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OBJECTIVE: To determine whether hysterosalpingo-foam sonography (HyFoSy) is a less painful first line tubal patency test than serial hysterosalpingography (HSG). DESIGN: A two-center, prospective, open-label, randomized, controlled trial. SETTING: University hospital and teaching hospital. PATIENT(S): 40 subfertile women, ages 18 to 41 years, with an indication for tubal patency testing as part of the fertility workup according to the Dutch Nederlandse Vereniging voor Obsteterie & Gynaecologie-guidelines. INTERVENTION(S): Tubal patency testing by HyFoSy versus serial HSG. MAIN OUTCOME MEASURE(S): Visual Analogue Scale (VAS) pain scores during tubal patency testing. RESULT(S): The median VAS score for pain perception during the HyFoSy procedure was 1.7 cm (interquartile range: 2.1) compared with 3.7 cm (interquartile range: 4.2) during HSG. The HyFoSy procedure also had a statistically significantly shorter procedure time compared with HSG, with a median of 5.0 minutes (interquartile range: 3.0) for HyFoSy versus 12.5 minutes (interquartile range: 16.0) for HSG. CONCLUSION(S): The HyFoSy procedure is a less painful and less time-consuming tubal patency test compared with HSG. CLINICAL TRIAL REGISTRATION NUMBER: Netherlands National Trial Register NTR3457. | Fallopian Tube Patency Tests |
The "Visual Retinal Profile" can be obtained in the complete office evaluation of patients with night vision disorders, unexplained poor visual acuity, or undiagnosed retinal and/or choroidal diseases. This profile allows later follow-up evaluations and comparisons of previous tests to document improvement or progression of disease. The profile consists of the usual ophthalmologic evaluation plus color vision testing Amsler grid, stereoacuity, visual fields, electroretinogram (ERG), and electrooculogram (EOG). This entire set of tests, though time consuming, can be performed in the office by an ophthalmic assistant and greatly add to the ophthalmologists ability to evaluate and diagnose subtle retinal and/or choroidal diseases. A portable ERG/EOG and light source will be described that can be used in the office, clinic, nursing home, or operating room by trained office personnel." | Diagnostic Techniques, Ophthalmological |
A case of hydrometrocolpos with vaginal opening to the bladder is presented. A newborn female presented abdominal distention and postaxial polydactyly at birth. Clinical investigation revealed hydrometrocolpos, precocious puberty, urogenital sinus and other multiple malformations. The vagina was open to the bladder with a small orifice. Vaginal pull-through surgery and closure of the communication was performed. Over a hundred cases of hydrometrocolpos have been reported previously. However, we could not find a case of hydrometrocolpos with vaginal opening to the bladder among them. | Vaginal Diseases |
OBJECTIVE: Lumican (LUM) is a major extracellular matrix glycoprotein in adult articular cartilage and its expression is known to be upregulated upon cartilage degeneration. LUM is associated with the pathogen-associated molecular pattern (PAMP) activation of the TLR4 signalling cascade, with TLR4 being highly associated with inflammation in rheumatic diseases. However, the main role of the LUM structural molecule in osteoarthritis (OA) remains elusive. The aim of this study was, therefore, to understand the role of LUM during TLR4-mediated activation in OA. METHODS: After measuring LUM levels in synovial fluid (SF) of OA patients and lipopolysaccharide (LPS)-induced TLR4 activation, the role of LUM in the expression of pro-inflammatory molecules and cartilage degradation was assessed in vitro and ex vivo in a cartilage explant model. Primary macrophage activation and polarization were studied upon LUM co-stimulation with LPS. RESULTS: We demonstrate that LUM is not only significantly upregulated in SF from OA patients compared to healthy controls, but also that LUM increases lipopolysaccharide (LPS)-induced TLR4 activation. Furthermore, we show that a pathophysiological level of LUM augments the LPS-induced TLR4 activation and expression of downstream pro-inflammatory molecules, resulting in extensive cartilage degradation. LUM co-stimulation with LPS also provided a pro-inflammatory stimulus, upregulating primary macrophage activation and polarization towards the M1-like phenotype. CONCLUSIONS: These findings strongly support the role of LUM as a mediator of PAMP-induced TLR4 activation of inflammation, cartilage degradation, and macrophage polarization in the OA joint and potentially other rheumatic diseases. | Lumican |
Coenzyme B(12) is one of the most complex cofactors found in nature and synthesized de novo by certain groups of bacteria. Although its use in various enzymatic reactions is well characterized, only recently an unusual light-sensing function has been ascribed to coenzyme B(12). It has been reported that the coenzyme B(12) binding protein CarH, found in the carotenoid biosynthesis pathway of several thermostable bacteria, binds to the promoter region of DNA and suppresses transcription. To overcome the harmful effects of light-induced damage in the cells, CarH releases DNA in the presence of light and promotes transcription and synthesis of carotenoids, thereby working as a photoreceptor. CarH is able to achieve this by exploiting the photosensitive nature of the CoC bond between the adenosyl moiety and the cobalt atom in the coenzyme B(12) molecule. Extensive structural and spectroscopy studies provided a mechanistic understanding of the molecular basis of this unique light-sensitive reaction. Most studies on CarH have used the ortholog from the thermostable bacterium Thermus thermophilus, due to the ease with which it can be expressed and purified in high quantities. In this chapter we give an overview of this intriguing class of photoreceptors and report a step-by-step protocol for expression, purification and spectroscopy experiments (both static and time-resolved techniques) employed in our laboratory to study CarH from T. thermophilus. We hope the contents of this chapter will be of interest to the wider coenzyme B(12) community and apprise them of the potential and possibilities of using coenzyme B(12) as a light-sensing probe in a protein scaffold. | Cobamides |
The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives. | Arachnodactyly |
Different fermentation strategies were employed for the cultivation of a new poly(3-hydroxybutyrate)-accumulating thermophilic bacterium, Chelatococcus sp. strain MW10, with the aim of achieving high-cell-density (HCD) growth and high poly(3-hydroxybutyrate) [poly(3HB)] productivity. Enhanced cultivation was achieved by a cyclic fed-batch fermentation (CFBF) technique (42-liter scale). Maximal poly(3HB) productivity was obtained during the second cycle [16.8 +/- 4.2 g poly(3HB)/liter]. At the end of CFBF (265 h), an HCD of up to 115.0 +/- 4.3 g cell dry weight/liter was achieved. | Beijerinckiaceae |
PIWI-interacting RNA (piRNA) is a germline-specific class of small non-coding RNAs that repress transposons in the gonads. Mael, which comprises a high mobility group box and a MAEL domain, is one of the key players in piRNA-mediated transposon silencing. However, the mechanism whereby Mael is involved in this pathway remains unknown. Recent biochemical and structural studies, along with bioinformatic analyses of Mael-associating RNAs in vivo, have shed light on the functional aspects of Mael in the piRNA pathway. We summarize the current understanding of Mael functions in the piRNA pathway, particularly in Drosophila and in mice. | Carrier Proteins |
Some metabolic pathways involve two different cell components, for instance, cytosol and mitochondria, with metabolites traffic occurring from cytosol to mitochondria and vice versa, as seen in both glycolysis and gluconeogenesis. However, the knowledge on the role of mitochondrial transport within these two glucose metabolic pathways remains poorly understood, due to controversial information available in published literature. In what follows, we discuss achievements, knowledge gaps, and perspectives on the role of mitochondrial transport in glycolysis and gluconeogenesis. We firstly describe the experimental approaches for quick and easy investigation of mitochondrial transport, with respect to cell metabolic diversity. In addition, we depict the mitochondrial shuttles by which NADH formed in glycolysis is oxidized, the mitochondrial transport of phosphoenolpyruvate in the light of the occurrence of the mitochondrial pyruvate kinase, and the mitochondrial transport and metabolism of L-lactate due to the L-lactate translocators and to the mitochondrial L-lactate dehydrogenase located in the inner mitochondrial compartment. | Phosphoenolpyruvate |
Follicular lymphoma (FL) is a B-cell tumor arising in germinal centers and retaining features of its normal B-cell counterpart. Lymphomagenesis appears stepwise from the t(14;18) translocation, through FL-like cells, to FL in situ, then to overt FL. Surface Ig is mandatory and carries a striking V-region modification because of introduction of glycan addition sites during somatic mutation. These are positively selected and acquire unusual high mannoses, which interact with lectins. The Ig-associated mannoses appear essential for FL, providing a disease- specific target for antibody attack. Antibody therapy is currently focused on anti-CD20 (rituximab), which appears to rely predominantly on the Fcgamma module recruiting suitably activated macrophages. Immunogloblulin and, to some extent, CD20, can each escape antibody attack in vitro by modulation, but this is difficult to demonstrate clinically. Instead, studies of anti-CD20 therapy of FL suggest that effector modulation, similar to that seen in the suppression of autoimmune inflammation by infusions of normal human IgG, may be important. Both antigenic and effector modulations might be minimized by repeated small doses of more potent antibodies. Clearly, mechanisms of attack vary with the malignancy, the target molecule, and the antibody design, offering opportunities for optimizing this promising strategy. | Antigenic Modulation |
Streptococcus pneumoniae is a major human pathogen associated with many diseases worldwide. Capsular polysaccharides (CPSs) are the major virulence factor. The biosynthetic pathway of D-arabinitol, which is present in the CPSs of several S. pneumoniae serotypes, has never been identified. In this study, the genes abpA (previously known as abp1) and abpB (previously known as abp2), which have previously been reported to be responsible for nucleoside diphosphate (NDP)-D-arabinitol (the nucleotide-activated form of D-arabinitol) synthesis, were cloned. The enzyme products were overexpressed, purified, and analyzed for their respective activities. Novel products produced by AbpA- and AbpB-catalyzing reactions were detected by capillary electrophoresis, and the structures of the products were elucidated using electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. As a result, abpA was identified to be a D-xylulose-5-phosphate cytidylyltransferase-encoding gene, responsible for the transfer of CTP to D-xylulose-5-phosphate (D-Xlu-5-P) to form CDP-D-xylulose, and abpB was characterized to be a CDP-D-xylulose reductase-encoding gene, responsible for the conversion of CDP-D-xylulose to CDP-D-arabinitol as the final product. The kinetic parameters of AbpA for the substrates D-Xlu-5-P and CTP and those of AbpB for the substrate CDP-D-xylulose and the cofactors NADH or NADPH were measured, and the effects of temperature, pH, and cations on the two enzymes were analyzed. This study confirmed the involvement of the genes abpA and abpB and their products in the biosynthetic pathway of CDP-D-arabinitol. | Cytidine Diphosphate |
Ice cream samples were made with a mix composition of 11% milk fat, 11% milk solids-not-fat, 13% sucrose, 3% corn syrup solids (36 dextrose equivalent), 0.28% stabilizer blend, or 0.10% emulsifier and vanilla extract. Mixes were high temperature short time pasteurized at 80 degrees C for 25 s, homogenized at 141 kg/cm2 pressure on the first stage and 35 kg/cm2 pressure on the second, and cooled to 3 degrees C. The study included six treatments from four batches of mix. Mix from batch one contained 0.10% emulsifier. Half of this batch (treatment 1), was subsequently frozen and the other half (upon exiting the pasteurizer) was reheated to 60 degrees C, rehomogenized at 141 kg/cm2 pressure on the first stage and 35 kg/cm2 pressure on the second (treatment 2), and cooled to 3 degrees C. Mix from batch two contained 0.28% stabilizer blend. Half of this batch was used as the control (treatment 3), the other half upon exiting the pasteurizer was reheated to 60 degrees C, rehomogenized at 141 kg/cm2 pressure on the first stage and 35 kg/cm2 pressure on the second (treatment 4), and cooled to 3 degrees C. Batch three, containing 0.10% emulsifier and 1% whey protein concentrate substituted for 1% nonfat dry milk, upon exiting the pasteurizer was reheated to 60 degrees C, rehomogenized at 141 kg/cm2 pressure on the first stage and 35 kg/cm2 pressure on the second (treatment 5), and cooled to 3 degrees C. Batch four, containing 0.28% stabilizer blend and 1% whey protein concentrate substituted for 1% nonfat dry milk, upon exiting the pasteurizer was reheated to 60 degrees C, rehomogenized at 141 kg/ cm2 pressure on the first stage and 35 kg/cm2 pressure on the second (treatment 6), and cooled to 3 degrees C. Consistency was measured by flow time through a pipette. Flow time of treatment 3 was greater than all treatments, and the flow times of treatments 4 and 6 were greater than treatments 1, 2, and 5. Flow time was increased in ice cream mix by the addition of stabilizer. Double homogenization lowered ice cream mix flow time in the presence of stabilizer, but no difference in flow time was observed without stabilizer addition. Treatment 4 had a lower mean ice crystal size at 10 d postmanufacture compared with treatment 3; however, overall texture acceptability between treatments 3 and 4 was similar. Mean ice crystal size of treatment 6 was less at 18 wk postmanufacture compared with treatment 3; however, overall texture acceptability for treatments 3, 4, and 6 was similar. Mean ice crystal sizes of treatments 1, 2, and 5 were greater at 10 d and 18 wk compared with treatment 3. Sensory evaluation indicated that treatments 3, 4, and 6 had higher mean scores for icy, coldness intensity, and creaminess than treatments 1, 2, and 5 at 10 d and 18 wk postmanufacture. | Ice Cream |
This study evaluated the efficacy of a 915 MHz microwave with 3 different electric power levels to inactivate three pathogens in peanut butter with different aw. Peanut butter inoculated with Escherichia coli O157:H7, Salmonella enterica serovar Typhimurium and Listeria monocytogenes (0.3, 0.4, and 0.5 aw) were treated with a 915 MHz microwave with 2, 4, and 6 kW for up to 5 min. Six kW 915 MHz microwave treatment for 5 min reduced these three pathogens by 1.97 to >5.17 log CFU/g. Four kW 915 MHz microwave processing for 5 min reduced these pathogens by 0.41-1.98 log CFU/g. Two kW microwave heating did not inactivate pathogens in peanut butter. Weibull and Log-Linear + Shoulder models were used to describe the survival curves of three pathogens because they exhibited shouldering behavior. Td and T5d values were calculated based on the Weibull and Log-Linear + Shoulder models. Td values of the three pathogens were similar to D-values of Salmonella subjected to conventional heating at 90 degrees C but T5d values were much shorter than those of conventional heating at 90 degrees C. Generally, increased aw resulted in shorter T5d values of pathogens, but not shorter Td values. The results of this study can be used to optimize microwave heating pasteurization system of peanut butter. | Butter |
Bioluminescence is the fascinating natural phenomenon by which living creatures produce light. Bioluminescence occurs when the oxidation of a small-molecule luciferin is catalysed by an enzyme luciferase to form an excited-state species that emits light. There are over 30 known bioluminescent systems but the luciferin-luciferase pairs of only 11 systems have been characterised to-date, whilst other novel systems are currently under investigation. The different luciferin-luciferase pairs have different light emission wavelengths and hence are suitable for various applications. The last decade or so has seen great advances in protein engineering, synthetic chemistry, and physics which have allowed luciferins and luciferases to reach previously uncharted applications. The bioluminescence reaction is now routinely used for gene assays, the detection of protein-protein interactions, high-throughput screening (HTS) in drug discovery, hygiene control, analysis of pollution in ecosystems and in vivo imaging in small mammals. Moving away from sensing and imaging, the more recent highlights of the applications of bioluminescence in biomedicine include the bioluminescence-induced photo-uncaging of small-molecules, bioluminescence based photodynamic therapy (PDT) and the use of bioluminescence to control neurons. There has also been an increase in blue-sky research such as the engineering of various light emitting plants. This has led to lots of exciting multidisciplinary science across various disciplines. This review focuses on the past, present, and future applications of bioluminescence. We aim to make this review accessible to all chemists to understand how these applications were developed and what they rely upon, in simple understandable terms for a graduate chemist. | Luciferins |
Amount of ATP in HeLa cells in various phases of growth was measured after He-Ne laser irradiation (100 J/m2, 10 W/m2, 10 s) by a bioluminescent luciferin-luciferase method. In cells of the exponential phase of growth, the amount of ATP (basal level 8 x 10(-16) mole/cell) starts to increase in 15 min after the irradiation with a maximum (170% above the basal level) at 20 min, and then decreases gradually to the basal level. The sensitivity of the cells to He-Ne laser radiation is lowest in lag-phase of growth, then increases to a plateau (approximately 185% above the control level) from 5th day of cultivation. | HeLa Cells |
When exposed to actual or threatened death or serious injury in austere settings, expedition members are at risk of acute stress reactions, as are search and rescue members involved with extricating the patient. Acute stress reactions are a normal response to significant trauma and commonly resolve on their own. If they do not, they can lead to post-traumatic stress disorder (PTSD), a set of persistent symptoms that cause significant effects on the person's life. Medication has a limited preventive role in the field for treatment of stress partly because so few are trained to administer it. Contrastingly, psychological first aid can be performed by lay team members with minimal training. Psychological first aid consists of interventions attempting to encourage feelings of safety, calm, self-efficacy, connection, and hope. These are interventions that provide guidance to not make the situation emotionally worse and might have a preventive effect on later development of PTSD. They are valuable in the field not only for the patient but also for affected team members as well as for search and rescue team members who may be indirectly affected by the trauma and experience repercussions later. | Psychological First Aid |
The two second-generation Vinca alkaloids, vinorelbine and vinflunine, affect microtubule dynamics very differently from vinblastine, a first generation Vinca alkaloid. For example, vinblastine strongly suppresses the rate and extent of microtubule shortening in vitro, whereas vinorelbine and vinflunine suppress the rate and extent of microtubule growing events. We asked whether these differences result in differences in mitotic spindle organization that might be responsible for the superior antitumor activities of the two second-generation Vinca alkaloids. IC(50) values for inhibition of HeLa cell proliferation for vinflunine, vinorelbine, and vinblastine were 18, 1.25, and 0.45 nM, respectively, similar to the concentrations that induced mitotic block at the metaphase/anaphase transition (38, 3.8, and 1.1 nM, respectively), indicating that mitotic block is a major contributor to antiproliferative action for all three drugs. Mitotically blocked cells exhibited aberrant spindles, consistent with induction of block by suppression of microtubule dynamics. Despite differences in their actions on individual dynamic instability parameters, morphologically detectable differences in spindle effects among the three drugs were minimal, indicating that overall suppression of dynamics may be more important in blocking mitosis than specific effects on growth or shortening. We also found that the peak intracellular drug concentration at the mitotic IC(50) value was highest for vinflunine (4.2 +/- 0.2 microM), intermediate for vinorelbine (1.3 +/- 0.1 microM), and more than 10-fold lower for vinblastine (130 +/- 7 nM), suggesting that intracellular binding reservoir(s) may be partially responsible for vinflunine's high efficacy and minimal side effects. | Vinca Alkaloids |
BACKGROUND: It has been speculated that women's productivity decreases after maternity leave. In this study, we measured if surgeon clinical productivity decreases after a maternity leave or other types of leave. METHODS: Data from a large medical center was used to measure surgeon productivity before (pre) and after (post) a leave of absence. Post-to-pre productivity ratios were calculated for each leave based on operative volumes and Relative Value Units (RVUs). Multivariate linear regression analysis was performed for the post/pre productivity ratios, adjusting for surgeon characteristics. RESULTS: Fifty leaves of absence, from 30 surgeons, were analyzed. There was no significant difference between post and pre leave productivity for maternity leave or other types of leave. There was also no significant difference when comparing post/pre productivity ratios between maternity leaves versus other types of leave (volume: 0.06, p = 0.52; RVU: 0.08, p = 0.58). CONCLUSION: Surgeons do not significantly reduce clinical productivity after maternity or other types of leaves. | Family Leave |
The genome of living cells is continuously exposed to endogenous and exogenous attacks, and this is particularly amplified at high temperatures. Alkylating agents cause DNA damage, leading to mutations and cell death; for this reason, they also play a central role in chemotherapy treatments. A class of enzymes known as AGTs (alkylguanine-DNA-alkyltransferases) protects the DNA from mutations caused by alkylating agents, in particular in the recognition and repair of alkylated guanines in O(6)-position. The peculiar irreversible self-alkylation reaction of these enzymes triggered numerous studies, especially on the human homologue, in order to identify effective inhibitors in the fight against cancer. In modern biotechnology, engineered variants of AGTs are developed to be used as protein tags for the attachment of chemical ligands. In the last decade, research on AGTs from (hyper)thermophilic sources proved useful as a model system to clarify numerous phenomena, also common for mesophilic enzymes. This review traces recent progress in this class of thermozymes, emphasizing their usefulness in basic research and their consequent advantages for in vivo and in vitro biotechnological applications. | Thermoproteus |
Electromagnetic-guided placement of nasoenteral feeding tubes by nurses is an alternative to endoscopic placement by gastroenterologists. During placement, the electromagnetic signal that is emitted by the tip of the guidewire enables visualisation of the position of the tube on a portable monitor. The procedure can be performed by a trained endoscopy nurse at the bedside of the patient. This could have logistic advantages, as the patient transport is not necessary and confirmation of the position of the tube by an abdominal X-ray is not required. Other possible advantages of the new technique are no preprocedural fasting and no need for sedation. If the tube coils in the stomach, it can be repositioned without the need for a repeat procedure. A randomised multicentre trial found electromagnetic nasoenteral placement of feeding tubes to be non-inferior on comparison with endoscopic placement by gastroenterologists, and it can be considered as the preferred technique. | Intubation, Gastrointestinal |
The vagus nerve innervates visceral organs providing a link between key metabolic cues and the CNS. However, it is not clear whether vagal neurons can directly respond to changing lipid levels and whether altered lipid sensing" by the vagus nerve regulates energy balance. In this study, we systematically profiled the expression of all known nuclear receptors in laser-captured nodose ganglion (NG) neurons. In particular, we found PPARgamma expression was reduced by high-fat-diet feeding. Deletion of PPARgamma in Phox2b neurons promoted HFD-induced thermogenesis that involved the reprograming of white adipocyte into a brown-like adipocyte cell fate. Finally, we showed that PPARgamma in NG neurons regulates genes necessary for lipid metabolism and those that are important for synaptic transmission. Collectively, our findings provide insights into how vagal afferents survey peripheral metabolic cues and suggest that the reduction of PPARgamma in NG neurons may serve as a protective mechanism against diet-induced weight gain." | Nodose Ganglion |
Flaviviruses encode one, two, or no N-linked glycosylation sites on their envelope proteins. Glycosylation can impact virus interactions with cell surface attachment factors and also may impact virion stability and virus replication. Envelope protein glycosylation has been identified as a virulence determinant for multiple flaviviruses, but the mechanisms by which glycosylation mediates pathogenesis remain unclear. In this Gem, we summarize current knowledge on flavivirus envelope protein glycosylation and its impact on viral infection and pathogenesis. | Flavivirus |
Uncharacteristic clinical symptoms such as cardiac arrhythmias, restlessness, changes in weight or hair loss may signify hyperthyroidism, whereas impairment of physical or mental vigilance may be a manifestation of hypothyroidism. In many cases the diagnosis can be established only on the basis of laboratory investigations, and, on account of the difficulty in establishing a differential diagnosis, these should not be stinted. However, when it comes to interpreting findings, consideration must be given to drug interference, such diseases as the nephrotic syndrome, serious general diseases or pregnancy. In the event of pathological laboratory findings, ultrasonography and scintigraphy are helpful further diagnostic measures. Antihyperthyroid drugs, surgery or radioiodine therapy are the leading therapeutic options for hyperthyroidism. As in the case of hypothyroidism treated with L-thyroxine, the primary target parameter is titration of TSH into the normal range. | Endocrine System Diseases |
Pentameric ligand gated ion channels (pLGICs) are ionotropic receptors that mediate fast intercellular communications at synaptic level and include either cation selective (e.g., nAChR and 5-HT3) or anion selective (e.g., GlyR, GABAA and GluCl) membrane channels. Among others, 5-HT3 is one of the most studied members, since its first cloning back in 1991, and a large number of studies have successfully pinpointed protein residues critical for its activation and channel gating. In addition, 5-HT3 is also the target of a few pharmacological treatments due to the demonstrated benefits of its modulation in clinical trials. Nonetheless, a detailed molecular analysis of important protein features, such as the origin of its ion selectivity and the rather low conductance as compared to other channel homologues, has been unfeasible until the recent crystallization of the mouse 5-HT3A receptor. Here, we present extended molecular dynamics simulations and free energy calculations of the whole 5-HT3A protein with the aim of better understanding its ion transport properties, such as the pathways for ion permeation into the receptor body and the complex nature of the selectivity filter. Our investigation unravels previously unpredicted structural features of the 5-HT3A receptor, such as the existence of alternative intersubunit pathways for ion translocation at the interface between the extracellular and the transmembrane domains, in addition to the one along the channel main axis. Moreover, our study offers a molecular interpretation of the role played by an arginine triplet located in the intracellular domain on determining the characteristic low conductance of the 5-HT3A receptor, as evidenced in previous experiments. In view of these results, possible implications on other members of the superfamily are suggested." | Cysteine Loop Ligand-Gated Ion Channel Receptors |
Acute kidney injury (AKI) is common and often preventable. Nurses should be able to recognise it and respond when it occurs. Through prevention or early detection, nurses can help to reduce morbidity and mortality associated with AKI, improving patients' quality of life and reducing the financial impact of AKI on the NHS. | Acute Kidney Injury |
Pemphigus is an autoimmune cutaneous disease characterized by circulating autoantibodies that cause blistering and erosions on skin and mucous membranes. Circulating autoantibodies bind to epidermal cell membrane and cause cell-cell detachment (acantholysis), leading to epidermal tissue damage and cell death. The principal target of pemphigus vulgaris autoantibodies (PV-IgG) is desmosomal cadherin desmoglein 3 (Dsg3), a constituent of desmosomes, mediating cell-cell adhesion. Several hypotheses for the mechanisms of acantholysis induction by PV-IgG exist, but the actual mechanism is not clear as yet. We have previously reported on apoptosis induction in PV-IgG-mediated epidermal tissue and cell damage as a possible mechanism of acantholysis and cell death (Wang et al. 2004, Apoptosis, 9:131-143). In this study we investigated the involvement of the EGFR and intracellular signal transduction pathways in the PV-IgG-induced apoptosis. We show here that PV-IgG induced activation/autophosphorylation of EGFR in cultured keratinocytes in vitro. The specific tyrosine kinase inhibitor AG1478 abrogated EGFR autophosphorylation, cell death, FasL appearance and acantholysis, all induced by PV-IgG, in parallel, confirming the involvement of EGFR in this Fas apoptotic cascade. Activation of EGFR was followed by phosphorylation of its downstream substrates, MAP kinase ERK and transcription factor c-Jun, and internalization of EGFR. Pharmacological inactivation of the EGFR and ERK kinase activities, by use of specific inhibitors AG1478 and PD98059 respectively, blocked PV-IgG-induced phosphorylation of EGFR, ERK and c-Jun and cellular apoptosis, measured by flow cytometry and caspase 3 activity. Prolonged activation of EGFR by PV-IgG led to dramatic internalization of this receptor, possibly reducing the ability of the cell to perform survival signals. This suggests that activation of EGFR, followed by its internalization, is pivotal for intracellular apoptotic signal transduction via ERK/c-Jun pathways, leading to acantholysis. Our experimental data indicate that the EGFR is instrumental in transducing apoptotic/acantholytic signals in keratinocytes cultures in response to PV-IgG treatment. The acantholytic effect caused by PV-IgG binding to cell surface receptors begins with and depends on cell surface receptor (EGFR) activation of intracellular signaling pathways (ERK pathway) and apoptosis induction (FasR pathway), which later lead to major cell-cell separation (acantholysis) and cell death. | Acantholysis |
Unilateral testicular enlargement was detected in a 5-years-old domestic ferret during a routine sterilization. The right testicle showed two different types of proliferative lesions: (i) round nodules, well demarcated, showing a soft yellow tissue; (ii) white nodules, firm, with irregular-shaped invaginations. Microscopically, the neoplastic proliferations were identified as an interstitial neoplasm and Sertoli cell tumour, respectively. The left testicle was small and showed intense testicular atrophy. Clinical evaluation of the ferret did not show any other apparent pathological processes. This study is the first case reporting the concomitant occurrence of a Sertoli cells tumour and an interstitial cell tumour in a domestic ferret. | Testicular Neoplasms |
The Department of Family Practice, College of Medicine, in partnership with the University of Illinois at Chicago, was responsible for the reorganization of the Student Health Service into a health maintenance organization (HMO), Campus Care. Historically, the two campuses of the University of Illinois at Chicago operated student health as an infirmary model. Reorganization of student health into the Campus Care HMO provided expanded health care services to students, preserved more health care dollars in the university system, and provided a nonincremental increase in the size and responsibility of the Department of Family Practice. One year's experience showed that while the capitation was low compared with standard HMOs, the variable and less frequent use of services by the student population resulted in a fiscally viable operation. Numerous transition difficulties were encountered, including the need for rapid systems conversion within a complex university system, reeducation of students as well as traditional university-based practitioners for operation in a managed care system, and the rapid expansion of a small family practice department. The positive experience of the University of Illinois at Chicago supports the notion that family practice is better suited to providing student health care than other primary care disciplines. Three issues are paramount to success: (1) approval, support, and protection by higher level administration from university territorialism, (2) a core family practice faculty with strong leadership and experience in high-volume clinical activity, and (3) a close examination of financial resources in light of expected utilization. | Student Health Services |
The bacterium Leptothrix cholodnii generates filaments encased in a sheath comprised of woven nanofibrils. In static liquid culture, L. cholodnii moves toward the air-liquid interface, where it forms porous pellicles. Observations of aggregation at the interface reveal that clusters consisting of only a few bacteria primarily grow by netting free cells. These growing clusters hierarchically enlarge through the random docking of other small clusters. We find that the bacteria swim using their polar flagellum toward the interface, where their sheath assists them in intertwining with others and thereby promotes the formation of small clusters. In contrast, sheathless hydrophobic mutant cells get stuck to the interface. We find that the nanofibril sheath is vital for robust pellicle formation as it lowers cell surface hydrophobicity by 60%, thereby reducing their adsorption and enabling cells to move toward and stick together at the air-liquid interface. IMPORTANCE Efficient and sustainable management of water resources is becoming a fundamental issue for supporting growing populations and for developing economic activity. Fundamental to this management is the treatment of wastewater. Microorganisms are the active component of activated sludge that is employed in the biodegradation process of many wastewater treatment facilities. However, uncontrolled growth of filamentous bacteria such as Sphaerotilus often results in filamentous bulking, lowering the efficiency of water treatment systems. To prevent this undesirable condition, strategies based on a fundamental understanding of the ecology of filamentous bacteria are required. Although the filamentous bacterium Leptothrix cholodnii, which is closely related to Sphaerotilus, is a minor inhabitant of activated sludge, its complete genome sequence is known, making gene manipulation relatively easy. Moreover, L. cholodnii generates porous pellicles under static conditions, which may be a characteristic of filamentous bulking. We show that both swimming motility and nanofibril-mediated air-liquid interface attachment are required for porous pellicle formation. These insights are critical for a better understanding of the characteristics of filamentous bulking and might improve strategies to control activated sludge. | Leptothrix |
Gossypol treatment of endometriosis and uterine myomas in 15 cases was started with a daily dose of 20 mg of gossypol-acetic acid twice a day for 20 days as a loading dose, followed by 40 mg (20 mg twice weekly). A maintenance dose of 20 mg was given weekly. The total course of treatment lasted about 6 months. Light and electron microscopic examination of the endometrium was carried out before treatment and 2, 3, 4, and 6 months after gossypol treatment. After gossypol treatment three different characteristics of the endometrium were noted: (1) irregular secretory activity, (2) proliferative activity, and (3) atrophy. On electron microscopic examination it was shown that there were important changes of the organelles, indicating suppressed secretory activity. Based on the above results, the nature and significance of the ultrastructural changes of the endometrium induced by gossypol were analyzed and the possibility of developing a new field of research in female contraception with gossypol was considered. | Gossypol |
The histologic appearance of the molded tympanic heterograft developed at the ENT Clinic of the University of Parma, Italy, is investigated with light and electron microscopy. Evaluation of the graft before insertion disclosed a unique structure of interwoven collagen bundles. Examination of grafted tympanic membrane showed a structure closely resembling the normal human tympanic membrane. The fate of the heterologous material and the host reaction to it are discussed in relation to histologic findings. | Tympanic Membrane |
PURPOSE: To explore the efficacy and safety of 500 mg of fulvestrant for the postmenopausal patients with estrogen receptor (ER)-positive metastatic breast cancer, and to analyze the factors affecting the prognosis of patients. METHODS: A retrospective analysis was conducted on the clinical data of 86 postmenopausal patients with ER-positive metastatic breast cancer, who were admitted to our hospital from January 2015 to December 2016, and these patients were treated with 500 mg of fulvestrant. The clinical efficacy and incidence of adverse reactions were evaluated. Moreover, the patients were followed up for recording the survival and disease progression. Finally, survival analysis was carried out using the Kaplan-Meier method, log-rank test and Cox's proportional hazards regression model. RESULTS: Among the 86 patients, 7 achieved partial response (PR), with an objective response rate (ORR) of 8.1%, and 44 (51.2%) had stable disease (SD), including 21 cases of SD >/=24 weeks, and the clinical benefit rate (CBR) [proportion of cases of complete response (CR) + PR +SD >/=24 weeks] was 36.0% (31/86). The remaining 35 (40.7%) patients suffered from progressive disease (PD) according to the initial efficacy assessment at 2-3 months after treatment. According to the follow-up results, the median overall survival (mOS) and median progression-free survival (mPFS) of patients were 26.7+/-6.9 months and 6.5+/-4.1 months, respectively. The 1-year and 2-year OS rates were 60.5% and 33.7%, respectively showing that the risk of PD in patients with visceral metastasis and taking tamoxifen was 2.443 times higher vs those not taking tamoxifen (p=0.031 vs (p=0.024). Besides, the mPFS was significantly prolonged in patients undergoing no endocrine therapy previously, and patients receiving first-line therapy of fulvestrant in this study [hazard ratio (HR) =1.942, 95% CI: 0.774-2.483, p=0.037, HR=0.863, 95% CI: 0.688-0.981, p=0.013). CONCLUSION: Fulvestrant has definite efficacy in treating ER-positive metastatic breast cancer and results in tolerable adverse reactions, while it notably extends the mPFS of patients who have no visceral metastasis and receive no prior tamoxifen or endocrine therapy, but the first-line fulvestrant therapy in this study. | Fulvestrant |
This technical note reports for the first time the simultaneous vapor generation of 16 rare-earth elements (REEs) via reaction with sodium tetrahydroborate (THB). Significant improvement in REE vapor generation efficiency was discovered in the presence of arsenazo III (ARS). Subsequent to a critical evaluation on the impacts of various experimental variables, including the concentrations of acids, THB, and ARS, blank-limited (reagent contamination and impurity from ARS) detection limits (LODs) in the range of 0.004-0.15 mug L(-1) were achieved based on three times the standard deviation of the method blank by the proposed vapor generation inductively coupled plasma mass spectrometry (ICP-MS). The nature of released REE species was studied by various approaches and identified to be REE nanoparticles and REE-ARS chelates; a dual-route mechanism for the vapor generation of REEs was thereby proposed. | Arsenazo III |
Clinical efficacy of netilmicin was evaluated at 22 newborns (body weight from 1000 to 3600 g, delivery on pregnancy period from 28 to 41 weeks) with pneumonia caused by artificial pulmonary ventilation. Pneumonia was moderate at 13 patients and severe at 9 patients. Microorganisms isolated from tracheobronchial aspirates were mainly (in 19 cases of 22) susceptible to netilmicin. The usage of netilmicin in combination with cephalosporins was effective at the main part of the newborns and resulted with the full recovery of 11 newborns (all the patients with moderate pneumonia), in 9 cases improvement was registered (including 7 newborns with severe pneumonia). Newborns with severe pneumonia had a slow pathogens elimination. | Pneumonia, Bacterial |
Zebrafish (Danio rerio) is an emerging model for integrative physiological research. In this mini-review, we discuss recent advances in the neuroendocrine control of ionic balance in this species, and identify current knowledge gaps and issues that would benefit from further investigation. Zebrafish inhabit a hypo-ionic environment and therefore are challenged by a continual loss of ions to the water. To maintain ionic homeostasis, they must actively take up ions from the water and reduce passive ion loss. The adult gill or the skin of larvae are the primary sites of ionic regulation. Current models for the uptake of major ions in zebrafish incorporate at least three types of ion transporting cells (also called ionocytes); H(+)-ATPase-rich cells for Na(+) uptake, Na(+)/K(+)-ATPase-rich cells for Ca(2+) uptake, and Na(+)/Cl(-)-cotransporter expressing cells for both Na(+) and Cl(-) uptake. The precise molecular mechanisms regulating the paracellular loss of ions remain largely unknown. However, epithelial tight junction proteins, including claudins, are thought to play a critical role in reducing ion losses to the surrounding water. Using the zebrafish model, several key neuroendocrine factors were identified as regulators of epithelial ion movement, including the catecholamines (adrenaline and noradrenaline), cortisol, the renin-angiotensin system, parathyroid hormone and prolactin. Increasing evidence also suggests that gasotransmitters, such as H2S, are involved in regulating ion uptake. | Zebrafish Proteins |
Axon fasciculation is thought to be a critical step in neural circuit formation and function. Recent studies have revealed various molecular mechanisms that underlie axon fasciculation; however, the impacts of axon fasciculation, and its corollary, defasciculation, on neural circuit wiring remain unclear. Corticospinal (CS) neurons in the sensorimotor cortex project axons to the spinal cord to control skilled movements. In rodents, the axons remain tightly fasciculated in the brain and traverse the dorsal funiculus of the spinal cord. Here we show that plexinA1 (PlexA1) and plexinA3 (PlexA3) receptors are expressed by CS neurons, whereas their ligands, semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B) are expressed in the medulla at the decussation site of CS axons to inhibit premature defasciculation of these axons. In the absence of Sema5A/5B-PlexA1/A3 signaling, some CS axons are prematurely defasciculated in the medulla of the brainstem, and those defasciculated CS axons aberrantly transverse in the spinal gray matter instead of the spinal dorsal funiculus. In the absence of Sema5A/Sema5B-PlexA1/A3 signaling, CS axons, which would normally innervate the lumbar spinal cord, are unbundled in the spinal gray matter, and prematurely innervate the cervical gray matter with reduced innervation of the lumbar gray matter. In both Sema5A/5B and PlexA1/A3 mutant mice (both sexes), stimulation of the hindlimb motor cortex aberrantly evokes robust forelimb muscle activation. Finally, Sema5A/5B and PlexA1/A3 mutant mice show deficits in skilled movements. These results suggest that proper fasciculation of CS axons is required for appropriate neural circuit wiring and ultimately affect the ability to perform skilled movements.SIGNIFICANCE STATEMENT Axon fasciculation is believed to be essential for neural circuit formation and function. However, whether and how defects in axon fasciculation affect the formation and function of neural circuits remain unclear. Here we examine whether the transmembrane proteins semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B), and their receptors, plexinA1 (PlexA1) and plexinA3 (PlexA3) play roles in the development of corticospinal circuits. We find that Sema5A/Sema5B and PlexA1/A3 are required for proper axon fasciculation of corticospinal neurons. Furthermore, Sema5A/5B and PlexA1/A3 mutant mice show marked deficits in skilled motor behaviors. Therefore, these results strongly suggest that proper corticospinal axon fasciculation is required for the appropriate formation and functioning of corticospinal circuits in mice. | Axon Fasciculation |
Endoscopic retrograde cholangiopancreatography remains an important tool for the management of biliary and pancreatic disease. Endoscopic removal of common bile duct stones is the procedure of choice for retained stones and is a common option preoperatively with the gallbladder in place. Cholangitis is best treated by endoscopic sphincterotomy and stenting along with intravenous antibiotics initially with the possibility of definitive treatment with endoscopic stone removal and/or dilatation and stenting for strictures. Endoscopic sphincterotomy is also recommended in severe or rapidly worsening gallstone pancreatitis or in those with combined pancreatitis and rising bilirubin or cholangitis. Palliation with internal stents for malignant strictures has been possible with good outcome and very little difference in efficacy, complications, mortality, and long-term survival compared to surgical treatment. Biliary fistulae are easily treated by endoscopic stenting, particularly when the source is the cystic or an accessory duct. Benign biliary strictures can be dilated and stented for prolonged periods with good long-term success in selected cases. Pancreatic stenting is useful to treat pancreatic duct strictures and duct hypertension with considerable improvement of pain. Endoscopic drainage of pancreatic pseudocyst appears to be a safe, effective, and definitive treatment for patients in whom anatomic considerations allow its use. In summary, therapeutic uses of ERCP are of broad interest to the general surgeon and should be understood and utilized appropriately by the surgical community. | Bile Duct Diseases |
BACKGROUND: Every year, more than 700,000 people die from vector-borne diseases, mainly transmitted by mosquitoes. Vector surveillance plays a major role in the control of these diseases and requires accurate and rapid taxonomical identification. New approaches to mosquito surveillance include the use of acoustic and optical sensors in combination with machine learning techniques to provide an automatic classification of mosquitoes based on their flight characteristics, including wingbeat frequency. The development and application of these methods could enable the remote monitoring of mosquito populations in the field, which could lead to significant improvements in vector surveillance. METHODS: A novel optical sensor prototype coupled to a commercial mosquito trap was tested in laboratory conditions for the automatic classification of mosquitoes by genus and sex. Recordings of > 4300 laboratory-reared mosquitoes of Aedes and Culex genera were made using the sensor. The chosen genera include mosquito species that have a major impact on public health in many parts of the world. Five features were extracted from each recording to form balanced datasets and used for the training and evaluation of five different machine learning algorithms to achieve the best model for mosquito classification. RESULTS: The best accuracy results achieved using machine learning were: 94.2% for genus classification, 99.4% for sex classification of Aedes, and 100% for sex classification of Culex. The best algorithms and features were deep neural network with spectrogram for genus classification and gradient boosting with Mel Frequency Cepstrum Coefficients among others for sex classification of either genus. CONCLUSIONS: To our knowledge, this is the first time that a sensor coupled to a standard mosquito suction trap has provided automatic classification of mosquito genus and sex with high accuracy using a large number of unique samples with class balance. This system represents an improvement of the state of the art in mosquito surveillance and encourages future use of the sensor for remote, real-time characterization of mosquito populations. | Chain of Infection |
Treatment options for eosinophilic esophagitis (EoE) include drugs, diets and esophageal dilation. Esophageal dilation can be performed using either through-the-scope balloons or wire-guided bougies. Dilation can lead to long-lasting symptom improvement in EoE patients presenting with esophageal strictures. Esophageal strictures are most often diagnosed when the 8- to 9-mm outer diameter adult gastroscope cannot be passed any further or only against resistance. A defined esophageal diameter to be targeted by dilation is missing, but the majority of patients have considerable symptomatic improvement when a diameter of 16-18 mm has been reached. A high complication rate, especially regarding esophageal perforations, has been reported in small case series until 2006. Several large series were published in 2007 and later that demonstrated that the complication risk (especially esophageal perforation) was much lower than what was reported in earlier series. The procedure can therefore be regarded as safe when some simple precautions are followed. It is noteworthy that esophageal dilation does not influence the underlying eosinophil-predominant inflammation. Patients should be informed before the procedure that postprocedural retrosternal pain may occur for some days, but that it usually responds well to over-the-counter analgesics such as paracetamol. Dilation-related superficial lacerations of the mucosa should not be regarded and reported as complications, but instead represent a desired effect of the therapy. Patient tolerance and acceptance for esophageal dilation have been reported to be good. | Eosinophilic Esophagitis |
Activation-Induced cytidine Deaminase (AID) initiates affinity maturation and isotype switching by deaminating deoxycytidines within immunoglobulin genes, leading to somatic hypermutation (SHM) and class switch recombination (CSR). AID thus potentiates the humoral response to clear pathogens. Marking the 20th anniversary of the discovery of AID, we review the current understanding of AID function. We discuss AID biochemistry and how error-free forms of DNA repair are co-opted to prioritize mutagenesis over accuracy during antibody diversification. We discuss the regulation of DNA double-strand break (DSB) repair pathways during CSR. We describe genomic targeting of AID as a multilayered process involving chromatin architecture, cis- and trans-acting factors, and determining mutagenesis - distinct from AID occupancy at loci that are spared from mutation. | Immunogenetic Phenomena |
Photosynthesis research employs several biophysical methods, including the detection of fluorescence. Even though fluorescence is a key method to detect photosynthetic efficiency, it has not been applied/adapted to single-cell confocal microscopy measurements to examine photosynthetic microorganisms. Experiments with photosynthetic cells may require automation to perform a large number of measurements with different parameters, especially concerning light conditions. However, commercial microscopes support custom protocols (through Time Controller offered by Olympus or Experiment Designer offered by Zeiss) that are often unable to provide special set-ups and connection to external devices (e.g., for irradiation). Our new system combining an Arduino microcontroller with the Cell plus sign in circleFinder software was developed for controlling Olympus FV1000 and FV1200 confocal microscopes and the attached hardware modules. Our software/hardware solution offers (1) a text file-based macro language to control the imaging functions of the microscope; (2) programmable control of several external hardware devices (light sources, thermal controllers, actuators) during imaging via the Arduino microcontroller; (3) the Cell plus sign in circleFinder software with ergonomic user environment, a fast selection method for the biologically important cells and precise positioning feature that reduces unwanted bleaching of the cells by the scanning laser. Cell plus sign in circleFinder can be downloaded from http://www.alga.cz/cellfinder. The system was applied to study changes in fluorescence intensity in Synechocystis sp. PCC6803 cells under long-term illumination. Thus, we were able to describe the kinetics of phycobilisome decoupling. Microscopy data showed that phycobilisome decoupling appears slowly after long-term (>1 h) exposure to high light. | Microscopy, Confocal |
BACKGROUND: The use of surgically implanted electronic devices for vagus nerve stimulation (VNS) is expanding in contemporary allopathic medical practice as a treatment option for selected clinical conditions, such as epilepsy, depression, tremor, and pain conditions, that are unresponsive to standard pharmacologic interventions. Although VNS device surgeries are considered minimally invasive, they are costly and have surgical and device-related risks; they can also cause serious adverse effects from excessive vagus nerve stimulation. OBJECTIVES: For millennia, acupuncturists have treated those same clinical conditions by piquering acupoints that are located proximate to the sternocleidomastoid muscle site where the VNS device is implanted on the vagus nerve. The hypothesis of this study is that these acupuncture points produce clinical benefits through stimulation of the vagus nerve and/or its branches in the head and neck region. METHODS: By using reference anatomic and acupuncture texts, classical and extraordinary acupoints in the head and neck region were identified that are anatomically proximate to vagus nerve pathways there, where the VNS electrode is surgically implanted. The clinical indications of these acupuncture points, as described in the acupuncture reference texts, were examined for similarities to those of VNS. RESULTS: This analysis demonstrated marked correspondences of the indications for those lateral head and neck acupoints to the clinical effects (beneficial and adverse) documented for the VNS device in the medical literature. This clinical correspondence, in conjunction with the anatomic proximity of the acupoints to the vagus nerve in the lateral neck, strongly suggests that vagus nerve (and hence the autonomic nervous system) stimulation is fundamental in producing the clinical effects of the acupoints. CONCLUSION: By having anatomic access to the vagus nerve and parasympathetic chain that permits electrical stimulation of those nerves in clinical practice, acupuncture may offer a less costly and safer alternative to implanted VNS devices for treating medically refractory epilepsy, tremor, depression, and pain conditions. | Vagus Nerve Stimulation |
Bioluminescence of a variety of marine organisms, mostly cnidarians and ctenophores, is carried out by Ca(2+)-dependent photoproteins. The mechanism of light emission operates via the same reaction in both animal families. Despite numerous studies on the ctenophore photoprotein family, the detailed catalytic mechanism and arrangement of amino acid residues surrounding the chromophore in this family are a mystery. Here, we report the crystal structure of Cd(2+)-loaded apo-mnemiopsin1, a member of the ctenophore family, at 2.15 A resolution and used quantum mechanics/molecular mechanics (QM/MM) to investigate its reaction mechanism. The simulations suggested that an Asp-156-Arg-39-Tyr-202 triad creates a hydrogen-bonded network to facilitate the transfer of a proton from the 2-hydroperoxy group of the chromophore coelenterazine to bulk solvent. We identified a water molecule in the coelenteramide-binding cavity that forms a hydrogen bond with the amide nitrogen atom of coelenteramide, which, in turn, is hydrogen-bonded via another water molecule to Tyr-131. This observation supports the hypothesis that the function of the coelenteramide-bound water molecule is to catalyze the 2-hydroperoxycoelenterazine decarboxylation reaction by protonation of a dioxetanone anion, thereby triggering the bioluminescence reaction in the ctenophore photoprotein family. | Ctenophora |
Infection-related development of phytopathogenic fungi is initiated by sensing and responding to plant surface cues. This response can result in the formation of specialized infection structures, so-called appressoria. To unravel the program inducing filaments and appressoria in the biotrophic smut fungus Ustilago maydis, we exposed cells to a hydrophobic surface and the cutin monomer 16-hydroxy hexadecanoic acid. Genome-wide transcriptional profiling at the pre-penetration stage documented dramatic transcriptional changes in almost 20% of the genes. Comparisons with the U. maydis sho1 msb2 double mutant, lacking two putative sensors for plant surface cues, revealed that these plasma membrane receptors regulate a small subset of the surface cue-induced genes comprising mainly secreted proteins including potential plant cell wall degrading enzymes. Targeted gene deletion analysis ascribed a role to up-regulated GH51 and GH62 arabinofuranosidases during plant penetration. Among the sho1/msb2-dependently expressed genes were several secreted effectors that are essential for virulence. Our data also demonstrate specific effects on two transcription factors that redirect the transcriptional regulatory network towards appressorium formation and plant penetration. This shows that plant surface cues prime U. maydis for biotrophic development. | Ustilago |
An in vivo analysis of stearyl alcohol and stearic acid films on the skin surface using polarized infrared-external reflection spectroscopy revealed that whether the sample molecules adopt an energetically stable conformation and orientation strongly depends on the molecular functionalities and sample preparation conditions. For stearic acid, even the difference in solute concentration between 0.1 and 0.5â¯wt% results in a different molecular conformation and orientation. This illustrates that the molecular organization of the adsorbate on the skin surface is sensitively determined by the kinetics of the sample film growth, not by the simple thermodynamic equilibrium with the skin temperature. | Stearic Acids |
The catalytic domain (residues 128-449) of the Orpinomyces sp. Y102 CelC7 enzyme (Orp CelC7) exhibits cellobiohydrolase and cellotriohydrolase activities. Crystal structures of Orp CelC7 and its cellobiose-bound complex have been solved at resolutions of 1.80 and 2.78 A, respectively. Cellobiose occupies subsites +1 and +2 within the active site of Orp CelC7 and forms hydrogen bonds to two key residues: Asp248 and Asp409. Furthermore, its substrate-binding sites have both tunnel-like and open-cleft conformations, suggesting that the glycoside hydrolase family 6 (GH6) Orp CelC7 enzyme may perform enzymatic hydrolysis in the same way as endoglucanases and cellobiohydrolases. LC-MS/MS analysis revealed cellobiose (major) and cellotriose (minor) to be the respective products of endo and exo activity of the GH6 Orp CelC7. | Neocallimastigomycota |
METHODS: We measured the 2,3-diphosphoglycerate inraerythrocytic concentration in 24 normal controls and in 24 hypertensives before and following drug therapy. RESULTS: In hypertensives the 2,3-diphosphoglycerate concentration was higher than that of the controls (14.96 mumol/g Hb vs 13.26 mumol/g Hb respectively); the difference is statistically significant (p < 0.001). Following control of the hypertension by drug therapy, the 2,3 DPG levels in the patients studied do not seem to differ statistically from those of the controls. CONCLUSIONS: This may be a consequence of lower cardiac output in hypertension which results to a lower tissue perfusion, leading to an increased concentration of deoxygenated haemoglobin in the vein blood. Measurement of 2,3-diphosphoglucerate may prove of value in estimating tissue perfusion in hypertension. | 2,3-Diphosphoglycerate |
Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT." | Bronchiolitis Obliterans Syndrome |
A new dsRNA virus from the oomycete Phytophthora pluvialis has been characterized and designated as Phytophthora pluvialis RNA virus 1 (PplRV1). The genome of the PplRV1 reference genome is 6742 bp that encodes two predicted open reading frames (ORFs). ORF1 and ORF2 overlap by a 47 nt slippery" frameshift sequence. ORF1 encodes a putative protein of unknown function. ORF2 shows high similarity to the RNA-dependent RNA polymerase (RdRp) of other dsRNA viruses. Phylogenetic analysis of the putative PplRV1 RdRp and its most closely related viruses showed PplRV1 is distinct from other known viruses (below 33% amino acid similarity), which indicates this virus may belong to a new virus family. Analyses of the geographical distribution of PplRV1 in relation to two genetically distinct classes of its host revealed two corresponding genotypes of the PplRV1 (termed a and b), which share 92.3% nt identity. The reference genome for the second genotype is 6760 bp long and a prediction of its genetic organization shows three ORFs, with ORF2 being split into two ORFs, ORF2a and ORF2b, that is conserved in seven of eleven genotype b isolates. Additionally, a quick and simple diagnostic method using qPCR has been developed, which is suitable for large scale screens to identify PplRV1 in Phytophthora." | Double Stranded RNA Viruses |
Psychotic-like episodes in divers exposed to high pressure have been attributed to either the high-pressure neurological syndrome, confinement in pressure chamber, the subject's personality, or the addition of nitrogen or hydrogen to the basic helium-oxygen breathing mixture used for deep diving. Alternatively, it is suggested that these disorders are in fact paroxysmal narcotic symptoms that result from the sum of the individual narcotic potencies of each inert gas in the breathing mixture. This hypothesis is tested against a variety of lipid solubility theories of narcosis. The results clearly support the hypothesis and provide new information about the cellular interactions between inert gases at raised pressure and pressure itself." | High Pressure Neurological Syndrome |
This study seeks to determine the effect of ionic ligands on the drug delivery characteristics of biodegradable polyurethane materials synthesized from lysine diisocyanate (LDI) and glycerol. Two naturally occurring, structurally related ionic species, choline chloride (CC) and isethionic acid (ISE), along with 3,3-dimethyl-butanol (DMB), their neutral carbon analog, were covalently incorporated into LDI-glycerol polyurethane materials. Selected organometallic and tertiary amine catalysts were used to fashion films and foams, respectively. The potent anticancer compound DB-67, a fluorescent camptothecin derivative, was also covalently linked to the polyurethane constructs. It was first determined that the sulfonate functional group on ISE does not react to a significant degree with isocyanate. The morphological characteristics of the polyurethane films and foams were assessed via scanning electron microscopy, showing significant differences related to the ionic ligands. The ionic materials displayed increased swelling in aqueous media over the neutral control materials. Differences in the distribution of DB-67 throughout the films and foams were then detected by fluorescence microscopy. The drug delivery characteristics of the materials were then evaluated in vitro, revealing accelerated release from ionic materials. The results of this study demonstrate the unique effects that incorporation of ionic ligands into LDI-glycerol polyurethanes have on the morphology and drug distribution of the materials. These differences have a significant impact on the drug delivery characteristics of the materials, and this information should prove useful in the design and synthesis of biodegradable controlled release systems. | Isethionic Acid |
BACKGROUND: Cancer-induced 'emergency' myelopoiesis plays a key role in tumor progression by inducing the accumulation of myeloid cells with a suppressive phenotype peripherally and in the tumor. Chemokine receptors (CCRs) and, in particular, CCR1, CCR2, CCR5, and CCR7 are emerging as key regulators of myeloid cell trafficking and function but their precise role has not been completely clarified yet because of the signal redundancy, integration, and promiscuity of chemokines and of the expression of these CCRs on other leukocyte subsets. METHODS: We used the 4PD nanoparticle for the in vivo targeted silencing of CCR1, CCR2, CCR5, and/or CCR7 in the myeloid cells of tumor bearing mice to evaluate the effect of treatments on tumor growth, myeloid cell trafficking and polarization. We used flow and image cytometry and functional assays to monitor changes in the tumor microenvironment and depletion experiments and immune deficient mice to determine the role of Ly6G(+)cells during tumor progression. We further evaluated in vitro the impact of chemokine receptor inhibition and tumor derived factors on myeloid cell differentiation from mouse and human hematopoietic stem and precursors cells (HSPCs) using flow cytometry, transcriptome analysis, cytokines beads arrays, functional assays, and mice deficient for CCR1 or CCR5. RESULTS: 4PD-mediated in vivo silencing of CCR1 and CCR5 on myeloid cells and myeloid precursors was necessary and sufficient to inhibit tumor progression. Functional studies indicated that this antitumor effect was not mediated by alteration of myeloid cell chemotaxes but rather by the repolarization of polymorphonuclear myeloid-derived suppressor cells (MDSCs) into tumoricidal neutrophils. Transcriptome functional and cytokine analysis indicated that tumor derived factors induced CCL3 and CCL4 in HSPCs that, through the autocrine engagement of CCR1 and CCR5, induced HSPCs differentiation in MDSCs. These finding were confirmed across mice with different genetic backgrounds and using HSPCs from umbilical cord blood and peripheral blood of patients with cancer. CONCLUSIONS: Our data support the notion that CCR1 and CCR5 and their ligands are a master immunological hub activated by several tumor derived factors. Activation of this pathway is necessary for the differentiation of MDSCs and protumoral macrophages. | Myelopoiesis |
We studied the activities of xanthine dehydrogenase and xanthine oxidase in rat forebrain after complete ischaemia. Complete ischaemia was induced by decapitation after transcardiac infusion with saline. The activities of xanthine dehydrogenase and xanthine oxidase immediately after ischaemia were 93.3 +/- 38.7 and 18.8 +/- 7.7 microU/mg protein, respectively, and at 24 h after ischaemia were 183.5 +/- 75.1 and 60.8 +/- 15.2 microU/mg protein, respectively. The ratios of xanthine dehydrogenase/xanthine oxidase immediately and 24 h after ischaemia were 5.04 +/- 1.03 and 3.04 +/- 0.99, respectively. These data indicate that xanthine dehydrogenase and xanthine oxidase activities were maintained even 24 h after complete ischaemia. Conversion of xanthine dehydrogenase to xanthine oxidase proceeds slowly during complete ischaemia. | Xanthine Dehydrogenase |
Pro-angiogenic therapy provides a promising new perspective in tackling of many common and severe pathological conditions, such as central and peripheral vascular diseases. Pro-angiogenic therapy also finds interesting applications in the regenerative medicine for the treatment of chronic wounds and in tissue engineering. However, clinical studies on therapeutic angiogenesis, mainly performed by administrating growth factors, have not led to convincing results until now, mainly due to the unfavorable pharmacokinetic and to safety concerns. Thus, the research of new pro-angiogenic molecules endowed of improved pharmacological profile is strongly encouraged. This review focuses on Vascular Endothelial Growth Factor (VEGF) mimetic peptides exerting a pro-angiogenic activity, which are considered among the most promising alternatives to the VEGF based therapy. Peptides show a great potential in drug discovery, as they feature straightforward development approaches, robust and cheap synthetic methodologies for their preparation and functionalization, improved safety and efficacy profiles. Thus, pro-angiogenic peptides represent a valuable alternative to traditional drugs for biomedical applications in cardiovascular diseases and regenerative medicine. | Angiogenic Proteins |
Countries where adult male circumcision has reached high coverage should consider national early infant male circumcision (EIMC) programs where EIMC is feasible and culturally acceptable. Ministries of health that intend to set up a routine offer of EIMC should put systems in place to ensure that its introduction (1) does not compromise adult male circumcision programs, (2) does not weaken routine service delivery platforms, (3) is done safely, and (4) adheres to the rights of the child. | Voluntary Programs |
Most human pancreatic cancer cells are resistant to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. However, the mechanisms by which pancreatic cancer cells utilize their extracellular molecules to counteract the proapoptotic signaling mediated by the TNF family are largely unknown. In this study, we demonstrate for the first time that DcR3, a secreted decoy receptor that malignant pancreatic cancer cells express at a high level, acts as an extracellular antiapoptotic molecule by binding to TRAIL and counteracting its death-promoting function. The reduction of DcR3 with siRNA unmasked TRAIL and greatly enhanced TRAIL-induced apoptosis. Gemcitabine, a first-line drug for pancreatic cancer, also reduced the level of DcR3. The addition of DcR3 siRNA further enhanced gemcitabine-induced apoptosis. Notably, our in vivo study demonstrated that the therapeutic effect of gemcitabine could be enhanced via further reduction of DcR3, suggesting that downregulation of DcR3 in tumor cells could tip the balance of pancreatic cells towards apoptosis and potentially serve as a new strategy for pancreatic cancer therapy." | Receptors, Tumor Necrosis Factor, Member 6b |
This study entails the measurement of the specific activity of natural radionuclides ((226)Ra, (40)K and (232)Th) in 18 tooth samples obtained from the clinic of the Universiti Sains Malaysia (USM), Penang, by using an HPGe detector. The specific activity of (226)Ra, (40)K and (232)Th was measured to estimate the hazard index of the radionuclides, radium equivalent activities (Ra(eq)), external, internal hazard indices (H(ex), H(in)), and absorbed dose (D(out), D(in)). The maximum values of concentration of (226)Ra, (232)Th and (40)K in the tooth samples were found to be 60.82, 60.29 and 594.22 Bq kg(-1), respectively. Maximum values of Ra(eq), H(ex), H(in), D(out) and D(in) were found to be 192.78 Bq kg(-1), 0.520, 0.685, 89.29 and 169.81 nGy h(-1), Igamma and Ialpha as 0.702 and 0.304, respectively. The results were lower than the average world value (UNSCEAR). In addition, a strong correlation was found between the concentrations of (226)Ra and Ra(eq), between energy and net area, as well as between radionuclides ((226)Ra, (40)K and (232)Th) in tooth samples and age of volunteers. This study showed that the concentrations and hazard indices of tooth samples are below the recommended safe levels; therefore, the study area is considered safe in terms of radiological health hazards. | Potassium Radioisotopes |
In mammals, virtually all body cells harbor cell-autonomous and self-sustained circadian oscillators that rely on delayed negative feedback loops in gene expression. Transcriptional activation and repression play a major role in keeping these clocks ticking, but numerous post-translational mechanisms-and particularly the phosphorylation of core clock components by protein kinases-are also critically involved in setting the pace of these timekeepers. In this issue of Genes & Development, Klemz and colleagues (pp. 1161-1174) now show how dephosphorylation of BMAL1 by protein phosphatase 4 (PPP4) participates in the modulation of circadian timing. | CLOCK Proteins |
BACKGROUND: The concomitant role of the Central Executive, the Saliency and the Social Cognition networks in autism spectrum disorder (ASD) in demanding ecological tasks remains unanswered. We addressed this question using a novel task-based fMRI virtual-reality task mimicking a challenging daily-life chore that may present some difficulties to individuals with ASD: the EcoSupermarketX. METHODS: Participants included 29 adolescents: 15 with ASD and 15 with typical neurodevelopment (TD). They performed the EcoSupermarketX (a shopping simulation with three goal-oriented sub-tasks including no cue", "non-social" or "social" cues), during neuroimaging and eye-tracking. RESULTS: ASD differed from TD only in total time and distance to complete the "social cue" sub-task with matched eye-tracking measures. Neuroimaging revealed simultaneous hyperactivation across social, executive, and saliency circuits in ASD. In contrast, ASD showed reduced activation in the parahippocampal gyrus, involved in scene recognition. CONCLUSIONS: When performing a virtual shopping task matching the performance of controls, ASD adolescents hyperactivate three core networks: executive, saliency and social cognition. Parahippocampal hypoactivation is consistent with effortless eidetic scene processing, in line with the notion of peaks and valleys of neural recruitment in individuals with ASD. These hyperactivation/hypoactivation patterns in daily life tasks provide a circuit-level signature of neural diversity in ASD, a possible intervention target." | Social Cognition |
In our times, sexuality has become an essential part of life for aging people. For the aging, psychosocial and biological changes, as well as increasing morbidity present challenges to a satisfying sexual life. Hence, the demand grows for health-care providers with basic sexological knowledge and counseling abilities. This article discusses relationships between frequent sexual difficulties and aging related organic processes. A therapeutic concept, the Sexocorporal Approach", is introduced. This approach is based on a model of ongoing sexual development throughout the lifetime enabling adaptation to new life phases and limiting circumstances through sexual learning processes. Aside from pharmacological treatment, the encouragement of sexual learning presents an effective therapeutic approach for practitioners that can be easily learned and applied." | Sex Counseling |
The effects of bromocriptine in patients with Parkinson's disease manifesting various problems in levodopa therapy were tested in a double-blind manner with the collaboration of 59 institutions. The slow and low principle was in part adopted. Either bromocriptine or placebo was added to levodopa. Twenty-nine % of the bromocriptine-treated patients (n = 108), in contrast to 14.8% of the placebo-treated (n = 108), showed either marked or moderate improvement (P less than 0.05). Twenty to 37% improvement was noted in most of the symptoms studied in those treated with bromocriptine. The significant superiority of bromocriptine was also noted in the effects on wearing-off phenomena and frozen gait. No irreversible side effects were noted. It is concluded that bromocriptine is useful in patients who are manifesting various difficulties in levodopa therapy. Our results are comparable to those using higher maintenance doses. Dopamine antagonistic actions were not observed. This is unlike the case with experimental animals. | Bromocriptine |
OBJECTIVES: Prehospital triage of trauma patients is of paramount importance because adequate trauma center referral improves survival. We developed a simple score that is easy to calculate in the prehospital phase. DESIGN: Multicenter prospective observational study. SETTING: Prehospital physician-staffed emergency system in university and nonuniversity hospitals. INTERVENTIONS: We evaluated 1360 trauma patients receiving care from a prehospital mobile intensive care unit in 22 centers in France during 2002. The association of prehospital variables with in-hospital death was tested using logistic regression, and a simple score (the Mechanism, Glasgow coma scale, Age, and Arterial Pressure [MGAP] score) was created and compared with the triage Revised Trauma Score, Revised Trauma Score, and Trauma Related Injury Severity Score. The model was validated in 1003 patients from 2003 through 2005. MEASUREMENTS AND MAIN RESULTS: Four independent variables were identified, and each was assigned a number of points proportional to its regression coefficient to provide the MGAP score: Glasgow Coma Scale (from 3-15 points), blunt trauma (4 points), systolic arterial blood pressure (>120 mm Hg: 5 points, 60 to 120 mm Hg: 3 points), and age <60 yrs (5 points). The area under the receiver operating characteristic curve of MGAP was not significantly different from that of the triage Revised Trauma Score or Revised Trauma Score, but when sensitivity was fixed >0.95 (undertriage of 0.05), the MGAP score was more specific and accurate than triage Revised Trauma Score and Revised Trauma Score, approaching those of Trauma Related Injury Severity Score. We defined three risk groups: low (23-29 points), intermediate (18-22 points), and high risk (<18 points). In the derivation cohort, the mortality was 2.8%, 15%, and 48%, respectively. Comparable characteristics of the MGAP score were observed in the validation cohort. CONCLUSION: The MGAP score can accurately predict in-hospital death in trauma patients. | Glasgow Coma Scale |
Cashew allergy is an evolving clinical problem. A retrospective chart review of 213 children with peanut or tree nut allergy was undertaken over a 42 month period. Anaphylaxis to cashew nut was more common than to peanut (74.1% v 30.5%). Children with cashew allergy are at risk of anaphylaxis. | Carya |
1. The development of resistance to all chemotherapeutic agents increases and needs to be addressed. We are interested in resistance in parasitic nematodes to the anthelmintic levamisole. During studies on methyridine, we found that it gave us a new insight into pharmacological changes associated with levamisole resistance. Initially, electrophysiological investigation using a two-micropipette current-clamp recording technique revealed that methyridine acts as a cholinergic agonist on nematode muscle receptors (Ascaris suum). Methyridine (>30 microm) produced reversible concentration-dependent depolarizations and increases in input conductance. Mecamylamine (30 microm) and paraherquamide (0.3 microm) produced reversible antagonism of the depolarization and conductance responses to methyridine. These observations suggest that methyridine, like acetylcholine and levamisole, gates ion channels on the muscle of parasitic nematodes. 2. The antagonistic effects of dihydro-beta-erythroidine and paraherquamide on methyridine-induced contractions of A. suum muscle flaps were then examined to determine if methyridine showed subtype selectivity for N-subtype (nicotine-sensitive) or L-subtype (levamisole-sensitive) acetylcholine receptors. Dihydro-beta-erythroidine weakly antagonized the effects of methyridine (but had no effect on levamisole responses). The antagonism of methyridine (pA2, 5.9) and nicotine (pA2, 6.1) by paraherquamide was similar, but was less than the antagonism of levamisole (pA2, 7.0). The antagonist profiles suggested that methyridine has a selective action on the N-subtype rather than on the L-subtype. 3. A novel use for a larval inhibition migration assay was made using L3 larvae of Oesophagostomum dentatum. Inhibitory effects of nicotine, levamisole, pyrantel and methyridine on the migration of larvae of levamisole-sensitive (SENS) and levamisole-resistant (LEV-R) isolates were tested at different concentrations. Levamisole and pyrantel (putative L-subtype-selective agonists) concentration-response plots were displaced to the right in LEV-R isolates. Nicotine (an N-subtype-selective agonist) and methyridine produced little shift in concentration-response plots in the LEV-R isolates. Resistance dose ratios were used to calculate the relative selectivity, rhoL, for the L-type receptor (levamisole rhoL=1.0; pyrantel rhoL=0.93; methyridine rhoL=0.17; nicotine rhoL=0.06). These observations reveal an N-subtype-selective action of methyridine and suggest that levamisole resistance may be associated with a loss of the L-subtype, but not the N-subtype receptors. The pharmacology of methyridine suggests an approach for the treatment of levamisole-resistant parasites. | Bephenium Compounds |
PROBLEM: The aim of this study was to investigate seminal sperm-agglutinating antibodies, intra-acrosomal proteins, sperm head abnormalities, and cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70 TNF-alpha, and IFN-gamma) in men from infertile couples. METHOD OF STUDY: The direct mixed anti-immunoglobulin reaction test for IgG, IgA, and IgE in semen, and immunocytochemical method using monoclonal antibodies and indirect immunofluorescence for the examination of intra-acrosomal proteins in the spermatozoa were used. Cytokines in seminal plasma were determined by multiplex immunoanalytic xMAP (LUMINEX) technology. RESULTS: Sperm-agglutinating antibodies, IgG and IgA, in seminal plasma were found to be more in asthenospermatic and oligoasthenospermatic men than in normospermatic men. Sperm head pathology and very low amounts of acrosomal proteins were frequently detected in pathologic semen samples. Cytokine levels defined as 'high' (based on the 75 percentile for each cytokine in all groups) were obtained especially for IL-8, IL-5, IL-6, and IL-10. The high cellularity in semen was correlated with higher IL-5. CONCLUSION: Immunologic cause of male infertility is a very important risk factor in the pathogenesis of sperm cells. Sperm autoantibodies and the presence of intra-acrosomal factors must be studied together, cytokines according to accessory cellularity in the semen. | Sperm Agglutination |
Primary hyperparathyroidism (HPT) is a common disorder that mainly afflicts elderly women. It can be diagnosed in at least 1% of all postmenopausal females and autopsy studies indicate an even higher frequency. Although the widespread use of automated serum calcium analyses has increased the awareness of HPT, only 10% of all cases seem to be identified. The diagnosis relies on the demonstration of an inappropriately elevated serum concentration of parathyroid hormone (PTH) relative to the serum calcium value, which need not be markedly raised. Measurements of intact PTH with immunometric methods have considerably improved the diagnostic precision but it is still difficult to evaluate patients with only marginal hypercalcemia. Few patients with diagnosed HPT are completely without symptoms. Symptoms commonly encountered are psychiatric and neuromuscular disturbances. Subclinical bone disease might be relevant but there is insufficient information about its importance in otherwise asymptomatic individuals. Various cardiovascular risk factors appear more commonly in patients with HPT and untreated disease is associated with an increased risk of premature death. | Hyperparathyroidism |
The conformational flexibility of a human immunoglobulin kappaIV light-chain variable domain, LEN, which can undergo conversion to amyloid under destabilizing conditions, was investigated at physiological and acidic pH on a residue-specific basis by multidimensional solution-state nuclear magnetic resonance (NMR) methods. Measurements of backbone chemical shifts and amide (15)N longitudinal and transverse spin relaxation rates and steady-state nuclear Overhauser enhancements indicate that, on the whole, LEN retains its native three-dimensional fold and dimeric state at pH 2 and that the protein backbone exhibits limited fast motions on the picosecond to nanosecond time scale. On the other hand, (15)N Carr--Purcell--Meiboom--Gill (CPMG) relaxation dispersion NMR data show that LEN experiences considerable slower, millisecond time scale dynamics, confined primarily to three contiguous segments of about 5-20 residues and encompassing the N-terminal beta-strand and complementarity determining loop regions 2 and 3 in the vicinity of the dimer interface. Quantitative analysis of the CPMG relaxation dispersion data reveals that at physiological pH these slow backbone motions are associated with relatively low excited-state protein conformer populations, in the ~2-4% range. Upon acidification, the minor conformer populations increase significantly, to ~10-15%, with most residues involved in stabilizing interactions across the dimer interface displaying increased flexibility. These findings provide molecular-level insights about partial protein unfolding at low pH and point to the LEN dimer dissociation, initiated by increased conformational flexibility in several well-defined regions, as being one of the important early events leading to amyloid assembly." | Immunoglobulin Variable Region |
OBJECTIVES: To investigate the long-term safety and efficacy of a treatment switch to dual ART with atazanavir/ritonavir + lamivudine versus continuing a standard regimen with atazanavir/ritonavir + 2NRTI in virologically suppressed patients. METHODS: ATLAS-M is a 96 week open-label, randomized, non-inferiority (margin -12%) trial enrolling HIV-infected adults on atazanavir/ritonavir + 2NRTI, with stable HIV-RNA <50 copies/mL and CD4 counts >200 cells/mm3. At baseline, patients were randomized 1:1 to switch to atazanavir/ritonavir + lamivudine or to continue the previous regimen. Here, we report the 96 week efficacy and safety data. The study was registered with ClinicalTrials.gov, number NCT01599364. RESULTS: Overall, 266 subjects were enrolled (133 in each arm). At 96 weeks, in the ITT population, patients free of treatment failure totalled 103 (77.4%) with atazanavir/ritonavir + lamivudine and 87 (65.4%) with triple therapy (difference +12.0%, 95% CI +1.2/+22.8, P = 0.030), demonstrating the superiority of dual therapy. Two (1.5%) and 9 (6.8%) virological failures occurred in the dual-therapy arm and the triple-therapy arm, respectively, without development of resistance to any study drug. Clinical adverse events occurred at similar rates in both arms. A higher frequency of grade 3-4 hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) occurred with dual therapy, although this never led to treatment discontinuation. A significant improvement in renal function and lumbar spine bone mineral density occurred in the dual-therapy arm. The evolution of CD4, HIV-DNA levels and neurocognitive performance was similar in both arms. CONCLUSIONS: In this randomized study, a treatment switch to atazanavir/ritonavir + lamivudine was superior over the continuation of atazanavir/ritonavir + 2NRTI in virologically suppressed patients, with a sustained benefit in terms of improved renal function and bone mineral density. | Atazanavir Sulfate |
Multiple endocrine neoplasia type 1 is a rare genetic syndrome, characterized by the co-occurrence, in the same individual or in related individuals of the same family, of hyperparathyroidism, duodenopancraetic neuroendocrine tumors, pituitary adenomas, adrenocortical tumors, and neuroendocrine tumors (carcinoids) in the thymus, the bronchi, or the stomach. Multiple endocrine neoplastic type 2 is a rare genetic syndrome, characterized by the familial occurrence of medullary thyroid carcinoma either isolated or associated with pheochromocytoma, primary hyperparathyroidism, or typical features (Marfanoid habitus, mucosal neuromas). Subjects with clinical MEN1 and those who carry a mutation in the MEN1 gene should be offered biochemical and imaging screening in order to detect tumors and evaluate their progression over time. Children with mutation in the RET gene should have prophylactic total thyroidectomy according to the category of aggressiveness of the detected mutation whereas those with clinical MEN2 should be operated on upon diagnosis. In MEN1 patients, special attention should be paid to evaluate the progression duodenopancraetic neuroendocrine tumors because of their malignant potential. Also, thymic neuroendocrine tumors should be detected as soon as possible because they represent the most lethal tumor. In MEN2, calcitonin and carcinoembryonic antigen (CEA) serve as excellent tumor markers for medullary thyroid carcinoma. Their preoperative levels are correlated with tumor size and predict postoperative cure. Moreover, calcitonin or CEA doubling time has important prognostic value. In both MEN syndromes, multidisciplinary approaches are very important in the care of affected patients. Moreover, those patients should be comprehensively informed and enabled to participate in the decision-making procedure. In addition to multidisciplinary approaches, every effort should be made to follow the recommendations and guidelines issued by national (the French Group of Endocrine Tumors) and international groups. | Multiple Endocrine Neoplasia |
A general picture of the role of expression divergence in the evolution of duplicate genes is emerging, thanks to the availability of completely sequenced genomes and functional genomic data, such as microarray data. It is now clear that expression divergence, regulatory-motif divergence and coding-sequence divergence all increase with the age of duplicate genes, although their exact interrelationships remain to be determined. It is also clear that gene duplication increases expression diversity and enables tissue or developmental specialization to evolve. However, the relative roles of subfunctionalization and neofunctionalization in the retention of duplicate genes remain to be clarified, especially for higher eukaryotes. In addition, the relationship between gene duplication and evolution of transcriptional regulatory networks is largely unexplored. | Genes, Duplicate |
Sanhuang tablets is one of common traditional Chinese patent preparation, it has effects of clear fever, detoxifcation, dispel inflammation, purgation. It was contained in the ministerial standards of Ministry of Health in 1997, and was contained in Chinese pharmacopoeia version 1 of 2000 and 2005. Its improvement of dosage form, preparation technique, quality analysis, pharmacology and clinical usage were reviewed in this paper. | Coptis |
The diving reflex" (DR) is a very powerful autonomic reflex that facilitates survival in hypoxic/anoxic conditions and could trigger multifaceted physiologic effects for the treatment of various diseases by modulating the cardiovascular, respiratory, and nervous systems. The DR can be induced by cold water or noxious gases applied to the anterior nasal mucosa and paranasal regions, which can stimulate trigeminal thermo- or chemo-receptors to send afferent signals to medullary nuclei which mediate the sympathetic and parasympathetic nervous systems. Although promising, these approaches have yet to be adopted in routine clinical practice due to the inability to precisely control exposure-response relationships, lack of reproducibility, and difficulty implementing in a clinical setting. In this study, we present the ability of electrical Trigeminal (Infraorbital) Nerve Stimulation (eTINS) to induce the DR in a dose-controllable manner. We found that eTINS not only triggered specific physiological changes compatible with the pattern of "classic" DR observed in animals/humans, but also controlled the induced-DR at varying levels. This study demonstrates, for the first time, that the intensity of the DR is controllable by dose and opens possibility to investigate its protective mechanism against various pathologies in well-controlled research settings." | Diving Reflex |
OBJECTIVE: Medical schools are charged with assisting medical students to acquire the confidence, knowledge and skills for behavior change conversations in primary healthcare. The present study evaluated teaching brief motivational interviewing (MI) to pre-clinical medical students. METHODS: Forty-six students participated in an educational intervention premised on the Learn, See, Practice, Prove, Do, Maintain pedagogical framework, comprising 2 x 2-h lectures, a 2-h role-play triad session, and 3 x 2-h small group simulated patient encounters supported by scaffolding strategies. Measures of brief MI knowledge (MI Knowledge and Attitudes Test & Multiple-Choice Knowledge Test) and confidence (MI Confidence Scale) were taken at baseline, post-training, and 3-month follow-up, and skills (Behavior Change Counseling Index) were assessed at three intervals during simulated patient encounters. RESULTS: Students who received brief MI training improved in knowledge and confidence from baseline to post-training and gains remained at 3-months. Brief MI skills improved across the simulation sessions. CONCLUSION: Pre-clinical medical students can attain knowledge, confidence and skills in brief MI after participation in a short intervention and improvements are sustainable. PRACTICE IMPLICATIONS: Our results support the use of an evidence-based pedagogical framework for teaching brief MI in pre-clinical years of medical curricula and our scaffolding strategy affords promise. | Motivational Interviewing |
This study aimed to analyze the chemical composition and the IgG concentration of the colostrum, transitional milk, and mature milk of Santa Ines ewes as well as the transfer of passive immunity to lambs. Thirty-two pregnant ewes and 38 lambs were used. Ewes were milked immediately after lambing and at 12, 24, 36 h and 10 d postpartum. Colostrum was provided to the lambs at 40+/-15 min (mean+/-SE) after birth and then at 30-min intervals for obtaining the intake closest to 10% of body weight, and transitional milk was provided ad libitum. Blood from the lambs was collected 36 h after birth for measuring the serum concentrations of IgG, total protein, albumin, and gamma-globulin. The production was lower in primiparous than in multiparous ewes with body condition score (BCS)<2.75, but did not differ between primiparous and multiparous with BCS>/=2.75 (interaction parity and BCS). The IgG concentration and fat, protein, lactose, and defatted dry extract percentages were not affected by the BCS of the ewe at lambing or by the parity. The total solids percentage in the colostrum was higher in ewes with BCS<2.75 (interaction BCS and time). The production and the protein, total solid, and defatted dry extract percentages showed quadratic behavior, the fat percentage decreased linearly, and the lactose percentage increased linearly with time postpartum. The IgG concentration in the colostrum was not correlated with the ewe's weight or BCS at the time of lambing. Moreover, the parity, the BCS, the ewe's type of gestation, and the lamb's sex did not influence the serum concentrations of IgG, total protein, albumin, and gamma-globulin in lambs. Adequate passive immune transfer (PIT) was observed in lambs for which the IgG intake was higher than 30 g. Failure in PIT was observed in 39.5% of lambs when considering a serum IgG concentration lower than 15 mg/mL and in 21% when considering a serum total protein concentration lower than 45 mg/mL. The mean apparent efficiency of absorption was 38.10%, with values between 0.02% and 98.80%. The serum IgG concentration was correlated with the total protein concentration (according to the enzymatic colorimetric method), the gamma-globulin concentration, and the absorption efficiency. The extreme variation on apparent efficiency of absorption may have an effect on the success of PIT. Lambs should consume at least 30 g of IgG in the first 24 h of life to ensure adequate PIT. | Sheep |
The effects of the chloroform extract of Maytenus obtufisolia MART. roots on locomotor activity, catalepsy test, amphetamine-induced toxicity and active-avoidance test were studied. The results revealed that the extract caused a decrease in spontaneous activity and induced catalepsy in mice up to 240 min. The extract significantly protected the mice against amphetamine-induced toxicity and decreased the conditioned response in rats, in a dose-related manner. The results suggest that the chloroform extract of Maytenus obtusifolia MART. possesses neuroleptic-like properties. | Maytenus |
The pattern of expression of fos and jun family immediate early genes following the induction of long-term potentiation (LTP) was investigated in the dentate gyrus of awake rats. Rapid, transient increases in the levels of c-jun and jun-B mRNA and protein, and in the levels of Fos-related proteins (FRAs), occurred in the dentate gyrus after LTP-inducing tetanization of the perforant path. A delayed, and more prolonged induction occurred for jun-D mRNA and protein. The induction of c-Jun, Jun-B, Jun-D and Fos-related proteins was prevented by administration of an N-methyl-D-aspartate receptor antagonist, which also blocked LTP induction, and by pentobarbital, which reduced but did not block LTP. These findings show that differential expression of fos and jun gene family members occurs in a distinct pattern following LTP in awake rats. The responsive genes may participate in the biochemical cascade leading to the long-term stabilization of synaptic modifications. | Proto-Oncogenes |
Structured cis-regulatory RNAs have evolved across all domains of life, highlighting the utility and plasticity of RNA as a regulatory molecule. Homologous RNA sequences and structures often have similar functions, but homology may also be deceiving. The challenges that derive from trying to assign function to structure and vice versa are not trivial. Bacterial riboswitches, viral and eukaryotic IRESes, CITEs, and 3' UTR elements employ an array of mechanisms to exert their effects. Bioinformatic searches coupled with biochemical and functional validation have elucidated some shared and many unique ways cis-regulators are employed in mRNA transcripts. As cis-regulatory RNAs are resolved in greater detail, it is increasingly apparent that shared homology can mask the full spectrum of mRNA cis-regulator functional diversity. Furthermore, similar functions may be obscured by lack of obvious sequence similarity. Thus looking beyond homology is crucial for furthering our understanding of RNA-based regulation. | Untranslated Regions |
Autoradiographic study of an experimentally-induced tumour following local irradiation in a dose of 600 rad showed no retardation of the cell cycle 6 to 12 hours after the irradiation. Marked reduction of the mitotic index (MI) and of the labeled nuclei index (LNI) was noted to the 96th hour after the irradiation. In repeated irradiation in a dose of 1200 rad at an interval of 18 hours there was revealed a marked reduction of the MI and of the LNI as a result of the block of the passage of cells from the G1-period into S. However, restoration of the cell proliferation uas noted by the 24th-48th hours. A high MI revealed at all the periods of investigation after repeated tumour irradiation at an interval of 24 hours was possibly caused by an increase in the time of mitosis proper, this also being confirmed by a significant accumulation of the number of late mitotic phases. | Sarcoma, Experimental |
PURPOSE: The purpose of this paper was to develop a deep learning algorithm to detect retinal vascular leakage (leakage) in fluorescein angiography (FA) of patients with uveitis and use the trained algorithm to determine clinically notable leakage changes. METHODS: An algorithm was trained and tested to detect leakage on a set of 200 FA images (61 patients) and evaluated on a separate 50-image test set (21 patients). The ground truth was leakage segmentation by two clinicians. The Dice Similarity Coefficient (DSC) was used to measure concordance. RESULTS: During training, the algorithm achieved a best average DSC of 0.572 (95% confidence interval [CI] = 0.548-0.596). The trained algorithm achieved a DSC of 0.563 (95% CI = 0.543-0.582) when tested on an additional set of 50 images. The trained algorithm was then used to detect leakage on pairs of FA images from longitudinal patient visits. Longitudinal leakage follow-up showed a >2.21% change in the visible retina area covered by leakage (as detected by the algorithm) had a sensitivity and specificity of 90% (area under the curve [AUC] = 0.95) of detecting a clinically notable change compared to the gold standard, an expert clinician's assessment. CONCLUSIONS: This deep learning algorithm showed modest concordance in identifying vascular leakage compared to ground truth but was able to aid in identifying vascular FA leakage changes over time. TRANSLATIONAL RELEVANCE: This is a proof-of-concept study that vascular leakage can be detected in a more standardized way and that tools can be developed to help clinicians more objectively compare vascular leakage between FAs. | Fluorescein Angiography |
Custom made maxillary mouthguards made from thermoplastic materials using dental impressions give valuable protection to the teeth and jaws of participants in contact sports. A bimaxillary mouthguard has been described which offers enhanced protection, but with considerable increase in cost. This paper describes a modification to current maxillary mouthguard design that is comfortable to wear, inexpensive to make and which may provide protection comparable to that of a bimaxillary type, while retaining other desirable features of the more complex appliance. | Mouth Protectors |
Craniofacial surgery in craniofacial dysostosis on airway obstruction was studied retrospectively in a consecutive series of patients. The records of 76 patients were reviewed, 27 with Apert syndrome, 47 with Crouzon's syndrome, and two with Pfieffer's syndrome. Of 172 operations, 148 were done for cosmetic reasons, hydrocephalus, or papillary oedema, and 24 were done for airway distress. Forty patients (23%) were children less than 13 years of age, and 22 underwent midface advancement procedures. Only 13 of these operations had been done for airway distress. Two were cured by operation and seven improved. After operation had failed to relieve the airway obstruction, a nasal continuous positive airway pressure device (nCPAP) was fitted to seven patients. The nCPAP relieved or improved airway obstruction recorded by a sleep study. As midface advancement in childhood rarely results in lasting improvement in breathing or aesthetics, it may well be advisable to postpone operation until the early teens. We conclude that with nCPAP operation can in most cases be deferred until a time when a permanent result can be achieved. | Craniofacial Dysostosis |
Vibroarthrography (VAG) is a non-invasive and potentially widely available method supporting the joint diagnosis process. This research was conducted using VAG signals classified to five different condition classes: three stages of chondromalacia patellae, osteoarthritis, and control group (healthy knee joint). Ten new spectral features were proposed, distinguishing not only neighboring classes, but every class combination. Additionally, Frequency Range Maps were proposed as the frequency feature extraction visualization method. The results were compared to state-of-the-art frequency features using the Bhattacharyya coefficient and the set of ten different classification algorithms. All methods evaluating proposed features indicated the superiority of the new features compared to the state-of-the-art. In terms of Bhattacharyya coefficient, newly proposed features proved to be over 25% better, and the classification accuracy was on average 9% better. | Chondromalacia Patellae |
This article describes a new method of external traction elevation which is applied to the breast in order to perform an oncologically thorough glandular removal and axillary dissection followed by immediate autologous reconstruction while significantly reducing wound morbidity and greatly improving cosmesis. | Mastectomy, Subcutaneous |
Eighteen patients with severe symptoms of the carcinoid syndrome were assessed for hepatic embolisation. Four were too ill, and one had mild symptoms; thus 13 received a periembolisation regimen of cyproheptadine, fenclonine, aprotinin, methylprednisolone, tobramycin, flucloxacillin, and metronidazole. Embolisation was not performed in one patient with an occluded portal vein and was unsatisfactory in two others, in one because she was moribund and in the other because the hepatic artery had been ligated. Dramatic improvement in symptoms occurred in the nine patients in whom embolisation was successfully carried out, with abolition of flushing, severe abdominal pain, and wheeze and reduction in diarrhoea from 10.5 (SD 7.6) to 1.6 (0.9) stools/day. Urinary excretion of 5-hydroxyindole acetic acid fell from 1048 (716) to 289 (184) mumol/24 h (200 (137) to 55 (35) mg/24 h). Complications included one death from septicaemia, a hepatic abscess requiring surgical drainage, abdominal pain in three patients, pleural effusion in two, and transient encephalopathy in one. Relief of symptoms lasted for one to 24 months, and second embolisation in two patients produced further remissions of four to six months. Five patients died, one to 40 months after embolisation, in four cases because of metastases or heart failure. Hepatic embolisation is the treatment of choice for symptoms of the carcinoid syndrome resistant to medical treatment. | Malignant Carcinoid Syndrome |
Interactions in social groups can promote behavioural specialization. One way this can happen is when individuals engage in activities with two behavioural options and learn which option to choose. We analyse interactions in groups where individuals learn from playing games with two actions and negatively frequency-dependent payoffs, such as producer-scrounger, caller-satellite, or hawk-dove games. Group members are placed in social networks, characterized by the group size and the number of neighbours to interact with, ranging from just a few neighbours to interactions between all group members. The networks we analyse include ring lattices and the much-studied small-world networks. By implementing two basic reinforcement-learning approaches, action-value learning and actor-critic learning, in different games, we find that individuals often show behavioural specialization. Specialization develops more rapidly when there are few neighbours in a network and when learning rates are high. There can be learned specialization also with many neighbours, but we show that, for action-value learning, behavioural consistency over time is higher with a smaller number of neighbours. We conclude that frequency-dependent competition for resources is a main driver of specialization. We discuss our theoretical results in relation to experimental and field observations of behavioural specialization in social situations. | Game Theory |
The 'weak and ill-defined' standards of care imposed by the Registered Homes Act of 1984 have meant that quality of care in nursing homes is monitored unevenly or not at all, says Yumiko Arai. | Nursing Homes |
BACKGROUND: Postoperative pulmonary complications (PPC) may result in longer duration of in-hospital stay and even mortality. Both thoracic surgery and intraoperative mechanical ventilation settings add considerably to the risk of PPC. It is unclear if one-lung ventilation (OLV) for thoracic surgery with a strategy of intraoperative high positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM) reduces PPC, compared to low PEEP without RM. METHODS: PROTHOR is an international, multicenter, randomized, controlled, assessor-blinded, two-arm trial initiated by investigators of the PROtective VEntilation NETwork. In total, 2378 patients will be randomly assigned to one of two different intraoperative mechanical ventilation strategies. Investigators screen patients aged 18 years or older, scheduled for open thoracic or video-assisted thoracoscopic surgery under general anesthesia requiring OLV, with a maximal body mass index of 35 kg/m(2), and a planned duration of surgery of more than 60 min. Further, the expected duration of OLV shall be longer than two-lung ventilation, and lung separation is planned with a double lumen tube. Patients will be randomly assigned to PEEP of 10 cmH(2)O with lung RM, or PEEP of 5 cmH(2)O without RM. During two-lung ventilation tidal volume is set at 7 mL/kg predicted body weight and, during OLV, it will be decreased to 5 mL/kg. The occurrence of PPC will be recorded as a collapsed composite of single adverse pulmonary events and represents the primary endpoint. DISCUSSION: PROTHOR is the first randomized controlled trial in patients undergoing thoracic surgery with OLV that is adequately powered to compare the effects of intraoperative high PEEP with RM versus low PEEP without RM on PPC. The results of the PROTHOR trial will support anesthesiologists in their decision to set intraoperative PEEP during protective ventilation for OLV in thoracic surgery. TRIAL REGISTRATION: The trial was registered in clinicaltrials.gov ( NCT02963025 ) on 15 November 2016. | One-Lung Ventilation |
Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated. | Herpesvirus 2, Human |
Vaccination against H5N1 highly pathogenic avian influenza in endemically affected areas is a potentially attractive option for local prevention and control. In Indonesia the majority of local outbreaks have occurred in back yard flocks with native chickens, and it is therefore of interest to determine whether these birds can be protected against infection by vaccination. To this end two transmission experiments were carried out with H5N1 virus (A/chicken/Legok/2003) in vaccinated and unvaccinated native chickens. The vaccine contained an inactivated heterologous H5N2 strain (A/turkey/England/N28/73 H5N2). Birds were vaccinated at 4 and 7 weeks of age and challenged at 10 weeks of age. During 10 days post-challenge tracheal and cloacal swabs were taken for virus isolation, and serum blood was collected regularly to measure haemaglutinin inhibiting (HI) antibody responses. The results show that transmission of H5N1 virus was rapid and efficient in unvaccinated birds, that infection and transmission were completely prevented in vaccinated birds, and that vaccinated birds that were exposed to unvaccinated inoculated birds were still protected from infection. These findings indicate that vaccination with a heterologous H5N2 vaccine is able to prevent virus transmission in flocks of native chickens." | Influenza A Virus, H5N2 Subtype |
This paper presents a preliminary assessment of the geographic extent and estimates of the incidence and the population at risk of dracunculiasis in Africa. Nineteen countries are known to be affected, in a belt extending right across the northern part of the continent south of 18 degrees N, and in east Africa extending almost to the equator. Annual incidence is estimated to be 3.32 million, and the at-risk population is approximately 120 million. These data provide an initial baseline on which the success of control measures now being initiated in Africa can be assessed. | Dracunculiasis |
Juvenile idiopathic arthritis (JIA) is the commonest rheumatic disease in children and JIA-associated uveitis its most frequent extra-articular manifestation. The uveitis is potentially sight-threatening and so carries a considerable risk of morbidity. The commonest form of uveitis seen in JIA is chronic anterior uveitis which is almost always asymptomatic in the initial stages. Therefore, screening for JIA-associated uveitis in at-risk patients is essential. The aim of early detection and treatment is to minimise intra-ocular inflammation and avoid complications leading to visual loss, resulting from both disease activity and medications. There is increasing evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. Two randomised controlled trials of adalimumab in JIA-associated uveitis provide convincing evidence for the use of this biologic in patients who fail to respond adequately to methotrexate. Tocilizumab and baricitinib are being investigated as alternatives to anti-tumour necrosis factor drugs. | Arthritis, Juvenile |
The Institute of Medicine (IOM) has published a set of eight standards for guideline development groups (GDGs) to derive trustworthy clinical practice guidelines (CPGs). We investigated the adherence of these IOM guidelines to its own standards. The IOM document passed two of its own standards ("GDG-Systematic Review Team Interaction" and "GDG Composition"), only partially passed two others ("Articulation of Recommendation" and "External Review") and failed to pass four ("Establishing Transparency," "Management of Conflict of Interest," "Establishing Evidence Foundations" and "Updating"). The IOM standards for the development of CPGs do not meet their own criteria of trustworthiness. Further study is needed to determine the best methodology to evaluate CPGs." | National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division |
OBJECTIVES: The decline in the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis during normal aging might be involved in the changes in body composition associated with increasing age. We conducted a study to investigate serum IGF-I levels across different age categories and a possible association between serum IGF-I and measurements of body composition in older people. DESIGN: A cross-sectional analysis of community dwelling older people, which participated in a large longitudinal cohort study (Longitudinal Aging Study Amsterdam). SUBJECTS: 1319 subjects, 644 men, mean age 75.6 +/- 6.6 years and 675 women, mean age 75.4 +/- 6.6 years. MAIN OUTCOME MEASUREMENTS: IGF-I, body mass index (BMI), waist, waist-hip ratio (WHR), fat mass, lean body mass and total bone mineral density. RESULTS: IGF-I levels were significantly lower in the highest age categories. BMI and biceps skinfold measurements were lower in the lowest IGF-I quartile in men aged > or =75.5 years. In men with a low total physical activity score (<131 min/day), BMI, WHR and skinfolds were significantly lower in the lowest IGF-I quartile. In women with a high total physical activity score (>174 min/day), WHR was lower in the lowest IGF-I quartiles. CONCLUSION: In this large cohort of community dwelling older people, we observed lower serum IGF-I levels in the higher age categories. A low serum IGF-I was associated with significantly lower measurements of body composition, such as BMI, skinfolds and WHR. These results do not support previous findings that high IGF-I levels are favourable for a healthy body composition in community dwelling older people. | Insulin-Like Growth Factor I |
Thyronine (T4), triiodothyronine (T3), and reverse-triiodothyronine (rT3) levels were evaluated in cerebrospinal fluid (CSF) and in serum of 12 patients with definite amyotrophic lateral sclerosis (ALS) by specific radioimmunoassays. Circulating microsomal and thyroglobulin antibodies were also evaluated. In all patients serum levels of T4, T3 and rT3 were within normal limits. In CSF, the rT3 levels were significantly elevated to 0.118 micrograms/l (mean), the T4 levels were not significantly elevated, and the T3 levels were below the detection limit of 0.03 micrograms/l. A correlation between the elevated rT3 levels in CSF and the severity or type of ALS could not be demonstrated by this study. The antithyroid antibodies (thyroglobulin antibodies, microsomal antibodies) showed normal titres and did not suggest disturbances of thyroid autoimmunity in the patients with ALS. | Thyronines |
Immortal hepatocyte cell lines are widely used to elucidate insulin-dependent signalling pathways and regulation of hepatic metabolism, although the often tumorigenic origin might not represent the metabolic state of healthy hepatocytes. We aimed to investigate if murine cell line AML12 and human cell line THLE-2, which are derived from healthy liver cells, are comparable to hepatoma cell line HepG2 for studying acute insulin signalling and expression of gluconeogenic enzymes and hepatokines. Insulin responsiveness of AML12 and THLE-2 cells was impaired when cells were cultured in the recommended growth medium, but comparable with HepG2 cells by using insulin-deficient medium. THLE-2 cells showed low abundance of insulin receptor, while protein levels in HepG2 and AML12 were comparable. AML12 and THLE-2 cells showed only low or non-detectable transcript levels of G6PC and PCK1 Expression of ANGPTL4 was regulated similarly in HepG2 and AML12 cells upon peroxisome proliferator-activated receptor delta activation but only HepG2 cells resemble the in vivo regulation of hepatic ANGPTL4 by cAMP. Composition of the culture medium and protein expression levels of key signalling proteins should be considered when AML12 and THLE-2 are used to study insulin signalling. With regard to gluconeogenesis and hepatokine expression, HepG2 cells appear to be closer to the in vivo situation despite the tumorigenic origin. | Angiopoietin-Like Protein 4 |
(+/-)-Quassidine K (1), a pair of new bis-beta-carboline alkaloid enantiomers, were isolated from Picrasma quassioides. Their structures were determined on the basis of detailed spectroscopic data analysis. The absolute configurations of (+)-S-quassidine K (1a) and (-)-R-quassidine K (1b) were determined by comparing with the reported experimental ECD spectra after chiral separation. The cytotoxicity assay showed activity against HeLa cells with IC50 values of 15.8 and 20.1 muM, respectively. | Picrasma |
A new ajmaline-type alkaloid, 21-Omicron-methylisoajmaline (1), together with twenty-one known compounds, a mixture of beta-sitosterol (2) and stigmasterol (3), reserpinine (4); tetrahydroalstonine (5), reserpine (6), venoterpine (7), yohimbine (8), 6'-O-(3,4,5-trimethoxybenzoyl)glomeratose A (9), isoajmaline (10), 3-epi-alpha-yohimbine (11), methyl 3,4,5-trimethoxy-trans-cinnamate (12), a mixture of beta-sitosterol 3-Omicron-beta-D-glucopyranoside (13) and stigmasterol 3-Omicron-beta-D- glucopyranoside (14), rescidine (15), 7-deoxyloganic acid (16), ajmaline (17), suaveoline (18), (+)-tetraphyllicine (19), loganic acid (20), 3-hydroxysarpagine (21), and sarpagine (22), were isolated from the roots of Rauvolla serpentina. Their structures were elucidated by spectroscopic data analysis and comparison with literature data. Compounds 11, 12 and 15 were for the first time identified from the genus Rauvolfla and 5, 7, 11, 12, 15, 18 and 22 were found from R. sepentina for the first time. Compound 11 showed moderate anticholinesterase activity with IC(5)(0) value of 15.58 muM, whereas 6 exhibited strong vasorelaxant activity with the EC(5)(0) value of 0.05 muM. | Ajmaline |
AIM: The major objective of the present study was to clarify genetic relationship of isolates of Edwardsiella ictaluri in Japan, which was first found from ayu Plecoglossus altivelis in Japanese rivers in 2007. METHODS AND RESULTS: Ten isolates of Edw. ictaluri in 2007-2008 from ayu and the 1 isolate from bagrid catfish Pelteobagrus nudiceps in Japan were subjected to amplified-fragment length polymorphism (AFLP) analysis. The strains isolated from catfish in United States (ATCC strains) or Indonesia were used as reference strains. The AFLP profiles were all the same among the isolates from Japan, while the polymorphic DNA bands were observed among the strains from United States or Indonesia. The isolates from Japan and Indonesia constituted a genogroup different from the ATCC strains on a dendrogram constructed from the AFLP profiles. CONCLUSION: No DNA polymorphisms were found among Japanese Edw. ictaluri isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: A single clonality of the Edw. ictaluri isolates in Japan suggests the single source of the organism, and the infection in ayu is in the early stage of epidemics. | Edwardsiella |
We describe the unique case of a 51-year-old lady who developed a contralateral lumbosacral plexopathy two days after a lumbar microdiscectomy. This is the first report to date of this complication occurring following this procedure. We review the literature regarding lumbosacral plexopathy and discuss the evidence base behind investigating and managing this condition and the potential pathophysiological mechanisms which underlie its development. We draw comparisons with the more widely recognised post-operative brachial neuritis, characterised by delayed onset brachial plexopathy developing after cervical decompression, and propose an immune-mediated inflammatory mechanism linking the two conditions. | Brachial Plexus Neuropathies |
A database of 7.9 million compounds commercially available from 29 suppliers in 2008-2009 was assembled and analyzed. 5.2 million structures of this database were identified to be unique and were subjected to an assessment of physical and biological properties and estimation of molecular diversity. The rules of Lipinski and Veber were applied to the molecular weight, the calculated water/n-octanol partition coefficients (Clog P), the calculated aqueous solubility (log S), the numbers of hydrogen-bond donors and acceptors, and the calculated Caco-2 membrane permeability to identify the drug-like compounds, whereas the toxicity/reactivity filters were used to remove the structures with biologically undesired functional groups. This filtering resulted in 2.0 million (39%) structures perfectly suitable for high-throughput screening of biological activity. Modified filters applied to identify lead-like structures revealed that 16% of the unique compounds could be potential leads. Assessment of the biological activities, the analysis of diversity, and the sizes of exclusive sets of compounds are presented. | Organic Chemicals |
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