium channel genes cause periodic paralysis of the same type (Andersen-Tawil syndrome or hypokalemic periodic paralysis). In contrast, distinct mutations in the muscle sodium channel gene are responsible for all different types of periodic paralyses (hyper-, normo-, and hypokalemic). The physiological consequences of the mutations have been studied by patch-clamp techniques and electromyography (EMG). Globally speaking, ion channel mutations modify the cycle of muscle membrane excitability which results in a loss of function (paralysis). Clinical physiological studies using EMG have shown a good correlation between symptoms and EMG parameters, enabling the description of patterns that greatly enhance molecular diagnosis accuracy. The understanding of the genetics and pathophysiology of periodic paralysis has contributed to refine and rationalize therapeutic intervention and will be without doubts the basis of further advances. | Paralyses, Familial Periodic |
The nervous system communicates in a language of electrical activities. The motivation to replace function lost through injury or disease through electrical prostheses has gained traction through steady advances in basic and translational science addressing the interface between electrical prostheses and the nervous system. Recent experiments suggest that electrical activity, signaling through specific molecular pathways, promotes neuronal survival and regeneration. Such data suggests that electrical prostheses, in addition to replacing lost function, may slow underlying degenerative disease or induce regenerative response. Here we review these data with a focus on retinal neurons, and discuss current efforts to translate this effect of electrical activity into clinically applicable treatments. | Retinal Neurons |
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