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Following unilateral vestibular damage (UVD), vestibular compensation restores both static and dynamic vestibular reflexes. The cerebellar cortex provides powerful GABAergic inhibitory input to the vestibular nuclei which is necessary for compensation. Metabotropic GABA type B (GABA(B)) receptors in the vestibular nuclei are thought to be involved. However, the contribution of GABA(B) receptors may differ between static and dynamic compensation. We tested static and dynamic postural reflexes and gait in young mice, while they compensated for UVD caused by injection of air into the vestibular labyrinth. The effects of an agonist (baclofen), an antagonist (CGP56433A) and a positive allosteric modulator (CGP7930) of the GABA(B) receptor were evaluated during compensation. Static postural reflexes recovered very rapidly in our model, and baclofen slightly accelerated recovery. However, CGP56433A significantly impaired static compensation. Dynamic reflexes were evaluated by balance-beam performance and by gait; both showed significant decrements following UVD and performance improved over the next 2 days. Both CGP56433A and baclofen temporarily impaired the ability to walk on a balance beam after UVD. Two days later, there were no longer any significant effects of drug treatments on balance-beam performance. Baclofen slightly accelerated the recovery of stride length on a flat surface, but CGP7930 worsened the gait impairment following UVD. Using immunohistochemistry, we confirmed that GABA(B) receptors are abundantly expressed on the vestibulospinal neurons of Deiters in mice. Our results suggest that GABA(B) receptors contribute to the compensation of static vestibular reflexes following unilateral peripheral damage. We also conclude that impairment of the first stage of compensation, static recovery, does not necessarily result in an impairment of dynamic recovery in the long term. | Vestibular Nucleus, Lateral |
Sialoadenectomy for sialolithiasis is necessary when the stone cannot be removed through the salivary duct. In addition, extracorporeal. shock-wave lithotripsy has recently become available for this purpose. The safety and efficacy of this method was assessed in 52 outpatients bearing stones with an average diameter of 6.76 mm in the submandibular or parotid gland. Anesthetics, sedatives, and analgesics were not required. Twenty-four of the 36 patients with submandibular gland calculi and all 16 with parotid sialolithiasis had complete stone disintegration or fragmentation of the calculi, with possible spontaneous clearance. Untoward effects were observed in 15 patients, namely localized skin petecchiae, transitory swelling of the gland, and self-limiting bleeding from the duct. No persistent damage of the salivary glands or adjacent structures was noted during a mean follow-up period of 10 months. | Submandibular Gland Diseases |
OBJECTIVE: Due to high sustained virological response (SVR) rates, sofosbuvir-based regimens are currently a mainstay for hepatitis C virus (HCV) therapies. The addition of pegylated interferon (PEG-IFN) and ribavirin impacts patients' quality of life during treatment. This study aimed to compare severe adverse events (SAEs) amongst therapeutic combinations for HCV in a community clinic setting. METHODS: From December 2013 to July 2014, 128 chronic HCV-infected patients were treated with sofosbuvir, ribavirin and weekly PEG-IFN for 12 weeks (cohort 1), 12 or 24 weeks of sofosbuvir and ribavirin (cohorts 2 and 3) or sofosbuvir plus simeprevir for 12 weeks (cohort 4). Adverse events were recorded from baseline to 12 or 24 weeks of treatment. RESULTS: SAEs appeared in 15.6-53.8% of ribavirin-inclusive treated patients compared to 4.8% of the ribavirin-free regimen. PEG-IFN, sofosbuvir plus ribavirin had the highest frequencies of fatigue, headache and rash compared to either 12 or 24 weeks of ribavirin and sofosbuvir. However, sofosbuvir and ribavirin regimens led to significant increases in dyspnea, need for ribavirin dose reductions and withdrawal from treatment due to SAEs. Anemia was also more frequent in ribavirin-inclusive combinations (P < 0.001). Conversely, sofosbuvir plus simeprevir reached similar SVR rates at week 12 post-treatment compared to all ribavirin-containing regimens, but with significantly fewer adverse events (P = 0.006). At week 12 post-treatment, cirrhotic patients experienced a higher virological relapse rate than non-cirrhotic patients (P = 0.019). CONCLUSIONS: Ribavirin-inclusive HCV therapies increased the frequencies of SAEs, had higher dropout rates and increased patient morbidity. | Sofosbuvir |
Orally administered methanol extract of Passiflora edulis rind (10 mg/kg or 50 mg/kg) or luteolin (50 mg/kg), which is one of consistent polyphenols of the extract, significantly lowered systolic blood pressure in spontaneously hypertensive rats (SHRs). Quantitative analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) showed that the extract contained 20 microg/g dry weight of luteolin and 41 microg/g dry weight of luteolin-6-C-glucoside. It also contained gamma-aminobutyric acid (GABA, 2.4 mg/g dry weight by LC-MS/MS or 4.4 mg/g dry weight by amino acid analysis) which has been reported to be an antihypertensive material. Since the extract contained a relatively high concentration of GABA, the antihypertensive effect of the extract in SHRs might be due mostly to the GABA-induced antihypertensive effect and partially to the vasodilatory effect of polyphenols including luteolin. | Passifloraceae |
Involving citizen scientists in research has become increasingly popular in natural resource management and allows for an increased research effort at low cost, distribution of scientific information to relevant audiences, and meaningful public engagement. Scientists engaging fishing tournament participants as citizen scientists represent ideal scenarios for testing citizen science initiatives. For example, the Texas Shark Rodeo has begun shifting to conservation-oriented catch-and-release practices, which provides a unique opportunity to collect data on a large scale for extended periods of time, particularly through tagging large numbers of sharks for very little cost compared to a directed scientific study. However, critics are somewhat skeptical of citizen science due to the potential for lack of rigor in data collection and validation. A major management concern for shark fisheries is the ability of anglers to identify species. We tested some of the assumptions and value of citizen-collected data by cross-verifying species identification. Specifically, the purpose of this study was to evaluate the accuracy of shark species identifications made by anglers fishing in the Texas Shark Rodeo using photographs that were submitted as a requirement for tournament participation. Using a confusion matrix, we determined that anglers correctly identified 97.2% of all shark catches submitted during the Texas Shark Rodeo from 2014-2018; however, smaller sharks and certain species, including blacknose and spinner sharks, were more difficult to identify than others. Most commonly confused with blacktip sharks, spinner sharks were most commonly identified incorrectly (76.1% true positive rate [TPR]) followed by blacknose (86.8% TPR), finetooth (88.0% TPR), and Atlantic sharpnose sharks (93.8% TPR). This study demonstrated that citizen scientists have the ability to identify sharks with relatively low error. This is important for science and management, as these long-term datasets with relatively wide geographic scope could potentially be incorporated into future assessments of sharks in the Gulf of Mexico. | Citizen Science |
Tumor necrosis factor (TNF)-alpha is a potent cytokine that regulates critical cellular processes including apoptosis. TNF-alpha usually triggers both survival and apoptotic signals in various cell types. Heat shock protein 27 (HSP27), an important cellular chaperone, is believed to protect cells from apoptosis. HSP27 can be phosphorylated and changed its cellular function according to different stimuli. However, available reports on the role of HSP27 phosphorylation in apoptosis remain elusive. In this study, we investigated the role of HSP27 phosphorylation in TNF-alpha induced apoptosis in human cervical carcinoma (HeLa) cells. We found that TNF-alpha induced apoptosis was enhanced if we suppressed the TNF-alpha induced HSP27 phosphorylation by specific inhibitor CMPD1 or MAPKAPK2 (MK2) knockdown or by overexpression of non-phosphorylatable mutant HSP27-3A. Through co-immunoprecipitation and confocal microscopy, we observed that HSP27 associated with transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1) in response to TNF-alpha stimulation. By blocking MK2 activity or overexpressing phospho-mimetic mutant Hsp27-3D, we further showed that HSP27 phosphorylation facilitated the TNF-alpha induced ubiquitination and phosphorylation of TAK1 and the activations of p38 MAPK and ERK, the TAK1 downstream pro-survival signaling. In addition, we also found that increased HSP27 phosphorylation inhibited TRADD ubiquitination but did not influence the binding between TRADD and FADD in a pro-apoptotic complex. Taken together, our data indicated that HSP27 phosphorylation was involved in modulating the TNF-alpha induced apoptosis via interacting with TAK1 and regulating TAK1 post-translational modifications in HeLa cells. This study demonstrates that HSP27 phosphorylation serves as a novel regulator in TNF-alpha-induced apoptosis, and provides a new insight into the cytoprotective role of HSP27 phosphorylation." | TNF Receptor-Associated Death Domain Protein |
BACKGROUND: Alternative selection of splice sites in tandem donors and acceptors is a major mode of alternative splicing. Here, we analyzed whether in-frame tandem sites leading to subtle mRNA insertions/deletions of 3, 6, or 9 nucleotides are under natural selection. RESULTS: We found multiple lines of evidence that the human protein coding sequences are under selection against such in-frame tandem splice events, indicating that these events are often deleterious. The strength of selection is not homogeneous within the coding sequence as protein regions that fold into a fixed 3D structure (intrinsically ordered) are under stronger selection, especially against sites with a strong minor splice site. Investigating structures of functional protein domains, we found that tandem acceptors are preferentially located at the domain surface and outside structural elements such as helices and sheets. Using three-species comparisons, we estimate that more than half of all mutations that create NAGNAG acceptors in the coding region have been eliminated by selection. CONCLUSION: We estimate that ~2,400 introns are under selection against possessing a tandem site. | RNA Splice Sites |
The effect of long-term room temperature storage on the stability of ethanol in whole blood specimens was investigated. One hundred and seventeen preserved whole blood case samples (110 of 117 with two tubes of blood in each case) were used for this study. One tube from each case was initially tested for blood alcohol concentration (BAC) for criminal driving under the influence proceedings. Cases positive for ethanol ranged in BAC from 0.023 to 0.281 g/dL. The second tube, if present, remained sealed. All blood samples were then stored at room temperature. After 5.4-10.3 years, the opened tubes were reanalyzed for BAC by the same laboratory that performed the initial testing using the same method and same instrumentation. After the same storage period, the unopened tubes were sent to a different laboratory, using a different method and different instrumentation, and reanalyzed for BAC after a total of 5.6-10.5 years of room temperature storage. Seven samples initially negative for alcohol remained negative. All samples initially positive for ethanol demonstrated a decrease in BAC over time with a statistically significant difference in loss observed based on blood sample volume and whether or not the tube had been previously opened. The decrease in BAC ranged from 0.005 to 0.234 g/dL. Tubes that were not previously opened and were more than half full demonstrated better BAC stability with 89% of these tubes demonstrating a loss of BAC between 0.01 and 0.05 g/dL. | Blood Alcohol Content |
PURPOSE: To investigate the relationship between exfoliation syndrome (XFS) and systemic diseases. METHODS: A population-based, retrospective study with control group was conducted using the electronic medical database of Maccabi Health Services, the second largest Health Maintenance Organization (HMO) in Israel. Study population included Maccabi members from January 2003 to April 2016. Cases consisted of patients diagnosed with XFS regardless of glaucoma. The control group included Maccabi members without XFS, matched on age, sex, and ancestry, that were examined by an ophthalmologist within the last year. MAIN OUTCOME MEASURES: Associations between XFS and systemic diseases. RESULTS: We identified 16,388 patients with XFS, in whom 40.3% (n = 6613) had glaucoma. The control group included 14,015 patients. Mean age was 78.3 +/- 8.9 years and 76.2 +/- 8.5 years for the XFS and control group, respectively. In unconditional logistic regression analyses, after adjusting for age, sex, and ancestry, XFS was significantly associated with risk of cardiovascular diseases including hypertension (OR 1.07, 95% CI 1.01-1.13, p = 0.02), myocardial infarction (OR 1.21, 95% CI 1.17-1.31, p < 0.0001), and congestive heart failure (OR 1.70, 95% CI 1.55-1.88, p < 0.0001) as well as higher risk for high creatinine (OR 1.28, 95% CI 1.2-1.37, p < 0.0001). Diabetes mellitus and body mass index were inversely associated with XFS (OR 0.70, 95% CI 0.67-0.73, p < 0.0001 and OR 0.88, 95% CI 0.84-0.93, p < 0.0001, respectively). Overall cancer diagnoses were more common in the XFS group (OR 1.05, 95% CI 1.0-1.1, p = 0.05). XFS was associated with more hospitalizations (mean 5 +/- 5.3 hospitalizations in the XFS group and 3.3 +/- 4.0 in the controls, p < 0.0001). CONCLUSION: XFS is significantly associated with cardiovascular systemic diseases (in a population living in Israel and predominantly born in Russia). | Exfoliation Syndrome |
22 believers and 20 skeptics of extrasensory perception (ESP) participated in a telepathy experiment. Subjects were asked to judge the covariation between transmitted symbols and the corresponding feedback given by a receiver. Believers overestimated the number of successful transmissions ('hits'). Skeptics were characterized by accurate hit judgments. For believers, positive correlations between hit-responses, their heart rates, and their experienced arousal were found. In addition, subjective arousal was positively associated with the hit estimates given at the end of the experiment. This response pattern was absent in the group of skeptics. It is concluded that covariation bias as a psychophysiological concept plays an important role in the maintenance of paranormal belief. | Parapsychology |
Polymyxin B is increasingly used as a treatment of last resort against multidrug-resistant Gram-negative infections. Using a mammalian kidney cell line, we demonstrated that polymyxin B uptake into proximal tubular epithelial cells was saturable and occurred primarily through the apical membrane, suggesting the involvement of transporters in the renal uptake of polymyxin B. Megalin might play a role in the uptake and accumulation of polymyxin B into renal cells. | Polymyxin B |
A high percentage of knee osteoarthritis finally need a knee replacement. Previous treatments used including viscosupplementation with hyaluronic acid can delay the knee replacement. The objective of this study was to estimate the economic impact in the short, medium and long term of the knee replacement delay, by conducting a budget impact analysis of the incorporation of viscosupplementation to the treatment of knee osteoarthritis. From the data of patients treated at a specialized Knee Osteoarthritis Unit we built a discrete event simulation model that reproduced the progress of patients, as it could represent changes in the health status of an individual and their interaction with the system. The model allowed the number of prostheses and replacements performed each year to be calculated in a population including 1,000 patients each year according to the use of viscosupplementation. The budget impact analysis was estimated for 10 years by adding the cost of each treatment. A total of 224 patient candidates to receive a knee replacement were studied. The viscosupplementation use delayed the need to perform the knee replacement by 2.67 years The budgetary impact would lead to net savings during the 10 years. However, it is much greater in the earlier years. The sum of the savings in the first three years would be 36 million euros. The study concludes that the use of viscosupplementation reduced the economic burden of knee osteoarthritis in the health system as a result of delayed knee replacement. The simulation model enabled the economic impact in both the short and long term to be analysed. | Viscosupplementation |
The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)- and 2-oxoglutarate-dependent dioxygenases that efficiently repair N(1)-methyladenine and N(3)-methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N(1)-methyladenine and N(3)-methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment." | AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase |
Cirrhosis, the twelfth leading cause of death, accounts for 1.1% of all deaths in the United States. Although there are multiple pulmonary complications associated with liver disease, the most important complications that cause significant morbidity and mortality are hepatopulmonary syndrome, hepatic hydrothorax, and portopulmonary hypertension. Patients with cirrhosis who complain of dyspnea should be evaluated for these complications. This article reviews these complications. | Hepatopulmonary Syndrome |
Elongation of the upper lip, in particular the philtrum, and nose widening are common postoperative changes after a Le Fort I osteotomy. These changes can be induced by the transection of soft tissue and loosening of the underlying musculature. A methodology for soft tissue redraping was developed to limit these undesirable nasolabial changes. This study evaluates the effectiveness of the technique and influence of maxillary translocation on the nasolabial form. Anthropometric measurements, lip, philtrum length, and nose width, were taken two weeks prior to, and one year after, surgery. The mean postoperative changes were minimised to less than 1mm except for lip length in the extrusion groups, which was less than 1.5mm. Statistical analysis showed a stable result for lip length after maxillary advancement and/or intrusion as limited lengthening mainly occurred at the vermilion. Conversely, lip lengthening after extrusion mainly occurred at the philtrum. The mean nose width was maintained after maxillary advancement, decreased after extrusion, and increased after intrusion. The type of maxillary translocation only influenced the nasolabial soft tissue in case of intrusion and extrusion, not after advancement. | Osteotomy, Le Fort |
BACKGROUND: Anatomically, cortical-basal ganglia-thalamo-cortical (CBGTC) circuits have an essential role in the expression of tics. At the biochemical level, the proper conveyance of messages through these circuits requires several functionally integrated neurotransmitter systems. In this manuscript, evidence supporting proposed pathophysiological abnormalities, both anatomical and chemical is reviewed. In addition, the results of standard and emerging tic-suppressing therapies affecting nine separate neurotransmitter systems are discussed. The goal of this review is to integrate our current understanding of the pathophysiology of Tourette syndrome (TS) with present and proposed pharmacotherapies for tic suppression. METHODS: For this manuscript, literature searches were conducted for both current basic science and clinical information in PubMed, Google-Scholar, and other scholarly journals to September 2018. RESULTS: The precise primary site of abnormality for tics remains undetermined. Although many pathophysiologic hypotheses favor a specific abnormality of the cortex, striatum, or globus pallidus, others recognize essential influences from regions such as the thalamus, cerebellum, brainstem, and ventral striatum. Some prefer an alteration within direct and indirect pathways, whereas others believe this fails to recognize the multiple interactions within and between CBGTC circuits. Although research and clinical evidence supports involvement of the dopaminergic system, additional data emphasizes the potential roles for several other neurotransmitter systems. DISCUSSION: A greater understanding of the primary neurochemical defect in TS would be extremely valuable for the development of new tic-suppressing therapies. Nevertheless, recognizing the varied and complex interactions that exist in a multi-neurotransmitter system, successful therapy may not require direct targeting of the primary abnormality. | Tics |
Formulating a treatment plan for infertility associated with endometriosis is difficult due to the lack of a cause-and-effect relationship between the disease and infertility. Several molecular and cellular mechanisms have been postulated as playing roles in endometriosis-associated infertility; they are reviewed here. Several medical and surgical treatment options are discussed, including danocrine, medroxyprogesterone acetate and gonadotropin releasing hormone agonists. A combined medical and surgical approach and occasional expectant management remain the treatments of choice. | Infertility, Female |
The cesarean delivery rate in the United States has risen steadily over the past 5 decades such that approximately one in three women now undergo cesarean section. The rise in repeat operations and accompanying decline in trial of labor after cesarean (TOLAC) have been major contributors to this phenomenon. The appropriate use of TOLAC continues to be a topic of interest with the recognition that most women with a history of prior cesarean are candidates for trial of labor. The NICHD MFMU Network Cesarean Registry conducted from 1999 to 2002 provided contemporary data concerning the risks and benefits of TOLAC, which in turn have helped inform practitioners and women considering their options for childbirth following cesarean delivery. | Vaginal Birth after Cesarean |
Efficient bioconversion of d-xylose into various biochemicals is critical for lignocelluloses application. Candida glycerinogenes, expressing the xylitol dehydrogenase (XYL2) gene, has the ability to produce glycerol from xylose entered into pentose phosphate pathway. In this study, we demonstrate that low expression levels of the XYL2 gene derived from Scheffersomyces stipitis in C. glycerinogenes is a major bottleneck in efficient xylose fermentation. Through a metabolic engineering approach using an integrative expression, XYL2 was identified as an overexpression target for improving xylose metabolism. Two recombinant strains with XYL2 overexpression were constructed to ferment a mixture of glucose and xylose simultaneously in batch fermentation. Compared with C. glycerinogenes (wild type), glycerol production from xylose by C. glycerinogenes (PURGAPX2) and C. glycerinogenes (PURGPDX2) was increased by 94.5% and 103.3%, respectively. It was also found that additional overexpression of XYL2 under the control of strong promoters in a xylose-fermenting strain not only reduced xylitol accumulation but also increased glycerol yields. As the expression levels of XYL2 increased, the glycerol yields gradually improved from 30.6 to 63.3 g/L, whereas the xylitol yields significantly decreased from 38.7 to 19.9 g/L. These results suggest that strong expression of XYL2 is a necessary condition for developing efficient xylose-fermenting strains. | D-Xylulose Reductase |
Repeat proteins are made with tandem copies of similar amino acid stretches that fold into elongated architectures. These proteins constitute excellent model systems to investigate how evolution relates to structure, folding, and function. Here, we propose a scheme to map evolutionary information at the sequence level to a coarse-grained model for repeat-protein folding and use it to investigate the folding of thousands of repeat proteins. We model the energetics by a combination of an inverse Potts-model scheme with an explicit mechanistic model of duplications and deletions of repeats to calculate the evolutionary parameters of the system at the single-residue level. These parameters are used to inform an Ising-like model that allows for the generation of folding curves, apparent domain emergence, and occupation of intermediate states that are highly compatible with experimental data in specific case studies. We analyzed the folding of thousands of natural Ankyrin repeat proteins and found that a multiplicity of folding mechanisms are possible. Fully cooperative all-or-none transitions are obtained for arrays with enough sequence-similar elements and strong interactions between them, while noncooperative element-by-element intermittent folding arose if the elements are dissimilar and the interactions between them are energetically weak. Additionally, we characterized nucleation-propagation and multidomain folding mechanisms. We show that the global stability and cooperativity of the repeating arrays can be predicted from simple sequence scores." | Repetitive Sequences, Amino Acid |
Diflubenzuron (DFB), a potent inhibitor of insect chitin synthesis, was administered to Swiss Webster mice in a 30-day oral intubation study. Animal groups received either no treatment, vehicle control (Polyethylene glycol 400), or DFB suspensions at doses of 125, 500, and 2,000 mg/kg body weight. Hepatic glutathione S-transferase activity as well as morphological characteristics were studied. DFB was shown to elicit hepatocellular changes at all dose levels. The activities of three glutathione S-transferases (S-aryl, S-aralkyl, and S-epoxide) were all altered after DFB administration. Light microscopy revealed radial arrays of hepatocellular vacuolization between the portal and central vein areas. Electron-microscopic examination, verified by morphometric analysis, revealed degenerative changes as well as an increased volume density of the endoplasmic reticulum. | Juvenile Hormones |
There is solid evidence that a sudden change in mitochondrial membrane permeability (mitochondrial permeability transition, MPT) plays a critical role in reperfusion-induced myocardial necrosis. We hypothesized that sarcoplasmic reticulum (SR) Ca(2+) cycling may induce partial MPT in microdomains of close anatomic proximity between mitochondria and SR, resulting in hypercontracture and cell death. MPT (mitochondrial calcein release), cell length, and sarcolemmal rupture (Trypan blue and lactate dehydrogenase release) were measured in adult rat cardiomyocytes submitted to simulated ischemia (NaCN/2-deoxyglucose, pH 6.4) and reperfusion. On simulated reperfusion, 83 +/- 2% of myocytes developed hypercontracture. In 22 +/- 6% of cases, hypercontracture was associated with sarcolemmal disruption [Trypan blue(+)]. During simulated reperfusion there was a 25% release of cyclosporin A-sensitive mitochondrial calcein (with respect to total mitochondrial calcein content). Simultaneous blockade of SR Ca(2+) uptake and release with thapsigargin and ryanodine, respectively, significantly reduced mitochondrial calcein release, hypercontracture, and cell death during simulated reperfusion. SR Ca(2+) blockers delayed mitochondrial Ca(2+) uptake in digitonin-permeabilized cardiomyocytes but did not have any effect on isolated mitochondria. Pretreatment with colchicine to disrupt microtubule network reduced the degree of fluorescent overlap between SR and mitochondria and abolished the protective effect of SR Ca(2+) blockers on MPT, hypercontracture, and cell death during reperfusion. We conclude that SR Ca(2+) cycling during reperfusion facilitates partial mitochondrial permeabilization due to the close anatomic proximity between both organelles, favoring hypercontracture and cell death. | Ischemic Contracture |
HPLC-ELSD was applied to explore the absorption mechanism of pulchinenosides (B3, BD, B7, B10, B11) in rats. The experimental results showed that the absorption rate constant, Ka value (B3, BD) and Permeability coefficient, Peff value (B3, B7) displayed significant difference (P <0.05) in various intestinal segments, The Ka value and Peff value of PRS was different from each other with the highest absorption in duodenum (duodenum > jejunum > colon > ileum); The PRS displayed excessive satuation as the concentration increased over 0.05-2.5 g . L(-1). There were no obvious linear correlations between Peff values and concentrations in duodenum (0.6007 </= R2 </= 0.7727); Ka and Peff value declined when the PRS was perfused with P-glycoprotein promoter digoxin, on the other hand, inclined when perfused with P-glycoprotein inhibitor verapamil with significant difference among PRS B3, BD, B7, B11 (P <0.05). All the above results demonstrated that B3, BD, B7 were greatly influenced by absorption sites, duodenum was the main absorption site; PRS didn't entirely transported in a concentration dependent manner, and the transporter-protein involved the transportation, so the intestinal absorption of the five pulchinenosides was not entirely passive diffusion; and PRS might be the substrates of P-glycoprotein. | Pulsatilla |
BACKGROUND AND AIM: The aim of this trial was to evaluate the effect of doxazosin as add-on therapy in patients with hypertension not adequately controlled on current antihypertensive therapy, and impaired glucose metabolism. The effect of doxazosin administered as add-on therapy was to be considered significant both from clinical and statistical viewpoints if the proportion of patients with adequate control of blood pressure (BP<130/85 mmHg) would be at least 30% after 16 weeks of combined therapy. METHOD AND RESULTS: It was an open, multicenter phase IV study, lasting 19 weeks: 3-week qualifying/placebo run-in period+16-week dose titration/add on therapy period, involving 264 out-patients (158 m and 106 f; mean age+/-SD: 60.9+/-8.6 years; mean BMI+/-SD: basal 29.5+/-5.1, final 30.2+/-4.6) with blood pressure still >130/85 mmHg in spite of the antihypertensive treatment (ACE inhibitors 44%, AT II antagonists 21%, Ca antagonists 12%, other drugs 8%, polytherapy 15%) and affected by type 2 diabetes (n=219), impaired fasting glucose (IFG; n=16) or impaired glucose tolerance (IGT; n=29). Following a run-in, 3-week qualifying phase during which placebo was added to ongoing antihypertensive treatment, 16-week treatment with doxazosin was added at dosages from 1 up to 8 mg/day. Main outcome measures were: the percentage of patients with blood pressure <130/85 mmHg at the end of treatment; the effects of the combination therapy on glyco-lipidic metabolism: fasting plasma glucose, fasting insulin, glycated hemoglobin, insulin resistance (HOMA-R), plasma lipids; and the effect on the 10-year CHD risk (Framingham equation). RESULTS: 35% of patients were responsive (BP<130/85 mmHg) to add-on treatment with doxazosin (CI 90%: 30.3%-40.4%; P<0.05, stat. an. intention to treat). During the run-in phase with placebo, mean SBP/DBP (+/-SD) decreased from 155.6+/-13.2/91.8+/-6.8 mmHg (Week -3) to 151.9+/-12.9/90.1+/-7.2 mmHg (Week -1) and to 151.2+/-11.5/90.1+/-6.9 mmHg (Week 0). During add-on treatment with doxazosin, mean SBP/DBP (+/-SD) further decreased to 144.9+/-15.2/86.3+/-8.3 mmHg (Week 4), 139.7+/-15.3/83.4+/-7.9 mmHg (Week 8), 135.5+/-14.3/81.7+/-7.6 mmHg (Week 12) and 136.4+/-14.5/81.0+/-7.0 mmHg (Week 16). Overall, mean BP changes reached a plateau of about -15 mmHg (SBP) and -9 mmHg (DBP) after 16 weeks of treatment; at each visit the mean decreases from baseline were statistically significant. The following mean values of metabolic parameters were reduced during the study: fasting plasma glucose (-4.1mg/dl; -2.8%), fasting insulin (-2 microU/ml; -12.3%; P<0.05), glycated hemoglobin (-0.12%; -1.7%), HOMA-R (-1.03; -18.2%; P<0.05), total cholesterol (-1.85 mg/dl; -1.1%), LDL cholesterol (-1.35 mg/dl; -0.8%) and triglycerides (-5.64 mg/dl; -2.4%); mean HDL cholesterol increased (+1.79 mg/dl; +3.9%; P<0.01). At the end of study treatment, the percentage of patients with lab values returned within normal ranges, in comparison with basal values, was statistically significant (P<0.05) for the following parameters: fasting plasma glucose (6.3%), fasting insulin (7.5%), LDL cholesterol (6.0%). Ten-year CHD risk (+/-SD) decreased from 16.4+/-7.8% to 13.6+/-7.4% (final vs. basal: -2.87+/-3.9; -17%; P<0.01). Six patients (2.3%) reported 8 adverse drug reactions: dizziness (3), edema (2), headache (2), asthenia (1). In one out of these 6 patients, in whom doxazosin was associated to the ACE inhibitor quinapril, adverse reaction (peripheral edema) led to treatment withdrawal. CONCLUSION: In patients not responsive to antihypertensive treatment and concomitantly affected by impaired glucose metabolism, achievement of target BP was obtained in more than one third of cases after 16-week add-on treatment with doxazosin. Changes in glyco-lipidic parameters and reduction of 10-year CHD risk observed during the study, although of moderate extent, confirm the overall favourable effect of antihypertensive combinations including doxazosin. | Doxazosin |
Negative-stain transmission electron microscopy (EM) is a technique that has provided nanometer resolution images of macromolecules for about 60 years. Developments in cryo-EM image processing have maximized the information gained from averaging large numbers of particles. These developments can now be applied back to negative-stain image analysis to ascertain domain level molecular structure (10 to 20 A) more quickly and efficiently than possible by atomic resolution cryo-EM. Using uranyl acetate stained molecular complexes of influenza hemagglutinin bound to Fab 441D6, we describe a simple and efficient means to collect several hundred micrographs with SerialEM. Using RELION, we illustrate how tens of thousands of complexes can be auto-picked and classified to accurately describe the domain level topology of this unconventional hemagglutinin head-domain epitope. By comparing to the cryo-EM density map of the same complex, we show that questions about epitope mapping and conformational heterogeneity can readily be answered by this negative-stain method. (c) 2019 The Authors." | Microscopy, Electron, Transmission |
Indole-pyruvic acid was studied for its short- and long-term effects on electroencephalographic sleep and on food intake in rats implanted with cortical and muscular electrodes. Following a single injection, indole-pyruvic acid (10-50 mg kg-1 i.p.) reduced by 16-23 min (range) the latency of the first slow-wave episode in a dose-related fashion and produced a significant increase in slow-wave sleep time (12-40%) in doses of 10-30 mg kg-1. Rapid eye movement sleep latency and rapid eye movement sleep time were increased (by 23-37 min) and reduced (57-71%) respectively. The effects of indole-pyruvic acid on slow-wave sleep time were still present after 3, 7 and 14 days of chronic administration (10 mg kg-1 day-1), whereas tolerance to the effect of indole-pyruvic acid on rapid eye movement sleep was observed. Daily food consumption was reduced (20-28%) by acute administration of indole-pyruvic acid (15-30 mg kg-1 i.p.), but tolerance developed after 5 days of repeated injections. These findings are in accordance with previous evidence suggesting that indole-pyruvic acid effects may be related to the activation of central serotonin neurons, which are involved in the inhibitory control of sleep and food intake. | Drinking |
The aim of this study was to verify the trypanocidal effectiveness of aqueous, methanolic, and ethanolic extracts of Achyrocline satureioides against Trypanosoma evansi in vitro. A. satureioides extracts, known as macela, were used on trypomastigotes at different concentrations (1, 5, 10, 50, 100, 500, and 1,000 microg/ml) and exposure times (0, 1, 3, 6, and 9 hr). A dose-dependent effect was observed when the 3 extracts were tested. The concentrations of 1, 5, and 10 microg/ml were not able to kill trypomastigotes until 3 hr after exposure, and the highest concentrations (500 and 1,000 microg/ml) were able to kill all trypomastigotes after 1 hr. When the time of exposure was increased up to 9 hr, the concentrations at 50 and 100 microg/ml were 100% effective to 3 extracts. The chemical analysis of the extracts revealed the presence of flavonoids, a trypanocidal compound already described. Based on the results, we can conclude that the A. satureioides extracts exhibit trypanocidal effects. | Achyrocline |
Vardenafil selectively inhibits phosphodiesterase type 5 (PDE5), an enzyme which hydrolyses cyclic guanosine monophosphate in the cavernosum tissue of the penis. Inhibition of PDE5 results in increased arterial blood flow leading to enlargement of the corpus cavernosum. Because of the increased tumescence, veins are compressed between the corpus cavernosum and the tunica albuginea, resulting in an erection. Vardenafil has a high bioavailabilty and is rapidly absorbed. An erection of >60% rigidity was maintained for approximately twice as long following visual stimulation in patients treated with vardenafil 10 or 20mg than in recipients of placebo. In a large, placebo-controlled trial in patients with mild to severe erectile dysfunction (ED), vardenafil 5, 10 or 20mg taken as needed over a 12-week period significantly improved the scores in questions 3 and 4 of the International Index of Erectile Function (IIEF). The rate of successful attempts at intercourse with ejaculation was also significantly higher with vardenafil (71 to 75%) than in the placebo group (39.5%), and significantly more patients treated with vardenafil than placebo responded 'yes' to a Global Assessment Question (GAQ) asking if treatment had improved erections. In a 26-week trial in 736 men with ED of varied aetiologies and severity patients receiving vardenafil 5, 10 or 20mg experienced significantly improved erections with 85% of vardenafil 20mg recipients reporting improved erectile function (assessed using the GAQ) compared with 28% of placebo recipients. Treatment with vardenafil also significantly improved scores in response to questions 3 and 4 of the IIEF compared with placebo. A 12-week trial in 452 men with ED associated with diabetes mellitus demonstrated that treatment with vardenafil 20mg compared with placebo significantly improved IIEF erectile function domain scores and the rate of positive responders to the erectile improvement GAQ. Similar results were reported in a placebo-controlled trial of vardenafil 10 to 20mg involving 440 patients with ED after radical prostatectomy. Adverse events associated with vardenafil were those commonly associated with PDE5 inhibitors: headache, flushing, dyspepsia and rhinitis. These were mostly dose-dependent and mild to moderate in intensity. | Vardenafil Dihydrochloride |
We investigated the relationship between tympanosclerosis, known atherosclerotic risk factors, and the intima-media thickness of bilateral carotid arteries using ultrasonography. A total of 122 patients admitted to our clinic with chronic otitis media between 2005 and 2010 were included in the study. The study group consisted of 61 patients with tympanosclerosis; the control group comprised 61 patients without tympanosclerosis. Internal carotid artery intima-media thickness (CAIMT), total cholesterol, triglyceride, low- and high-density lipoprotein cholesterol, C-reactive protein, and homocysteine levels were measured in all patients. Homocysteine, low-density lipoprotein, total cholesterol, and triglyceride levels in the study group were higher compared with those of the control group (p < 0.05). Right and left CAIMT was greater in the study group versus the control group (p </= 0.001). In conclusion, atherosclerosis and tympanosclerosis were associated with identical risk factors; in the tympanosclerosis group, CAIMT was increased significantly. | Myringosclerosis |
Laboratory evaluation of hyperthermophiles with the potential for Enhanced Oil Recovery (EOR) is often hampered by the difficulties in replicating the in situ growth conditions in the laboratory. In the present investigation, genome analysis was used to gain insights into the metabolic potential of a hyperthermophile to mobilize the residual oil from depleting high-temperature oil reservoirs. Here, we report the 1.9 Mb draft genome sequence of a hyperthermophilic anaerobic archaeon, Thermococcus sp. 101C5, with a GC content of 44%, isolated from a high-temperature oil reservoir of Gujarat, India. 101C5 possessed the genetic arsenal required for adaptation to harsh oil reservoir conditions, such as various heat shock proteins for thermo-adaptation, Trk potassium uptake system proteins for osmo-adaptation, and superoxide reductases against oxidative stress. Microbial Enhanced Oil Recovery (MEOR) potential of the strain was established by ascertaining the presence of genes encoding enzymes involved in the production of the metabolites such as hydrogen, bio-emulsifier, acetate, exopolysaccharide, etc. Production of these metabolites which pressurize the reservoir, emulsify the crude oil, lower the viscosity and reduce the drag, thus facilitating mobilization of the residual oil was experimentally confirmed. Also, the presence of crude oil degradative genes highlighted the ability of the strain to mobilize heavy residual oil, which was confirmed under simulated conditions in sand-pack studies. The obtained results demonstrated additional oil recoveries of 42.1% and 56.5% at 96 degrees C and 101 degrees C, respectively, by the strain 101C5, illustrating its potential for application in high-temperature oil reservoirs. To our best knowledge, this is the first report of genome analysis of any microbe assessed for its suitability for MEOR from the high-temperature oil reservoir. | Thermococcaceae |
OBJECTIVE: To systematically evaluate evidence against male circumcision (MC). METHODS: We searched PubMed, Google Scholar, EMBASE and Cochrane databases. RESULTS: Database searches retrieved 297 publications for inclusion. Bibliographies of these yielded 101 more. After evaluation we found: Claims that MC carries high risk were contradicted by low frequency of adverse events that were virtually all minor and easily treated with complete resolution. Claims that MC causes psychological harm were contradicted by studies finding no such harm. Claims that MC impairs sexual function and pleasure were contradicted by high-quality studies finding no adverse effect. Claims disputing the medical benefits of MC were contradicted by a large body of high-quality evidence indicating protection against a wide range of infections, dermatological conditions, and genital cancers in males and the female sexual partners of men. Risk-benefit analyses reported that benefits exceed risks by 100-200 to 1. To maximize benefits and minimize risks, the evidence supported early infant MC rather than arguments that the procedure should be delayed until males are old enough to decide for themselves. Claims that MC of minors is unethical were contradicted by balanced evaluations of ethical issues supporting the rights of children to be provided with low-risk, high-benefit interventions such as MC for better health. Expert evaluations of case-law supported the legality of MC of minors. Other data demonstrated that early infant MC is cost-saving to health systems. CONCLUSIONS: Arguments opposing MC are supported mostly by low-quality evidence and opinion, and are contradicted by strong scientific evidence." | Body Modification, Non-Therapeutic |
We describe a treatment strategy for an aberrant arterial aneurysm associated with pulmonary sequestration. A 58-year-old man with impending aberrant arterial aneurysm rupture underwent a 2-stage surgery that included an emergency thoracic endovascular aortic repair (TEVAR) of the descending aorta to occlude the origin of the aberrant artery, followed by lobectomy. TEVAR can lead to faster occlusion of the aneurysm and can avoid operative risk of aneurysm rupture during lobectomy. The aberrant artery was broad where it branched off the aorta and had a short neck, rendering primary ligation or stump-forming unsuitable. Pathological findings revealed the fragility of the aberrant artery; thus, its root was prone to breakdown of the stump after simple aneurysmectomy. Furthermore, TEVAR may reduce graft infection during lobectomy in the second surgery. The 2-stage surgery may be useful for aberrant aneurysms complicated by pulmonary sequestration. | Aortic Aneurysm, Thoracic |
Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila, a gut probiotic, ameliorates systemic inflammation by tightening the intestinal barrier. In this study, fractured mice intragastrically administrated with A. muciniphila were found to display better fracture healing than mice treated with vehicle. Notably, more preosteclasts positive for platelet-derived growth factor-BB (PDGF-BB) were induced by A. muciniphila at 2 weeks post fracture, coinciding with increased formation of type H vessels, a specific vessel subtype that couples angiogenesis and osteogenesis, and can be stimulated by PDGF-BB. Moreover, A. muciniphila treatment significantly reduced gut permeability and inflammation at the early stage. Dextran sulfate sodium (DSS) was used to disrupt the gut barrier to determine its role in fracture healing and whether A. muciniphila still can stimulate bone fracture healing. As expected, A. muciniphila evidently improved gut barrier, reduced inflammation and restored the impaired bone healing and angiogenesis in DSS-treated mice. Our results suggest that A. muciniphila reduces intestinal permeability and alleviates inflammation, which probably induces more PDGF-BB(+) preosteoclasts and type H vessel formation in callus, thereby promoting fracture healing. This study provides the evidence for the involvement of type H vessels in fracture healing and suggests the potential of A. muciniphila as a promising strategy for bone healing.This article has an associated First Person interview with the first author of the paper. | Akkermansia |
PURPOSE: We compared the long-term outcome of AUS between men and women who received the device for the management of stress urinary incontinence. MATERIALS AND METHODS: Between August 1983 and January 2004, 126 consecutive patients received the AUS AMS 800 at our center placed by the senior author (ACD). Of these patients 108 (53 men, 55 women) and 168 devices (88 in men, 80 in women) were available for review. Outcome measures include complications, duration and etiology of AUS failure, and satisfactory continence. RESULTS: Mean followup was 8.1 +/- 5.6 years. Of the 108 patients 18 (40%) men and 31 (56%) women had no complications (p = 0.09). Of the 168 devices 76 (45%) eventually failed (44 or 50% in men, 32 or 40% in women, p = 0.19). The incidences of failed device classified as mechanical, nonmechanical or iatrogenic were not significantly different (p = 0.07). Median device durations were 6.9 and 11.2 years in men and women, respectively (p = 0.002). Satisfactory continence was achieved in 82% of patients, in 43 (81%) men and in 46 (84%) women (p = 0.73), including 5 (9%) men and 35 (64%) women who were dry (0 pads, p = 0.01), 28 (53%) men and 4 (7%) women who wear 1 pad (p = 0.01), and 10 (19%) men and 7 (13%) women who use 2 pads per day. CONCLUSIONS: There were no differences in overall satisfactory continence and device failure rates. However, women have a higher dry rate (0 pad use) and longer functioning device duration compared to their male counterparts. | Urinary Sphincter, Artificial |
Especially in older pet birds, an unnecessary overconsumption of protein--presumably occurring in human custody--should be avoided in view of a potential decrease in the excretory organs' (liver, kidney) efficiency. Inevitable nitrogen (N)-losses enable the estimation of protein requirement for maintenance, because these losses have at least to be replaced to maintain N equilibrium. To determine the inevitable N losses in excreta of adult amazons (Amazona spp.), a frugivor-granivorous avian species from South America, adult amazons (n = 8) were fed a synthetic nearly N-free diet (in dry matter; DM: 37.8% starch, 26.6% sugar, 11.0% fat) for 9 days. Throughout the trial, feed and water intake were recorded, the amounts of excreta were measured and analysed for DM and ash content, N (Dumas analysis) and uric acid (enzymatic-photometric analysis) content. Effects of the N-free diet on body weight (BW) and protein-related blood parameters were quantified and compared with data collected during a previous 4-day period in which a commercial seed mixture was offered to the birds. After feeding an almost N-free diet for 9 days, under the conditions of a DM intake (20.1 g DM/bird/day) as in seeds and digestibility of organic matter comparable with those when fed seeds (82% and 76% respectively), it was possible to quantify the inevitable N losses via excrements to be 87.2 mg/bird/day or 172.5 mg/kg BW(0.75)/day. Assuming a utilization coefficient of 0.57 this leads to an estimated protein need of approximately 1.9 g/kg BW(0.75)/day (this value does not consider further N losses via feathers and desquamated cells; with the prerequisite that there is a balanced amino acid pattern). | Amazona |
This paper summarizes work done in this laboratory over the last two years on the cloning of microsporidian rRNA by homology PCR and its subsequent use in diagnostic tests and phylogenetic studies. Using highly conserved primers in the 16S or small subunit rRNA (SSU-rRNA) these genes were cloned from human intestinal biopsies with transmission electron microscopy proven Enterocytozoon bieneusi and Septata intestinalis. The SSU-rRNA genes were then used to design and test several primer pairs for the diagnosis of microsporidian infection. Utilizing the polymerase chain reaction and primers V1 and EB450 Ent. bieneusi infected duodenal aspirates or intestinal biopsies could be detected. Using V1 and SI500 infection with S. intestinalis could be detected. In addition to diagnostic tests, phylogenetic relationships were examined using sequence data from the fragment amplified by PCR by primer 530f in the SSU-rRNA and primer 580r in the large subunit rRNA. This data supported the placement of S. intestinalis in the family Encephalitozoonidae. In addition, it confirmed that Encephalitozoon cuniculi, E. hellem and S. intestinalis are distinct organisms. These techniques have broad applications to the study of other microsporidia and the development of a molecular phylogeny. | Microsporida |
The authors present a new classification for photodermatosis in five groups: 1. Primary toxic photodermatosis that means lesions produced in all human beings by non-ionized radiation. 2. Photodermatosis induced by drugs, with two subgroups--phototoxic and photoalergic--according to the mechanism of action of the drug. 3. Idiopathic photodermatosis in which the photonic effects are known but the chromophores are unknown; four conditions are included here polymorphous actinic eruption, solar urticaria, actinic reticuloid and hidroa vacciniforme. 4. Miscelanea group which includes several conditions of unknown mechanism which are not included in the other groups, such as: actinic cheilitis, actinic poikiloderma, actinic ceratoses, epitheliomas, melanomas and others. 5. Conditions precipitated or aggravated by solar radiation with two sub-groups: hereditary (xeroderma pigmentosum, Hartnup's syndrome and other) and acquired (lupus erythematosus, pellagra and other). In group 1, the authors propose the designation of actinic elastotic dermatosis to unify different conditions described by several authors such as: diffuse elastosis, citrein skin, cutis rhomboidalis, and others. | Photosensitivity Disorders |
Many functional food ingredients are poorly soluble in water, susceptible to chemical degradation, and incompatible with surrounding food matrix. Other issues are related to limited oral bioavailability, unpleasant sensory properties, and poor release profiles. Nanoencapsulation of functional food ingredients can help increase their water solubility/dispersibility in foods and beverages, improve their bioavailability by exhibiting good dose-dependent functionalities, mask undesired flavors/tastes to reduce the adverse effect on mouth-feel, enhance shelf-life and compatibility during production, storage, transportation and utilization of food products, and control release rate or specific delivery environment for better performance on their functionalities. This chapter provides an overview of different delivery systems for different functional food ingredients, the types of materials suitable for wall materials or building blocks of nanocapsules, the fabrication methods to assemble different delivery systems and release these active ingredients under different physiological conditions. | Food, Fortified |
BACKGROUND: Systemic inflammation is accompanied by unspecific physical and psychological symptoms of sickness, including pain and affective symptoms. These symptoms (commonly called sickness behavior") are mediated by the central nervous effects of immune messengers such as pro-inflammatory cytokines. While adaptive during acute inflammation, sickness symptoms can have detrimental effects on quality of life during chronic inflammation and may contribute to comorbidity in chronic pain conditions. Despite the high clinical relevance of sickness behavior, psychological interventions aiming to modulate sickness symptoms have hardly been investigated. One approach could be the use of expectation effects, since positive and negative expectations (placebo or nocebo effects) have been shown to have an influence on pain and affect-related symptoms. OBJECTIVES: Herein, we summarize immunological and psychobiological factors that contribute to pain in the context of sickness behavior, with a major focus on findings from experimental endotoxemia. Against this background, we discuss how expectations could help to improve immune-mediated sickness symptoms and outline potential psychological and psychobiological mechanisms underlying this putative effect." | Illness Behavior |
Drug-induced pancreatitis is a disease that is receiving increasing attention. This article reviews the advances in the incidence, risk factors, pathogenesis, diagnosis, treatment and prevention of drug-induced pancreatitis by reviewing the literature on drug-induced pancreatitis, especially in the literature of the latest 10 years. The incidence of drug-induced pancreatitis is relatively low, however, there is an increasing trend with the widespread use of drugs, and the incidence seems to be related to regional distribution. There is currently lack of data on the epidemiology of drug-induced pancreatitis in China. In recent years, research on the pathogenesis of drug-induced pancreatitis has made some progress, but further research is needed. Drug-induced pancreatitis is a diagnosis of exclusion. With further understanding and research, a new diagnostic approach has been proposed. Pharmacogenomics is expected to help prevent and perform an individual treatment of drug-induced pancreatitis. | Pancreatitis |
The isometric contractile properties of single myofibrils of rabbit skeletal muscle were studied at various sarcomere lengths. Single myofibrils were suspended between the tips of one rigid and one flexible glass microneedle, and their force production was determined by detecting the bending of the flexible microneedle photo-electronically. The active force vs. sarcomere length relation had an ascending limb (0.7-2.25 micron), a plateau (2.25-2.5 micron), and a descending limb (2.5-3.8 micron), which was similar to that of frog skeletal muscle. The passive force became increasingly apparent beyond a sarcomere length of 2.4 micron. These results can reasonably be explained based on the sliding filament mechanism by assuming the sarcomere geometry of rabbit muscle. The plateau, with a produced force of about 256 kN/m2, and the linear decline of force in the descending limb of the single myofibrils were essentially the same as those for frog muscle fibers. However, the slope of the force decline in the ascending limb was far steeper than that for frog muscle. This suggests that internal elements of sarcomeres are different between rabbit and frog muscles. | Myofibrils |
Cloud computing has increased its service area and user experience above traditional platforms through virtualization and resource integration, resulting in substantial economic and societal advantages. Cloud computing is experiencing a significant security and trust dilemma, requiring a trust-enabled transaction environment. The typical cloud trust model is centralized, resulting in high maintenance costs, network congestion, and even single-point failure. Also, due to a lack of openness and traceability, trust rating findings are not universally acknowledged. Blockchain is a novel, decentralised computing system. Its unique operational principles and record traceability assure the transaction data's integrity, undeniability, and security. So, blockchain is ideal for building a distributed and decentralised trust infrastructure. This study addresses the difficulty of transferring data and related permission policies from the cloud to the distributed file systems (DFS). Our aims include moving the data files from the cloud to the distributed file system and developing a cloud policy. This study addresses the difficulty of transferring data and related permission policies from the cloud to the DFS. In DFS, no node is given the privilege, and storage of all the data is dependent on content-addressing. The data files are moved from Amazon S3 buckets to the interplanetary file system (IPFS). In DFS, no node is given the privilege, and storage of all the data is dependent on content-addressing." | Blockchain |
Host-parasite interactions are an integral part of ecosystems that influence both ecological and evolutionary processes. Humans are currently altering environments the world over, often with drastic consequences for host-parasite interactions and the prevalence of parasites. The mechanisms behind the changes are, however, poorly known. Here, we explain how host-parasite interactions depend on two crucial steps--encounter rate and host-parasite compatibility--and how human activities are altering them and thereby host-parasite interactions. By drawing on examples from the literature, we show that changes in the two steps depend on the influence of human activities on a range of factors, such as the density and diversity of hosts and parasites, the search strategy of the parasite, and the avoidance strategy of the host. Thus, to unravel the mechanisms behind human-induced changes in host-parasite interactions, we have to consider the characteristics of all three parts of the interaction: the host, the parasite and the environment. More attention should now be directed to unfold these mechanisms, focusing on effects of environmental change on the factors that determine encounter rate and compatibility. We end with identifying several areas in urgent need of more investigations. | Parasites |
Immunotoxins and chimeric toxins are hybrid molecules constituted of antibodies, growth factor or cytokines coupled to peptide toxins. They are designed to selectively eliminate tumor cells. Some of these chimera have been shown to induce complete tumor regressions of human tumor xenografts in immunodeficient mice. In clinical trials, higher anti tumor response were observed in lymphoma, brain tumor, breast and colon cancers. Problems arose with normal tissue toxicity and the production of neutralising antibodies. Should the latest recombinant toxins conceived by rationale designed, solved these problems, chimeric toxins would be an alternative approach to target tumor cells and vascular endothelial cells in solid tumors. | Immunotoxins |
l-Mimosine, a plant amino acid, can reversibly block mammalian cells at late G1 phase and has been suggested to affect translation of mRNAs such as p27, the CDK inhibitor. However, the mechanism of this effect is not known. Regulation of translation generally occurs at the initiation step that, in mammalian cells, is a complex process that requires multiple eukaryotic initiation factors (eIFs) and ribosome. The effects of mimosine on initiation factors or regulators consequently will influence translation initiation. P170, a putative subunit of eIF3, has been suggested to be nonessential for eIF3 function to form preinitiation complexes and it may function as a regulator for translation of a subset of mRNAs. In this article, we tested this hypothesis and investigated whether eIF3 p170 mediates mimosine effect on mRNA translation. We found that p170 translation was dramatically reduced by mimosine due to its iron-chelating function. The decreased expression of p170 by mimosine caused diminished de novo synthesis of tyrosinated alpha-tubulin and elevated translation of p27 before cell cycle arrest. These observations suggest that p170 is likely an early response gene to mimosine treatment and a mediator for mimosine effect on mRNA translation. The effect of p170 on the synthesis of tyrosinated alpha-tubulin and p27 in a reciprocal manner also suggests that p170 functions as a regulator for mRNA translation. | Mimosine |
AIMS: We sought to investigate the correlation between speckle-tracking echocardiography (STE)-derived myocardial work (MW) and invasively measured contractility in a rat model of athlete's heart. We also assessed MW in elite athletes and explored its association with cardiopulmonary exercise test (CPET)-derived aerobic capacity. METHODS AND RESULTS: Sixteen rats underwent a 12-week swim training program and were compared to controls (n = 16). STE was performed to assess global longitudinal strain (GLS), which was followed by invasive pressure-volume analysis to measure contractility [slope of end-systolic pressure-volume relationship (ESPVR)]. Global MW index (GMWI) was calculated from GLS curves and left ventricular (LV) pressure recordings. In the human investigations, 20 elite swimmers and 20 healthy sedentary controls were enrolled. GMWI was calculated through the simultaneous evaluation of GLS and non-invasively approximated LV pressure curves at rest. All subjects underwent CPET to determine peak oxygen uptake (VO2/kg). Exercised rats exhibited higher values of GLS, GMWI, and ESPVR than controls (-20.9 +/- 1.7 vs. -17.6 +/- 1.9%, 2745 +/- 280 vs. 2119 +/- 272 mmHg.%, 3.72 +/- 0.72 vs. 2.61 +/- 0.40 mmHg/muL, all PExercise < 0.001). GMWI correlated robustly with ESPVR (r = 0.764, P < 0.001). In humans, regular exercise training was associated with decreased GLS (-17.6 +/- 1.5 vs. -18.8 +/- 0.9%, PExercise = 0.002) but increased values of GMWI at rest (1899 +/- 136 vs. 1755 +/- 234 mmHg.%, PExercise = 0.025). GMWI exhibited a positive correlation with VO2/kg (r = 0.527, P < 0.001). CONCLUSIONS: GMWI precisely reflected LV contractility in a rat model of exercise-induced LV hypertrophy and captured the supernormal systolic performance in human athletes even at rest. Our findings endorse the utilization of MW analysis in the evaluation of the athlete's heart." | Cardiomegaly, Exercise-Induced |
Billions of dollars are spent each year on treating pressure ulcers. With healthcare costs climbing and reform the order of the day, it is essential for researchers to identify a device which reduces pressure, is easy to use and is cost effective. This study used a Mini-Tipe pressure sensor to measure pressure readings over the sacral and trochanter areas of 17 subjects identified as being at risk for skin breakdown. Pressures were compared on a standard hospital mattress and an anatomically contoured mattress overlay. There was a 48 percent reduction in mean pressures over the sacral area and a 23 percent reduction over the trochanter. No correlations between pressures and demographic data were identified. Further research is warranted to determine the effects of variables found in an at risk" population on pressure reduction with various products." | Beds |
The selective action of nonantigenic tissue extracts on malignant cells was demonstrated using tissue culture techniques. The mitotic index of three strains of neoplastic cells was significantly reduced by the use of extracts which previously had proven effective in adversely affecting the development of spontaneous neoplasms. Under the same conditions the division rate of normal cells in tissue culture was not affected by the extracts. The malignant cells used were the Krebs 2, Sarcoma 180 and the L1210 leukemia. The normal cells were the L929 fibroblasts and epithelial-like cells from bone marrow and corneal tissue. | Carcinoma, Krebs 2 |
Superovulation is a widely used reproductive technique in livestock production, but the mechanism of sheep's superovulation is not yet clear. Here, a method of superovulation and estrus synchronisation was used to treat female Duolang sheep. After treatment, there were significant differences in serum FSH and LH levels and the number of dominant follicles between the two groups of sheep. We identified a total of 5021 differentially expressed genes (11, 13 and 15 days after treatment) and performed RT-qPCR analysis to identify several mRNA expression levels. GO and KEGG enrichment analysis revealed that differentially expressed genes were involved in the regulation of signalling pathways of follicular development, cell cycle, material synthesis, energy metabolism, such as COL3A1, RPS8, ACTA2, RPL7 RPS6 and TNFAIP6 may play a key role in regulating the development of follicles. Our results show a comprehensive expression profile after superovulation and estrus synchronisation treatment. We provide the basis for further research on breeding techniques to improve the ovulation rate and birth rate of livestock. | Estrus |
Since the inception of the P50 Research Center in Injury and Peri-operative Sciences (RCIPS) funding mechanism, the National Institute of General Medical Sciences has supported a team approach to science. Many advances in critical care, particularly burns, have been driven by RCIPS teams. In fact, burns that were fatal in the early 1970s, prior to the inception of the P50 RCIPS program, are now routinely survived as a result of the P50-funded research. The advances in clinical care that led to the reduction in postburn death were made by optimizing resuscitation, incorporating early excision and grafting, bolstering acute care including support for inhalation injury, modulating the hypermetabolic response, augmenting the immune response, incorporating aerobic exercise, and developing antiscarring strategies. The work of the Burn RCIPS programs advanced our understanding of the pathophysiologic response to burn injury. As a result, the effects of a large burn on all organ systems have been studied, leading to the discovery of persistent dysfunction, elucidation of the underlying molecular mechanisms, and identification of potential therapeutic targets. Survival and subsequent patient satisfaction with quality of life have increased. In this review article, we describe the contributions of the Galveston P50 RCIPS that have changed postburn care and have considerably reduced postburn mortality." | National Institute of General Medical Sciences (U.S.) |
BACKGROUND: Cardiac surgery patients are at high risk for readmissions after hospital discharge- few of these readmissions are preventable by mitigating barriers underlying discharge care transitions. An in-depth evaluation of the nuances underpinning the discharge process and the use of tools to support the process, along with insights on patient and clinician experiences, can inform the design of evidence-based strategies to reduce preventable readmissions. OBJECTIVE: The study objectives are 3-fold: elucidate perceived factors affecting the postsurgical discharge care transitions of cardiac surgery patients going home; highlight differences among clinician and patient perceptions of the postsurgical discharge experiences, and ascertain the impact of these transitions on patient recovery at home. METHODS: We conducted a prospective multi-stakeholder study using mixed methods, including general observations, patient shadowing, chart reviews, clinician interviews, and follow-up telephone patient and caregiver surveys/interviews. We followed thematic and content analyses. FINDINGS: Participants included 49 patients, 6 caregivers, and 27 clinicians. We identified interdependencies between the predischarge preparation, discharge education, and postdischarge follow-up care phases that must be coordinated for effective discharge care transitions. We identified several factors that could lead to fragmented discharges, including limited preoperative preparation, ill-defined discharge education, and postoperative plans. To address these, clinicians often performed behind-the-scenes work, including offering informal preoperative preparation, tailoring discharge education, and personalizing postdischarge follow-up plans. As a result, majority of patients reported high satisfaction with care transitions and their positive impact on their home recovery. DISCUSSION AND CONCLUSIONS: Articulation work by clinicians (ie, behind the scenes work) is critical for ensuring safety, care continuity, and overall patient experience during care transitions. We discuss key evidence-based considerations for re-engineering postsurgical discharge workflows and re-designing discharge interventions. | Patient Care |
Organisms with complex life cycles commonly exhibit adaptive plasticity in the timing of transitions between life stages. While the threat of predation is predicted to induce earlier transitions, empirical support has been equivocal. When predation risk affects both the propensity to transition to the next life stage and the ability to reach the energetic thresholds necessary to complete the transition, only those individuals in the best physiological condition may be able to accelerate development and emerge earlier. To test this hypothesis, we followed uniquely marked dragonfly larvae (Pachydiplax longipennis) through emergence in pools where we factorially manipulated the presence of a large heterospecific predator (Anax junius) and cannibalism risk via conspecific size variation. Consistent with our hypothesis, high-condition larvae were more likely to emerge in the presence of the heterospecific predator than in its absence, and low-condition larvae were more likely to emerge in its absence than in its presence. Moreover, high-condition larvae emerged earlier when cannibalism risk was high than when it was low. Predation risk therefore has condition-dependent effects on emergence. As predation risk frequently affects resource accumulation, similar mechanisms across taxa could commonly underlie the incongruence between empirical results and theoretical expectations for predator-induced life-history variation. | Cannibalism |
We intended to describe 2 digenean trematodes found from a Chinese sea snake, Laticauda semifasciata, as the new fauna in the Republic of Korea. The snake was caught offshore of Aewol-eup, Jeju-do, in August 2017. Two species of fluke were found in the lung and intestinal tract of the snake in the process of necropsy. They were identified as Pulmovermis cyanovitellosus Coil and Kuntz, 1960 and Harmotrema laticaudae Yamaguti, 1933, respectively based on the morphological characters. Pulmovermis cyanovitellosus showed elongated body with well-developed and elongated male genital system and compact vitelline. And H. laticaudae was characterized by linguiform body with heavily armed cirrus with excretory system. This is the first time both species have been reported and described off the Korean coast. We provide morphological descriptions with some comments on their biology and geographical distribution. In addition, the taxonomic validity of the genus Hydrophitrema Sandars, 1960 was discussed, in terms of morphological descriptions and host ranges. This study provides novel insight into digenean fluke species existing off the coast of Korea. | Laticauda |
The authors describe the case of a 39-year-old man who presented to our hospital with easy fatigability and malaise. On physical examination, hypertension was noted without any cushingoid appearance. Laboratory testing revealed normochromic-normocytic anaemia with positive results of occult blood in the stool, hyperglycaemia and hypokalemia. Upper endoscopy revealed active gastric ulcer with Helicobacter pylori infection, likely causing gastrointestinal bleeding. Endocrine examinations showed that both serum adrenocorticotropic hormone and cortisol were elevated with loss of diurnal variation. A diagnosis of Cushing's disease secondary to pituitary adenoma was made as results of brain MRI and blood sampling from inferior petrosal sinus. In a patient with peptic ulcer disease, physician should be alert to the possible endocrine background. | Pituitary ACTH Hypersecretion |
We develop a novel method for Western blot based on microfluidics, incorporating the internal molecular weight marker, loading control, and antibody titration in the same protocol. Compared with the conventional method which could detect only one protein, the microfluidic Western blot could analyze at least 10 proteins simultaneously from a single sample, and it requires only about 1% of the amount of antibody used in conventional Western blot. | Blotting, Western |
We have used organic synthesis to understand the role of L-iduronic acid conformational flexibility in the activation of antithrombin by heparin. Among known synthetic analogues of the genuine pentasaccharidic sequence representing the antithrombin binding site of heparin, we have selected as a reference compound the methylated anti-factor Xa pentasaccharide 1. As in the genuine original fragment, the single L-iduronic acid moiety of this molecule exists in water solution as an equilibrium between three conformers 1C4, 4C1 and 2S0. We have thus synthesized three analogues of 1, in which the L-iduronic acid unit is locked in one of these three fixed conformations. A covalent two atom bridge between carbon atoms two and five of L-iduronic acid was first introduced to lock the pseudorotational itinerary of the pyranoid ring around the 2S0 form. A key compound to achieve this connection was the D-glucose derivative 5 in which the H-5 hydrogen atom has been replaced by a vinyl group, which is a progenitor of the carboxylic acid. Selective manipulations of this molecule resulted in the 2S0-type pentasaccharide 23. Starting from the D-glucose derivative 28, a covalent two atom bridge was now built up between carbon atoms three and five to lock the L-iduronic acid moiety around the 1C4 chair form conformation, and the 1C4-type pentasaccharide 43 was synthesized. Finally the L-iduronic acid containing disaccharide 58 which, due to the presence of the methoxymethyl substituent at position five adopts a 4C1 conformation, was directly used to synthesize the 4C1-type pentasaccharide 61. The locked pentasaccharide 23 showed about the same activity as the reference compound 1 in an antithrombin-mediated anti-Xa assay, whereas the two pentasaccharides 43 and 61 displayed very low activity. These results clearly establish the critical importance of the 2S0 conformation of L-iduronic acid in the activation of antithrombin by heparin. | Iduronic Acid |
Complex lymphatic anomalies include a variety of disorders with overlapping clinical, histological and imaging features. The often-confusing nomenclature used for lymphatic anomalies limits timely diagnosis and treatment. The updated 2018 classification of the International Society for the Study of Vascular Anomalies divides lymphatic anomalies into several subsets.(1) Newer imaging techniques including intranodal and magnetic resonance lymphangiography have improved our understanding of anatomy and function of the lymphatic system. Advances in medical, interventional, and surgical treatments have opened a realm of new therapeutic options for patients with complex lymphatic disorders. | Osteolysis, Essential |
Lymphatic filariasis is a major tropical disease caused by the parasite Brugia malayi. Microfilariae (Mf) circulate in the peripheral blood for 2-3 hours in synchronisation with maximal feeding of the mosquito vector. When absent from the peripheral blood, Mf sequester in the capillaries of the lungs. Mf are therefore in close contact with vascular endothelial cells (EC) and may induce EC immune function and/or wound repair mechanisms such as angiogenesis. In this study, Mf were co-cultured with human umbilical vein EC (HUVEC) or human lung microvascular EC (HLMVEC) and the transendothelial migration of leukocyte subsets was analysed. In addition, the protein and/or mRNA expression of chemokine, cytokine and angiogenic mediators in endothelial cells in the presence of live microfilariae were measured by a combination of cDNA arrays, protein arrays, ELISA and fluorescence antibody tests.Surprisingly, our findings indicate that Mf presence partially blocked transendothelial migration of monocytes and neutrophils, but not lymphocytes. However, Mf exposure did not result in altered vascular EC expression of key mediators of the tethering stage of extravasation, such as ICAM-1, VCAM-1 and various chemokines. To further analyse the immunological function of vascular EC in the presence of Mf, we measured the mRNA and/or protein expression of a number of pro-inflammatory mediators. We found that expression levels of the mediators tested were predominantly unaltered upon B. malayi Mf exposure. In addition, a comparison of angiogenic mediators induced by intact Mf and Wolbachia-depleted Mf revealed that even intact Mf induce the expression of remarkably few angiogenic mediators in vascular EC. Our study suggests that live microfilariae are remarkably inert in their induction and/or activation of vascular cells in their immediate local environment. Overall, this work presents important insights into the immunological function of the vascular endothelium during an infection with B. malayi. | Brugia malayi |
Palladium-catalyzed desulfitative and denitrogenative arylation of azoles with arylsulfonyl hydrazides has been achieved. A broad scope of azoles and arylsulfonyl hydrazides has been used to produce arylated azoles in high yields. | Arylsulfonates |
In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-beta (Abeta) pathology, greater clinical efficacy may be achieved by clearing tau than Abeta aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects. | Tauopathies |
The Groningen Protocol, introduced in the Netherlands in 2005 and accompanied by revised guidelines published in a report commissioned by the Royal Dutch Medical Association in 2014, specifies conditions under which the lives of severely ill newborns may be deliberately ended. Its publication came four years after the Netherlands became the first nation to legalize the voluntary active euthanasia of adults, and the Netherlands remains the only country to offer a pathway to protecting physicians who might engage in deliberately ending the life of a newborn (DELN). In this paper, I offer two lines of argument. The first is a positive argument for the Protocol, grounded in the good of the newborn as unanimously determined by those in a position to determine it. The second addresses the widely shared belief that the killing of newborns is morally prohibited, where I offer two arguments-one grounded in the fact that the kinds of cases the Protocol is meant to govern are very rare and highly unusual, and the other focused more broadly on the role of pre-theoretical beliefs in moral reasoning-meant to undermine the strong role that the critic of the Protocol affords this belief. I argue that, given this second line of argument, the beliefs underlying my positive argument for the Protocol are in fact more secure than the widely shared belief underlying the critic's position. | Euthanasia, Active |
MOTIVATION: Gapped k-mer kernels with support vector machines (gkm-SVMs) have achieved strong predictive performance on regulatory DNA sequences on modestly sized training sets. However, existing gkm-SVM algorithms suffer from slow kernel computation time, as they depend exponentially on the sub-sequence feature length, number of mismatch positions, and the task's alphabet size. RESULTS: In this work, we introduce a fast and scalable algorithm for calculating gapped k-mer string kernels. Our method, named FastSK, uses a simplified kernel formulation that decomposes the kernel calculation into a set of independent counting operations over the possible mismatch positions. This simplified decomposition allows us to devise a fast Monte Carlo approximation that rapidly converges. FastSK can scale to much greater feature lengths, allows us to consider more mismatches, and is performant on a variety of sequence analysis tasks. On multiple DNA transcription factor binding site prediction datasets, FastSK consistently matches or outperforms the state-of-the-art gkmSVM-2.0 algorithms in area under the ROC curve, while achieving average speedups in kernel computation of approximately 100x and speedups of approximately 800x for large feature lengths. We further show that FastSK outperforms character-level recurrent and convolutional neural networks while achieving low variance. We then extend FastSK to 7 English-language medical named entity recognition datasets and 10 protein remote homology detection datasets. FastSK consistently matches or outperforms these baselines. AVAILABILITY AND IMPLEMENTATION: Our algorithm is available as a Python package and as C++ source code at https://github.com/QData/FastSK. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. | Support Vector Machine |
INTRODUCTION: Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar keratoderma and severe, early onset periodontitis, which results from deficiency of cathepsin C activity secondary to mutations in the cathepsin C gene. To date, 13 different cathepsin C mutations have been reported in PLS patients, all of which are homozygous for a given mutation, reflecting consanguinity. AIM: To evaluate the generality of cathepsin C mutations in PLS, we studied an ethnically diverse group of 20 unrelated families. METHODS: Mutations were identified by direct automated sequencing of genomic DNA amplified for exonic regions and associated splice site junctions of the cathepsin C gene. Long range PCR was performed to determine the genomic structure of the cathepsin C gene. RESULTS: The cathepsin C gene spans over 46 kb, with six introns ranging in size from 1.6 to 22.4 kb. Eleven novel mutations and four previously reported mutations were identified in affected subjects from 14 families. Missense mutations were most common (9/15), followed by nonsense mutations (3/15), insertions (2/15), and deletions (1/15). Among these 14 probands, two were compound heterozygotes. Affected subjects with transgressions of the dermal lesions onto the knees or elbows or both had mutations in both the pro- and mature regions of the enzyme, although most were in the mature region. CONCLUSION: Mutations in the mature region of cathepsin C were more likely to be associated with the transgressions of the dermatological lesions, although the results were not statistically significant. A comprehensive list of all cathepsin C mutations described to date, representing 25 mutations from 32 families with PLS and related conditions, is also presented. | Cathepsin C |
The most commonly performed feline ocular surgeries are described with emphasis on any anatomic or pathophysiologic differences that are unique to the feline eye, adnexa, and orbit. | Cats |
SHIP1 is at the nexus of intracellular signaling pathways in immune cells that mediate bone marrow (BM) graft rejection, production of inflammatory and immunosuppressive cytokines, immunoregulatory cell formation, the BM niche that supports development of the immune system, and immune cancers. This review summarizes how SHIP participates in normal immune physiology or the pathologies that result when SHIP is mutated. This review also proposes that SHIP can have either inhibitory or activating roles in cell signaling that are determined by whether signaling pathways distal to PI3K are promoted by SHIP's substrate (PI(3,4,5)P(3) ) or its product (PI(3,4)P(2) ). This review also proposes the "two PIP hypothesis" that postulates that both SHIP's product and its substrate are necessary for a cancer cell to achieve and sustain a malignant state. Finally, due to the recent discovery of small molecule antagonists and agonists for SHIP, this review discusses potential therapeutic settings where chemical modulation of SHIP might be of benefit." | Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases |
To explore the relationship between community support in tourist destinations and residents' psychological well-being in the post-COVID-19 pandemic period, this study adopts the questionnaire survey method and draws the following conclusions by constructing a structural equation model: (1) perceived community support is very helpful for the psychological well-being of residents, (2) psychological resilience significantly mediates the relationship between perceived community support and residents' psychological well-being, (3) the resident-tourist interaction mediates the relationship between perceived community support and residents' psychological well-being, and (4) the resident-tourist interaction and psychological resilience play an ordered chain-mediating role between perceived community support and residents' psychological well-being. These findings not only fill the gap in tourism research regarding destination-based community support studies but also provide a theoretical basis for maintaining residents' psychological well-being in a given destination in the context of the COVID-19 pandemic. To a certain extent, improving residents' well-being is helpful for promoting the healthy and sustainable development of tourism activities and realizing a win-win" situation in which tourist destinations develop economically while promoting their residents' living standards." | Community Support |
The health status of wild northern bobwhite quail (Colinus virginianus) from Lyon County, Kansas, was evaluated by conducting comprehensive health assessments on 25 birds. Gross lesions indicative of avian pox, ulcerative enteritis, and quail bronchitis were not present. Serologic tests for antibodies to Salmonella pullorum, Salmonella gallinarum, Pasteurella multocida, Mycoplasma gallisepticum, Mycoplasma synoviae, and avian adenoviruses were all negative. Intestinal coccidia (Eimeria spp.) were found in 36% of the birds. Only three species of helminth parasites were found: Dispharynx nasuta in two birds, Cyrnea colini in one bird, and larval Physaloptera sp. in four birds. Arthropod parasites (ticks, lice, mites, and/or chiggers) were present on 96% of the birds examined. Compared with wild bobwhite populations in the southeastern United States, the diversity, prevalence, and intensities of microbial and parasitic agents were low. | Colinus |
There is much evidence that demonstrates that programs and interventions based on the theoretical models of the Theory of Reasoned Action (TRA) and the Theory of Planned Behaviour (TPB) have been effective in the prevention of the sexual transmission of HIV. The objective of this work is to compare the effectiveness of both models in the prediction of condom use, distinguishing two components inside the variable Perceived Behavioural Control of the TPB model: self-efficacy and control. The perspective of gender differences is also added. The study was carried out in a sample of 601 Portuguese and Spanish university students. The results show that the females have a higher average in all the TPB variables than males, except in the frequency of condom use: females request the use of condoms less frequently than males. On the other hand, for both females and males the TPB model predicts better condom-use intention than the TRA. However there are no differences between the two models in relation to the prediction of condom-use behaviour. For prediction of intention, the most outstanding variable among females is attitude, while among males they are subjective norm and self-efficacy. Finally, we analyze the implications of these data from a theoretical and practical point of view. | Condoms, Female |
Left atrial (LA) volume and function are robust markers of cardiovascular risks and adverse cardiac outcomes. With advances in imaging technology, including tissue Doppler, strain, and strain rate imaging, we can now determine LA volume and function more precisely and this is anticipated to augment our ability to risk stratify, incremental to clinical risk profiling. There is increasing evidence that LA remodeling is treatable and is reversible. Serial LA volume and function assessment may provide a simple and quantifiable way of determining severity of risk and treatment impact. While reverse LA remodeling is expected to improve cardiac outcomes, data to confirm this remain forthcoming. | Cardiac Volume |
Pharmacophore-focused chemical libraries are continuously being created in drug discovery programs, yet screening assays to maximize the usage of such libraries are not fully explored. Here, we report a chemical proteomics approach to reutilizing a focused chemical library of 1,800 indole-containing molecules for discovering uncharacterized ligand-protein pairs. Gel-based protein profiling of the library using a photo-affinity indole probe 1 enabled us to find new ligands for glyoxalase 1 (Glo1), an enzyme involved in the detoxification of methylglyoxal. Structure optimization of the ligands yielded an inhibitor for Glo1 (9). Molecule 9 increased the cellular methylglyoxal levels in human cells and suppressed the osteoclast formation of mouse bone marrow-derived macrophages. X-ray structure analyses revealed that the molecule lies at a site abutting the substrate binding site, which is consistent with the enzyme kinetic profile of 9. Overall, this study exemplifies how chemical proteomics can be used to exploit existing focused chemical libraries. | Lactoylglutathione Lyase |
SCOPE: Evidence gathered in the last decades suggests that lipotoxicity and inflammation are the main factors connecting adipose tissue dysfunction to the development of metabolic diseases such as insulin resistance, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and certain types of cancer, among others. The mechanistic target of rapamycin (mTOR) is a serine threonine kinase that functions as the catalytic entity of two multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). These complexes are important components of signaling pathways activated by nutrients, growth factors, and inflammatory mediators and are therefore directly involved in the regulation of adipocyte and macrophage metabolism and function. METHODS AND RESULTS: In this article, studies that evaluate the involvement of mTORC1 and 2 in the regulation of macrophage and adipocyte function and their implication in the development of metabolic-disease-associated adipose tissue dysfunction are reviewed. CONCLUSION: In adipocytes, optimal levels of mTORC1 activity are required for its pro-lipogenic actions, while in macrophages, mTORC1 regulates features of both M1 and M2 polarization. mTORC2, on the other hand, promotes glucose uptake and de novo lipogenesis in adipocytes and counteracts macrophage inflammatory response." | Mechanistic Target of Rapamycin Complex 2 |
Previously we provided evidence that myosin subfragment 1 (S1) can bind either one (state 1) or two actin monomers (state 2) in solution and in muscle fiber. Here we present results of the kinetics study of binding of S1 to F-actin labeled with fluorescent dye pyrene. A transition from state 1 to state 2 depends on probability that the second actin is free, which is high when molar ratio of S1/actin (R) is less than 0.5, and it decreases dramatically when R>2.0 due to the parking problem. The kinetics data obtained at different molar ratios were well fitted by two binding states model. The sequential binding of myosin head initially with one actin monomer and then with the second actin monomer in F-actin can play a key role in force generation by actin-myosin and their directed movement. | Myosin Subfragments |
Diagnostic errors remain an underemphasised and understudied area of patient safety research. We briefly summarise the methods that have been used to conduct research on epidemiology, contributing factors and interventions related to diagnostic error and outline directions for future research. Research methods that have studied epidemiology of diagnostic error provide some estimate on diagnostic error rates. However, there appears to be a large variability in the reported rates due to the heterogeneity of definitions and study methods used. Thus, future methods should focus on obtaining more precise estimates in different settings of care. This would lay the foundation for measuring error rates over time to evaluate improvements. Research methods have studied contributing factors for diagnostic error in both naturalistic and experimental settings. Both approaches have revealed important and complementary information. Newer conceptual models from outside healthcare are needed to advance the depth and rigour of analysis of systems and cognitive insights of causes of error. While the literature has suggested many potentially fruitful interventions for reducing diagnostic errors, most have not been systematically evaluated and/or widely implemented in practice. Research is needed to study promising intervention areas such as enhanced patient involvement in diagnosis, improving diagnosis through the use of electronic tools and identification and reduction of specific diagnostic process 'pitfalls' (eg, failure to conduct appropriate diagnostic evaluation of a breast lump after a 'normal' mammogram). The last decade of research on diagnostic error has made promising steps and laid a foundation for more rigorous methods to advance the field. | Diagnostic Errors |
Currently in France, all the children born as a result of an assisted reproduction procedure, represent 2.5% of all births. Although this proportion is not high, it is not to be neglected, particularly with regard to the sociological issues raised by assisted reproduction technologies (ART) - i.e. removing anonymity of gamete donation, post mortem insemination, ART access to single women and gay couples, surrogacy - to name four of the most prominent debates. What is new with ART is that a new therapeutic target of medicine is being developed, in other words procreation. Now it is no longer necessary for a man and a woman to resort to sex to have a child. This is a profound questioning of the representation of what appeared to be intangible, with some sort of divine aura. How, in this context, developing an ethics for ART? From a fethnographic field survey, we show here how this ethos of ART develops and how, therefore, we consider the multiple ways of being a family today. | Posthumous Conception |
AIM: To measure the polymerization of light-cured (Variolink Veneer, VLV) and dual-cured (Variolink II, VLII) resin luting cements after light activation through different lengths of fibre post ex vivo. METHODOLOGY: Degree of conversion after prolonged direct light activation (PLA) [12 min after LED light activation for 3 min] was determined using ATR-FTIR. Models were then produced to allow samples of VLV and VLII (n = 5 each group) to be light-activated through 3, 6 and 9 mm lengths of fibre post (Fiber Lux). Degree of conversion was assessed by ATR-FTIR and expressed as a percentage of the degree of conversion achieved after PLA. Data were analysed using anova and Tukey's test (P < 0.05). RESULTS: Mean [SD] degree of conversion for VLV and VLII after PLA was 57.97% [1.51] and 54.71% [3.77], respectively. Light activation of VLV through a 3 mm post produced 81.62% of the PLA value, compared with 71.03% for the 6 mm and 46.04% for the 9 mm post. Conversion after activation through 9 mm posts was significantly less than through 3 mm and 6 mm posts (P < 0.05). For VLII, activation through a 3 mm post produced 66.51% of the PLA value, compared with 54.38% for the 6 mm and 41.56% for the 9 mm post. A significant decrease in degree of conversion was noted for VLII as post length increased (P < 0.05). CONCLUSIONS: The degree of conversion for VLV reduced after light activation through 9 mm posts when compared to 3 mm and 6 mm posts, whilst the degree of conversion for VLII decreased with every increase in post length." | Light-Curing of Dental Adhesives |
Multiple sclerosis is a chronic demyelinating disorder of the central nervous system. There are many cases of multiple sclerosis - like syndrome and demyelinating disorders in systemic lupus erythematosus, Sjogren disease, Behcet disease and other autoimmune conditions. Coexistence of ankylosing spondylitis and multiple sclerosis usually is rare but in this article we report 4 Russian patients with concomitant multiple sclerosis and ankylosing spondylitis diseases. None of these patients received anti-tumor necrosis factor alpha therapy prior to diagnosis of multiple sclerosis. Pathogenesis, diagnostic and treatment challenges are discussed. | Spondylitis, Ankylosing |
Current interests in glycobiology have stimulated the development of new tools for use to tackle major problems in the field, including, for example, glycoprotein synthesis, glycan array development and post-translational glycosylation monitoring. Recent advances in the synthesis of glycoproteins involve glycoprotein remodelling, native chemical ligation (NCL), expressed protein ligation (EPL), Staudinger ligation, sugar-assisted ligation and pathway engineering to effectively produce homogeneous glycoproteins with well defined glycans for structural and functional studies. Moreover, the development of glycan synthesis, such as one-pot, chemoenzymatic and solid-supported syntheses, has greatly simplified the process in creating various glycans for functional and array study. Glycan array requires little sample and is able to test and compare many carbohydrate-protein interactions simultaneously. Finally, the changes in post-translational glycosylation, which is an indicator of disease progression, can be monitored by bioorthogonal chemical reporters with the cell's metabolic machinery. The interdisciplinary cooperation in chemistry and biology has yielded new strategies and led to an explosion of research in this field. | Glycosylation |
INTRODUCTION: Benzothiazole scaffold comprises a bicyclic ring system and is known to exhibit a wide range of biological properties including antimicrobial and anticancer activities. Benzothiazole derivatives have long been therapeutically used for the treatment of various diseases. However, in recent years, 2-arylbenzothiazoles have emerged as an important pharmacophore in the development of antitumor agents. The promising biological profile and synthetic accessibility have been attractive in the design and development of new benzothiazoles and their conjugate systems as potential chemotherapeutics. AREAS COVERED: This review mainly focuses on the structural modifications of benzothiazole scaffold, development of various series of benzothiazoles and their conjugates as new antitumor agents. Furthermore, heterocyclic derivatives bearing benzothiazole moiety and their in vitro as well as in vivo screening, structure-activity relationships (SAR), mechanism, pharmacokinetics, clinical use and their future therapeutic applications are discussed here. EXPERT OPINION: A large number of benzothiazole derivatives discussed here possess potent anticancer activity and can be further developed as drug candidates. Benzothiazole conjugates could also display synergistic effect and still there is a need to use the drug combinations permitting lower dose and development of new generation of drugs. Despite encouraging results that have been observed for their response to tumor in clinical studies, full characterization of their toxicity is further required for their clinical usage as safe drugs for the treatment of cancer. We believe that this review gives a better understanding and scope for future drug design and development of benzothiazole-based compounds to implicate their use in cancer chemotherapy. | Benzothiazoles |
INTRODUCTION: Determine the consistency, accessibility, and adequacy of parental leave policies for adult and pediatric medicine fellowship programs. METHODS: We administered a 40-question survey to fellowship program directors (PDs) and trainees in adult and pediatric cardiology, hematology/oncology, gastroenterology, and pulmonology/critical care fellowship programs in the United States. We used Chi-square tests to compare proportions for categorical variables and t-tests to compare means for continuous variables. RESULTS: A total of 190 PDs from 500 programs (38.0%) and 236 trainees from 142 programs (28.4%) responded. Most respondents did not believe that parental leave policies were accessible publicly (322/426; 75.6%), on password-protected intranet (343/426; 80.5%), or upon request (240/426; 56.3%). The PDs and trainees broadly felt that parental leave for fellows should be 5-10 weeks (156/426; 36.6%) or 11-15 weeks (165/426; 38.7%). A majority of PDs felt that there was no increased burden upon other fellows (122/190; 64.2%) or change in overall well-being (110/190; 57.9%). When asked about the biggest barrier to parental leave support, most PDs noted time constrains of fellowship (101/190; 53.1%) and the limited number of fellows (43/190; 22.6%). Trainees similarly selected the time constraints of training (88/236; 37.3%), but nearly one-fifth chose the culture in medicine (44/236; 18.6%). There were no statistically significant differences in answers based on the respondents' sex, specialty, or subspecialty. DISCUSSION: Parental leave policies are broadly in place, but did not feel these were readily accessible, standardized, or of optimum length. PDs and trainees noted several barriers that undermine support for better parental leave policies, including time constraints of fellowship, the limited number of fellows for coverage, and workplace culture. Standardization of parental leave policies is advisable to allow trainees to pursue fellowship training and care for their newborns without undermining their educational experiences. | Parental Leave |
Grapevine canes are viticulture waste that is usually discarded without any further use. However, recent studies have shown that they contain significant concentrations of health-promoting compounds, such as stilbenes, secondary metabolites of plants produced as a response to biotic and abiotic stress from fungal disease or dryness. Stilbenes have been associated with antioxidant, anti-inflammatory, and anti-microbial properties and they have been tested as potential treatments of cardiovascular and neurological diseases, and even cancer, with promising results. Stilbenes have been described in the different genus of the Vitaceae family, the Vitis genera being one of the most widely studied due to its important applications and economic impact around the world. This review presents an in-depth study of the composition and concentration of stilbenes in grapevine canes. The results show that the concentration of stilbenes in grapevine canes is highly influenced by the Vitis genus and cultivar aspects (growing conditions, ultraviolet radiation, fungal attack, etc.). Different methods for extracting stilbenes from grapevine canes have been reviewed, and the extraction conditions have also been studied, underlining the advantages and disadvantages of each technique. After the stilbenes were extracted, they were analyzed to determine the stilbene composition and concentration. Analytical techniques have been employed with this aim, in most cases using liquid chromatography, coupled with others such as mass spectrometry and/or nuclear magnetic resonance to achieve the individual quantification. Finally, stilbene extracts may be applied in multiple fields based on their properties. The five most relevant are preservative, antifungal, insecticide, and biostimulant applications. The current state-of-the-art of the above applications and their prospects are discussed. | Vitis |
Esthesioneuroblatoma (ENB) is a rare tumor arising from the olfactory epithelium of the nasal vault which frequently invades the cranial base, cranial vault and orbit. ENB has a bimodal age distribution between 11 and 20 years and between 51 and 60 years. ENB accounts for approximately 1 to 5% of intranasal cancers and no consensus has been reached regarding treatment of this tumor. We report on a 66 year old female patient with a Kadish stage C tumor with frontal lobe invasion submitted a total craniofacial resection with a combined head neck and neurosurgeon team. The purpose of this study is to analyze the natural history, treatment and prognosis of this tumor, based on the literature review." | Esthesioneuroblastoma, Olfactory |
OBJECTIVES: To assess prevalence and perception of sleep paralysis and its relationship with socioeconomic determinants, and risk factors in a cross-sectional sample of Saudi general population from Al-Ahsa city. METHODS: A cross-sectional sampling survey was conducted during 2020 to 2021. The targets were aged above 18 and belonged to Al-Ahsa. Patients were sent self-reported anonymous questionnaires to complete. RESULTS: A total of 524 participants, whose ages ranged from 18 to 60 years, were analyzed. Among 85.7% of participants aged 55 years and over, compared to 65.8% of those who were aged under 35, 379 (72.3%) respondents were females. Moreover, 438 (83.6%) participants were university graduates, 271 (51.7%) were students and 40.8% had psychological disorders including anxiety (25.2%) and depression (5.7%). Family history of sleep paralysis was reported by 369 (70.4%) participants. A total of 97.5% study participants were aware of sleep paralysis. CONCLUSION: Sleep paralysis is a common occurrence in people residing in Al-Ahsa, Saudi Arabia. A considerable number of the society held wrong beliefs regarding sleep paralysis. Therefore, raising public of identity of sleep paralysis is crucial. We recommend applying the study in other cities within Saudi Arabia to identify common risk factors and perceptions among the society. | Sleep Paralysis |
Changes in microglial morphology are powerful indicators of the inflammatory state of the brain. Here, we provide an open-source microglia morphology analysis pipeline that first cleans and registers images of microglia, before extracting 62 parameters describing microglial morphology. It then compares control and 'inflammation' training data and uses dimensionality reduction to generate a single metric of morphological change (an 'inflammation index'). This index can then be calculated for test data to assess inflammation, as we demonstrate by investigating the effect of short-term high-fat diet consumption in heterozygous Cx3CR1-GFP mice, finding no significant effects of diet. Our pipeline represents the first open-source microglia morphology pipeline combining semi-automated image processing and dimensionality reduction. It uses free software (ImageJ and R) and can be applied to a wide variety of experimental paradigms. We anticipate it will enable others to more easily take advantage of the powerful insights microglial morphology analysis provides. | CX3C Chemokine Receptor 1 |
BACKGROUND: Extended-release, intramuscular (IM) naltrexone can be an effective and convenient medication option for alcohol use disorder. We sought to assess the clinical impact of an alternate, if inadvertent, administration of IM naltrexone in the deltoid muscle instead of the recommended gluteal muscle. CASE SUMMARY: IM naltrexone was prescribed to a hospitalized 28-year-old man with severe alcohol use disorder as part of an inpatient clinical trial. A nurse unfamiliar with naltrexone administration mistakenly administered the drug to the deltoid instead of the gluteal muscle recommended by the manufacturer. Despite concerns that injection of the large-volume suspension to the smaller muscle would potentially contribute to increased pain and higher chance of adverse events owing to faster medication absorption, the patient experienced only mild discomfort to the deltoid region, without other adverse events on immediate physical and laboratory examinations. The patient later denied additional adverse events in the period after hospitalization, but he did not endorse any anti-craving effect of the medication, resuming drinking alcohol quickly following initial discharge. PRACTICE IMPLICATIONS: This case represents a unique procedural challenge of administering a medication in the inpatient setting that is typically given in the outpatient setting. Inpatient staff members frequently rotate and may be relatively unfamiliar with IM naltrexone, so handling should be limited to personnel who have received focused training on its administration. Fortunately, in this case deltoid administration of naltrexone was well-tolerated and even deemed quite acceptable" to the patient. Clinically, the medication was insufficiently effective, but biopsychosocial context may have made his AUD especially refractory. More research is needed to fully establish whether naltrexone given via deltoid muscle injection has comparable safety and efficacy to gluteal muscle administration." | Deltoid Muscle |
We have synthesized a library of estrogen analogues, including enantiomers of estradiol and A-ring substituted estrogens. These compounds have reduced or no binding to either estrogen receptor-alpha or estrogen receptor-beta, exhibit enhanced neuroprotective activity in in vitro models, and are potent in protecting brain tissue from cerebral ischemia/reperfusion injury. These potent, nonfeminizing estrogen analogues are prime candidates for use in stroke neuroprotection. | Estradiol Congeners |
Sensory gating is the brain's ability to filter out irrelevant information before it reaches high levels of conscious processing. In the current study we aimed to investigate the involvement of the noradrenergic and dopaminergic neurotransmitter systems in sensory gating. Furthermore, we investigated cross-species reliability by comparing effects in both healthy humans and rats, while keeping all experimental conditions as similar as possible between the species. The design of the human experiment (n=21) was a double-blind, placebo-controlled, cross-over study where sensory gating was assessed following a dose of either reboxetine (8 mg), haloperidol (2 mg), their combination or placebo at four separate visits. Similarly in the animal experiment sensory gating was assessed in rats, (n=22) following a dose of reboxetine (2 mg/kg), haloperidol (0.08 mg/kg), their combination or placebo. The sensory gating paradigms in both experiments were identical. In humans, we found significantly reduced P50 suppression following separate administration of reboxetine or haloperidol, while their combined administration did not reach statistical significance compared with placebo. In the rats, we found a similar significant reduction of sensory gating (N40) following treatment with haloperidol and the combination of haloperidol and reboxetine, but not with separate reboxetine treatment, compared with placebo. Our study indicates that even when experimental conditions are kept as similar as possible, direct human to rat cross-species translation of pharmacological effects on sensory gating is challenging, which calls for more focussed research in this important translational area. | Sensory Gating |
PURPOSE OF REVIEW: Fungal infections of the central nervous system, once a relatively rare occurrence, are increasingly common due to the expansion of immunocompromised populations at risk, and therefore are important to recognize early and manage appropriately. RECENT FINDINGS: The specific infectious risk posed by novel immune-modifying therapies can, in most cases, be predicted on the basis of the immune target and medication timing. In addition, major advances in noninvasive diagnostic tests (e.g. serum beta glucan and galactomannan assays), and the recent introduction of more effective antifungal therapies, have led to a dramatic improvement in clinical outcomes. SUMMARY: The current review provides approaches to patients with suspected central nervous system fungal infections based on host-risk factors, clinical syndromes and specific pathogens." | Central Nervous System Fungal Infections |
Genetic testing for Tay-Sachs and Canavan disease is particularly important for Ashkenazi Jews, because both conditions are more frequent in that population. This comparative case study was possible because of different patenting and licensing practices. The role of DNA testing differs between Tay-Sachs and Canavan diseases. The first-line screening test for Tay-Sachs remains an enzyme activity test rather than genotyping. Genotyping is used for preimplantation diagnosis and confirmatory testing. In contrast, DNA-based testing is the basis for Canavan screening and diagnosis. The HEXA gene for Tay-Sachs was cloned at the National Institutes of Health, and the gene was patented but has not been licensed. The ASPA gene for Canavan disease was cloned and patented by Miami Children's Hospital. Miami Children's Hospital did not inform family members and patient groups that had contributed to the gene discovery that it was applying for a patent, and pursued restrictive licensing practices when a patent issued in 1997. This led to intense controversy, litigation, and a sealed, nonpublic 2003 settlement that apparently allowed for nonexclusive licensing. A survey of laboratories revealed a possible price premium for ASPA testing, with per-unit costs higher than for other genetic tests in the Secretary's Advisory Committee on Genetics, Health, and Society case studies. The main conclusion from comparing genetic testing for Tay-Sachs and Canavan diseases, however, is that patenting and licensing conducted without communication with patients and advocates cause mistrust and can lead to controversy and litigation, a negative model to contrast with the positive model of patenting and licensing for genetic testing of cystic fibrosis. | Canavan Disease |
Nocturnal enuresis (NE), the involuntary passing of urine during sleep after the age at which bladder control would normally be anticipated, is a widespread and potentially disabling disorder for children. The treatment of NE constitutes several approaches and its pathophysiology remains unsolved. Careful consideration should be given to the work-up of NE since there may be concurrent symptoms that require attention either before or in conjunction with the treatment. Patient/family education and a cooperative approach usually produce the most favorable results in treating NE. | Enuresis |
Bombax malabaricum (family Bombacaceae) is used as anthelmintic in traditional system of medicine in Southern Punjab of Pakistan. The objective of this study was to evaluate the anthelmintic activity of the methanol extract of B. malabaricum leaves (MEBM). Live parasites (trematode: Paramphistomum explanatum) were collected from buffalo in 0.9% phosphate-buffered saline. It was incubated in Petri dishes at 37 +/- 1 degrees C in media containing either no extract (control) or MEBM, the test drug at 10, 25, 50, and 100 mg/ml dose level or albendazole, the standard drug at 10 mg/ml. The efficacy of the extract or albendazole was measured on the basis of the loss of spontaneous movement and/or death of the trematodes. Paralysis was considered when there is no movement unless shaken vigorously. Death was confirmed when the trematodes completely lost their motility, even when vigorously shaken or dipped in warm water (50 degrees C), followed by fading away of their body color. The trematodes, both drug treated and others, were further processed for SEM study using the standard method. All trematodes died with all the above-mentioned doses of MEBM within a short period of time (less than 45 min) which was statistically highly significant (p < 0.001). MEBM at 100 mg/ml showed maximum efficacy. It paralyzed and killed trematodes in 18.50 +/- 0.62 and 22.17 +/- 0.48 min, respectively. SEM study showed that MEBM-treated trematodes were stretched. The study established the anthelmintic activity of MEBM. | Bombax |
In Taiwan Mandarin, retroflex [s] is allegedly merging with dental [s], reducing the traditional three-way contrast between sibilant fricatives (i.e., dental [s]-retroflex [s]-alveopalatal [ÃÂ]) to a two-way contrast. Most of the literature on the observed merging focuses on the acoustic properties and perceptual identification of the sibilants, whereas much less attention has been drawn to the articulatory evidence accounting for the aforementioned sibilant merging. The current study employed ultrasound imaging techniques to uncover the tongue postures for the three sibilant fricatives [s, s, ÃÂ] in Taiwan Mandarin occurring before vowels [a], [i], and [o]. Results revealed varying classes of the [s-s] merger: complete merging (overlap), no merging (non-overlap), and context-dependent merging (context-dependent overlap, which only occurred before [a]). The observed [s-s] merger was also confirmed by the perceptual identification by trained phoneticians. Center of gravity (CoG), a reliable spectral moment of identifying different sibilant fricatives, was also measured to reflect the articulatory-acoustic correspondence. Results showed that the [s-s] merger varies across speakers and may also be conditioned by vowel contexts and that articulatory mergers may not be entirely reflected in CoG values, suggesting that auxiliary articulatory gestures may be employed to maintain the acoustic contrast. | Orthodontic Friction |
There is growing concern regarding potential occupational exposures to the ultra-potent synthetic opioid carfentanil. However, little data are available on the toxicity of carfentanil in humans, particularly for dermal exposures. To begin to address this, permeation of carfentanil formulated in three vehicles, water, ethanol, and hand sanitizer was measured under infinite-dose conditions in an in vitro static diffusion cell system using the EpiDerm (EPI-606-X) RhE model. The permeation rate was fastest for carfentanil in water (3.9â¯xâ¯10(-3)â¯cm/h), followed by hand sanitizer (1.2â¯xâ¯10(-3)â¯cm/h), and slowest for carfentanil in ethanol (0.2â¯xâ¯10(-3)â¯cm/h). In both ethanol and hand sanitizer, a lag-time between exposure and permeation of approximately 1.5â¯h was observed, while lag-time in water was approximately half an hour. Flux at steady-state was greater at 50.6â¯mug/ml than at 5.3â¯mug/ml for both water and ethanol; however, the percent of dose absorbed did not differ between doses for either vehicle. Slight differences in percutaneous permeation of carfentanil were observed between two brands of hand sanitizer, likely due to differences in relative proportion of alcohol and skin penetration enhancers. These data indicate that small skin exposures may not result in rapid, significant toxicity as previously reported. | Diffusion Chambers, Culture |
Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of beta1-integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of beta1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non-mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation. | Sphingolipids |
BACKGROUND AND AIMS: Treatments with morphine or opioid agonists cause constipation. Lubiprostone is approved for treatment of adult idiopathic constipation and constipation-predominant IBS in adult women. We tested whether lubiprostone can reverse morphine-suppression of mucosal secretion in human intestine and explored the mechanism of action. METHODS: Fresh segments of jejunum discarded during Roux-En-Y gastric bypass surgeries were used. Changes in short-circuit current (DeltaIsc) were recorded in Ussing flux chambers as a marker for electrogenic chloride secretion during pharmacological interactions between morphine, prostaglandin receptor antagonists, chloride channel blockers and lubiprostone. RESULTS: Morphine suppressed basal Isc. Lubiprostone reversed morphine suppression of basal Isc. Lubiprostone, applied to the mucosa in concentrations ranging from 3 nM to 30 muM, evoked increases in Isc in concentration-dependent manner when applied to the mucosal side of muscle-stripped preparations. Blockade of enteric nerves did not change stimulation of Isc by lubiprostone. Removal of chloride or application of bumetanide or NPPB suppressed or abolished responses to lubiprostone. Antagonists acting at CFTR channels and prostaglandin EP(4) receptors, but not at E(1), EP(1-3) receptors, partially suppressed stimulation of Isc by lubiprostone. CONCLUSIONS: Antisecretory action of morphine results from suppression of excitability of secretomotor neurons in the enteric nervous system. Lubiprostone, which does not affect enteric neurons directly, bypasses the action of morphine by directly opening mucosal chloride channels. | Lubiprostone |
The paper contains descriptions of the entomological methods which can be used in determining time of death. It based on the knowledge of groups of arthropods (waves of succession), characteristic for stages of decomposition of the corpse as well as the biology and longevity of development of necrophagous insects. | Entomology |
A new method significantly advantageous over the conventional spectrophotometric methods regarding simplicity, minimal data processing and applicability was developed. The new method is based on the fact that isoabsorptive points whenever present in an absorption spectrum will be retained even after division by a one component as a divisor in the ratio spectrum, in addition to a smart modification of the conventional ratio derivative and ratio subtraction methods. This modified method though simpler, enabled wider range of applications. The proposed method was applied for the analysis of brimonidine and timolol in laboratory prepared mixtures with mean percentage recoveries 100.64 +/- 1.10 and 100.96 +/- 1.16, respectively, and in their pharmaceutical formulation with mean percentage recoveries 100.88 +/- 0.34 and 100.84 +/- 0.72, respectively. The suggested method was validated according to USP guidelines and can be applied for routine analysis in quality control laboratories." | Brimonidine Tartrate, Timolol Maleate Drug Combination |
Cation-pi interactions to cognate ligands in enzymes have key roles in ligand binding and enzymatic catalysis. We have deciphered the key functional role of both charged and aromatic residues within the choline binding subsite of CTP:phosphocholine cytidylyltransferase and choline kinase from Plasmodium falciparum. Comparison of quaternary ammonium binding site structures revealed a general composite aromatic box pattern of enzyme recognition sites, well distinguished from the aromatic box recognition site of receptors." | Choline-Phosphate Cytidylyltransferase |
PRCIS: In primary angle closure suspects (PACS), self-identified Black race was a risk factor for intraocular pressure (IOP) elevation and iritis following laser peripheral iridotomy (LPI). Laser type was not associated with either immediate post-LPI IOP elevation or iritis in multivariate analysis. PURPOSE: The aim was to determine the impact of laser type and patient characteristics on the incidence of IOP elevation and iritis after LPI in PACS. MATERIALS AND METHODS: The electronic medical records of 1485 PACS (2407 eyes) who underwent either neodymium-doped yttrium-aluminum-garnet or sequential argon and neodymium-doped yttrium-aluminum-garnet LPI at the University of Pennsylvania between 2010 and 2018 were retrospectively reviewed. Average IOP within 30 days before LPI (baseline IOP), post-LPI IOP within 1 hour, laser type, laser energy, and the incidence of new iritis within 30 days following the procedure were collected. Multivariate logistic regression accounting for intereye correlation was used to assess factors associated with incidence of post-LPI IOP elevation and iritis, adjusted by age, sex, surgeon, and histories of autoimmune disease, diabetes, and hypertension. RESULTS: The incidence of post-LPI IOP elevation and iritis were 9.3% (95% confidence interval: 8.1%-10.5%) and 2.6% (95% CI: 1.9%-3.2%), respectively. In multivariate analysis, self-identified Black race was a risk factor for both IOP elevation [odds ratio (OR): 2.08 compared with White; P=0.002] and iritis (OR: 5.07; P<0.001). Higher baseline IOP was associated with increased risk for post-LPI IOP elevation (OR: 1.19; P<0.001). Laser type and energy were not associated with either post-LPI IOP elevation or iritis (P>0.11 for all). CONCLUSIONS: The incidence of immediate IOP elevation and iritis following prophylactic LPI was higher in Black patients independent of laser type and energy. Heightened vigilance and increased medication management before and after the procedure are suggested to help mitigate these risks. | Iritis |
OBJECTIVE: To quantify the efficacy of chemoprophylaxis against leprosy. METHOD: Literature searching of Medline and Embase databases, hand-searching of references and correspondence with investigators. STUDY SELECTION: published papers relating to the prevention of leprosy and the use of chemotherapy in leprosy were identified for critical appraisal. Trials were selected and grouped into three categories according to study design and control groups. DATA ANALYSIS: the relative risks (RR) with 95% confidence intervals were calculated from the original data using a random effects model. To assess the cost-effectiveness of chemoprophylaxis, a further analysis of the rates of disease in the trial and control groups was done based on the numbers needed to be treated (NNT) to prevent one new case of leprosy. RESULTS: A total of 14 trials were identified from 127 published papers on chemoprophylaxis of leprosy. The trials were categorized into randomized controlled trials, non-randomized controlled trials, and uncontrolled trials. The overall results of the meta-analysis shows that chemoprophylaxis gives around 60% protection against leprosy. The NNT are low in trials of household contacts. CONCLUSIONS: The evidence shows that chemoprophylaxis against leprosy is an effective way to reduce the incidence of leprosy, particularly in household contacts. The role of chemoprophylaxis needs to be re-examined using newer drugs given the continuing case detection rates globally. | Acedapsone |
OBJECTIVE: To express truncated TssB protein of Burkholderia mallei and to evaluate its diagnostic efficacy for serological detection of glanders among equines. MATERIALS AND METHODS: In an attempt to develop recombinant protein based enzyme-linked immunosorbent assay (ELISA), N-terminal 200 amino acid sequences of B. mallei TssB protein-a type 6 secretory effector protein--were expressed in prokaryotic expression system. Diagnostic potential of recombinant TssB protein was evaluated in indirect ELISA using a panel of glanders positive (n = 49), negative (n = 30), and field serum samples (n = 1811). Cross-reactivity of the assay was assessed with equine disease control serum and human melioidosis positive serum. RESULTS: In comparison to CFT, diagnostic sensitivity and specificity of ELISA were 99.7% and 100%, respectively. CONCLUSIONS: The indirect ELISA method using the truncated TssB offered safer and more rapid and efficient means of serodiagnosis of glanders in equines. These data highlight the use of TssB as potential diagnostic antigen for serological diagnosis of glanders. | Glanders |
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