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Given the present high incidence of melanoma and skin cancer, interest in potential drugs of plant origin has increased significantly. Pentacyclic lupane-type triterpenes are widely distributed in plants, offering numerous pharmacological benefits. Betulin is an important compound in the bark of Betula pendula Roth and has important therapeutic properties, including antitumor activities. Its biological effect is limited by its poor water solubility, which can be improved by cyclodextrin complexation. The best results have been obtained by using a novel cyclodextrin derivative, octakis-[6-deoxy-6-(2-sulfanyl ethanesulfonate)]-gamma-CD. The complexes between betulin and the previously mentioned cyclodextrin were analyzed by scanning electron microscopy (SEM)and differential scanning calorimetry (DSC) and pharmacologically evaluated in vitro (MTT and immunocytochemistry tests) and in vivo in C57BL/6J mice. The solubility of betulin is improved by cyclodextrin complexation, which creates a stable complex that improves the in vitro and in vivo properties of the active compound. | Caspase 2 |
A 6-yr-old female orangutan presented with a history of dark urine that turned brown upon standing since birth. Repeated routine urinalysis and urine culture were unremarkable. Urine organic acid analysis showed elevation in homogentisic acid consistent with alkaptonuria. Sequence analysis identified a homozygous missense variant, c.1081G>A (p.Gly361Arg), of the homogentisate 1,2-dioxygenase (HGD) gene. Familial studies, molecular modeling, and comparison to human variant databases support this variant as the underlying cause of alkaptonuria in this orangutan. This is the first report of molecular confirmation of alkaptonuria in a nonhuman primate. | Pongo abelii |
A fourth staphylococcal enterotoxin was identified serologically with antiserum to the very crude enterotoxic products of growth of a strain which also produces enterotoxin C, and then with antiserum to the considerably purified enterotoxic antigen of a strain which produces only the new enterotoxin. The identification of this antigen as enterotoxin D was based on the following observations. It was produced by strains which do not produce enterotoxins A, B, or C; it was absent in the growth products of nonenterotoxigenic strains; when appreciably purified, it was associated with emetic activity in the cat, and its biological activity was neutralized only by antisera containing its specific antibody and not by antibodies to enterotoxins A, B, and C. Staphylococcal strain 494 (ATCC 23235) was selected as the prototype strain. The production of this enterotoxin alone and together with enterotoxin A by strains of food-poisoning origin indicates that its role in food poisoning is second in frequency only to that of enterotoxin A. The incidence of production of enterotoxins A, B, C, and D, and of unidentified cat emetic substances by strains from several source categories, is presented. | Staphylococcal Food Poisoning |
The plastid genome regions of two intergenic spacers, psbA-trnH and trnL-trnF, were sequenced to study the nucleotide diversity and phylogenetic relationships among Gladiolus cultivars. Nucleotide diversity of psbA-trnH region was higher than trnL-trnF region of chloroplast. We employed Bayesian, maximum parsimony (MP) and neighbour-joining (NJ) approaches for phylogenetic analysis of Gladiolus and related taxa using combined datasets from chloroplast genome. The psbA-trnH and trnL-trnF intergenic spacers of Gladiolus and related taxa-like Babiana, Chasmanthe, Crocus, Iris, Moraea, Sisyrinchium, Sparaxis and two out group species (Hymenocallis littoralis and Asphodeline lutea) were used in the present investigation. Results showed that subfamily Iridoideae have sister lineage with subfamily Ixioideae and Crocoideae. H. littoralis and A. lutea were separately attached at the base of tree as the diverging Iridaceae relative's lineage. Present study revealed that psbA-trnH region are useful in addressing questions of phylogenetic relationships among the Gladiolus cultivars, as these intergenic spacers are more variable and have more phylogenetically informative sites than the trnL-trnF spacer, and therefore, are suitable for phylogenetic comparison on a lower taxonomic level. Gladiolus cultivars are extensively used as an ornamental crop and showed high potential in floriculture trade. Gladiolus cultivation still needs to generate new cultivars with stable phenotypes. Moreover, one of the most popular methods for generating new cultivars is hybridization. Hence, information on phylogenetic relationships among cultivars could be useful for hybridization programmes for further improvement of the crop. | Iridaceae |
Effects of propranolol (10(-9) to 10(-4) Gm/ml) on various electrophysiologic properties of human papillary muscles obtained from patients undergoing corrective open heart surgery were studied to have an insight into the mechanism of its antiarrhythmic activity in man. Propranolol (10(-8) to 10(-6) Gm/ml) produced significant decreases in the action potential duration, effective refractory period and dv/dt of depolarization phase of action potential without significantly affecting the resting potential and amplitude of action potential. These effects were concentration dependent. High concentration (10(-4) Gm/ml) of propranolol not only produced greater decreases in the above parameters but also reduced the resting potential and amplitude of action potential. Although propranolol decreased both the action potential duration and effective refractory period, the shortening of the action potential duration was greater than the shortening of the effective refractory period. It shifted the membrane responsiveness curve to the right and down. It produced frequency dependent decreases in the dv/dt of phase 0 of action potential and the rate of repolarization. Propranolol also increased the threshold of stimulation. Propranolol produced electrophysiologic changes in the human myocardium qualitatively similar to those in canine myocardium. The probable mechanism of its antiarrhythmic activity in man has been discussed. | Papillary Muscles |
Many elderly complain about oral dryness. This complaint can be the result of the use of drugs, because many drugs, such as anti-depressives, anti-psychotics and anti-hypertensives, have an anti-cholinergic or anti-adrenergic action. Knowledge of this potential side-effect of drugs as well as adjustment of schedules of drug usage may result in (partly) relief of dryness-related complaints. In this paper first of all mechanisms that underly negative regulation of salivary secretion are discussed. An overview is given of drugs with an salivary secretion inhibitory action. In addition, suggestions are presented to manage drug-induced hyposalivation. | Salivation |
Killer Ig-like receptor (KIR) genes are a multigene family on human chromosome 19. KIR genes occur in various combinations on different haplotypes. Additionally, KIR genes are polymorphic. To examine how allelic polymorphism diversifies KIR haplotypes with similar or identical combinations of KIR genes, we devised methods for discriminating alleles of KIR2DL1, -2DL3, -3DL1, and -3DL2. These methods were applied to 143 individuals from 34 families to define 98 independent KIR haplotypes at the allele level. Three novel 3DL2 alleles and a chimeric 3DL1/3DL2 sequence were also identified. Among the A group haplotypes were 22 different combinations of 2DL1, 2DL3, 3DL1, and 3DL2 alleles. Among the B group haplotypes that were unambiguously determined were 15 distinct haplotypes involving 9 different combinations of KIR genes. A and B haplotypes both exhibit strong linkage disequilibrium (LD) between 2DL1 and 2DL3 alleles, and between 3DL1 and 3DL2 alleles. In contrast, there was little LD between the 2DL1/2DL3 and 3DL1/3DL2 pairs that define the two halves of the KIR gene complex. The synergistic combination of allelic polymorphism and variable gene content individualize KIR genotype to an extent where unrelated individuals almost always have different KIR types. This level of diversity likely reflects strong pressure from pathogens on the human NK cell response. | Receptors, KIR3DL1 |
The folding of epithelial cell sheets is a fundamental process that sculpts developing tissues and organs into their proper shapes required for normal physiological functions. In the absence of detailed biochemical regulations, the epithelial sheet folding may simply proceed through buckling due to mechanical compression arising extrinsically from the surroundings or intrinsically within the sheets. Previous studies hypothesized that the formation of an expanding supracellular actomyosin ring within epithelial sheets could result in compression that ultimately leads to epithelial folding during tracheal development in the Drosophila (fruit fly) embryo. However, the exact mechanism by which the formation of epithelial folds is coordinated by the ring expansion remains unclear. Using a vertex-based mechanical model, here I systematically study the dependence of epithelial fold formation on the physical properties of expanding supracellular contractile rings. The simulations show that depending on the contractile strength, epithelial cell sheets can undergo distinct patterns of folding during ring expansion. The formation of folds in particular is robust against fluctuations in the ring properties such as ring numbers and tensions. These findings provide a systematic view to understand how the expansion of supracellular contractile rings in epithelial sheets mediates epithelial folding morphogenesis. | Cytokinesis |
Background: The aim of this study was to evaluate the impact of certain single-nucleotide polymorphisms (SNPs) in cabazitaxel activity and toxicity in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: 56 SNPs in five genes (CYP3A4, CYP3A5, ABCB1, TUBB1 and CYP2C8) were genotyped in 67 mCRPC patients and their correlation with outcomes analyzed. Results:TUBB1-rs151352 (hazard ratio: 0.52) and CYP2C8-rs1341164 (hazard ratio: 0.53) were associated with better overall survival, and CYP2C8-rs1058932 with biochemical progression (odds ratio: 6.60) in multivariate analysis. ABCB1-rs17327624 correlated with severe toxicity >/=grade 3 (odds ratio: 8.56) and CYP2C8-rs11572093 with asthenia (odds ratio: 8.12). Conclusion: Genetic variants in mCRPC patients could explain different outcomes with cabazitaxel. Nonetheless, the small sample size and the high number of SNPs analyzed mean that the results are only hypothesis-generating and require further validation. | Cytochrome P-450 CYP2C8 |
The importance of molecules with antiradical potency that are produced in the human body has significantly increased. Among others, neurotransmitters and their metabolites act as the first line of defense against oxidative stress in the peripheral endocrine and the central nervous systems. Dopamine (DO), epinephrine (EP), norepinephrine (NE), l-DOPA, catechol, and three metabolites of dopamine (3-methoxytyramine (3-MT), homovanillic acid (HO), and 3,4-dihydrophenylacetic acid (DOPAC)) were investigated for their antiradical potency via computational methods and DPPH assay. Density functional theory calculations were used to determine the most probable reaction mechanism based on the thermodynamic parameters. These results suggested that hydrogen atom transfer (HAT)/proton-coupled electron transfer (PCET) and sequential proton loss electron transfer (SPLET) mechanisms are preferable in polar solvents. Several techniques were employed to differentiate between HAT and PCET mechanisms via examination of the transition state structures. Kinetic studies of HAT/PCET and electron transfer (ET) reactions, the second step of SPLET, have proven that ET is much faster for an order of 10(5)-10(6). Based on this, it was concluded that SPLET was the dominant mechanism for the antiradical activity towards DPPH radicals in polar solvents. The findings suggest that all the investigated molecules can be classified as excellent antiradical scavengers, except for 3-MT and homovanillic acid. | Dopamine |
We used an indirect cohort analysis in children under 5 years-old from 2002 to 2018 to examine vaccine effectiveness (VE) of the 7-valent pneumococcal conjugate vaccine (PCV) (3 + 1 doses in most regions) and the 13-valent PCV (2 + 1 doses in all regions) against invasive pneumococcal disease (IPD) caused by vaccine serotypes in children in Canada. Cases were identified from the Canadian Immunization Monitoring Program ACTive (IMPACT), a national active surveillance network of 12 tertiary care pediatric hospitals that represent about 90% of tertiary care hospital beds in Canada. There were 1477 children evaluated for PCV7 VE and 489 for PCV13 VE. PCV7 VE in children with vaccination up to date for their age was 96% (95% CI: 67-99%) after a single dose and 95% (95% CI: 92-97%) after >/=2 doses. The VE was 91% (95% CI: 85-94%) in children who had received doses but were not up to date for their age. PCV13 VE in children with vaccinations up to date for their age was 55% (95% CI: 28-72%) after >/=2 doses. The PCV13-vaccine serotypes causing breakthrough IPD in children up to date for their age with 2+ doses of PCV13 were 3 (13/27, 48.2%),19A (11/27, 40.7%), and 19F (3/27, 11.1%). When serotype 3 and 19A were excluded, the VE of PCV13 against the remaining vaccine serotypes was 89% (95% CI: 64-97%) in children with >/=2 doses. The lower VE of PCV13 may be due to lower effectiveness against serotypes 3 and 19A, which could be influenced by the change in dosing schedule from 4 to 3 total doses with the introduction of PCV13, combined with vaccine uptake of 80%. However, PCV13 still provides the benefit of protection against more serotypes than PCV7, and good VE against all serotypes except 3 and 19A." | Heptavalent Pneumococcal Conjugate Vaccine |
The aim of this study was to determine whether blood plasma progesterone is a reliable indicator of pregnancy in mink at an early stage of gestation. We also attempted to establish the threshold value of progesterone as a pregnancy indicator. The analysis was carried out at a production farm on 42 standard female mink aged 1 year, which were grouped both according to the observed success of mating (mated" and "unmated") and the level of blood serum progesterone measured afterwards ("pregnant" and "nonpregnant"). It was next verified whether a particular female had been assigned to the proper group in the first place. An analysis of accuracy of mating success assessment within the group of unmated females revealed that more than one-third of decisions were wrong, since some females that had been considered unmated ultimately whelped. This suggests that mating supervision by farm workers lacks reliability. A progesterone test for verification of such management decisions should limit the risk of err,or. We suggest that progesterone tests could be carried out using the threshold values 1.9 ng/ml and 20 ng/ml in blood sampled on 25 March and 8 April, respectively, although some level of uncertainty should be taken into account." | Mink |
BACKGROUND: Morphine is an opioid analgesic used to relieve moderate-to-severe pain, including pain in neonates at the intensive care unit. In our previous study, we showed that repeated morphine exposure during early life could trigger long-lasting implications on the developing nervous system, such as long-term neurochemical and behavioral alterations in adult rats. AIMS: The aim of our study was to determine the short-, intermediate-, and long-term effects of repeated morphine administration during early life on the thermal and mechanical thresholds and on the central levels (cerebral cortex and brainstem) of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and cytokines (interleukin-6 [IL-6] and IL-10). METHODS: Male Wistar rats were administered morphine (5mug/day, s.c.) or saline for 7days from postnatal day 8 (P8) until P14. The nociceptive effect was assessed by evaluating the thermal response using the hot plate test (HPT) and the mechanical response by Von Frey (VFT) and Randall-Selitto (RST) tests at P16, P30, and P60. BDNF, NGF, IL-6, and IL-10 levels were measured in the cerebral cortex and brainstem. RESULTS: In HPT, no difference in latency was observed at P16; however, at P30 and P60, the morphine-treated group exhibited a less increase in the nociceptive threshold compared to the saline group. VFT and RST demonstrated an interaction between group and age, where the morphine group showed a less pronounced increase in latency with age, which is indicative of allodynia. In the cerebral cortex, an association between BDNF and NGF levels and age was observed, where neurotrophin level increased with age in the saline group, and decreased with age in the morphine group. In addition, IL-10 levels decreased with age in both groups; however, there was no significant difference in IL-6 levels. In the brainstem, BDNF, NGF, IL-6, and IL-10 levels increased with age. DISCUSSION: Repeated morphine exposure during neonatal life triggered alterations in the nociceptive behavior, including thermal hyperalgesia and mechanical allodynia, as well as decreased levels of BDNF and NGF in the cerebral cortex. Our study highlights the importance of extensive comprehension of the pharmacological interventions during CNS maturation. | Nociception |
The tandem nucleophilic addition and 5-exo-cyclization of (2-(alkynyl)benzylidene)malonates with imidazole derivatives in the presence of t-BuOK is reported. This reaction proceeds smoothly under mild conditions with high selectivity to afford the corresponding 1-(1H-imidazol-1-yl)-3-methylene-1H-indene-2,2(3H)-dicarboxylates in good to excellent yields. | Indenes |
Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is a promising alternative strategy as it is expected to generate less-selective resistance to treatment compared to antibiotics. Capitalizing on our nonligand-based benzamide-benzimidazole (BB) core structure compounds reported to efficiently block the activity of the P. aeruginosa multiple virulence factor regulator MvfR, here we report the first class of inhibitors shown to interfere with PqsBC enzyme activity, responsible for the synthesis of the MvfR activating ligands HHQ and PQS, and the first to target simultaneously MvfR and PqsBC activity. The use of these compounds reveals that inhibiting PqsBC is sufficient to block P. aeruginosa's acute virulence functions, as the synthesis of MvfR ligands is inhibited. Our results show that MvfR remains the best target of this QS pathway, as we show that antagonists of this target block both acute and persistence-related functions. The structural properties of the compounds reported in this study provide several insights that are instrumental for the design of improved MvfR regulon inhibitors against both acute and persistent P. aeruginosa infections. Moreover, the data presented offer the possibility of a polypharmacology approach of simultaneous silencing two targets in the same pathway. Such a combined antivirulence strategy holds promise in increasing therapeutic efficacy and providing alternatives in the event of a single target's resistance development. | Regulon |
We have studied the integration of adenovirus type 12 (Ad12) DNA in transformed and hamster tumor cells over many years. Upon infection of hamster cells with Ad12, viral DNA has been found in association with hamster chromosomes, possibly in part integrated into the host genome. Ad12 DNA integration is not sequence specific. Transcriptionally active sites of the host genome show a preponderance for foreign DNA insertion. We are pursuing the mechanism of Ad12 DNA integrative recombination in a cell-free system prepared from hamster cell nuclear extracts. In a number of Ad12-transformed hamster cell lines or in cell lines carrying foreign DNA, we have located the inserted Ad12 DNA copies on hamster chromosomes by fluorescent in situ hybridization (FISH). Among the consequences of Ad12 DNA integration, we have studied the de novo methylation of the integrated foreign (Ad12) DNA and increases in DNA methylation in several cellular genes and DNA segments in Ad12-transformed and hamster tumor cells. Several lines of evidence argue for the notion that parameters in addition to nucleotide sequence, in particular site of integration and/or the chromatin configuration of the integrated DNA, are important in generating de novo methylation patterns. The de novo methylation of integrated foreign DNA can be interpreted as an old cellular defense mechanism against the activity of foreign genes in an established genome. Pursuing this concept, we have asked for the most likely portal of entry of foreign DNA, supposedly the gastrointestinal tract in most animals. This hypothesis has been tested by feeding mice linearized or circular, double-stranded bacteriophage M13mp18 DNA.(ABSTRACT TRUNCATED AT 250 WORDS) | DNA, Viral |
BACKGROUND: An accurate assessment of transcription 'rate' is often desired to describe the promoter activity. In plants, isolation of transcriptionally active nuclei and their subsequent use in nuclear run-on assays has been challenging and therefore limit an accurate measurement of gene transcription 'rate'. Catharanthus roseus has emerged as a model medicinal plant as it exhibits an unsurpassed spectrum of chemodiversity, producing over 130 alkaloids through the terpenoid indole alkaloid (TIA) pathway and therefore serves as a 'molecular hub' to understand gene expression profiles. RESULTS: The protocols presented here streamline, adapt and optimize the existing methods of nuclear run-on assay for use in C. roseus. Here, we fully describe all the steps to isolate transcriptionally active nuclei from C. roseus leaves and utilize them to perform nuclear run-on transcription assay. Nuclei isolated by this method transcribed at a level consistent with their response to external stimuli, as transcription rate of TDC gene was found to be higher in response to external stimuli i.e. when seedlings were subjected to UV-B light or to methyl jasmonate (MeJA). However, the relative transcript abundance measured parallel through qRT-PCR was found to be inconsistent with the synthesis rate indicating that some post transcriptional events might have a role in transcript stability in response to stimuli. CONCLUSIONS: Our study provides an optimized, efficient and inexpensive method of isolation of intact nuclei and nuclear 'run-on' transcription assay to carry out in-situ measurement of gene transcription rate in Catharanthus roseus. This would be valuable in investigating the transcriptional and post transcriptional response of other TIA pathway genes in C. roseus. Isolated nuclei may also provide a resource that could be used for performing the chip assay as well as serve as the source of nuclear proteins for in-vitro EMSA studies. Moreover, nascent nuclear run-on transcript could be further subjected to RNA-Seq for global nuclear run-on assay (GNRO-Seq) for genome wide in-situ measurement of transcription rate of plant genes. | Catharanthus |
Lead-like drugs, or drugs below molecular weight 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chemistry practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescribed medications, as well as provide case studies on recently approved lead-like drugs. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of their medicinal chemistry optimization being the choice of a low molecular weight starting point and maintaining low molecular weight during the optimization. However, the identification of low molecular weight starting points may be limited by the availability of suitable low molecular weight screening sets. To increase the discovery rate of lead-like drugs, we suggest an increased focus on inclusion and prosecution of lead-like starting points in screening libraries. | Molecular Weight |
Protein-based methodologies are catching up with established DNA-based methods at an astonishing speed. Recent developments in mass spectrometry enable high-throughput automated identification of proteins as is already the case with DNA sequencing methods. Furthermore, methods for the quantitation of relative protein abundance at the protein level are getting more advanced, which should complement gene expression monitoring at the mRNA level. | Sequence Analysis, Protein |
The formation of a replication loop on the lagging strand facilitates coordinated synthesis of the leading- and lagging-DNA strands and provides a mechanism for recycling of the lagging-strand DNA polymerase. As an Okazaki fragment is completed, the loop is released, and a new loop is formed as the synthesis of a new Okazaki fragment is initiated. Loop release requires the dissociation of the complex formed by the interactions among helicase, DNA polymerase, and DNA. The completion of the Okazaki fragment may result in either a nick or a single-stranded DNA region. In the replication system of bacteriophage T7, the dissociation of the polymerase from either DNA region is faster than that observed for the dissociation of the helicase from DNA polymerase, implying that the replication loop is released more likely through the dissociation of the lagging-strand DNA from polymerase, retaining the polymerase at replication fork. Both dissociation of DNA polymerase from DNA and that of helicase from a DNA polymerase . DNA complex are much faster at a nick DNA region than the release from a ssDNA region. These results suggest that the replication loop is released as a result of the nick formed when the lagging-strand DNA polymerase encounters the previously synthesized Okazaki fragment, releasing lagging-strand DNA and retaining DNA polymerase at the replication fork for the synthesis of next Okazaki fragment. | DNA Primase |
INTRODUCTION: Many conditions of pelvic and sexual dysfunction can be addressed successfully through pelvic floor physical therapy (PFPT) through various manual therapy techniques, neuromuscular reeducation, and behavioral modifications. The field of pelvic rehabilitation, including sexual health, continues to advance to modify these techniques according to a biopsychosocial model. AIM: To provide an update on peer-reviewed literature on the role of PFPT in the evaluation and treatment of pelvic and sexual dysfunctions in men and women owing to the overactive and the underactive pelvic floor. METHODS: A literature review to provide an update on the advances of a neuromusculoskeletal approach to PFPT evaluation and treatment. MAIN OUTCOME MEASURE: The use and advancement of PFPT methods can help in successfully treating pelvic and sexual disorders. RESULTS: PFPT for pelvic muscle overactivity and underactivity has been proven to be a successful option for pelvic and sexual dysfunction. Understanding the role of the organs, nerves, fascia, and musculoskeletal system in the abdomino-pelvic and lumbo-sacro-hip region and how pelvic floor physical therapists can effectively evaluate and treat pelvic and sexual health. It is important for the treating practitioner to know when to refer to PFPT. CONCLUSION: Neuromusculoskeletal causes of pelvic floor disorders affect a substantial proportion of men, women, and children and PFPT is a successful and non-invasive option. Pelvic floor examination by healthcare practitioners is essential in identifying when to refer to PFPT. Use of a biopsychosocial model is important for the overall well-being of each patient. Further research is needed. Stein A, Sauder SK, Reale J. The role of physical therapy in sexual health in men and women: Evaluation and treatment. Sex Med Rev 2019;7:46-56. | Pelvic Floor Disorders |
Data are presented showing that the anomalous dissolution behavior of ticrynafen in simulated intestinal fluid without enzyme is due to the presence of potassium ions in the dissolution medium. Solubility studies indicate that an insoluble 1:1 complex is formed between ticrynafen and its potassium salt. This complex apparently creates an insoluble barrier that prevents complete dissolution of ticrynafen. To determine whether this might also occur in clinical use, a three-way cross-over study in 12 subjects was done. Data from this investigation show that concomitant administration of ticrynafen tablets and potassium in the form of a commercial supplement does not adversely affect bioavailability. | Glycolates |
Klenow and Klentaq are the large fragment domains of the Pol I DNA polymerases from Escherichia coli and Thermus aquaticus, respectively. Herein, we show that both polymerases can significantly stimulate complementary intermolecular end-joining ligations by E.coli DNA ligase when the polymerases are present at concentrations lower than that of the DNA substrates. In contrast, high polymerase concentrations relative to the DNA substrates inhibit the intermolecular ligation activity of DNA ligase. Neither polymerase was able to stimulate the DNA ligase from T4 bacteriophage. Additionally, nick-closure by E. coli DNA ligase (but not T4 ligase) is slightly stimulated by both polymerases, but only at about 10% of the magnitude seen for end-joining enhancement. The data represent one of the first observations of direct polymerase-ligase interactions in prokaryotes, and suggest that the polymerases stabilize the associated DNA ends during intermolecular ligation, and that such a complex can be taken advantage of by some, but not all, DNA ligases. | DNA Polymerase I |
PURPOSE: To provide expert guidance to clinicians and policymakers in resource-constrained settings on the management of patients with late-stage colorectal cancer. METHODS: ASCO convened a multidisciplinary, multinational Expert Panel that reviewed existing guidelines, conducted a modified ADAPTE process, and used a formal consensus process with additional experts for two rounds of formal ratings. RESULTS: Existing sets of guidelines from four guideline developers were identified and reviewed; adapted recommendations from five guidelines form the evidence base and provided evidence to inform the formal consensus process, which resulted in agreement of >/= 75% on all recommendations. RECOMMENDATIONS: Common elements of symptom management include addressing clinically acute situations. Diagnosis should involve the primary tumor and, in some cases, endoscopy, and staging should involve digital rectal exam and/or imaging, depending on resources available. Most patients receive treatment with chemotherapy, where chemotherapy is available. If, after a period of chemotherapy, patients become candidates for surgical resection with curative intent of both primary tumor and liver or lung metastatic lesions on the basis of evaluation in multidisciplinary tumor boards, the guidelines recommend patients undergo surgery in centers of expertise if possible. On-treatment surveillance includes a combination of taking medical history, performing physical examinations, blood work, and imaging; specifics, including frequency, depend on resource-based setting.Additional information is available at www.asco.org/resource-stratified-guidelines. | Colorectal Neoplasms |
The activities of the pristinamycin and its two components (RP 12536 and RP 27404) were investigated using the reference agar dilution method M11A3, on 175 anaerobic strains in comparison with that of erythromycin, clindamycin, metronidazole, amoxycillin either alone or combined with clavulanic acid, piperacillin, cefoxitin, cefotetan and cefotaxime. beta-lactamase production was detected for all the 55 B. fragilis group strains and 8/12 Prevotella and 2/18 Fusobacterium strains, respectively. On the whole anaerobes, resistance rates (%) were respectively: RP 27404 (69), RP 12536 (64), pristinamycin (5) erythromycin (31), clindamycin (17), metronidazole (7) amoxycillin (24), amoxycillin-clavulanic acid (2), piperacillin (7), cefoxitin (14), cefotetan (21) and cefotaxime (27). RP 27404 and 12536 had low activities on anaerobes but acted synergistically as pristinamycin. The greatest anti-anaerobic potencies were obtained with amoxycillin-clavulanic acid combination, pristinamycin, metronidazole and piperacillin. As resistance was not found for pristinamycin among Prevotella, Fusobacterium, Gram+ rods and Peptostreptococcus, this streptogramin may be an appropriate agent for the treatment of periodontitis, pulmonary, ENT, gynecologic and soft tissue infections where these anaerobes are frequently involved. | Pristinamycin |
Neurosurgery as an independent discipline in Serbia has a distinguished history, beginning in 1938 when Dr. Milivoje Kostic, Professor and Chairman of Surgery, opened the Department of Neurosurgery within the Clinic of Surgery in Belgrade. Since then, thanks to the founding fathers' efforts and their successors' work, the Clinic for Neurosurgery in Belgrade has become a highly specialized health, scientific, and educational institution that is part of the University of Belgrade and is a referral center for all neurosurgical clinics in Serbia. Currently, the Clinic for Neurosurgery, with 160 patient beds, is one of the largest European institutions of its kind. Neurosurgery at the Clinical Center of Serbia (CCS) involves a wide range of patients and resources, with an average daily inpatient census of 15 to 20 patients. Each year, there are more than 3000 admissions at the neurosurgical service. Approximately 3500 operations per year are performed in the main campus neurosurgical operating rooms of CCS, while approximately 15,000 patients alone are evaluated in emergency room or inpatient consultations. Despite economic restraints, the department continues to grow in strength, and we remain optimistic of exciting times ahead for neurosurgery at the CCS. | Neurosurgery |
The organophosphates, diisopropyl phosphorofluoridate and soman have a common mechanism of action (inhibition of acetylcholinesterase), but result in very different behavioral responses in the rat. Soman rapidly produced persistent tonic convulsions whereas diisopropyl phosphorofluoridate only infrequently produced transient convulsive-like activity. Soman increased local cerebral glucose use in most of the cortex, striato-pallido-nigral pathway, limbic system and in specific thalamic nuclei whereas diisopropyl phosphorofluoridate increased glucose use in a limited fashion, primarily in the dorsal striato-pallido-nigral pathway. When diazepam blocked soman-induced convulsions, the pattern of glucose use was strikingly similar to that caused by diisopropyl phosphorofluoridate. Soman or diisopropyl phosphorofluoridate depressed local cerebral glucose use in rats pretreated with the antidotal mixture of trimedoxime, atropine and benactyzine (muscarinic antagonists). Also, this antidotal mixture blocked the increased glucose use in the dorsal striato-pallido-nigral system produced by either acetylcholinesterase inhibitor, indicating that muscarinic receptors mediate the excitation of this pathway. Both diisopropyl phosphorofluoridate and soman activate the striato-pallido-nigral pathway but soman also causes spread of activity producing overt motor convulsions. Possible explanations for this difference in response to the organophosphates are differential responses in cholinergic actions within specific brain regions or some non-cholinergic action of soman. | Benactyzine |
Cancer is a public health problem in the world and breast cancer is the most frequently cancer in women. Approximately 15% of the breast cancers are triple-negative. Apoptosis regulates normal growth, homeostasis, development, embryogenesis and appropriate strategy to treat cancer. Bax is a protein pro-apoptotic enhancer of apoptosis in contrast to Bcl-2 with antiapoptotic properties. Initiator caspase-9 and caspase-8 are features of intrinsic and extrinsic apoptosis pathway, respectively. NF-kappaB is a transcription factor known to be involved in the initiation and progression of breast cancer. Noscapine, an alkaloid derived from opium is used as antitussive and showed antitumor properties that induced apoptosis in cancer cell lines. The aim of the present study was to determine the apoptotic effect of noscapine in breast cancer cell lines compared to breast normal cell line. Three cell lines were used: i) a control breast cell line MCF-10F; ii) a luminal-like adenocarcinoma triple-positive breast cell line MCF-7; iii) breast cancer triple-negative cell line MDA-MB-231. Our results showed that noscapine had lower toxicity in normal cells and was an effective anticancer agent that induced apoptosis in breast cancer cells because it increases Bax gene and protein expression in three cell lines, while decreases Bcl-xL gene expression, and Bcl-2 protein expression decreased in breast cancer cell lines. Therefore, Bax/Bcl-2 ratio increased in the three cell lines. This drug increased caspase-9 gene expression in breast cancer cell lines and caspase-8 gene expression increased in MCF-10F and MDA-MB-231. Furthermore, it increased cleavage of caspase-8, suggesting that noscapine-induced apoptosis is probably due to the involvement of extrinsic and intrinsic apoptosis pathways. Antiapoptotic gene and protein expression diminished and proapoptotic gene and protein expression increased noscapine-induced expression, probably due to decrease in NF-kappaB gene and protein expression and also by increase of IkappaBalpha gene expression induced by this drug. | Noscapine |
We have biotinylated the terminal glycose of digoxin by reaction of the periodate-oxidized steroid with biotin hydrazide. A biotinylated product (BD-1) was formed which retained significant digoxin receptor (Na+/K+ ATPase) binding activity. Sustained reaction resulted in a second biotinylated product (BD-2) which showed reduced receptor binding activity. The products were characterized by FAB mass spectroscopy and shown to be the mono- and di-biotinylated digoxin conjugates of the oxidized glycose moiety. These analogues may prove useful in determining the subcellular site of digoxin binding. | Digoxin |
Cerebral venous sinus thrombosis (CVST) is an uncommon cerebrovascular disorder that gained massive media attention in 2021, when an association between COVID-19 and its vaccines was found in several reported cases, raising the suspicion of a causative relation that is still debated. Three cases of CVST unrelated to COVID-19 are reported in this article to highlight the difficulty in the early recognition and management of this condition, as it occurs in a variety of diseases with different clinical and pathological manifestations. When the diagnosis cannot be achieved in the clinical setting, the role of the pathologist becomes essential in the determination of the cause of death and in the identification of the etiology of CVST. During the autopsy, coordination between the physician and the forensic pathologist is crucial to correlate the clinical presentation with the pathological picture." | Sinus Thrombosis, Intracranial |
Gasification is an important option for the swift implementation of biomass combined heat and power processes in the Danish energy supply system. Tar-water produced by the gas-cleaning system of gasifiers may contain substances toxic to nitrifying bacteria. As the gasification plants are small and often located in the catchment area of small wastewater treatment plants, discharge of the tar-water may be critical for wastewater treatment plants operated with nitrogen removal. Tar-water from a full-scale updraft gasifier has been thoroughly examined with respect to inhibition of nitrification and the toxicity for nitrifying bacteria has been evaluated for the dominating constituents in the tar-water. Simple organic substances make up the dominating part of the organic matter but phenol and phenolic compounds are also present in significant concentrations. The identified substances are biologically degradable and it has been demonstrated that most of the organic matter together with the toxicity can be eliminated in an aerobic activated sludge process. | Tar-Water |
Thermal properties are necessary for the design and control of processes and storage facilities of food materials. This study proposes the measurement of thermal properties using easily constructed probes with specific heat capacity calculated, as opposed to the use of Differential Scanning Calorimeter (DSC) or other. These probes were constructed and used to measure thermal properties of white radish in the temperature range of 80-20 degrees C and moisture content of 91-6.1% wb. Results showed thermal properties were within the range of 0.71-0.111 Wm-1 C-1 for thermal conductivity, 1.869x10-7-0.72x10-8 m2s-1 for thermal diffusivity and 4.316-1.977 kJ kg-1C-1for specific heat capacity. These results agree with reports for similar products studied using DSC and commercially available line heat source probes. Empirical models were developed for each property through linear multiple regressions. The data generated would be useful in modeling and control of its processing and equipment design. | Thermal Conductivity |
The published data on the lipids composition of influenza virus, the significance of lipid-protein interactions for support of the virion structure are reviewed. The roles of viral and cellular membrane lipids in the different stages of viral interaction with the host cell: viral adsorption to the cellular surface, penetration into the cell, maturation and assembly of virions are discussed. The data on the significance of lipid composition phenotype of the virus and host cell in realization of the viral infection of the cell are reviewed. | Orthomyxoviridae |
Partial veneer gold restorations, such as gold onlays, have changed little in preparation design over the past 40 years, as evidenced by textbooks that have long been in print. Such designs must have been based on the assumption that restorations would be luted with zinc phosphate cement but have not altered, despite the introduction of stronger luting cement classes, such as resin composite and resin-modified glass ionomer cements. It is well-established that both porcelain and base metal materials, which have been etched on the intaglio surface, can be combined with resin composite luting cements to produce restorations retained largely through adhesion. However, neither of these materials can equal the combination of minimal tooth reduction and margin adaptation that is possible with high noble gold restorative materials. Although high noble gold alloys cannot be etched, air abrasion of the intaglio surface of restorations likely improves micromechanical retention, but it is unknown whether this, along with a strong luting cement, is sufficient to stabilize high noble gold alloys in preparations with considerably less retention and resistance form than traditional designs. | Cracked Tooth Syndrome |
Isometric tension, unloaded shortening velocity (Vus), and myosin light chain phosphorylation were measured with skinned chicken gizzard fibers at various Ca2+ concentrations and at two concentrations of free Mg2+, 0.7 and 2.2 mM. At low free Mg2+, an increase in Ca2+ from pCa 8.0 to 6.4 resulted in an increase of all three parameters. Between pCa 6.4 and 5.0, isometric tension and phosphorylation remained constant but Vus continued to increase. At low free Mg2+, therefore, Vus showed a dependence both on phosphorylation and on Ca2+. At high free Mg2+, tension and Vus increased as phosphorylation increased and both were maximum at pCa 6.4, where phosphorylation became constant. Therefore, at high free Mg2+, Vus was dependent only on phosphorylation and did not show an additional Ca2+ dependence. Incubation of the Ca2+-independent kinase (approximately 3 microM) with skinned fibers under various conditions resulted in a constant level of phosphorylation (49-58%). At high free Mg2+ plus the Ca2+-independent kinase Vus was independent of Ca2+, whereas at low free Mg2+ Vus increased from pCa 6.4 to 5.0. These data are consistent with the hypothesis that Ca2+ binding to the Ca2+-Mg2+ sites of myosin increase Vus and that this occurs at Ca2+ concentrations higher than those necessary to saturate calmodulin. | Stomach, Avian |
The cell plasma membrane is a complex system, which is thought to be capable of exhibiting non-random lateral organization. Studies of live cells and model membranes have yielded mechanisms responsible for the formation, growth, and maintenance of nanoscopic heterogeneities, although the existence and mechanisms that give rise to these heterogeneities remain controversial. Small-angle neutron scattering (SANS) is a tool ideally suited to interrogate lateral heterogeneity in model membranes, primarily due to its unique spatial resolution (i.e., ~5-100nm) and its ability to resolve structure with minimal perturbation to the membrane. In this review we examine several methods used to analyze the SANS signal arising from freely suspended unilamellar vesicles containing lateral heterogeneity. Specifically, we discuss an analytical model for a single, round domain on a spherical vesicle. We then discuss a numerical method that uses Monte Carlo simulation to describe systems with multiple domains and/or more complicated morphologies. Also discussed are several model-independent approaches that are sensitive to membrane heterogeneity. The review concludes with several recent applications of SANS to the study of membrane raft mixtures. | Scattering, Small Angle |
Torque curves were recorded during passive and active ankle joint movements at three preset angular velocities (30, 60 and 120 degrees/s) with the subject in the supine position and 45 degrees hip and knee angles. Recordings were performed in normal subjects (n = 11), patients with clinical spasticity (n = 10) and patients with Parkinson's disease (n = 7). The torque curves recorded during passive dorsiflexion followed by plantar flexion showed a counterclockwise hysteresis loop with minimal area in the normal subjects and a large area in patients, especially at the highest velocity. The torque increase during dorsiflexion was proportional to the angular velocity in the patients with spasticity but not in the patients with Parkinson's disease. In the patients with spasticity, a good correlation was found between clinical assessment of hypertonia and measurements of torque during passive movements but not torque values during maximal voluntary dorsiflexion. A model for data reduction and estimation of instant slope values on different parts of the torque-angle curve is suggested. The use of ankle torque recordings for evaluation of treatment effects is exemplified. | Muscle Hypertonia |
Anorectal disorders affect men and women of all ages. Their management is not limited to the evaluation and treatment of hemorrhoids. Rather, a spectrum of anorectal disorders ranges from benign and irritating (pruritus ani) to potentially life-threatening (anorectal cancer). Symptoms are nonspecific, which can make the evaluation of patients difficult. In addition, treatment can be frustrating because clinicians are hamstrung by a lack of well-designed, prospective, clinical trials. Some of the most common anorectal disorders include fecal incontinence, pelvic floor dyssynergia, anal fissures, pruritus ani, proctalgia fugax, and solitary rectal ulcer syndrome. This article provides an update on the evaluation and treatment of common anorectal disorders. | Rectal Diseases |
Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene are associated with familial and sporadic cases of Parkinson's disease but are also found in immune-related disorders such as inflammatory bowel disease, tuberculosis and leprosy. LRRK2 is highly expressed in immune cells and has been functionally linked to pathways pertinent to immune cell function, such as cytokine release, autophagy and phagocytosis. Here, we examine the current understanding of the role of LRRK2 kinase activity in pathway regulation in immune cells, drawing upon data from multiple diseases associated with LRRK2 to highlight the pleiotropic effects of LRRK2 in different cell types. We discuss the role of the bona fide LRRK2 substrate, Rab GTPases, in LRRK2 pathway regulation as well as downstream events in the autophagy and inflammatory pathways." | Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 |
This report concerns the antenatal visualization and velocimetry of an arterioarterial and a venovenous anastomosis in a monochorionic twin pregnancy using color Doppler sonography. The phenomenon of 'interference beating' occurs when two flow velocity waveforms are superimposed in one blood vessel. This characteristic image can be generated antenatally to confirm the existence of a vascular communication. We were able to reveal these anastomoses postnatally using the dye injection technique. | Arteriovenous Anastomosis |
Encephalitis is an inflammatory process involving the parenchyma of the brain. It typically presents as a clinical syndrome characterised by fever, headache and altered conscious level, often with focal neurological deficits and fits. The clinical presentation overlaps with other diseases of the central nervous system including viral and bacterial meningitis, and brain abscess. The causes of encephalitis are legion, and include principally viral but also bacterial, parasitic and fungal pathogens. Noninfectious aetiologies, especially autoimmune conditions such as potassium channel voltage gated antibodies and anti-NDMA receptor antibodies, are increasingly recognised. Diagnosis comes from clinical examination, neuroimaging and laboratory testing. With such a wide range of potential pathogens a syndromic approach to diagnosis is preferred, testing for a range of organisms. Traditional techniques such as cell culture and direct virus antigen detection have little or no role nowadays. Laboratory diagnosis of viral encephalitis is ideally based on examination of cerebrospinal fluid (CSF) for cells, protein and glucose, followed by nucleic acid amplification tests (NAAT) such as polymerase chain reaction (PCR) for a range of viral targets. Samples other than CSF sometimes give a definitive or probable aetiological diagnosis; examples include skin biopsy in rabies, and serum NAAT and antibody tests for some arboviruses and enteroviruses. Newer approaches to amplification and to multitarget detection are becoming increasingly important. Detection of intrathecal antibody production against specific viruses retains a place in diagnosis where NAAT is negative. Some of the laboratory techniques available will be discussed in this article. | Encephalitis Viruses |
OBJECTIVE: To investigate the infection of ginsenoside Re on the absorption of glucose in Caco-2 cells. METHODS: The Ca-co-2 cells were incubated with phloretin and ginsenoside Re. LC-MS/MS was used to detect the absorption of glucose in cells through the stable isotope tracer technique, and to detect the GLUT2 protein and mRNA expression level. RESULTS: Phloretin could inhibit the absorption of glucose significantly. 50 micromol/L ginsenoside Re could improve the glucose absorption inhibited by phloretin,and increase the GLUT2 protein and mRNA expression level. CONCLUSION: Ginsenoside Re can promote the absorption of glucose in Caco-2 cells and reverse the inhibition of phloretin, the mechanism of improving glucose absorption was maybe through regulating GLUT2. | Glucose Transporter Type 2 |
This work compared the presence of phospholipase A(2) inhibitors (PLIs) in the serum of 19 snake species maintained at Instituto Butantan to better understand the mechanisms of venom resistance in snakes and improve the treatment of snakebite. PLI was isolated from blood of 19 snake species by one-step chromatography and identified in all samples, besides its identity was confirmed through the interaction with both phospholipase A(2) and anti-gammaPLI. These findings highlight the diversity of snake serum PLIs and emphasize the importance of structure-function studies. | Phospholipase A2 Inhibitors |
The dried powder of Paracoccus carotinifaciens (PANAFERD-AX((R))) contains (3S,3'S)-astaxanthin as a major carotenoid. Administration of PANAFERD-AX((R)) for pigmentation of the prawn Penaeus japonicus was examined. Total carotenoid contents in the carapace, muscle, and head of the prawn were dose-dependently increased depending on the amount of PANAFERD-AX((R)) administered. Furthermore, not only the amounts of astaxanthins (astaxanthin diester, astaxanthin monoester, and free astaxanthin) but also the amounts of yellow xanthophylls, isoastaxanthin (1), 5,6-dihydropenaeusxanthin (2), penaeusxanthin (3), tetrahydroxypirardixanthin (4), and curstaxanthin (5), were dose-dependently increased with the administration of PANAFERD-AX((R)). 5,6-Dihydropenaeusxanthin (2) and penaeusxanthin (3) are new carotenoids isolated from the prawn P. japonicus. These structures were determined to be (3R,4S,5R,6R,6'S)-5,6-dihydro-3,4,4'- trihydroxy-beta,epsilon-caroten-3'-one (2) and (3R,4S,6'S)-3,4,4'-trihydroxy-beta,epsilon-caroten-3'-one (3) by UV/vis, ESI TOF MS, (1)H NMR, and CD spectral data. The metabolism of astaxanthin to these yellow xanthophylls in the prawn was discussed. | Xanthophylls |
ETHNOPHARMACOLOGICAL RELEVANCE: Boophone disticha (Amaryllidaceae) is one of the most common bulbous plants used for medicinal purposes by the indigenous people of southern Africa. Its use as a narcotic substance by the Khoi/San tribes has been known for several centuries, while the Sotho, Xhosa and Zulu people are known to use the plant to treat a host of ailments, including inflammation, wounds, gynaecological conditions and psychosis. AIM OF THE STUDY: Much of the pharmacological work on the plant, such as affinity to the serotonin transporter, has been based on its reputed usage for narcotic purposes. However, its widespread use to treat wounds and infections has not been linked to a specific chemical entity. In this regard, Boophone disticha was here examined for its phytochemical composition which could shed light on the use of the plant for such purposes. MATERIALS AND METHODS: The known crinane alkaloids buphanidrine and distichamine were isolated via column chromatography of the ethanolic extract of bulbs of Boophone disticha. Structural details of the compounds were determined by high field 2D NMR and mass spectroscopic techniques. Microbial activity against selected Gram-positive and Gram-negative bacteria was ascertained according to the micro-dilution assay. RESULTS: Both buphanidrine and distichamine were uncovered as novel, broad spectrum moderately active, antibacterial agents with the best MIC value detected at 0.063mg/ml for Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae. MIC values for Bacillus subtilis were two-fold less than that observed for the other three bacteria, suggesting that the extract and pure compounds were selective in their interaction with the bacterial pathogens. CONCLUSION: Phytochemical investigation of Boophone disticha has led to the identification of two known crinanes, buphanidrine and distichamine. Based on the reputed traditional use of the plant for wounds and infections, both compounds were screened for antibacterial activity which revealed them to be novel, broad spectrum antibacterial agents with the best MIC value set at 0.063mg/ml. Their close structural similarity may have bearing on their similar activity profiles. | Amaryllidaceae Alkaloids |
OBJECTIVE: Vulvar vestibulitis syndrome (VVS) is thought to be the most frequent cause of dyspareunia in premenopausal women and is one of the major subtypes of vulvodynia. Vulvar vestibulitis is a chronic, persistent clinical syndrome characterized by severe pain on vestibular touch or attempted vaginal entry, exquisite tenderness to a cotton-swab palpation of the vestibular area, and physical findings confined to vestibular erythema. The purpose of this paper is to critically review the descriptive, diagnostic, etiologic, and treatment studies on VVS. Methodological problems are highlighted, and future guidelines for research are proposed. DATA SOURCES: References were obtained from a MEDLINE search covering the period from January 1984 until June 1995. The indexing term vulvar vestibulitis" was used, and the search was constrained to English-language articles. References from other relevant sources, such as texts and bibliographies, were also included. STUDY SELECTION: All articles pertaining to VVS were reviewed. DATA EXTRACTION: All data relevant to the descriptive, diagnostic, etiologic, and treatment aspects of VVS were included. DATA SYNTHESIS: Pain symptomatology tends to be underemphasized in the current descriptive studies. The trend in etiological research is to focus on biomedical factors such as candidiasis and human papillomavirus (HPV). Only a few studies adopt a nonreductionnist approach. Surgery is the treatment option with the highest reported success rate. Medical management is underinvestigated, considering its widespread use. Pain management techniques such as biofeedback and behavior therapy show promising results. CONCLUSIONS: A pain syndrome conceptualization is suggested as the most useful approach for solving current empirical and clinical problems." | Vulvar Diseases |
Objective The aims of this study were to: (1) identify the characteristics of patients with chronic hepatitis B (CHB) who do not attend their hospital liver clinic appointments; and (2) raise awareness among general practitioners (GP) of alternative pathways to care for CHB in order to prevent long-term complications of CHB (liver cancer and cirrhosis). Methods This prospective study was conducted between May 2018 and January 2019 at one site of a tertiary referral hospital in western Melbourne. Patients with minimal liver complications who did not attend their first two initial appointments were included in the study, in addition to referring GPs of new CHB patients to the liver clinic who had minimal liver complications (characterised by minimal fibrosis (<7kPa)) and no liver comorbidities (including cirrhosis and/or hepatocellular carcinoma). GPs of patients who failed to attend the liver clinic as a new patient were sent an alternative discharge letter that included information on alternative pathways to care in the community for their patients. A follow-up survey to referring GPs was conducted afterwards for feedback. Demographic data was also collected for included patients. Results Thirty patients with non-complicated CHB were included in the study (median age 32.5 years). Patients were from 11 different countries and six regions. The mean wait time from referral to clinic date was 424 days (SD 218.9). Only four GPs responded to the letter, with non-responding GPs surveyed primarily not participating due to having over 1 year of no contact from the patient or hospital. Conclusion This study showed that there were long waiting lists for CHB referrals and alerting GPs to alternative pathways after patients failed to attend appointments was ineffective. There needs to be improved coordination between tertiary and primary services to provide timely and effective care for patients with CHB. What is known about this topic? There are 239000 Australians living with CHB: most recent estimates indicate that only 62% have been diagnosed, 15% are being monitored and 6% of those requiring treatment are receiving antiviral therapy. The complications of CHB (liver cancer and cirrhosis) can be averted by routine monitoring and timely commencement of highly effective oral antiviral therapy. In Australia, both GPs and specialists in gastroenterology and infectious diseases are involved in the management of CHB patients, but most prescribing occurs in specialist services. The current specialist-centred model of CHB care has been described as neither practical nor sustainable given the limited resources and capacity of specialist services, and the challenges for people with CHB to access public hospitals for routine care. What does this paper add? Non-attending patients were a primarily young population. The median wait time for a clinic appointment in this hospital setting was 424 days, with some patients waiting >/=800 days for an appointment. This extensive wait time for a largely asymptomatic condition may have affected attendance rates. Although this particular intervention to engage GPs in collaborative care had limited results, it is clear that management of CHB by GPs, transparency in wait lists and adequate resourcing of specialist services would help alleviate the referral burden on hospitals. What are the implications for practitioners? GPs should be aware that waiting lists for liver clinic appointments can be extensive in public hospital settings due to the high referral burden and limited resources of these services. Alternative pathways to care, such as GPs trained to prescribe Schedule 100 drugs, are an effective means of alleviating this burden while also ensuring CHB patients are seen in a timely manner and receive routine monitoring. | Hepatitis B, Chronic |
Pepper spray launchers are more precise and wind stable compared to conventional pepper sprays and are commonly used as a self-defensive tool. With the advanced potential, they may also harbour a greater risk for injuries, especially if they are not used within the suggested safety distance. If the shooting distance is below 1.5 m, energy densities may exceed the threshold energy density for the penetration of skin leading to skin laceration. We present a case where a man is hit by the liquid jet of a JPX Jet Protector(R) with an estimated shooting distance of 0.3 m. The man suffered from a bleeding skin laceration, which had to be sewed in the hospital. This case report furthermore outlines the potentially dangerous effect of pepper spray launchers and thereby their role in forensic investigations. | Lacerations |
Two neuropeptides, neuropeptide B (NPB) and prolactin-releasing peptide (PrRP), have been suggested to play important roles in control of the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The aim of the present study was to clarify the central actions of NPB or PrRP in sheep. Ovariectomized ewes were surgically implanted with a cannula directed to the lateral ventricle. They received intracerebroventricular (icv) administration of 400 mul of artificial cerebrospinal fluid, NPB (0.05, 0.5 or 5 nmol), PrRP (0.5, 5 or 50 nmol) or corticotropin-releasing hormone (CRH, 0.5 or 5 nmol) through the cannula, and blood samples were taken 30 and 0 min prior to and 15, 30, 60 and 90 min after the injection. Cortisol concentrations in plasma were determined by enzyme immunoassay. Administration of 0.5 nmol NPB resulted in a significant increase in the cortisol concentration compared with the vehicle control, whereas the cortisol concentration after lower or higher doses of NPB did not differ from the control value. Thus, an icv injection of NPB produced a bell-shaped dose-response of cortisol concentration. Administration of PrRP had no significant effect on the cortisol concentrations at any dose examined. Icv injection of CRH dose-dependently increased plasma cortisol concentrations. These results demonstrate that central NPB stimulates cortisol secretion, suggesting that this neuropeptide plays some roles in control of the HPA axis in sheep. On the other hand, unlike its role in rodents, PrRP is unlikely to be involved in control of the HPA axis in this species. | Prolactin-Releasing Hormone |
Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott-Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects." | Wiskott-Aldrich Syndrome Protein Family |
BACKGROUND: A new technique in plastic surgery termed Osteogenesis Modulation is described. This technique uses a surgically implanted, battery-operated medical device to deliver customized electrical pulses to produce mandibular bone growth. This device was designed to be a temporary, nonpermanent implant. The purpose of this study was to review both the safety and efficacy of Osteogenesis Modulation. METHODS: This study comprises two phases. Phase I involved experimental technology development and animal experiments. Phase II included technology development for clinical use and a clinical trial. In Phase II, four patients with a diagnosis of mandibular hypoplasia and microgenia underwent surgical implantation of the novel medical device over the chin bone. Once a satisfactory change of contour of mandibular bone was achieved, the devices were removed. In all patients, the devices were left in place for 12 months, then surgically removed under local anesthesia. Preoperative and long-term postoperative cephalometric controls were done. RESULTS: In all patients, symmetrical mandibular bone growth was observed with good-to-excellent aesthetic results. The overall follow-up period was 39 months. Cephalometric controls taken 3 to 6 months after the device removal showed an average increase in mandible length of 5.26mm (range, 2.83-7.60mm) CONCLUSIONS: Preliminary clinical results suggest that Osteogenesis Modulation is a safe, minimally invasive, and effective alternative treatment for the correction of mandibular hypoplasia in selected cases. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . | Genioplasty |
BACKGROUND: Shenmai injection (SM), as a traditional Chinese medicine injection, is widely used for chronic cor pulmonale heart failure in mainland China. It is essential to systematically assess the efficacy and safety of SM as an adjuvant treatment for chronic cor pulmonale heart failure. METHODS: Eight English and Chinese electronic databases were searched, from inception to December 2014, to identify randomized controlled trials (RCTs) of SM for chronic cor pulmonale heart failure. The Cochrane Risk of Bias tool was used to evaluate the methodological quality of eligible studies. Meta-analysis was performed by Review Manager 5.2. RESULTS: Twenty-seven RCTs with 2045 participants were identified. The methodological quality of the included studies was generally low. Only one trial reported data on death. None of the included trials reported quality of life. The meta-analysis indicated that compared to conventional treatment, the combination of SM and conventional treatment was more effective in terms of the New York Heart Association classification (RR, 1.26; 95% CI, 1.20-1.32; P < 0.00001), Left Ventricular Ejection Fraction (MD, 11.33; 95% CI, 8.59-14.07; p < 0.00001), partial pressure of oxygen (MD, 1.00; 95% CI, 0.64-1.36; P < 0.00001) and partial pressure of carbon dioxide (MD, 0.83; 95 % CI, 0.58-1.08; p < 0.00001). In addition, two trials reported that SM plus conventional treatment was superior to the conventional treatment alone to reduce B-type natriuretic peptide. No serious adverse drug events or reactions were reported. CONCLUSIONS: SM plus conventional treatment appeared to be effective and relatively safe for chronic cor pulmonale heart failure. However, due to the generally low methodological quality and small sample size, this review didn't find evidence to support routine use of SM as an adjuvant treatment for chronic cor pulmonale heart failure. | Adjuvants, Pharmaceutic |
Although dehydration of >/= 2% body weight (BW) loss significantly impairs endurance performance, dehydration remains prevalent among athletes and may be owing to a lack of knowledge in relation to fluid requirements. The aim of this study was to assess the hydration status of university/club level athletes (n = 430) from a range of sports/activities (army officer cadet training; bootcamp training; cycling; Gaelic Athletic Association camogie, football and hurling; golf; hockey; netball; rugby; running (sprinting and endurance); Shotokan karate and soccer) immediately before and after training/competition and to assess their nutritional knowledge. Urine specific gravity (USG) was measured immediately before and after exercise and BW loss during exercise was assessed. Nutritional knowledge was assessed using a validated questionnaire. 31.9% of athletes commenced exercise in a dehydrated state (USG >1.020) with 43.6% of participants dehydrated posttraining/competition. Dehydration was particularly prevalent (>40% of cohort) among karateka, female netball players, army officer cadets, and golfers. Golfers that commenced a competitive 18 hole round dehydrated took a significantly higher number of strokes to complete the round in comparison with their euhydrated counterparts (79.5 ÃÂ+/- 2.1 vs. 75.7 ÃÂ+/- 3.9 strokes, p = .049). Nutritional knowledge was poor among participants (median total score [IQR]; 52.9% [46.0, 59.8]), albeit athletes who were euhydrated at the start of exercise had a higher overall score in comparison with dehydrated athletes (55.2% vs. 50.6%, p = .001). Findings from the current study, therefore, have significant implications for the education of athletes in relation to their individual fluid requirements around exercise. | Sports Nutritional Sciences |
Excessive ingestion of magnesium may lead to hypermagnesemia even without kidney dysfunction. Several cases of development of hypermagnesemia after overdose of magnesium hydroxide have been reported. Although magnesium hydroxide is widely used as laxative, its overdose may induce diarrhea, which is followed by excessive magnesium loss. I report a case of paradoxical hypomagnesemia developed after excessive ingestion of magnesium hydroxide. A 39-year-old woman was presented to the emergency department complaining of severe watery diarrhea and carpopedal spasm after ingesting a handful of magnesium hydroxide tablets. The laboratory tests detected hypomagnesemia, hypocalcemia, and normokalemia. Calcium gluconate was given to the patient, but her symptom did not improve shortly. The symptom disappeared spontaneously 2 days after the watery diarrhea subsided. This case shows that overdose of magnesium hydroxide, which leads to massive diarrhea, might induce hypomagnesemia unexpectedly. This case also suggests that it should be treated, as well as typical magnesium deficiency. | Magnesium Hydroxide |
Migraine is a devitalizing neurovascular disorder that affects millions of people worldwide. This study was directed against the determination of the effectiveness of carvacrol against migraine. In silico results revealed that carvacrol possesses specific scoring values of - 4.4 to - 6 against selected targets. In vivo studies showed that carvacrol (25-50 mg/Kg) decreased migraine pain by reversing thermal allodynia, mechanical allodynia, number of head-scratching, and light phobicity in rats. Levels of glutathione, glutathione-s-transferase, and catalase enhanced in the cortex and trigeminal nucleus caudalis of the animal's brain tissues, i.e., cortex and trigeminal nucleus caudalis with the use of carvacrol, while a significant decrease in lipid peroxide level was seen. Histopathological evaluation showed improvement in cellular architecture and a decrease in expression of certain inflammatory markers such as tumor necrosis factor-alpha, nuclear factor kappa B, interleukin-18, and prostaglandin E2 validated by enzyme-linked immune sorbent assay, immunohistochemistry, and western blot analysis. This study indicates that carvacrol exhibits binding affinities against different targets involved in migraine pathology and possesses anti-migraine action, mediated through anti-inflammatory and anti-oxidant pathways. | Cymenes |
Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry is a rapid and accurate tool for the identification of many microorganisms. We assessed this technology for the identification of 103 Haemophilus parainfluenzae, Aggregatibacter aphrophilus, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae (HACEK) clinical isolates and 20 Haemophilus influenzae clinical isolates. Ninety-three percent of HACEK organisms were identified correctly to the genus level using the Bruker database, and 100% were identified to the genus level using a custom database that included clinical isolates. | Pasteurellaceae |
The formation of an iron-nitrogen compound in an electrospray ionization instrument is reported. The iron was released from the stainless steel electrospray needle by acetic acid added to displace trifluoroacetic acid and the nitrogen was present as the drying gas. The product is an iron nitride ion, [N(2)FeOH](1+), m/z 100.9438, and is capable of addition to peptides and proteins. | Electrophoresis, Paper |
Psychiatric disorders induced by drugs are of most concern when they occur in the context of therapeutic use of a drug. Such iatrogenic psychiatric disturbances may interfere considerably with the treatment of the primary illness and may cause concern to patients, their relatives and the medical staff. Because many drugs are often used simultaneously in seriously ill patients, it may be difficult to be sure which drug may have been responsible. The best procedure is to remove those drugs which are most probable causes of the psychiatric disturbances as well as any drugs that are not truly essential for the treatment of the patient. Problems involved in evaluating the relationship between use of drugs and psychiatric disorders are considerable. Many reports are isolated cases and the denominators which might provide some idea of the potential risk are unknown. Many relationships are still controversial, such as the association of depression with sedatives, antihypertensives and oral contraceptives. Areas of uncertainty are great. Psychomotor impairment may be caused by a drug that can alter consciousness, or any drugs that can produce more delineated psychiatric syndromes. Sedative drugs are those most commonly associated with psychomotor impairment, and may include psychotherapeutic drugs, sedative antihistamines, narcotic analgesics and, of course, the widely used social drug, alcohol. Delirious states are most often associated with drugs that possess central anticholinergic actions. These include not only drugs clearly identified as anticholinergics, but also tricyclic antidepressants and anti-Parkinson drugs. Cimetidine, which is often used parenterally in seriously ill patients, is also a prominent cause. Delirium is most often seen in elderly patients and in those who have received rather large doses of drugs. The association of schizophrenic-like psychoses with dopaminomimetic drugs tends to support the prevailing dopamine hypothesis of schizophrenia. Levodopa, the dopamine precursor, and bromocriptine, a direct dopamine agonist, are examples of such relationships. Abuse of social drugs has also been thought to provide a useful model of schizophrenia. Hallucinogens are probably a rather poor model, abuse of amphetamines may provide a better model, and possibly the best is the psychotic state elicited by phencyclidine. Manic reactions are clinically difficult to differentiate from schizophrenic-like psychoses and are often produced by similar drugs. Corticosteroids may produce either manic or schizophrenic-like disorders, as well as occasionally confusion and depression.(ABSTRACT TRUNCATED AT 400 WORDS) | Psychoses, Substance-Induced |
An international conference on Inter- and Intracellular Dynamics of ssDNA Plant Pathogens: Implications for Improving Resistance'' was sponsored by the United States-Israel Binational Agricultural Research and Development Fund (BARD) and organized in Eilat, Israel in November 2005. The topic of this meeting was single-stranded plant pathogens, their inter- as well as intra-cellular dynamics and their implications for improving resistance. Most of the talks concentrated on new and very new findings on principles of virus and bacterium-host interactions, studies that no doubt will lead eventually to the establishment of plants resistant to viral and bacterial infections." | DNA, Single-Stranded |
In 2009, investigators using ultra-performance liquid chromatography-tandem mass spectrometry to measure, by selected reaction monitoring, 3',5'-cAMP in the renal venous perfusate from isolated, perfused kidneys detected a large signal at the same m/z transition (330 --> 136) as 3',5'-cAMP but at a different retention time. Follow-up experiments demonstrated that this signal was due to a positional isomer of 3',5'-cAMP, namely, 2',3'-cAMP. Soon thereafter, investigative teams reported the detection of 2',3'-cAMP and other 2',3'-cNMPs (2',3'-cGMP, 2',3'-cCMP, and 2',3'-cUMP) in biological systems ranging from bacteria to plants to animals to humans. Injury appears to be the major stimulus for the release of these unique noncanonical cNMPs, which likely are formed by the breakdown of RNA. In mammalian cells in culture, in intact rat and mouse kidneys, and in mouse brains in vivo, 2',3'-cAMP is metabolized to 2'-AMP and 3'-AMP; and these AMPs are subsequently converted to adenosine. In rat and mouse kidneys and mouse brains, injury releases 2',3'-cAMP, 2'-AMP, and 3'-AMP into the extracellular compartment; and in humans, traumatic brain injury is associated with large increases in 2',3'-cAMP, 2'-AMP, 3'-AMP, and adenosine in the cerebrospinal fluid. These findings motivate the extracellular 2',3'-cAMP-adenosine pathway hypothesis: intracellular production of 2',3'-cAMP --> export of 2',3'-cAMP --> extracellular metabolism of 2',3'-cAMP to 2'-AMP and 3'-AMP --> extracellular metabolism of 2'-AMP and 3'-AMP to adenosine. Since 2',3'-cAMP has been shown to activate mitochondrial permeability transition pores (mPTPs) leading to apoptosis and necrosis and since adenosine is generally tissue protective, the extracellular 2',3'-cAMP-adenosine pathway may be a protective mechanism [i.e., removes 2',3'-cAMP (an intracellular toxin) and forms adenosine (a tissue protectant)]. This appears to be the case in the brain where deficiency in CNPase (the enzyme that metabolizes 2',3'-cAMP to 2-AMP) leads to increased susceptibility to brain injury and neurological diseases. Surprisingly, CNPase deficiency in the kidney actually protects against acute kidney injury, perhaps by preventing the formation of 2'-AMP (which turns out to be a renal vasoconstrictor) and by augmenting the mitophagy of damaged mitochondria. With regard to 2',3'-cNMPs and their downstream metabolites, there is no doubt much more to be discovered. | Cyclic AMP |
The platinum-based drug cisplatin (cis-diamminedichloroplatinum (II)) is widely used in cancer therapy. However, cancer cells can develop resistance after exposure to cisplatin. Recently, many studies have pointed to the involvement of plasma membrane ion channels in a cell's response to cisplatin. Our group has found that pretreatment with cisplatin enhanced the activity of volume-sensitive C-channels in human epidermoid cancer KB cells; cisplatin-resistant KCP-4 cells derived from KB cells, on the other hand, lacked functional expression of these channels. This suggests that the activity of volume-sensitive Cl(-) channels is an important factor in determining the sensitivity of cancer cells to cisplatin. Furthermore, when volume-sensitive Cl(-) channel function was partially restored in cisplatin-resistant KCP-4 cells treated with a histone deacetylase inhibitor, KCP-4 cells exhibited a restoration of sensitivity to cisplatin; this increased sensitivity was inhibited by a volume-sensitive Cl(-) channel blocker. We therefore propose that impaired activity of the volume-sensitive Cl(-) channel is involved in the acquired cisplatin resistance of these cancer cells. In this review, we will outline the relationship between volume-sensitive Cl(-) channels, cisplatin-induced apoptosis, and cisplatin resistance. Activating the volume-sensitive outwardly-rectifying Cl(-) channel may be a new strategy in treating clinical cisplatin resistance. | KB Cells |
Sensory Substitution Devices (SSDs) convey visual information through audition or touch, targeting blind and visually impaired individuals. One bottleneck towards adopting SSDs in everyday life by blind users, is the constant dependency on sighted instructors throughout the learning process. Here, we present a proof-of-concept for the efficacy of an online self-training program developed for learning the basics of the EyeMusic visual-to-auditory SSD tested on sighted blindfolded participants. Additionally, aiming to identify the best training strategy to be later re-adapted for the blind, we compared multisensory vs. unisensory as well as perceptual vs. descriptive feedback approaches. To these aims, sighted participants performed identical SSD-stimuli identification tests before and after ~75 minutes of self-training on the EyeMusic algorithm. Participants were divided into five groups, differing by the feedback delivered during training: auditory-descriptive, audio-visual textual description, audio-visual perceptual simultaneous and interleaved, and a control group which had no training. At baseline, before any EyeMusic training, participants SSD objects' identification was significantly above chance, highlighting the algorithm's intuitiveness. Furthermore, self-training led to a significant improvement in accuracy between pre- and post-training tests in each of the four feedback groups versus control, though no significant difference emerged among those groups. Nonetheless, significant correlations between individual post-training success rates and various learning measures acquired during training, suggest a trend for an advantage of multisensory vs. unisensory feedback strategies, while no trend emerged for perceptual vs. descriptive strategies. The success at baseline strengthens the conclusion that cross-modal correspondences facilitate learning, given SSD algorithms are based on such correspondences. Additionally, and crucially, the results highlight the feasibility of self-training for the first stages of SSD learning, and suggest that for these initial stages, unisensory training, easily implemented also for blind and visually impaired individuals, may suffice. Together, these findings will potentially boost the use of SSDs for rehabilitation. | Acoustic Stimulation |
To study the relationship between morphologic changes and alteration of lung function, the excised lobes of 21 smokers and one nonsmoker who required lobectomy for small peripheral tumors were inflated and fixed in formalin, and measurements of bronchiolar narrowing and degree of emphysema were made. All patients had comprehensive pulmonary function tests (including diffusing characteristics, the single-breath N2 test, measurements of elastic recoil, and flow-volume measurements with air and helium) performed before lobectomy. Eight of the lobes excised from the smokers had emphysema of grade 15 or more, the greatest being grade 50. Lobes from 11 patients had evidence of airway narrowing. There were 6 lobes with both emphysema and airway narrowing. Pulmonary function was abnormal in some aspect in all lobes except that from the nonsmoker. Whereas the tests of diffusing capacity, particularly the fractional uptake of CO, correlated with the degree of emphysema, the tests of elastic recoil were not predictive of this early degree of emphysema. The degree of small-airway narrowing correlated with maximal mid-expiratory flow rate and the single-breath N2 test. The maximal flow/static recoil pressure curves were the most sensitive indicators of airway abnormality in the patients with emphysema." | Maximal Midexpiratory Flow Rate |
Legionella-contaminated hot water systems and moist sanitary areas in six hospitals were sampled for amoebae by following a standardized collection protocol. Genus identifications and temperature tolerance determinations were made. Amoebae identified as Hartmannella vermiformis (65%), Echinamoebae spp. (15%), Saccamoebae spp. (12%), and Vahlkampfia spp. (9%) were detected in 29 of 56 (52%) hot water samples. Twenty-three of 49 (47%) swabs obtained from moist areas were amoeba positive. The following genera were identified: Acanthamoeba (22%), Naegleria (22%), Vahlkampfia (20%), Hartmannella (15%), and Vanella (7%). The temperature tolerance of amoebae from hot water systems was strikingly different from that of amoebae from moist areas. At 44 degrees C on agar, 59% of amoebic isolates sampled from hot water systems showed growth. The corresponding value for isolates from moist areas was only 17%. Six Acanthamoeba isolates from the moist areas were considered potential pathogens. Four Hartmannella and two Saccamoeba isolates from hot water could be cultured at 53 degrees C. | Hartmannella |
The Short Course in Human and Mammalian Genetics and Genomics (aka the Short Course" or the "Bar Harbor course") is one of Victor McKusick's landmark contributions to medical genetics. Conceived in 1959 as a way to increase the contribution of genetic advances to medicine, it has directly affected more than 7000 students and 600 participating faculty from around the world. Now, more than 10 years after his death, it continues to be a vibrant disseminator of genetics, and genomics knowledge for medicine, a catalytic agent for ongoing research and a source of collegiality in our field. What an extraordinary gift!" | Human Genetics |
We describe a 71-year-old patient with slowly progressive pure alexia in which analysis of her fluorodeoxyglucose FDG-PET scan revealed an area of focal hypometabolism in the visual word form area. She presented with difficulty reading. Examination revealed pure alexia with preservation of other cognitive domains. Brain MRI revealed only slight atrophy. A Fluorodeoxyglucose F18 positron emission tomography scan revealed hypometabolism in the occipital cortex bilaterally, left greater than right, with normal metabolism elsewhere in the brain. This case highlights the utility of FDG-PET scan in evaluating focal neurodegenerative conditions before clear atrophy can be seen on MRI. | Alexia, Pure |
DNA double-strand break (DSB) is one of the most deleterious types of DNA lesions threatening genome integrity. Cells have evolved several exquisite pathways to repair these breaks. Homologous recombination (HR) is an essential DSB repair mechanism that utilizes an intact homologous sequence as a template to repair DSBs with high fidelity. To initiate the HR repair, the 5'-ends of DSBs have to be nucleolytically cleaved by nucleases to generate 3'-single-strand DNA (ssDNA). Exposed 3'-ssDNA recruits the ssDNA binding protein complex RPA to activate the DNA damage checkpoint. RPA is subsequently replaced by Rad51 recombinase to form Rad51 nucleoprotein filament that catalyzes strand invasion and formation of the D-loop. Processing of 5'-ends (called resection) is a crucial step that determines the choice of repair pathways. Here we introduce an assay for monitoring the dynamics of resection at different locations from a site-specific DSB in yeast. | Blotting, Southern |
MOTIVATION: The molecular dynamics simulation package GROMACS is a widely used tool used in a broad range of different applications within physics, chemistry and biology. It is freely available, user friendly and extremely efficient. The GROMACS software is force field agnostic, and compatible with many molecular dynamics force fields; coarse-grained, unified atom, all atom as well as polarizable models based on the charge on a spring concept. To validate simulations, it is necessary to compare results from the simulations to experimental data. To ease the process of setting up topologies and structures for simulations, as well as providing pre-calculated physical properties along with experimental values for the same we provide a web-based database, containing 145 organic molecules at present. RESULTS: Liquid properties of 145 organic molecules have been simulated using two different force fields, OPLS all atom and Generalized Amber Force Field. So far, eight properties have been calculated (the density, enthalpy of vaporization, surface tension, heat capacity at constant volume and pressure, isothermal compressibility, volumetric expansion coefficient and the static dielectric constant). The results, together with experimental values are available through the database, along with liquid structures and topologies for the 145 molecules, in the two force fields. AVAILABILITY: The database is freely available under http://virtualchemistry.org. | Models, Molecular |
Seminal plasma hypersensitivity manifests as a spectrum of systemic and/or localized clinical symptoms after exposure to specific protein components in seminal fluid. The prevalence of this disease is largely unknown, but it is believed to affect up to 40,000 women in the United States. Although no definitive risk factors have been confirmed, women with systemic reactions are frequently atopic. Prostate-specific antigen is believed to be the major allergen involved in the disorder, but other proteins are likely involved. Interestingly, up to 40%-50% of both systemic and localized seminal plasma hypersensitivity cases can occur after first-time intercourse. Diagnosis is based on clinical history. The gold standard for diagnosing seminal plasma hypersensitivity is prevention of symptoms with the use of a condom. Patients with seminal plasma hypersensitivity demonstrate positive prick skin test and/or serum-specific immunoglobulin E to whole seminal fluid or fractionated seminal plasma proteins. Treatment of seminal plasma hypersensitivity involves either avoidance with the use of condoms, intravaginal graded challenge using dilutions of whole seminal fluid, or subcutaneous desensitization to relevant fractionated seminal plasma proteins obtained from the woman's sexual partner. In most cases, treatment using one or more of the above approaches has been very successful. Infertility has not been demonstrated to be directly related to seminal plasma hypersensitivity, although women with the condition frequently have difficulty conceiving due to their inability to have unprotected sexual intercourse. | Hypersensitivity, Immediate |
BACKGROUND: Tumors of the cauda equina usually require surgery due to their impingement on neighboring nerve roots, often resulting in pain and neurological deficits. METHOD: The Authors first give a brief introduction on cauda equina tumors, followed by a description of the surgical anatomy, and then develop the microsurgical technique. In particular, tricks to avoid complications are presented, underlining the importance of intraoperative neuromonitoring. CONCLUSION: Both microsurgical technique and neuromonitoring are important in cauda equina tumor surgery, the goal of which is to achieve complete resection while at the same time preserving neurological function. | Cauda Equina |
In the present study we have utilized comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship paradigm, to explore the physico-chemical requirements for binding to the Ah (dioxin) receptor. Recent developments by Gillner et al. [(1993) Mol. Pharmacol. 44, 336-345] prompted us to review and revise our previous CoMFA/QSAR model [Waller, C. L., and McKinney, J. D. (1992) J. Med. Chem. 36, 3660-3666] to include a structurally-diverse training set of Ah receptor ligands ranging in size from naphthalene to indolo[3,2-b]carbazole nuclei. An exhaustive validation process utilizing external test sets and hierarchical cluster analysis routines was employed during model construction and is discussed herein. The limitations of the approach presented herein are discussed with respect to predictive ability of the CoMFA/QSAR models, which is demonstrated to be dependent on a balance between structural diversity and redundancy in the molecules comprising the training set. The results of our modified CoMFA/QSAR model are consistent with and unify all previously established structure-activity relationships established for less structurally-diverse training sets of Ah receptor ligands. As a result of the more complete nature of the series of molecules under examination in the present study, the CoMFA/QSAR steric and electrostatic field contour plots as well as the essential and excluded volume plots provide for a more detailed characterization of the molecular binding domain of the Ah receptor. The implications of the CoMFA/QSAR model presented herein are explored with respect to quantitative hazard identification of potential toxicants. | Receptors, Aryl Hydrocarbon |
A 21-year-old mentally challenged man presented with a fixed plaque lesion on the right foot, which had been present for 10 years. Dermatologic examination revealed an erythematous, painful, firm, fixed plaque-nodular lesion on the plantar aspect of the right foot (Figure 1A). Nothing of distinction was noted from his family history or his laboratory tests. An incisional biopsy revealed parallel, regular bundles composed of uniform, plump spindle cells. Thin collagen fibers were seen in contact with and located between the spindle cells. This mass was separated from the surrounding soft tissue by an irregular, unclear border (Figure 2A). Immunohistochemically, the spindle cells showed diffuse, strong reactivity to vimentin (Figure 2B) and smooth muscle actin. | Fibromatosis, Plantar |
OBJECTIVES: The aim of this study was to evaluate the relationship between periapical lesions with and without clinical symptoms. MATERIAL AND METHOD: This study was performed on cases with chronic periapical lesion diagnosis. During oral surgery procedures, 80 tissue samples were obtained. Anamnesis data were taken from each subject included in the study. Periapical tissue samples were processed for laboratory procedures including: histological and pathological examination of lesions by light microscopy analysis and microbiological status assessment by qualitative and semi-quantitative analysis of bacteriological findings. RESULTS AND CONCLUSION: The results obtained illustrate that symptomatic apical periodontitis was more frequent with teeth without previous endodontic therapy. Even though a pathological type of periapical inflammation is significantly associated with the presence or absence of clinical symptoms (p=0.0002), they do not have an effect on making a clinical diagnosis. Statistical analysis showed no significant difference (p>0.05). Comparative analysis of symptom persistence and infection severity was performed. It was found that positive symptoms were in relation to the quantity of the bacterial growth only in the group previous endodontically treated and these two factors do show relation with an accuracy of 95%. The growth of a mixture of several, mainly anaerobic, bacterial species is closely related to the presence of clinical symptoms. | Periapical Tissue |
Inferring the true biological sequences from amplicon mixtures remains a difficult bioinformatics problem. The traditional approach is to cluster sequencing reads by similarity thresholds and treat the consensus sequence of each cluster as an operational taxonomic unit" (OTU). Recently, this approach has been improved by model-based methods that correct PCR and sequencing errors in order to infer "amplicon sequence variants" (ASVs). To date, ASV approaches have been used primarily in metagenomics, but they are also useful for determining homeologs in polyploid organisms. To facilitate the usage of ASV methods among polyploidy researchers, we incorporated ASV inference alongside OTU clustering in PURC v2.0, a major update to PURC (Pipeline for Untangling Reticulate Complexes). In addition, PURC v2.0 features faster demultiplexing than the original version and has been updated to be compatible with Python 3. In this chapter we present results indicating that using the ASV approach is more likely to infer the correct biological sequences in comparison to the earlier OTU-based PURC and describe how to prepare sequencing data, run PURC v2.0 under several different modes, and interpret the output." | Consensus Sequence |
Frostbite is a condition that is associated with people living in countries with an extremely cold climate. It can also, however, affect people who are involved in winter sports, and is also associated with the homeless, people with a psychiatric illness, and those who misuse drugs and alcohol. We describe the case of a 47-year-old homeless man who was diagnosed with severe frostbite in both lower legs. The lesion consisted of hemorrhagic blistering with already visible demarcation. When sepsis developed both lower legs had to be amputated as a matter of urgency. We describe the assessment and management of a patient with frostbite and identify the challenges of managing these complex tissue injuries. | Frostbite |
Empirical models are central to effective conservation and population management, and should be predictive of real-world dynamics. Available modelling methods are diverse, but analysis usually focuses on long-term dynamics that are unable to describe the complicated short-term time series that can arise even from simple models following ecological disturbances or perturbations. Recent interest in such transient dynamics has led to diverse methodologies for their quantification in density-independent, time-invariant population projection matrix (PPM) models, but the fragmented nature of this literature has stifled the widespread analysis of transients. We review the literature on transient analyses of linear PPM models and synthesise a coherent framework. We promote the use of standardised indices, and categorise indices according to their focus on either convergence times or transient population density, and on either transient bounds or case-specific transient dynamics. We use a large database of empirical PPM models to explore relationships between indices of transient dynamics. This analysis promotes the use of population inertia as a simple, versatile and informative predictor of transient population density, but criticises the utility of established indices of convergence times. Our findings should guide further development of analyses of transient population dynamics using PPMs or other empirical modelling techniques. | Styracaceae |
PURPOSE: This study aims to give an integrative answer on which speech stereotypes exist toward German gay and straight men, whether and how acoustic correlates of actual and perceived sexual orientation are connected, and how this relates to masculinity/femininity. Hence, it tests speech stereotype accuracy in the context of sexual orientation. METHOD: Twenty-five gay and 26 straight German speakers provided data for a fine-grained psychological self-assessment (e.g., masculinity/femininity) and explicit speech stereotypes. They were recorded for an extensive set of read and spontaneous speech samples using microphones and nasometry. Recordings were analyzed for a variety of acoustic parameters (e.g., fundamental frequency and nasalance). Seventy-four listeners categorized speakers as gay or straight on the basis of the same sentence. RESULTS: Most relevant explicitly expressed speech stereotypes encompass voice pitch, nasality, chromaticity, and smoothness. Demonstrating implicit stereotypes, speakers were perceived as sounding straighter, the lower their median f0, center of gravity in /s/, and mean F2. However, based on actual sexual orientation, straight men only showed lower mean F1 than gay men. Additionally, we found evidence that actual masculinity/femininity and the degree of sexual orientation were reflected in gay and straight men's speech. CONCLUSION: Implicit and explicit speech stereotypes about gay and straight men do not contain a kernel of truth, and differences within groups are more important than differences between them. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.6484001. | Femininity |
The recent progress were focused on: the identification of the general immunological mechanism of the hansenian neuritis, demonstrated by endoneural biopsies; the different pathology of the two categories of neuritis; the pathophysiologic derangements, inducing hypoxia or anoxia in the truncular involved segment. The adjuvant role of the canals is important; the clinical differences of the two categories of neuritis and the cases we shall treat by emergency; the importance of antireactionnal treatment and of the notation by tests for the study of the results. The goals are the hemodynamic decompression, useful in the first stage of ENL neuritis, the mechanical decompression of neural fasciculus and the urgent exeresis of necroses or evacuation of febrile abscess. Three technics a re studied: Extraneural and epineural decompression fascicular endoneural necrosis, neurolysis and complex neurolysis for evaluated ENL neuritis and for endoneural necrosis. The different indication according to the two categories: medico-surgical treatment for ENL neuritis, and according the precocity and the delay of the antireactional treatment, and also the absolute emergency of the necrosis and febrile abscess. The results of the treatment of 258 cases of recent neuritis are presented. | Neuritis |
OBJECTIVE: To investigate the incidence of subsequent lumbar spine, hip, and ankle-foot injuries after a diagnosis of patellofemoral pain. DESIGN: Retrospective cohort study. SETTING: Military Health System. PARTICIPANTS: Individuals (n = 92,319) ages 17-60 diagnosed with patellofemoral pain between 2010-2011. INTERVENTIONS: Therapeutic exercise. MAIN OUTCOME MEASURES: Frequency of adjacent joint injuries in the 2-year period after initial patellofemoral pain injury, and hazard ratios (HR) with 95% confidence interval (CI) and Kaplan-Meier survival curves for risk of adjacent joint injury based on receiving therapeutic exercise for the initial injury. RESULTS: After initial patellofemoral pain diagnosis, 42,983 (46.6%) individuals sought care for an adjacent joint injury. Of these, 19,587 (21.2%) were subsequently diagnosed with a lumbar injury, 2837 (3.1%) a hip injury, and 10,166 (11.0%) an ankle-foot injury. One in five (19.5%; n = 17,966) received therapeutic exercise which reduced the risk of having a subsequent lumbar (HR = 0.78, 95% CI 0.76-0.81), hip (HR = 0.93, 95% CI 0.87-0.98) or ankle-foot (HR = 0.86, 95% CI 0.83-0.90) injury. CONCLUSION: The results suggest that a high number of individuals with patellofemoral pain will sustain an adjacent joint injury within 2 years although causal relationships cannot be determined. Receiving therapeutic exercise for the initial knee injury reduced the risk of sustaining an adjacent joint injury. This study helps provide normative data for subsequent injury rates in this population and guide development of future studies designed to understand causal factors. | Patellofemoral Pain Syndrome |
Nonmetastatic gestational trophoblastic disease encompasses a variety of related neoplasms of the human placenta. With the advent of effective chemotherapy, nearly all of these patients can be cured using a variety of regimens with acceptable toxicity. Hysterectomy is useful in selected patients to decrease the amount of chemotherapy required to produce remission and to salvage patients who have failed initial chemotherapy. The majority of patients can retain child-bearing capacity and often have normal pregnancies after therapy. | Trophoblastic Neoplasms |
Apolipoproteins C (apo C-II, apo C-III0, apo C-III1 and apo C-III2) from delipidated very low density lipoproteins (VLDL) of 522 normo- and hyperlipoproteinemic Caucasians were screened by analytical isoelectric focusing. The immobilized pH gradient used was pH 4.0-5.0 with 7 M urea, which raised the apparent pH range to 4.8-5.7. As identified by immunoblotting, six unrelated persons had two major isoforms of apo C-II, the normal apo C-II-1 (which focuses between apo C-III0 and apo C-III1) and a variant, designated apo C-II-v according to Huff et al., focusing between apo C-III1 and apo C-III2 due to a more acidic pI. In narrow pH gradients, apo C-II-v can readily be discriminated from the minor isoform, apo C-II-2, due to its slightly more basic pI, corresponding to a difference of 0.01 pH units. Neuraminidase treatment did not alter the pI of apo C-II-v and on two-dimensional electrophoresis the molecular weights of apo C-II-1 and apo C-II-v were indistinguishable. The frequency of apo C-II-v was 1.2%. It was the same in males and females and was independent of hypertriglyceridemia. The autosomal codominant inheritance could be demonstrated in the pedigree of one family. Electroblotting of apo C-II-1 and apo C-II-v onto activated glass fiber sheets, followed by amino acid sequence analysis of the amino terminal ends, revealed an exchange of the amino acid lysine at position 19 by threonine in apo C-II-v.(ABSTRACT TRUNCATED AT 250 WORDS) | Apolipoprotein C-II |
The objectives were to characterize oral cavity cancer (OCC) funding from the National Institutes of Health (NIH) with a secondary aim of comparing NIH support provided to OCC and other malignancies. NIH awards supporting OCC inquiry from 2000 to 2014 were accessed from the NIH RePORTER database. These data were used to evaluate temporal trends and the role of human papilloma virus and to determine the academic training and professional profiles of the principal investigators. Comparison of 2014 funding levels with other malignancies was also performed, controlling for incidence. Overall funding totals decreased considerably after 2009. Funding administered through the National Institute of Dental and Craniofacial Research (NIDCR) was 6.5 times greater than dollars awarded by the National Cancer Institute in 2000. During the period evaluated, NIDCR support decreased in most years, while National Cancer Institute support increased and approached NIDCR funding levels. Funding for human papilloma virus-related projects gradually rose, from 3.4% of dollars in 2000 to 2004 to 6.2% from 2010 to 2014 ( P < 0.05). A majority of principal investigators had a PhD omnia solus (57%), and 13% possessed dual PhD/clinical degrees. Among clinicians with specialty training, otolaryngologists and oral/maxillofacial pathologists garnered the most funding. OCC had a 2014 funding:incidence ratio of $785, much lower than for other malignancies. There has been increased volatility in funding support in recent years possibly due to budget cuts and sequestration. The National Cancer Institute has played an increasingly important role in supporting OCC research, concomitant with decreasing NIDCR support. Our findings suggest that OCC is underfunded relative to other non-oral cavity malignancies, indicating a need to increase the focus on rectifying the disparity." | United States Government Agencies |
The final cascade of amyotrophic lateral sclerosis (ALS) coincides with the onset of clinical neurological deficits and involves multifactorial interactive mechanisms. These terminal events include excitotoxicity, free radical accumulation and possibly immunological disturbances. They are probably predated by months or years by thus far unidentified triggers. Selective vulnerability of the corticomotneuronal system in ALS is likely due to degradation of several gene products essential to transmitter, receptor and nerve growth factor maintenance specific to this functional system. Therapeutic strategies involve neuroprotection, symptomatic and combination neuronal therapy targeted to the final cascade of ALS. | Amyotrophic Lateral Sclerosis |
The H(+)-electrochemical gradient was originally considered as a driving force for solute transport only across cellular membranes of bacteria, plants and yeast. However, in the mammalian small intestine, a H(+)-electrochemical gradient is present at the epithelial brush-border membrane in the form of an acid microclimate. Over recent years, a large number of H(+)-coupled cotransport mechanisms have been identified at the luminal membrane of the mammalian small intestine. These transporters are responsible for the initial stage in absorption of a remarkable variety of essential and non-essential nutrients and micronutrients, including protein digestion products (di/tripeptides and amino acids), vitamins, short-chain fatty acids and divalent metal ions. Proton-coupled cotransporters expressed at the mammalian small intestinal brush-border membrane include: the di/tripeptide transporter PepT1 (SLC15A1); the proton-coupled amino-acid transporter PAT1 (SLC36A1); the divalent metal transporter DMT1 (SLC11A2); the organic anion transporting polypeptide OATP2B1 (SLC02B1); the monocarboxylate transporter MCT1 (SLC16A1); the proton-coupled folate transporter PCFT (SLC46A1); the sodium-glucose linked cotransporter SGLT1 (SLC5A1); and the excitatory amino acid carrier EAAC1 (SLC1A1). Emerging research demonstrates that the optimal intestinal absorptive capacity of certain H(+)-coupled cotransporters (PepT1 and PAT1) is dependent upon function of the brush-border Na(+)-H(+) exchanger NHE3 (SLC9A3). The high oral bioavailability of a large number of pharmaceutical compounds results, in part, from absorptive transport via the same H(+)-coupled cotransporters. Drugs undergoing H(+)-coupled cotransport across the intestinal brush-border membrane include those used to treat bacterial infections, hypercholesterolaemia, hypertension, hyperglycaemia, viral infections, allergies, epilepsy, schizophrenia, rheumatoid arthritis and cancer. | Membrane Transport Proteins |
OBJECTIVE: To describe three-dimensional (3D) magnetic resonance imaging (MRI) pelvimetry methods and to establish the pelvimetric reference in a large population of Chinese females at term pregnancy. METHODS: Three-hundred one pregnant women at term who underwent MRI were included. Three-dimensional pelvic models were reconstructed using Mimics. 10.0 software based on MRI data sets, and measurements of these models were made. Pelvimetric results according to delivery modality were presented. Additionally, the previously described CT 3D pelvimetry method for predicting cephalopelvic disproportion (CPD) was used to validate its accuracy. RESULTS: Two hundred ten women underwent vaginal delivery, and 13 underwent caesarean delivery for CPD. 3D modelling of the pelvis of pregnant women was feasible using MR data sets. Pelvimetric parameters in the vaginal delivery group were as follows: transverse diameter, 134.7 mmâ¯+/-â¯7.5; obstetric conjugate, 126.9 mmâ¯+/-â¯8.3; interspinous distance, 113.4 mmâ¯+/-â¯8.2; sagittal midpelvis, 117.8 mmâ¯+/-â¯8.1; intertuberous distance, 127.1 mmâ¯+/-â¯10.4; sagittal outlet, 110.2 mmâ¯+/-â¯8.9, and posterior sagittal outlet, 59.7 mmâ¯+/-â¯8.1. According to the previously described CT 3D pelvimetry method for predicting CPD, 67.6% (142/210) of women in the vaginal delivery group were diagnosed with CPD. CONCLUSION: 3D MR pelvimetry is a novel method for determining pelvic dimensions at term pregnancy. A prospective trial is needed to establish a useful value for predicting CPD in Chinese females at high risk of CPD. | Cephalopelvic Disproportion |
Many arthropods undergo a seasonal dormancy termed diapause" to optimize timing of reproduction in highly seasonal environments. In the North Atlantic, the copepod Calanus finmarchicus completes one to three generations annually with some individuals maturing into adults, while others interrupt their development to enter diapause. It is unknown which, why and when individuals enter the diapause program. Transcriptomic data from copepods on known programs were analyzed using dimensionality reduction of gene expression and functional analyses to identify program-specific genes and biological processes. These analyses elucidated physiological differences and established protocols that distinguish between programs. Differences in gene expression were associated with maturation of individuals on the reproductive program, while those on the diapause program showed little change over time. Only two of six filters effectively separated copepods by developmental program. The first one included all genes annotated to RNA metabolism and this was confirmed using differential gene expression analysis. The second filter identified 54 differentially expressed genes that were consistently up-regulated in individuals on the diapause program in comparison with those on the reproductive program. Annotated to oogenesis, RNA metabolism and fatty acid biosynthesis, these genes are both indicators for diapause preparation and good candidates for functional studies." | Diapause |
We review how studies on the first Spemann-Mangold organizer marker, the homeobox gene goosecoid, led to the discovery of secreted factors that pattern the vertebrate embryo. Microinjection of goosecoid mRNA formed secondary axes and recruited neighboring cells. These non-cell autonomous effects are mediated in part by the expression of secreted factors such as chordin, cerberus and Frzb-1. Unexpectedly, many of the molecules secreted by the Spemann-Mangold organizer turned out to be antagonists that bind growth factors in the extracellular space and prevent them from binding to their receptors. The case of chordin is reviewed in detail, for this molecule has provided biochemical insights into how patterning by Spemann's organizer can be regulated by diffusion and proteolytic control. The study of the BMP-binding repeats of Chordin, which are present in many extracellular proteins, may provide a new paradigm for how cell-cell signaling is regulated in the extracellular space not only in embryos, but also in adult tissues. | Goosecoid Protein |
BACKGROUND: The RNA recognition motif (RRM) is one of the largest families of RNA binding domains. The RRM is modulated so that individual proteins containing RRMs can specifically recognize RNA targets with diverse sequences and structures. Understanding the principles governing this specificity will be important for the rational modification and design of RRM-RNA complexes. RESULTS: In this paper we have investigated the origins of specificity of the N terminal RRM of the U1A protein for stem loop 2 (SL2) of U1 snRNA by substituting modified bases for essential purines in SL2 RNA. In one series of modified bases, hydrogen bond donors and acceptors were replaced by aliphatic groups to probe the importance of these functional groups to binding. In a second series of modified bases, hydrogen bond donors and acceptors were incorrectly placed on the purine bases to analyze the origins of discrimination between cognate and non-cognate RNA. The results of these experiments show that three different approaches are used by the U1A protein to gain specificity for purines. Specificity for the first base in the loop, A1, is based primarily on discrimination against RNA containing the incorrect base, specificity for the fourth base in the loop, G4, is based largely on recognition of the donors and acceptors of G4, while specificity for the sixth base in the loop, A6, results from a combination of direct recognition of the base and discrimination against incorrectly placed functional groups. CONCLUSION: These investigations identify different roles that hydrogen bond donors and acceptors on bases in both cognate and non-cognate RNA play in the specific recognition of RNA by the U1A protein. Taken together with investigations of other RNA-RRM complexes, the results contribute to a general understanding of the origins of RNA-RRM specificity and highlight, in particular, the contribution of steric and electrostatic repulsion to binding specificity. | RNA, Spliced Leader |
AIM: To ascertain the role of cardiovascular risk factors, cardiovascular diseases, standard treatments and other diseases in the development of ischemic colitis (IC). METHODS: A retrospective, case-control study was designed, using matched data and covering 161 incident cases of IC who required admission to our hospital from 1998 through 2003. IC was diagnosed on the basis of endoscopic findings and diagnostic or compatible histology. Controls were randomly chosen from a cohort of patients who were admitted in the same period and required a colonoscopy, excluding those with diagnosis of colitis. Cases were matched with controls (ratio 1:2), by age and sex. A conditional logistic regression was performed. RESULTS: A total of 483 patients (161 cases, 322 controls) were included; mean age 75.67 +/- 10.03 years, 55.9% women. The principal indications for colonoscopy in the control group were lower gastrointestinal hemorrhage (35.4%), anemia (33.9%), abdominal pain (19.9%) and diarrhea (9.6%). The endoscopic findings in this group were hemorrhoids (25.5%), diverticular disease (30.4%), polyps (19.9%) and colorectal cancer (10.2%). The following variables were associated with IC in the univariate analysis: arterial hypertension (P = 0.033); dyslipidemia (P < 0.001); diabetes mellitus (P = 0.025); peripheral arterial disease (P = 0.004); heart failure (P = 0.026); treatment with hypotensive drugs (P = 0.023); angiotensin-converting enzyme inhibitors; (P = 0.018); calcium channel antagonists (P = 0.028); and acetylsalicylic acid (ASA) (P < 0.001). Finally, the following variables were independently associated with the development of IC: diabetes mellitus [odds ratio (OR) 1.76, 95% confidence interval (CI): 1.001-3.077, P = 0.046]; dyslipidemia (OR 2.12, 95% CI: 1.26-3.57, P = 0.004); heart failure (OR 3.17, 95% CI: 1.31-7.68, P = 0.01); peripheral arterial disease (OR 4.1, 95% CI: 1.32-12.72, P = 0.015); treatment with digoxin (digitalis) (OR 0.27, 95% CI: 0.084-0.857, P = 0.026); and ASA (OR 1.97, 95% CI: 1.16-3.36, P = 0.012). CONCLUSION: The development of an episode of IC was independently associated with diabetes, dyslipidemia, presence of heart failure, peripheral arterial disease and treatment with digoxin or ASA. | Colitis, Ischemic |
The development of lipid-based delivery systems has attracted much attention over the last years and a wide variety of strategies and formulations are currently available to encapsulate, protect, and target delivery of bioactive and functional lipophilic constituents within the food and pharmaceutical industries. Waxes are crystalline lipid material, consisting of a complex mixture of long-chain fatty acids and fatty alcohols, hydrocarbons, aldehydes, and ketones and show great promises as constituents of carrier systems. Most of waxes are classified under food-grade category and show high availability at a low cost. This review article has provided a comprehensive summary of research on major carriers containing wax as one of the main constituents, including solid lipid nanoparticles, nanostructured lipid carriers, oleogels, and Pickering emulsions, with a focus on their food applications. The physical and chemical nature of natural waxes are described in the first while the second part deals with the structure, formulation, main methods of preparation, characterization, and finally utilization of each type of wax-based delivery system for specific food applications. | Waxes |
In this multicentre, randomised, double-blind, cross-over study, we evaluated and compared the effects of nitrendipine (a calcium entry blocker of the dihydropyridine group) and mefruside (a diuretic) on BP, cardiac output, cerebral blood flow and metabolic parameters in 22 elderly hypertensives. Eight weeks of treatment with nitrendipine (27.3 mg daily) and mefruside (30.7 mg daily) significantly reduced BP values to almost the same extent. Heart rate, cardiac output (n = 14), cerebral blood flow (n = 20), renin activity and aldosterone remained unchanged during nitrendipine and mefruside treatment. Nitrendipine did not alter any metabolic parameter (electrolytes, lipid values and blood glucose); in patients treated with mefruside serum potassium fell by 0.4 mmol/l (P < 0.001). Minor adverse events were reported in both treatment groups, mostly due to vasodilation. We conclude that both drugs possess potent and comparable haemodynamic and anti-hypertensive properties. They reduce BP by reducing total peripheral vascular resistance with maintained autoregulation of cerebral blood flow. The metabolic disturbances induced by mefruside seem to be less pronounced than that observed with other thiazide diuretics. | Mefruside |
Anisocoria describes asymmetric pupillary diameter, which can result from traumatic, pharmacologic, inflammatory, or ischemic effects on the eye. In many cases, anisocoria represents a normal physiologic variant. Morbidity associated with anisocoria is directly related to the inciting cause and can vary from benign to life-threatening. A thorough understanding by emergency physicians of normal ocular neuroanatomy, and of common causes of pathologic anisocoria, including medication-induced anisocoria, can facilitate appropriate resource utilization and timely subspecialty consultation, and can help prevent irreversible ocular injury and patient morbidity. We describe a patient who presented to the emergency department with acute onset of blurry vision with anisocoria. | Anisocoria |
Nuclear receptor crosstalk represents an important mechanism to expand the functions of individual receptors. The liver X receptors (LXR, NR1H2/3), both the alpha and beta isoforms, are nuclear receptors that can be activated by the endogenous oxysterols and other synthetic agonists. LXRs function as cholesterol sensors, which protect mammals from cholesterol overload. LXRs have been shown to regulate the expression of a battery of metabolic genes, especially those involved in lipid metabolism. LXRs have recently been suggested to play a novel role in the regulation of drug metabolism. The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic receptor that regulates the expression of drug-metabolizing enzymes and transporters. Disruption of CAR alters sensitivity to toxins, increasing or decreasing it depending on the compounds. More recently, additional roles for CAR have been discovered. These include the involvement of CAR in lipid metabolism. Mechanistically, CAR forms an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the LXRs, in exerting its effect on lipid metabolism. Retinoid-related orphan receptors (RORs, NR1F1/2/3) have three isoforms, alpha, beta and gamma. Recent reports have shown that loss of RORalpha and/or RORgamma can positively or negatively influence the expression of multiple drug-metabolizing enzymes and transporters in the liver. The effects of RORs on expression of drug-metabolizing enzymes were reasoned to be, at least in part, due to the crosstalk with LXR. This review focuses on the CAR-LXR and ROR-LXR crosstalk, and the implications of this crosstalk in drug metabolism and lipid metabolism. | Orphan Nuclear Receptors |
An 11-year-old black girl with excessive tissue growth from the conjunctiva and adjacent tissue, of several years' duration, was treated with excision of the tissue and topical steroids. Histopathologic examination revealed eosinophilic and plasma cell infiltration with a few lymphocytes and polymorphonuclear cells. Proliferation of the capillary endothelium was also noted. To our best knowledge, this type of inflammatory reaction of the anterior aspects of the globe has not yet been reported. | Conjunctivitis |
1. Electrical discharge of thirty-nine single splenic and renal postganglionic nerve fibres was recorded in artificially respired, chloralose-anaesthetized cats. 2. Ongoing discharge rates, averaged over 10 s periods, did not differ between renal and splenic fibres. All neurones of both groups had irregular discharge frequencies. 3. Half of the splenic population and all renal fibres had cardiac-related discharge patterns. Of those tested for respiratory-related firing, 30% of the splenic fibres and 69% of the renal fibres exhibited this pattern. 4. Firing of splenic fibres was less inhibited than that of renal fibres by stimulation of pressoreceptors with phenylephrine-induced increases in blood pressure. Firing of splenic fibres also was less excited than that of renal fibres by unloading pressoreceptors with depressor doses of sodium nitroprusside. 5. Chemical stimulation of splenic afferent nerves with bradykinin consistently elicited greater increases in splenic than renal nerve discharge by causing large increases in firing of all splenic fibres and smaller excitatory responses in 75% of the renal fibres. 6. Application of bradykinin to the intestinal serosa produced greater increases in renal than splenic nerve discharge by consistently causing increased firing of renal fibres and by causing excitation, inhibition, or no change in splenic fibre discharge. 7. Responses of splenic and renal fibres to stimulation of splenic and intestinal afferent nerves after spinal cord transection were similar to those responses elicited when the neuraxis was intact. 8. In conclusion, the differential reflex responses of splenic and renal neuronal populations can be due to the heterogeneity or to the intensity of responses within a neuronal population." | Autonomic Fibers, Postganglionic |
Detection of volatile organic compounds is a useful approach to non-invasive diagnosis of diseases through breath analysis. Our experimental study presents a newly developed prototype gas sensor, based on organically-functionalized gold nanoparticles, and results on formaldehyde detection using fluctuation-enhanced gas sensing. Formaldehyde was easily detected via intense fluctuations of the gas sensor's resistance, while the cross-influence of ethanol vapor (a confounding factor in exhaled breath, related to alcohol consumption) was negligible. | Formaldehyde |
BACKGROUND: Interventions designed to improve the delivery of primary care, including Patient-Centered Medical Homes and electronic health records, require an understanding of clinical workflow to be successfully implemented. However, there is a lack of tools to describe and study primary care physician workflow. We developed a comprehensive list of primary care physician tasks that occur during a face-to-face patient visit. METHODS: A validated list of tasks performed by primary care physicians during patient clinic visits was developed from a secondary data analysis of observation data from two studies evaluating primary care workflow. Thirty primary care physicians participated from a convenience sample of 17 internal medicine and family medicine clinics in Wisconsin and Iowa across rural and urban settings and community and academic settings. RESULTS: The final task list has 12 major tasks, 189 subtasks, and 191 total tasks. The major tasks are: Enter Room, Gather Information from Patient, Review Patient Information, Document Patient Information, Perform, Recommend / Discuss Treatment Options, Look Up, Order, Communicate, Print / Give Patient (advice, instructions), Appointment Wrap-up, and Leave Room. Additional subcodes note use of paper or EHR and the presence of a caregiver or medical student. CONCLUSIONS: The task list presented here is a tool that will help clinics study their workflows so they can plan for changes that will take place because of EHR implementation and/or transformation to a patient centered medical home. | Physicians, Primary Care |
In higher plants, P450s participate in the biosynthesis of many important secondary metabolites. Here we reported for the first time the isolation of a new cytochrome P450 cDNA that expressed in a stem-specific manner from Camptotheca acuminata (designated as CaSS), a native medicinal plant species in China, using RACE-PCR. The full-length cDNA of CaSS was 1735 bp long containing a 1530 bp open reading frame (ORF) encoding a polypeptide of 509 amino acids. Bioinformatic analysis revealed that CASS contained a heme-binding domain PFGXGRRXCX and showed homology to other plant cytochrome P450 monooxygenases and hydroxylases. Southern blotting analysis revealed that there was only one copy of the CaSS present in the genome of Camptotheca acuminata. Northern blotting analysis revealed that CaSS expressed, in a tissuespecific manner, highly in stem and lowly in root, leaf and flower. Our study suggests that CaSS is likely to be involved in the phenylpropanoid pathway. | Camptotheca |
In this article we present a new bioassay to assess the resistance status of ticks to acaricides. The Larval Tarsal Test (LTT) is a sensitive, highly time-effective in vitro test. It allows the investigation of a large number of compounds and doses on the cattle tick Rhipicephalus (Boophilus) microplus in a short period of time. The ability of the LTT to assess the lethal concentration at 50% mortality (LC(50)) and resistance ratios (RRs) of a susceptible and a resistant R. microplus strain was compared with the FAO-recommended Larval Packet Test (LPT). Representative compounds of the carbamate, organophosphate (OP), synthetic pyrethroid (SP), formamidine (FOR), macrocyclic lactone and pyrazole classes were used for this comparison. The resistance status against OP, SP and FOR of the resistant R. microplus strain was confirmed in vivo. The LTT resulted in resistance ratios comparable to those obtained with the LPT. However, the lethal concentrations were up to 150-fold lower in the LTT than in the LPT. The advantage of the LTT is to simplify the methodology by avoiding the handling of larvae and using multi-well plates. The LTT is therefore a suitable test for the assessment of the level of resistance of R. microplus and is very promising to evaluate the resistance profile of field strains. Additionally, the LTT is also suitable to test other ixodid species. | Acaricides |
Rationale: Chronic pressure overload is a major trigger of cardiac pathological hypertrophy that eventually leads to heart disease and heart failure. Understanding the mechanisms governing hypertrophy is the key to develop therapeutic strategies for heart diseases. Methods: We built chronic pressure overload mice model by abdominal aortic constriction (AAC) to explore the features of Yes-associated protein 1 (YAP1). Then AAV-cTNT-Cre was applied to Yap1(F/F) mice to induce mosaic depletion of YAP1. Myh6(CreERT2); H11(CAG-LSL-YAP1) mice were involved to establish YAP1 overexpression model by Tomaxifen injection. ATAC-seq and bioChIP-seq were used to explore the potential targets of YAP1, which were verified by a series of luciferase reporter assays. Dnm1l and Mfn1 were re-expressed in AAC mice by AAV-cTNT-Dnm1l and AAV-cTNT-Mfn1. Finally, Verteprofin was used to inhibit YAP1 to rescue cardiac hypertrophy. Results: We found that pathological hypertrophy was accompanied with the activation of YAP1. Cardiomyocyte-specific deletion of Yap1 attenuated AAC-induced hypertrophy. Overexpression of YAP1 was sufficient to phenocopy AAC-induced hypertrophy. YAP1 activation resulted in the perturbation of mitochondria ultrastructure and function, which was associated with the repression of mitochondria dynamics regulators Dnm1l and Mfn1. Mitochondrial-related genes Dnm1l and Mfn1, are significantly targeted by TEAD1/YAP complex. Overexpression of Dnm1l and Mfn1 synergistically rescued YAP1-induced mitochondrial damages and cardiac hypertrophy. Pharmacological repression of YAP1 by verteporfin attenuated mitochondrial damages and pathological hypertrophy in AAC-treated mice. Interestingly, YAP1-induced mitochondria damages also led to increased reactive oxidative species, DNA damages, and the suppression of cardiomyocyte proliferation. Conclusion: Together, these data uncovered YAP signaling as a therapeutic target for pressure overload-induced heart diseases and cautioned the efforts to induce cardiomyocyte regeneration by activating YAP. | Verteporfin |
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