Perspective on receptor-associated immune response to Candida albicans single and mixed infections: Implications for therapeutics in oropharyngeal candidiasis.
Oropharyngeal candidiasis (OPC), commonly known as 'thrush', is an oral infection that usually dismantles oral mucosal integrity and malfunctions local innate and adaptive immunities in compromised individuals. The major pathogen responsible for the occurrence and progression of OPC is the dimorphic opportunistic commensal Candida albicans. However, the incidence induced by non-albicans Candida species including C. glabrata, C. tropicalis, C. dubliniensis, C. parapsilosis, and C. krusei are increasing in company with several oral bacteria, such as Streptococcus mutans, S. gordonii, S. epidermidis, and S. aureus. In this review, the microbiological and infection features of C. albicans and its co-contributors in the pathogenesis of OPC are outlined. Since the invasion and concomitant immune response lie firstly on the recognition of oral pathogens through diverse cellular surface receptors, we subsequently emphasize the roles of epidermal growth factor receptor, ephrin-type receptor 2, human epidermal growth factor receptor 2, and aryl hydrocarbon receptor located on oral epithelial cells to delineate the underlying mechanism by which host immune recognition to oral pathogens is mediated. Based on these observations, the therapeutic approaches to OPC comprising conventional and non-conventional antifungal agents, fungal vaccines, cytokine and antibody therapies, and antimicrobial peptide therapy are finally overviewed. In the face of newly emerging life-threatening microbes (C. auris and SARS-CoV-2), risks (biofilm formation and interconnected translocation among diverse organs), and complicated clinical settings (HIV and oropharyngeal cancer), the research on OPC is still a challenging task.


Prostacyclin and thromboxane in gynecology and obstetrics.
The gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, are reviewed. In addition to the vascular wall and circulating platelets, which are primary sources for prostacyclin and thromboxane A2, respectively, reproductive tissues produce great amounts of these prostanoids, evidently for the regulation of the vascular tone and/or vascular platelet interaction. Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects. Patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future.


LRP5 and bone mass regulation: Where are we now?
The discovery of causal mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene underlying conditions of altered bone mass ushered in a new era in bone research. Since those original publications, the role of Lrp5 and the Wnt/β-catenin signaling pathway controlled by Lrp5 and its homologs, Lrp6 and Lrp4, in bone mass regulation has been an intense area of investigation. Studies to date have implicated this pathway in skeletal development, osteoblast differentiation and proliferation, osteoblast/osteocyte apoptosis, regulation of the balance between osteogenesis-chondrogenesis-adipogenesis, regulation of osteoclastogenesis and the response of bone to mechanical loading. Interestingly, the data from knockout and transgenic mice involving Lrp4/5/6 and/or their regulators, as well as β-catenin signaling pathway components, and in vitro studies have sometimes yielded conflicting results. Adding to the complexity of the system are the studies that suggested Lrp5 regulated bone mass through a gut-bone endocrine signaling system involving Lrp5 mediated control of gut serotonin synthesis. However, recent studies have called this into question and so this provocative concept remains an open question. Clearly, the manipulation of Lrp5/Wnt/β-catenin pathway presents as a major target for drug development to treat diseases of low bone mass such as osteoporosis and these new therapies are in full progress. At present, although it is clear that Lrp5 has a role in bone mass regulation, much of the details remain to be elucidated and this is a major and exciting challenge for future studies.


Tantalum-178--a short-lived nuclide for nuclear medicine: development of a potential generator system.
We describe a chemical separation that may form the basis of a generator system for the short-lived radionuclide Ta-178 (T 1/2 = 9 min). The parent nuclide W-178 (T 1/2 = 21.7 days) is loaded on an anion-exchange column and the daughter eluted with a mixture of dilute hydrochloric acid and hydrogen peroxide. The yields of tantalum and the breakthrough of the tungsten parent as a function of the eluting conditions are discussed, and preliminary animal distribution data are presented for various treatments of the eluant solution.


Introduction to the DICOM standard.
Digital Imaging and Communication in Medicine (DICOM) has become one of the most popular standards in medicine. In the beginning, DICOM was used for communication of image data between different systems. Actual developments of the standardisation enables increasingly more DICOM-based services for the integration of modalities and information systems (e.g. RIS, PACS). In this article a review of the historical background, the technological concept, the organizational structure and current developments is given.


Nomogram based on clinical characteristics and serological inflammation markers to predict overall survival of oral tongue squamous cell carcinoma patient after surgery.
Oral tongue squamous cell carcinoma (OTSCC) is a prevalent malignant disease that is characterized by high rates of metastasis and postoperative recurrence. The aim of this study was to establish a nomogram to predict the outcome of OTSCC patients after surgery. We retrospectively analyzed 169 OTSCC patients who underwent treatments in the Cancer Hospital of Shantou University Medical College from 2008 to 2019. The Cox regression analysis was performed to determine the independent prognostic factors associated with patient's overall survival (OS). A nomogram based on these prognostic factors was established and internally validated using a bootstrap resampling method. Multivariate Cox regression analysis revealed the independent prognostic factors for OS were TNM stage, age, lymphocyte-to-monocyte ratio and immunoglobulin G, all of which were identified to create the nomogram. The Akaike Information Criterion and Bayesian Information Criterion of the nomogram were lower than those of TNM stage (292.222 vs. 305.480; 298.444 vs. 307.036, respectively), indicating a better goodness-of-fit of the nomogram for predicting OS. The bootstrap-corrected of concordance index (C-index) of nomogram was 0.784 (95% CI 0.708-0.860), which was higher than that of TNM stage (0.685, 95% CI 0.603-0.767, P = 0.017). The results of time-dependent C-index for OS also showed that the nomogram had a better discriminative ability than that of TNM stage. The calibration curves of the nomogram showed good consistency between the probabilities and observed values. The decision curve analysis also revealed the potential clinical usefulness of the nomogram. Based on the cutoff value obtained from the nomogram, the proposed high-risk group had poorer OS than low-risk group (P < 0.0001). The nomogram based on clinical characteristics and serological inflammation markers might be useful for outcome prediction of OTSCC patient.


Six year disease free survival after liver transplantation in a patient with T3 gallbladder carcinoma: case presentation and review of the literature.
The incidence of gallbladder carcinoma in cirrhotics is unknown. Known risk factors are primary sclerosing cholangitis and polypoid masses. A sixty year old with primary sclerosing cholangitis, cirrhosis, and gallbladder polyps underwent liver transplantation. A polypoid lesion measuring 1.5 x 0.5 cm was found on the fundus of the gallbladder. Histological examination revealed moderately differentiated adenocarcinoma with full thickness penetration of the gallbladder encroaching liver parenchyma. Angiolymphatic invasion was noted. The lymph nodes, the cystic duct and the common duct were free of tumor (T3N0M0). Extensive evaluation did not demonstrate metastasis. No chemotherapy was given. He is currently six years post procedure and free of disease. "Incidentally" discovered stage IIA gallbladder carcinoma may not negatively affect long term survival after liver transplantation.


Critical review of dose-response options for F344 rat mammary tumors for acrylamide - additional insights based on mode of action.
Previous risk assessment reviews analyzed the potential for dietary acrylamide to increase breast cancer risk. Here, we critically review acrylamide animal bioassay data on mammary tumors for human relevance. We applied a systematic evaluation using reasonable standards of scientific certainty and a systematic weight of evidence (WOE) approach to evaluate several hypothesized modes of action (MOA), including (1) genotoxicity related to glycidamide formation and oxidative stress, (2) endocrine effects due to age-related hyperprolactinemia or secondary to neurotoxicity, and (3) epigenetic effects. We conclude that the appropriate approach for low-dose extrapolation of the rat mammary tumors can be narrowed to two options: (1) linear low-dose extrapolation (i.e., based on a MOA of mutagenicity from direct DNA interaction) from a point of departure (POD) for the combined incidence of adenomas and adenocarcinomas, since these tumor types are related; or (2) non-linear extrapolation, using uncertainty factors to estimate a Reference Dose (RfD) from a POD for tumor promotion derived using the combined fibroadenoma, adenoma and adenocarcinoma data. Non-linear extrapolation is used in the latter approach because these combined tumor types are unlikely to be exclusively caused by mutagenicity. Comparison of the WOE for each alternative MOA indicates that a non-linear approach (option 2) is more appropriate for evaluation of acrylamide-induced mammary tumors; a linear approach (option 1) is shown for comparison.


Increased matrix metalloproteinase levels and perineuronal net proteolysis in the HIV-infected brain; relevance to altered neuronal population dynamics.
HIV-associated neurocognitive disorders (HAND) continue to persist despite effective control of viral replication. Although the mechanisms underlying HAND are poorly understood, recent attention has focused on altered neuronal population activity as a correlate of impaired cognition. However, while alterations in neuronal population activity in the gamma frequency range are noted in the setting of HAND, the underlying mechanisms for these changes is unclear. Perineuronal nets (PNNs) are a specialized extracellular matrix that surrounds a subset of inhibitory neurons important to the expression of neuronal oscillatory activity. In the present study, we observe that levels of PNN-degrading matrix metalloproteinases (MMPs) are elevated in HIV-infected post-mortem human brain tissue. Furthermore, analysis of two PNN components, aggrecan and brevican, reveals increased proteolysis in HIV-infected brains. In addition, local field potential recordings from ex vivo mouse hippocampal slices demonstrate that the power of carbachol-induced gamma activity is increased following PNN degradation. Together, these results provide a possible mechanism whereby increased MMP proteolysis of PNNs may stimulate altered neuronal oscillatory activity and contribute to HAND symptoms.


FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression. Mice bearing high and low FGF19-expressing tumors were treated with FGF401 and/or vinorelbine, and the antitumor activity of both agents was assessed individually and in combination. Tumor vasculature and intratumoral hypoxia were also examined. High FGF19 expression was detected in 14.3% (9 of 63) of the HCC models tested and may represent a good target for HCC treatment. FGF401 potently inhibited the growth of high FGF19-expressing HCC models regardless of FGF19 gene amplification. Furthermore, FGF401 inhibited the FGF19/FGFR-4 signaling pathway, cell proliferation, and hypoxia, induced apoptosis and blood vessel normalization and prolonged the overall survival (OS) of mice bearing high FGF19 tumors. FGF401 synergistically acted with the microtubule-depolymerizing drug vinorelbine to further suppress tumor growth, promote apoptosis, and prolong the OS of mice bearing high FGF19 tumors, with no evidence of increased toxicity. Our study suggests that a subset of patients with high FGF19-expressing HCC tumors could benefit from FGF401 or FGF401/vinorelbine treatment. A high level of FGF19 in a tumor may serve as a potential biomarker for patient selection.


The histone demethylase PHF8 represses cardiac hypertrophy upon pressure overload.
Mammalian hearts undergo hypertrophy upon pressure overload to support increased workload. Sustained hypertrophy results in cardiac decompensation and subsequently heart failure. The mechanism that prevents the development of cardiac hypertrophy is still not fully understood. Here we elucidate the anti-hypertrophic role of the histone demethylase PHF8. PHF8 protein and mRNA levels were down-regulated in human failing hearts, mouse hypertrophic hearts and neonatal rat ventricle myocytes that underwent hypertrophy. Then we generated a cardiac-specific PHF8 transgenic mice, and found that PHF8 overexpression reversed cardiac dysfunction, hypertrophy and fibrosis upon pressure overload. In vivo evidence showed that PHF8 blocked protein synthesis and hypertrophic fetal genes expression. Furthermore, we found that PHF8 inhibited Akt-mTOR pathway in hypertrophic hearts and neonatal rat ventricle myocytes, and rapamycin treatment rescues the effects of PHF8 loss. These results indicate that PHF8 serves as an endogenous factor that the host uses to attenuate cardiac hypertrophy upon cardiac overload. Strategies based on its enhancement might be of benefit in the treatment of hypertrophic cardiomyopathy.


Prevention against carbon monoxide poisoning emanating from burning coal briquettes - Generation rate of carbon monoxide and ventilation requirement.
Carbon monoxide (CO) poisoning accidents occur every year in Japan, most of which are caused by the incomplete combustion of fuel, such as gasoline, light oil, and coal briquettes. To prevent CO poisoning in workers, it is essential to reduce the CO concentration in a working environment below the criteria threshold through ventilation. Although proper ventilation requirements for enclosed spaces are estimated from the generation rate of air pollutants, there is no empirical research evaluating the CO generation rate of coal briquettes. In this study, the author evaluated the CO generation rate of burning coal briquettes under controlled laboratory conditions and estimated the appropriate corresponding ventilation requirements. Despite the coal briquettes were burned under sufficient oxygen supply, the CO generation rates and the briquettes' consumption rates were 146-316 mL/min/kW and 1.65-3.61 g/min, respectively. Assuming the CO concentration limit was 50 ppm, the corresponding ventilation requirement was 174.9-378.7 m3/h/kW. The ventilation requirement was 43.7-94.7 m3/h/kW when the critical CO concentration was set at 200 ppm. Adopting the ventilation requirements set out in this study could facilitate proper ventilation and reduce the risk of CO poisoning.


Prognosis, course of disease, and treatment of the spondyloarthropathies.
Prognosis in the majority of patients with acute reactive arthritis is usually good, with most patients recovering in a few months. In about 15% to 30% of such patients, the disease progresses, and spondyloarthropathy and even ankylosing spondylitis develop in the following 10 to 20 years. A recurrent attack of reactive arthritis is common in patients with chlamydia-triggered arthritis, but it is rare in patients who have had enteroarthritis. In patients with chronic spondyloarthropathy without evidence of preceding infection, the disease can progress slowly into ankylosing spondylitis. When reactive chlamydia arthritis is indicated, a prolonged course of antibiotics is needed. For other forms of reactive arthritis, solid evidence in favor of antibiotic therapy is still lacking. Presence of hip pain, decreased mobility of thoracic cervical or thoracic spine, heel pain, inflammatory gut lesions, high erythrocyte sedimentation rate, positive family history, and presence of human leukocyte antigen B27 are indicators for chronicity. Sulfasalazine might be of use in chronic arthritis and ankylosing spondylitis, especially if the patient has peripheral arthritis.


Exposure to sunlight, vitamin D and schizophrenia.
The hypothesis that vitamin D deficiency in pregnancy or early infancy may contribute to the aetiology of schizophrenia was tested by examining the relationship between population exposure to sunlight, which promotes the synthesis of vitamin D in the summer months, and the monthly rate of schizophrenic births in two large data sets--22,000 schizophrenic patients born in England or Wales between 1921 and 1960, and 8000 born in Scotland between 1932 and 1960. No convincing relationship could be found in either cohort.


Plasmonic gold mushroom arrays with refractive index sensing figures of merit approaching the theoretical limit.
Localized surface plasmon resonance (LSPR)-based sensing has found wide applications in medical diagnosis, food safety regulation and environmental monitoring. Compared with commercial propagating surface plasmon resonance (PSPR)-based sensors, LSPR ones are simple, cost-effective and suitable for measuring local refractive index changes. However, the figure of merit (FOM) values of LSPR sensors are generally 1-2 orders of magnitude smaller than those of PSPR ones, preventing the widespread use of LSPR sensors. Here we describe an array of submicrometer gold mushrooms with a FOM reaching ~108, which is comparable to the theoretically predicted upper limit for standard PSPR sensors. Such a high FOM arises from the interference between Wood's anomaly and the LSPRs. We further demonstrate the array as a biosensor for detecting cytochrome c and alpha-fetoprotein, with their detection limits down to 200 pM and 15 ng ml(-1), respectively, suggesting that the array is a promising candidate for label-free biomedical sensing.


Gastrointestinal hormone secretion in women with polycystic ovary syndrome: an observational study.
Is the secretion of gastrointestinal hormones impaired in patients with polycystic ovary syndrome (PCOS)? Gastrointestinal hormone levels were abnormal in patients with PCOS. The hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) are both involved in signaling satiety. Secretion of GLP-1 and PYY in response to nutrients in the small intestine plays an important role in energy metabolism. Most PCOS patients are overweight or obese, which suggests dysregulation of appetite. In order to evaluate levels of gastrointestinal hormones in PCOS, a cohort study was undertaken, involving 30 PCOS patients and 29 BMI-matched healthy women recruited from Shanghai Renji Hospital between 1 March 2013 and 30 May 2014. After an overnight fast, all participants underwent an oral glucose tolerance test. Blood was sampled frequently for measurement of blood glucose and plasma insulin, total GLP-1 and PYY concentrations. Fasting and postprandial insulin levels were significantly higher in patients with PCOS compared with the healthy controls (P < 0.05). Fasting and postprandial GLP-1 (t = 0 and 30 min; mean ± SEM) were also higher in PCOS group (17.5 ± 1.07 pM versus 14.1 ± 1.16 pM, P < 0.05; 29.7 ± 2.39 pM versus 22.8 ± 2.09 pM, P < 0.05). However, there were no differences in plasma PYY between patients with PCOS and healthy controls either fasting or postprandially. PYY levels were lower in obese PCOS patients than in lean PCOS patients (P < 0.05). The study involved a small number of subjects with PCOS, and examined hormone responses to oral glucose rather than a physiological meal. Deficient secretion of GLP-1 and PYY does not contribute to excessive food intake in the pathophysiology of PCOS.


A novel method for the measurement of linear body segment parameters during clinical gait analysis.
Clinical gait analysis is a valuable tool for the understanding of motion disorders and treatment outcomes. Most standard models used in gait analysis rely on predefined sets of body segment parameters that must be measured on each individual. Traditionally, these parameters are measured using calipers and tape measures. The process can be time consuming and is prone to several sources of error. This investigation explored a novel method for rapid recording of linear body segment parameters using magnetic-field based digital calipers commonly used for a different purpose in prosthetics and orthotics. The digital method was found to be comparable to traditional in all linear measures and data capture was significantly faster with the digital method, with mean time savings for 10 measurements of 2.5 min. Digital calipers only record linear distances, and were less accurate when diameters were used to approximate limb circumferences. Experience in measuring BSPs is important, as an experienced measurer was significantly faster than a graduate student and showed less difference between methods. Comparing measurement of adults vs. children showed greater differences with adults, and some method-dependence. If the hardware is available, digital caliper measurement of linear BSPs is accurate and rapid.


Mitochondria-targeted Triphenylamine Derivatives Activatable by Two-Photon Excitation for Triggering and Imaging Cell Apoptosis.
Photodynamic therapy (PDT) leads to cell death by using a combination of a photosensitizer and an external light source for the production of lethal doses of reactive oxygen species (ROS). Since a major limitation of PDT is the poor penetration of UV-visible light in tissues, there is a strong need for organic compounds whose activation is compatible with near-infrared excitation. Triphenylamines (TPAs) are fluorescent compounds, recently shown to efficiently trigger cell death upon visible light irradiation (458 nm), however outside the so-called optical/therapeutic window. Here, we report that TPAs target cytosolic organelles of living cells, mainly mitochondria, triggering a fast apoptosis upon two-photon excitation, thanks to their large two-photon absorption cross-sections in the 760-860 nm range. Direct ROS imaging in the cell context upon multiphoton excitation of TPA and three-color flow cytometric analysis showing phosphatidylserine externalization indicate that TPA photoactivation is primarily related to the mitochondrial apoptotic pathway via ROS production, although significant differences in the time courses of cell death-related events were observed, depending on the compound. TPAs represent a new class of water-soluble organic photosensitizers compatible with direct two-photon excitation, enabling simultaneous multiphoton fluorescence imaging of cell death since a concomitant subcellular TPA re-distribution occurs in apoptotic cells.


(1,2-Diaminoethane-1,2-diyl)bis(N-methylpyridinium) Salts as a Prospective Platform for Designing Recyclable Prolinamide-Based Organocatalysts.
A new efficient and highly recyclable organocatalyst has been developed for asymmetric cross-aldol reactions under neat conditions in ketone-ketone, ketone-aldehyde, and aldehyde-aldehyde systems. The catalyst features two prolinamide fragments and a C2-symmetrical (1,2-diaminoethane-1,2-diyl)bis(N-methylpyridinium) group. The catalyst retained high activity and excellent stereoselection over the operating period of more than 830 h (25 cycles). An ab initio theoretical investigation explained the absolute configuration of the products and different stereoinduction levels for designed diastereomeric organocatalysts.


A meta-research study revealed several challenges in obtaining placebos for investigator-initiated drug trials.
To systematically assess the kind of placebos used in investigator-initiated randomized controlled trials (RCTs), from where they are obtained, and the hurdles that exist in obtaining them. PubMed was searched for recently published noncommercial, placebo-controlled randomized drug trials. Corresponding authors were invited to participate in an online survey. From 423 eligible articles, 109 (26%) corresponding authors (partially) participated. Twenty-one of 102 (21%) authors reported that the placebos used were not matching (correctly labeled in only one publication). The main sources in obtaining placebos were hospital pharmacies (32 of 107; 30%) and the manufacturer of the study drug (28 of 107; 26%). RCTs with a hypothesis in the interest of the manufacturer of the study drug were more likely to have obtained placebos from the drug manufacturer (18 of 49; 37% vs. 5 of 29; 17%). Median costs for placebos and packaging were US$ 58,286 (IQR US$ 2,428- US$ 160,770; n = 24), accounting for a median of 10.3% of the overall trial budget. Although using matching placebos is widely accepted as a basic practice in RCTs, there seems to be no standard source to acquire them. Obtaining placebos requires substantial resources, and using nonmatching placebos is common.


More surprises lying ahead. The endocannabinoids keep us guessing.
The objective of this review is to point out some important facts that we don't know about endogenous cannabinoids - lipid-derived signaling molecules that activate CB1 cannabinoid receptors and play key roles in motivation, emotion and energy balance. The first endocannabinoid substance to be discovered, anandamide, was isolated from brain tissue in 1992. Research has shown that this molecule is a bona fide brain neurotransmitter involved in the regulation of stress responses and pain, but the molecular mechanisms that govern its formation and the neural pathways in which it is employed are still unknown. There is a general consensus that enzyme-mediated cleavage, catalyzed by fatty acid amide hydrolase (FAAH), terminates the biological actions of anandamide, but there are many reasons to believe that other as-yet-unidentified proteins are also involved in this process. We have made significant headway in understanding the second arrived in the endocannabinoid family, 2-arachidonoyl-sn-glycerol (2-AG), which was discovered three years after anandamide. Researchers have established some of the key molecular players involved in 2-AG formation and deactivation, localized them to specific synaptic components, and showed that their assembly into a multi-molecular protein complex (termed the '2-AG signalosome') allows 2-AG to act as a retrograde messenger at excitatory synapses of the brain. Basic questions that remain to be answered pertain to the exact molecular composition of the 2-AG signalosome, its regulation by neural activity and its potential role in the actions of drugs of abuse such as Δ(9)-THC and cocaine. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.


Acrolein induces NLRP3 inflammasome-mediated pyroptosis and suppresses migration via ROS-dependent autophagy in vascular endothelial cells.
Acrolein is a common environmental pollutant that has been linked to cardiovascular diseases, such as atherosclerosis (AS). Increasing evidence demonstrates that acrolein impairs the cardiovascular system by targeting vascular endothelial cells, but the underlying mechanisms haven't been completely elucidated. In human umbilical vein endothelial cells (HUVECs), we observed that acrolein treatment induced cell reactive oxygen species (ROS) generation, autophagy, pyroptosis and reduced cell migration. In addition, exposure to acrolein resulted in NLRP3 inflammasome activation as evidenced by cleavage of caspase-1 and downstream mature interleukin (IL)-1β and IL-18 secretion. Knockdown of NLRP3 by small interfering RNA remarkably suppressed acrolein-induced pyroptosis and increased cell migration. Moreover, the scavenging ROS relieved the autophagy, NLRP3 inflammasome activation and pyroptosis. Furthermore, the role of autophagy in the acrolein-medicated pyroptosis and cell migration was investigated. In our study, 3-methyladenine (3-MA), an autophagy inhibitor, aggravated NLRP3 inflammasome activation, pyroptosis and decreased cell migration, rapamycin (Rapa), an autophagy inducer, alleviated aforementioned phenomenon under acrolein stress. Besides, we found damaged mitochondrion accentuated NLRP3 inflammasome and pyroptosis in acrolein-treated cells. In conclusion, it is possible that acrolein induced cell pyroptosis and suppressed cell migration via ROS-dependent autophagy. What's more, NLRP3 inflammasome activation plays a key role in this process.


Different response to balloon angioplasty of carotid and coronary arteries: effects on acute platelet deposition and intimal thickening.
PTCA is a well-established intervention to reduce the severity of atherosclerotic coronary stenosis. Its primary success rate is seriously handicapped by the high incidence of late restenosis. Given the clinical and social importance of this proliferative process, new strategies are needed to prevent or reduce restenosis. Several animal models as well as different arteries have been used to study neointimal proliferation after arterial injury. A number of agents have shown to reduce neointimal proliferation after arterial injury in the carotids and iliac arteries of rodent models. Unfortunately, these results have not been replicated in humans. We have compared the acute and late response to vascular injury of the carotid and coronary arteries in the pig. Arterial injury was induced by performing balloon angioplasty of the carotid (elastic) and coronary (muscular) arteries in swine. Acute platelet-thrombus formation was evaluated by quantitation of Indium-labeled platelets deposited on the injured segments 1 h after procedure. Measurement of intimal area was performed by morphometry of the most stenotic cross-section at 28 days after balloon angioplasty. Platelet deposition after mild and severe injury in carotids (4 +/- 1 and 56 +/- 13 x 10(6) platelets/cm2, respectively) and coronaries (15 +/- 5 and 141 +/- 20 x 10(6) platelets/cm2, respectively) are significantly greater in deep, than in mild injury (P < 0.005), and significantly greater in coronary than in carotid arteries after deep injury (P < 0.05). Likewise, late neointima formation was significantly greater (P < 0.05) after mild and severe injury in coronary (17 +/- 0.5 and 56 +/- 2%, respectively) than in carotid arteries (5 +/- 0.5 and 12 +/- 1%, respectively). Acute platelet-thrombus formation and late neointimal thickening are modulated by the degree of injury induced during the interventions; and after disruption of the internal elastic lamina, coronary arteries always had significantly more acute thrombus and neointimal thickening. This study emphasizes the importance of the animal species, the type of injury and the artery chosen for studies on restenosis post interventions.


[Prospects for the application and basic research on small regulatory peptides].
Specific properties of regulatory peptides, limiting their practical use and possibilities for avoiding these limitations are discussed. The level of knowledge on specific groups of regulatory peptides, actively investigated in our country, and application of these data for practical purposes are considered.


Randomized study of doxorubicin-based chemotherapy regimens, with and without sildenafil, with analysis of intermediate cardiac markers.
Doxorubicin chemotherapy is used across a range of adult and pediatric malignancies. Cardiac toxicity is common, and dysfunction develops over time in many patients. Biomarkers used for predicting late cardiac dysfunction following doxorubicin exposure have shown promise. Preclinical studies have demonstrated potential cardioprotective effects of sildenafil. We sought to confirm the safety of adding sildenafil to doxorubicin-based chemotherapy and assess N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) and high sensitivity cardiac troponin I (hsTnI) as early markers of anthracycline-induced cardiotoxicity. We randomized 27 patients (ages 31-77, 92.3% female) receiving doxorubicin chemotherapy using a blocked randomization scheme with randomly permuted block sizes to receive standard chemotherapy alone or with the addition of sildenafil. The study was not blinded. Sildenafil was dosed at 100 mg by mouth daily during therapy; patients took sildenafil three times daily on the day of doxorubicin. Doxorubicin dosing and schedule were dependent on the treatment regimen. Echocardiography was obtained prior to initiation of treatment and routinely thereafter up to 4 years. NT-proBNP and hsTnI were obtained with each cycle before, 1-3 h after, and 24 h after doxorubicin. Fourteen patients were randomized to receive standard doxorubicin chemotherapy alone (14 treated and analyzed), while 13 patients were randomized to the experimental doxorubicin and sildenafil arm (10 treated and analyzed). No toxicity signal was seen with the addition of sildenafil to doxorubicin-based regimens. There was no statistical difference between the treatment arms in relation to the change of mean left ventricular ejection fraction (LVEF) between the first and last evaluation. In both arms, hsTnI levels increased over time; however, elevated hsTnI was not associated with declines in LVEF. Adding sildenafil was safe, but did not offer cardioprotection following doxorubicin treatment. Increases in hsTnI levels were observed over time, but elevations during therapy did not correlate with subsequent decreases in LVEF. This clinical trial (NCT01375699) was registered at www.clinicaltrials.gov on June 17, 2011.


Preventing Overheating: Tight Control of Gut Innate Immunity in Health and Disease.
Innate immune responses are key to maintain adequate host-microbial interactions. However, those signals are needed to efficiently trigger rapid and targeted antimicrobial responses in case of pathogen encounter. Several molecules have evolved to regulate intensity and coordinate signaling to avoid detrimental consequences to the host. Regulation can occur at the cell surface, within the cytoplasm, and at the transcriptional level. Innate immune regulation seems to be equally important than stimulation, as disruption of immunoregulatory molecules modulates the risk for several diseases. This is the case for colitis and inflammatory bowel disease but also colorectal cancer and intestinal infections. In this review, we recapitulate the molecular mechanisms underlying regulation of innate immune signals and mention their implications in several disease states including inflammatory bowel disease.


Percutaneous occlusion of posttraumatic aortic arch pseudoaneurysm by catheter-based delivery of thrombin.
To report a patient in whom a posttraumatic pseudoaneurysm of the aortic arch was successfully treated by catheter-based delivery of thrombin with balloon occlusion of the entry tear. A 63-year-old male presented with pseudoaneurysm of the aortic arch after blunt chest trauma which was detected incidentally during routine chest X-ray. Using a percutaneous transfemoral approach, a 5 French Swan-Ganz catheter could be positioned into the aneurysm sac. Under balloon occlusion of the entry tear in order to prevent systemic embolization, 1,000 units of bovine thrombin were injected into the aneurysm sac resulting in complete occlusion of the aneurysm. Contrast-enhanced computed tomographic control showed complete thrombosis of the aneurysm over a follow-up period of 12 months. Percutaneous catheter-based delivery of thrombin is a feasible and effective minimally-invasive treatment alternative for patients with thoracic aortic pseudoaneurysms.


Intestinal pathology in the dog induced by sublethal doses of amiodarone.
Amiodarone (A), an unique antiarrhythmic agent and amphiphilic drug, induces at sublethal doses dyslipidic storage in animals. The present work demonstrates a distinct intestinal pathology or "Malabsorption Syndrome" in the dog induced by A. Signs of intestinal pathology were observed in all animals receiving 100 mg/kg, but not in those receiving less than 50 mg/kg, after one month. The malabsorption syndrome was demonstrated by a dynamic study of lipid absorption and pathological lesions (partial villous atrophy and the accumulation of macrophages with dyslipidic inclusions.


Investigation of wave propagation through head layers with focus on understanding blast wave transmission.
Blast-induced traumatic brain injury (bTBI) is a critical health concern. This issue is being addressed in terms of identifying a cause-effect relationship between the mechanical insult in the form of a blast and resulting injury to the brain. Understanding wave propagation through the head is an important aspect in this regard. The objective of this work was to study the blast wave propagation through the layered architecture of the head with an emphasis on understanding the wave transmission mechanism. Toward this end, one-dimensional (1D) finite element head model is built for a simplified surrogate, human, and rat. Motivated from experimental investigations, four different head layer configurations have been considered. These configurations are: (A) Skull-Brain, (B) Skin-Skull-Brain, (C) Skin-Skull-Dura-Arachnoid-CSF-Pia-Brain, (D) Skin-Skull-Dura-Arachnoid-AT-Pia-Brain. The validated head model is subjected to flattop and Friedlander loading implied in the blast, and the resulting response is evaluated in terms of brain pressures. Our results suggest that wave propagation through head parenchyma plays an important role in blast wave transmission. The thickness, material properties of head layers, and rise time of an input pulse govern the temporal evolution of pressure in the brain. The key findings of this work are: (a) Skin and meninges amplify the applied input pressure, whereas air sinus has an attenuation effect. (b) Model is able to describe experimentally recorded peak pressures and rise times in the brain, including variations within the aforementioned experimental head models of TBI. This reinforces that the wave transmission is an important loading pathway to the brain. (c) Equivalent layer theory for modeling meningeal layers as a single layer has been proposed, and it gives reasonable agreement with each meningeal layer modeled explicitly. This modeling approach has a great utility in 3D head models. The potential applications of 1D head model in evaluation of new helmet materials, brain sensor calibration, and brain pressure estimation for a given explosive strength have also been demonstrated. Overall, these results provide important insights into the understanding of mechanics of blast wave transmission in the head.


The NH2-terminal 21 amino acid residues are not essential for the papain-inhibitory activity of oryzacystatin, a member of the cystatin superfamily. Expression of oryzacystatin cDNA and its truncated fragments in Escherichia coli.
Oryzacystatin, a proteinaceous cysteine proteinase inhibitor (cystatin) in rice, is comprised of 102 residues (Met1-Ala102) (Abe, K., Emori, Y., Kondo, H., Suzuki, K., and Arai, S. (1987) J. Biol. Chem. 262, 16793-16797). We constructed an expression plasmid containing a full length oryzacystatin cDNA at the multi-cloning site of pUC18 and produced a lacZ'-oryzacystatin fusion protein in Escherichia coli. The partially purified expressed protein efficiently inhibits papain activity assayed using N-benzoyl-DL-arginine-2-naphthylamide as a substrate. We also constructed expression plasmids lacking the 5'- and 3'-regions of cDNAs that encode NH2- and COOH-terminally truncated oryzacystatins. An N-truncated oryzacystatin lacking Gly5 and retaining Gln53-Val54-Val55-Ala56-Gly57 inhibited papain as efficiently as the full length oryzacystatin, although both Gly5 and Gln53-Gly57 (oryzacystatin numbering) are conserved among members of most cystatin superfamilies. However, another N-truncated oryzacystatin lacking the NH2-terminal 38 residues was almost completely inactive. On the other hand, a COOH-terminally truncated oryzacystatin lacking the COOH-terminal 11 residues possesses potent papain-inhibitory activity, whereas another COOH-terminally truncated oryzacystatin lacking 35 residues shows much less inhibitory activity, although it retains the two well conserved features Gly5 and Gln53-Gly57. These results indicate that the NH2-terminal 21 residues containing Gly5 and the COOH-terminal 11 residues are not essential, suggesting that a portion of the polypeptide segment containing Gln53-Gly57 is necessary for oryzacystatin to elicite its papain-inhibitory activity efficiently.


Synthesis and characterization of cadmium selenide nanoparticles loaded on activated carbon and its efficient application for removal of muroxide from aqueous solution.
In the first, Cadmium selenide Nanoparticle loaded on activated carbon (CdSe-NP-AC) has been synthesized and characterized by different techniques including XRD and SEM. Then, this new adsorbent successfully has been applied for the removal of muroxide (MO) from aqueous solution in batch studies, while the effect of various experimental parameters like initial pH (pH(0)), contact time, amount of (CdSe-NP-AC) and initial MO concentration (C(0)) on its removal percentage was examined by one at a time optimization method. It was found following optimization of variable, the adsorption of MO onto (CdSe-NP-AC) followed pseudo-second-order kinetics and show Tempkin and Langmuir models for interpretation of experimental data. It was observed that by increasing the temperature the removal percentage was improved and the positive change in entropy (ΔS°) and heat of adsorption (ΔH°) show the endothermic nature of process, while the high negative value in Gibbs free energy change (ΔG°) indicates the feasible nature of adsorption process.


Common Dorsal Flaws Following Preservation Rhinoplasty: A Systemic Analysis.
There has recently been a resurgence of interest in preservation rhinoplasty (PR) for dorsal hump elimination or dorsal projection reduction. However, no studies have scrutinized aesthetic outcomes to identify common pattern of flaws seen in published images to aid those with ardent enthusiasm for this technique to become aware of the frequency of these flaws and find ways to reduce imperfections. A systematic literature review was performed using search terms ("preservation" OR "let down", "push down") AND "rhinoplasty" on PubMed, Cochrane, SCOPUS, and EMBASE databases for studies between January 2000 and December 2022. Patient images from these studies were analyzed by three reviewers (MWW, IAC, and BG) for dorsal flaws. Raw interrater agreement percentage and Krippendorff's alpha were calculated to determine interrater reliability. A descriptive and comparative analysis with Fisher's exact test was performed for the aggregate data. There were 59 patient images with 464 views from 24 studies included for final analysis. Optimal dorsal aesthetic lines (DAL) were noted in 12 patients (20.3%), while optimal profile was observed in 15 patients (25.4%) (p = 0.66). Combined ideal front and profile view of dorsum was not observed on any patients. The most common flaws were DAL irregularities (n = 45; 78.0%), dorsal deviation (n = 32, 54.2%), and residual hump (n = 25, 42.4%). There was excellent interrater agreement. While PR may have some advantages, it has shortcomings in outcomes, particularly dorsal irregularities, dorsal deviation, and residual humps. Awareness of these imperfections may compel those performing this procedure to modify their techniques and improve their results. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


The use of animals in medical education: a question of necessity vs. desirability.
An issue in current animal welfare ethics is the use of animals in medical education. At stake is the conflict of pain and suffering of the animals vs. the benefit to the students. The educator's role is to balance these two concepts. If the animals do suffer, this has to be justified by clearly establishing the necessity of their use. Neither this justification nor the methods for making the decision are clear. Addressed in this discussion are the arguments for and against animal use, alternatives, and proposals for the resolution of the controversy.


Cytotoxicity of an organic hydroperoxide and cellular antioxidant defense system against hydroperoxides in cultured mammalian cells.
The cytotoxicity of an organic hydroperoxide, tert-butyl hydroperoxide (t-BHP), was evaluated by inhibition of cell growth and of colony formation in cultured Chinese hamster V79 cells depleted or not depleted of cell glutathione (GSH). The hydroperoxide was cytostatic as shown by a marked decrease of mitotic cells, hence with a very low ability to form a colony. By depletion of GSH in the cells a killing effect of the hydroperoxide appeared. Iron chelation by O-phenanthroline markedly suppressed both inhibition of cell growth and of colony formation by t-BHP, indicating participation of divalent iron in the induction of cytotoxicity. Likewise, the pretreatment of GSH-depleted cells with cysteamine, an effective radical scavenger but without action as an electron donor in GSH peroxidase (GSH-Px) reaction, partly suppressed t-BHP-induced cell growth inhibition. These results suggest involvement of iron-catalyzed radical reaction in the induction of cytotoxicity by t-BHP. The inhibition of incorporation of tritiated thymidine and uridine by t-BHP was a little more sensitive than inhibition of leucine incorporation. GSH depletion evenly enhanced inhibition of incorporation of those precursors by t-BHP. The sensitivity to t-BHP of the cells with increased activity of GSH-Px by 1.5-2 times of control, which was achieved by treatment with 60 nM Na2SeO3, was not different from that of the cells with normal activity of the enzyme. On the other hand, t-BHP selectively inhibited GSH-Px activity without effect on glutathione reductase activity. These observations suggest that the cellular antioxidant system can not efficiently play a protective role against exogenous hydroperoxides and also that the increased cytotoxicity of t-BHP by GSH depletion is due strongly to a decrease of cell GSH as a radical scavenger than as an electron donor in GSH-Px reaction.


A combined in silico strategy to describe the variation of some 3D molecular properties of beta-cyclodextrin due to the formation of inclusion complexes.
A powerful in silico strategy based on the combined use of two computational tools (MLP and MIFs) able to calculate and visualize 3D molecular fields can give useful information about surface properties of macromolecules involved in the mechanisms of formation of complexes. In particular, this study investigated the variation in polar/hydrophobic pattern induced on the beta-CD alone (i.e. =without the ligand) by the inclusion of four ligands having different lipophilicities and small size. Results indicate that, in the presence of guests with P>0, the hydrophobicity of beta-CD increases in the cavity and its surroundings on the primary face.


Prevention of nitroglycerin tolerance with diuretics.
Tolerance to prolonged nitroglycerin (NTG) may be due to drug-induced intravascular expansion. To test the hypothesis that concomitant diuretics may reduce volume expansions and thus prevent NTG tolerance, we studied 23 healthy volunteers randomized to hydrochlorthiazide or placebo before and during 74-hour continuous NTG exposure. Venodilator response to NTG was tested serially with venous forearm plethysmography. In the preNTG patch phase venodilator response was similar in both the placebo and diuretic groups. Venodilator capacity was compared after "acute" (2-hour) and "chronic" (74-hour) NTG exposure with NTG patches. Attenuation to NTG was seen in the placebo group, but NTG venodilator activity was fully maintained in the diuretic group. These data suggest that diuretics may be helpful in the prevention of NTG tolerance.


Photointeraction of benzophenone triplet with lysozyme.
The quenching of the benzophenone triplet by lysozyme and its constituent amino acids in aqueous solutions have been studied. Native lysozyme quenches the benzophenone triplet with a high rate constant, 4 x 10(9) M-1 s-1. The quenching process takes place with production of significant amounts of free ketyl radicals, phi ketyl = 0.56, but with a very low benzophenone consumption yield (0.022). The consumption yield is considerably smaller than that observed for the free amino acids. This difference can be explained in terms of a dominant back hydrogen transfer to the protein in the disproportionation of the free radicals produced. Reduced and carboxymethylated lysozyme shows a higher quenching rate (7.8 x 10(9) M-1 s-1) and a larger benzophenone consumption yield (0.07). The deactivation of the benzophenone triplet by the native protein leads to its inactivation, with a quantum yield of 0.01. Tryptophan and arginine residues are destroyed with a quantum yield of 0.01. In the modified enzyme tyrosine and methionine groups are also consumed.


A review of physiological prestress adaptation: effects of duration and context.
This review focuses on 3 aspects of experimental designs for prestress, physiological adaptation periods: (1) effects of duration on stabilization of various physiological parameters:(2) effect of type of activity and instruction on prestress physiological adaptation: and (3) definitions of physiological baselines. Analyses of the literature revealed that for many physiological parameters it remains unclear how much time is required for stabilization and that for the remaining variables the necessary duration of prestress adaptation varies greatly, with blood pressure potentially being the slowest variable to stabilize. Effects of type of activity are essentially unknown. Instructions which create certainly about experimental procedures in subjects tend to facilitate adaptation to the laboratory environment. Baseline definitions were remarkably variable with no less than 15 different definitions being used across the 50 studies reviewed. Suggestions for future research and recommendations for prestress experimental designs are put forward in the discussion.


Muscle damage and repair in voluntarily running mice: strain and muscle differences.
Soleus, extensor digitorum longus and tibialis anterior muscles of mice voluntarily running in wheels for periods of 5 to 120 days were studied in spaced serial and serial cross-sections. Shortly after the onset of running and during the next 2 weeks, degeneration, necrosis, phagocytosis and regeneration of muscle fibers, satellite cell proliferation and cellular infiltration were found in soleus muscles of mice from all strains investigated (CBA/J, NMRI, C57bl, NIH, SWS and Balb/c). Tibialis anterior but not extensor digitorum longus muscles were also damaged. Predominantly high-oxidative fibers were affected (both slow-oxidative and fast oxidative glycolytic in soleus, fast-oxidative glycolytic in tibialis anterior). Denervated soleus muscles that had been passively stretched during running were not damaged. Evidence was found that, during the early period of running, split fibers form by myogenesis within (regeneration) or outside (satellite cell proliferation) necrotic muscle fiber segments. Split fibers persisted in solei of long-term (2 to 3 months) exercised CBA/J but not NMRI mice. In 6 out of 20 solei of CBA/J runners exercised for 2 months or longer, fiber-type grouping was observed in the areas where extensive damage usually occurred in the early periods. The results show that different muscles are damaged and repaired to varying degrees and that marked interstrain and inter-individual differences are present. It appears that acute muscle injury occurring upon onset of voluntary running is a usual event in the adaptation of muscles to altered use.


Penicillium species as a rare isolate in tracheal granulation tissue: a case series.
Granulation tissue formation is a major problem complicating the treatment of upper airway stenosis. We present two cases of recurrent tracheal granulation tissue colonisation by Penicillium species in patients undergoing laryngotracheal reconstructive surgery for post-intubation tracheal stenosis. We believe that although most Penicillium species do not cause invasive disease they can be a contributory factor to the occurrence of upper airway stenosis. A microbiological and mycological study of tracheal granulation tissue in two patients with recurrent laryngotracheal stenosis was carried out. Penicillium species was seen microscopically and cultured from tracheal granulation tissue. Neither patient grew any bacteria known to be associated with airway granulation tissue formation. Amphotericin B, itraconazole, flucytosine voriconazole and caspofungin were highly active against both isolates. A search for a fungal cause should form part of the investigation for recurrent tracheal granulation tissue during laryngotracheal reconstruction.


[Evidence-based medicine and applying new therapies in general practice: wish and reality].
In the last years some important therapies were introduced in the treatment of rheumatoid arthritis (RA), which represent a significant clinical advance. This concerns the introduction of TNF blockade with etanercept and inflixmab, the combination of DMARDs, leflunomide and the COX-2-specific inhibitors. In the year 2000 the restrictive social law in Germany, the collective and individual budgets for medicaments, did prevent a broader use of the very expensive therapy with TNF blockade. A rising number of international healthcare studies shows a profound potential for saving costs by improving the functional capacity (HAQ) in patients with RA. The biologicals and leflunomide have this potential. To realise the potential of reducing healthcare costs by an optimal therapy of RA some modification of the restrictive social law is necessary as well as the introduction of disease-management programs.


Entrepreneurship education of college students and entrepreneurial psychology of new entrepreneurs under causal attribution theory.
With the rapid development of information technology, the society's demand for innovative talents has become increasingly prominent. The purpose of this study is to optimize the teaching strategies of entrepreneurship education for college students, further cultivate college students' entrepreneurial ideas, and promote the formation of entrepreneurial values. The problems existing in entrepreneurship education in colleges and universities are studied based on entrepreneurial psychology and attribution theory. A questionnaire survey is conducted on the problems with a high probability of entrepreneurial failure of college students. The heads of new ventures in Xi'an are selected. Then, 300 questionnaires are distributed, and 209 are returned. The survey results are analyzed using failure attribution and failure learning. Suggestions are provided for management strategies of new ventures. The results show that the Corrected Item-Total Correlation (CITC) value of R-1 is 0.65, and the CITC value of R-2 is 0.35. In addition, the Kaiser-Meyer-Olkin (KMO) values of entrepreneurial failure attribution and entrepreneurial failure mode are both greater than 0.7, which indicates that the scale of entrepreneurial failure attribution has good validity and can be used for factor analysis. However, the KMO values of entrepreneurial failure attribution and entrepreneurial failure learning model are both greater than 0.7, and the significance of Bartlett sphericity test is 0.00, which indicates that the survey has good validity. The research has practical application and reference value for the cultivation of college students' innovative and entrepreneurial ability.


Effects of Dietary Multienzyme Complex Supplementation on Growth Performance, Digestive Capacity, Histomorphology, Blood Metabolites and Hepatic Glycometabolism in Snakehead (Channa argus).
The present study evaluated the impact of dietary multienzyme complex (MEC) supplementation on growth performance, digestive enzyme activity, histomorphology, serum metabolism and hepatopancreas glycometabolism in snakeheads (Channa argus). A total of 600 fish (initial weight, 69.70 ± 0.30 g) were randomly divided into four groups. Four diets were formulated: (1) control (basic diet); (2) E1 (400 U kg-1 amylase, 150 U kg-1 acid protease, 1900 U kg-1 neutral protease and basic diet); (3) E2 (800 U kg-1 amylase, 300 U kg-1 acid protease, 3800 U kg-1 neutral protease and basic diet); and (4) E3 (1200 U kg-1 amylase, 450 U kg-1 acid protease, 5700 U kg-1 neutral protease and basic diet). The results show that the E2 group increased the specific growth rate, weight gain rate and the final body weight, as well as decreasing the blood urea nitrogen, alanine aminotransferase and triglyceride. The mRNA levels and activities of digestive enzymes and key glucose metabolism enzymes in the hepatopancreas were enhanced in snakeheads fed the MEC. Meanwhile, moderate MEC diet (E2 groups) supplementation improved digestive tract morphology, increased the glycogen in the hepatopancreas and the lipids in the dorsal muscle. Moreover, plasma metabolomics revealed differential metabolites mainly involved in amino acid metabolism. These findings suggest that dietary supplementation with the MEC improved growth performance, digestive tract morphology, gene expression and the activity of digestive enzymes, enhanced the glycolysis-gluconeogenesis and amino acid metabolism of snakeheads, and the optimal composition of the MEC was group E2.


Inhibition of TNFα in peritoneal fluids of patients following colorectal resection attenuates the postoperative stress-related increase in colon cancer cell migration: A prospective, in vitro study.
Surgical trauma in patients undergoing colorectal cancer resection generates local and systemic inflammatory responses that can affect oncological outcomes. Post-operative peritoneal fluids of patients undergoing colorectal surgery increase the pro-malignant effect of cancer cells in vitro with correlation to elevated TNFα in these fluids. This study evaluated whether inhibiting TNFα in patients' postoperative fluid biopsies would attenuate this effect. Peritoneal fluids from 53 patients undergoing colorectal surgery were sampled before and daily after surgery via intra-abdominal drains. Fluid biopsies were evaluated for their impact on the migration capacity of colon cancer cells and for cytokine levels. TNFα was inhibited using infliximab and cell migration was reevaluated. Colon cancer migration capacity was increased in postoperative fluid biopsies from all patients (P < 0.005) and was elevated compared to pre-resection levels. Infliximab attenuated this effect in >90%, decreasing migration capacity by 30% (p < 0.001). Inhibition of TNFα in postoperative peritoneal fluids attenuates the increase in cancer cell migration capacity generated following colorectal resection. These findings correlate with other studies suggesting that attenuation of the post-operative inflammatory response may have oncological benefit. Clinical studies are needed to evaluate the effect of peri-operative TNFα inhibition in clinical settings.


Extracellular phospholipase A2 activity in two in vivo models of inflammation.
Two "in vivo" models of inflammation have been used to investigate the role of phospholipases A2 (PLA2) in inflammation. These models are casein-induced peritonitis in the rat and zymosan-induced peritonitis in the mouse. The extracellular PLA2 activities from peritoneal lavage fluid in these two models are similar: they are calcium dependent and have broad neutral pH optima. However, the relationship between extracellular PLA2 activity and cell influx in these models are not identical. In zymosan peritonitis, PLA2 activity preceded peak cell influx, reaching a maximum within 15 min after zymosan injection, while cell influx peaked by 8 hr. In casein-induced peritonitis, the PLA2 activity peaked at 24 hr, while cell influx continued through 48 hr. The origins of the PLA2 activities in both models remain unclear; one potential source is the plasma. Understanding the role of extracellular PLA2 activity in "in vivo" models, and investigating specific inhibitors in these models may aid in our understanding of the role of extracellular PLA2 in diseases such as rheumatoid arthritis, endotoxin shock and pancreatitis.


N-arylrolipram derivatives as potent and selective PDE4 inhibitors.
Derivatization of rolipram led to the identification of 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]-5-( 3- methoxybenzyloxy)-benzoic acid N',N'-dimethylhydrazide (4), a potent and selective inhibitor of PDE4, which inhibits the activation of human leukocytes with pIC50 values in the range of 7.3-7.8, and blocks antigen induced eosinophilia in Brown Norway rats at a dose of 1 mg/kg (i.t.).


The effects of Tubulin denaturation on the characterization of its polymerization behavior.
We report here upon a simulation study examining the effect of a dynamic mode of tubulin denaturation upon the kinetic and thermodynamic characterisation of the polymer formed for two idealized models of a tubulin polymerization reaction: (i) an irreversibly polymerizing system; and (ii) a reversibly polymerizing system. The effects of each denaturation mode upon the two model systems behavior are highlighted by interpretation of the data in terms of the classical Oosawa reversible condensation polymerization model. We reveal here findings which suggest that the measurement strategy in concert with Tubulin's instability over the time course of the experiment may bias the results obtained so as to make an irreversible system's behavior conform to the equilibrium model or alternatively distort the results obtained from a truly reversible system to produce values of the critical concentration quite seriously in error. It was also found that Tubulin denaturation may seriously distort parameter estimates gained from a kinetic characterization of the system (e.g. nucleus size and growth rate constant).


Nutritional and Phytochemical Composition of Vaccinium padifolium Sm Wild Berries and Radical Scavenging Activity.
Blueberries have a well-deserved reputation as a potential functional food, supported by studies which have identified and quantified various nutrients and bioactive phytochemicals with known benefits for human diet and health. Wild blueberries have attracted particular attention due to the levels and concentrations of those phytonutrients. This study aims to evaluate for the first time the chemical composition of Madeira Island's endemic Vaccinium padifolium Sm wild berry. Results show that this fruit contains high values of total soluble phenolic content (around 4 g GAE kg-1 FW), as well as significant values of total monomeric anthocyanin content (around 3 g eq. cyanidin kg-1 FW) and DPPH scavenging activity (around 86.72%). Additionally, results reveal that this fruit has water content of about 88% as well as low sugar content (17.98 and 29.73 g kg-1 for glucose and fructose, respectively). Results also confirm that this wild blueberry is a good source of dietary fiber, fat and minerals. The high level of terpenoid compounds stands out in the aroma profile analysis. This study is in line with the efforts of the scientific community to identify new sources of phytonutrients that are beneficial to human health, characterizing the wild Madeira blueberry in terms of phytonutrients that suggest there may be health benefits associated with its consumption. The findings of this research are very important for both the commercial and agricultural sectors that produce this fruit, and for consumers who seek phytonutrient-rich foods.


Biosynthesis of enterochelin in Escherichia coli K-12: separation of the polypeptides coded for by the entD, E, F and G genes.
Four enzymic components, coded for by the entD, entE, entF and entG genes, involved in the biosynthesis of enterochelin from 2,3-dihydroxybenzoate have been separated from cell extracts of mutant strains of Escherichia coli K-12. The starting material for fractionation of the E, F and G components was a cell extract of an entD mutant strain, which yielded the E, F and G enzymic components uncontaminated by a functional D component. The D component was isolated from cell extracts of an entE mutant strain. The conversion of 2,3-dihydroxybenzoate and L-serine into enterochelin is dependent on the presence of all four enzymic components. The E and F components were shown to catalyze ATP-pyrophosphate exchange reactions dependent on 2,3-dihydroxybenzoate and L-serine, respectively, whereas fractionated extracts of the entE and entF mutant strains lacked these reactions. These data provide firm evidence that the E and F components are involved in the initial activation of the substrates. The D and G components are necessary for subsequent and, as yet, undefinedd reactions.


Macrolide-Resistant Mycoplasma genitalium Impairs Clinical Improvement of Male Urethritis After Empirical Treatment.
Mycoplasma genitalium (MG) is associated with urethritis in men and could play a role in clinical outcome. We examined clinical improvement of symptoms in men receiving empirical treatment for urethritis and correlated the outcome with Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), MG, and MG macrolide resistance-associated mutations (MRAM) status. At the sexually transmitted infection clinic in Amsterdam, the Netherlands, empirical treatment for gonococcal urethritis is 1 g ceftriaxone and for nongonococcal urethritis 1 g azithromycin. In 2018 to 2019, we tested urine samples of men with urethritis for CT, NG, and MG using transcription-mediated amplification assays. Mycoplasma genitalium-positive samples were tested for MRAM using quantitative polymerase chain reaction. Two weeks after receiving therapy, men were sent a text message inquiring after clinical improvement. We evaluated 2505 cases of urethritis. The positivity rates of NG, CT, and MG were 26% (648 of 2489), 29% (726 of 2489), and 23% (522 of 2288), respectively. In 768 of 2288 of the cases (34%), no causative agent was detected. Most cases were infected with a single pathogen: NG, 417 of 2288 (18%); CT, 486 of 2288 (21%); and MG, 320 of 2288 (14%). The prevalence of MRAM among MG-positives was 74% (327 of 439). For 642 (25.6%) cases, we could evaluate clinical improvement after treatment of whom 127 (20%) indicated no improvement; 9% (15 of 174) in NG cases, 18% (35 of 195) in CT cases, 14% (4 of 28) in MG wild-type cases, and 40% (38 of 94) in MG-MRAM cases. Clinical improvement in MG-MRAM cases was significantly lower compared with all other groups (P < 0.001). Presence of MG-MRAM is associated with lack of clinical improvement in azithromycin-treated nongonococcal urethritis.


Human nails metabolite analysis: A rapid and simple method for quantification of uric acid in human fingernail by high-performance liquid chromatography with UV-detection.
A rapid and simple analytical method for the quantification of uric acid (UA) in human fingernails by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection is described. UA was extracted from human fingernail samples at 90°C for 20min, then separated on an Inertsil ODS-2 column (250×4.6mm I.D., 5.0μm, GL Sciences) by isocratic elution using methanol: 74mM phosphate buffer (pH 2.2) 2:98 (v/v). An UV detector was used to monitor at 284nm. The results indicated that under optimized measurement conditions results were achieved within 8.0min, and a good linearity was achieved from the calibration curves (r(2)>0.9999) in the range of 1.0-10000ng; the limit of detection (S/N=3) was 2.0pg, the inter-day and intra-day assay precisions were all less than 0.46% and the mean recoveries (%) of the uric acid spiked in the human fingernail were 101.95%. The amounts of UA in the fingernails of healthy volunteers were determined.


Human evolution: a legacy of cannibalism in our genes?
A new study of genetic variation in the human prion protein gene suggests that balancing selection has operated on an amino acid sequence polymorphism in the gene during the last five hundred thousand years. Is this a legacy of widespread cannibalism by our ancestors?


The Prevalence of Mild Cognitive Impairment (Mci) among Older Population of Rural Kerala: A Cross-Sectional Study.
There are only very few studies on estimating the prevalence of mild cognitive impairment (MCI) from India, particularly from a rural setting. The available studies were heterogeneous. The study estimated the prevalence of MCI in a rural setting in Kerala, India. We conducted a community-based, cross-sectional study among individuals aged 65 and above in rural Thiruvananthapuram, Kerala. A cluster-randomized sampling was adopted, the cluster being the wards in the village. It was a two-phase door-to-door survey. Grassroots-level health workers enrolled 366 elders in the selected four wards in the initial phase and collected information on the sociodemographic details, comorbidities, and other risk factors of the participants, using a semi-structured questionnaire. Additionally, the Everyday Abilities Scale for India (EASI) was administered to assess their activities of daily living. In the second phase, a neurologist and a psychologist examined those screened positive with EASI and diagnosed MCI and dementia based on the MCI Working Group of the European Consortium on Alzheimer's Disease and the DSM V criteria, respectively. The prevalence of MCI and dementia was 18.6% (95% confidence interval [CI] 14.7%-23.4%) and 6.8% (4.46%-10.1%), respectively, among the study participants. The prevalence of MCI was higher among the unemployed and those above 70 years of age. The community prevalence of MCI is more than three times that of dementia among the elderly in rural Kerala.


[Reconstruction of the nasal alar defect with the superiorly based nasolabial flap described by Burget: report of seven cases].
The reconstitution of a nasal alar rim and lobule defect represent a difficult challenge in consideration of his situation, anatomy and function. This article describes the technique and the interest of the nasolabial flap when used to cover the entire alar subunit. We present 7 cases of alar rim and lobule defect after skin cancer excision. In the series, there are two full-thickness with lining defect. The patients were reconstructed with a superiorly based nasolabial flap, according to the subunit principle as introduced by Burget. A free cartilage graft was used to restore structural support with marginal skin flaps were turned over for intranasal lining when necessary. The cosmetic and functional outcomes of each repair were judged from good to excellent by patients and surgeons. No case of flap infection or necrosis occurred. The superiorly based nasolabial flap, describe by Burget, provides an excellent choice for cosmetic and functional reconstruction of the nasal alar defect.


Sustained recovery of hematopoiesis and immunity following transplantation of fetal liver cells in dogs.
We studied the ability of fetal liver cells to reconstitute hematopoiesis and immunity in lethally irradiated dogs. Engraftment and sustained lymphoid and hematopoietic recovery was achieved when the recipients received a preparative regime of high-dose total body irradiation (TBI) alone followed by transplantation of DLA-identical fetal liver. The combination of high-dose TBI and cyclosporine allowed engraftment in DLA-mismatched fetal liver transplants. Typical features of graft-versus-host disease (GvHD) did not occur although autoimmune-like syndromes (myasthenia gravis, immune thrombocytopenia) were observed in some recipients. Hematopoietic recovery was rapid and complete. Recovery of T- and B-lymphocyte function was comparatively delayed, but sufficient to prevent opportunistic infections after the initial 3 months post transplant. These data indicate that cells from a single fetal liver can reconstitute hematopoiesis and immunity in DLA-mismatched recipients and suggest that human fetal liver cell transplantation may be an effective source of stem cells for patients who lack an HLA-identical donor for bone marrow transplantation.


Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave's disease: a metabolomic approach.
Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave's disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography-tandem mass spectrometry (GC-MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6, which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.


Proptosis secondary to closure of the lids posterior to the globe.
A five-year-old black male was seen with acute unilateral proptosis of one to two centimeters following blunt trauma with retraction of the eyelids behind the involved eye. The proptosis was cured by performing a lateral canthotomy and replacement of the eyelids in front of the globe.


Potential risk of colonization of Bulinus globosus in the mainland of China under climate change.
Bulinus globosus, the main intermediate snail host of Schistosoma haematobium. The increased contacts between Africa and China could even lead to large-scale dissemination of B. globosus in China. Temperature is the key factor affecting fresh-water snail transmission. This study predicted potential risk of colonization of B. globosus in the mainland of China under climate change. We investigated minimum and maximum temperatures for B. globosus eggs, juveniles and adult snails kept under laboratory conditions to find the most suitable range by pinpointing the median effective temperatures (ET50). We also assessed the influence of temperature on spawning and estimated the accumulated temperature (AT). The average air temperatures between 1955 and 2019 in January and July, the coldest and hottest months in China, respectively, were collected from national meteorological monitoring stations and investigated in a geographic information system (GIS) using empirical Bayesian Kriging to evaluate the theoretical possibility for distribution of B. globosus in southern China based on temperature. The effective minimum temperature (ET50min) for eggs, juveniles, adult snails and spawning were 8.5, 7.0, 7.0, 14.9 °C, respectively, with the corresponding maximum values (ET50max) of 36.6, 40.5, 40.2 and 38.1 °C. The AT was calculated at 712.1 ± 64.9 °C·d. In 1955, the potential B. globosus distribution would have had a northern boundary stretching from the coastal areas of Guangdong Province and Guangxi Autonomous Region to southern Yunnan Province. Since then, this line has gradually moved northward. Annual regeneration of B. globosus can be supported by the current climate conditions in the mainland of China, and a gradual expansion trend from south to north is shown in the study from 2015 to 2019. Thus, there is a potential risk of colonization of B. globosus in the mainland of China under climate change.


The small chromatin fragments released by micrococcal nuclease from hepatoma tissue cultured cell nuclei are strongly enriched in coding DNA sequences and are related to an actively transcribed single-stranded DNA fraction.
It was shown with the use of specific probes that mild micrococcal nuclease digestion released from chromatin actively-transcribed genes as small nucleosome oligomers. In the present work we demonstrate that most if not all of the active genes are accessible to the nuclease. It was found that the short released fragments are greatly enriched in transcribed DNA sequences, the most enriched being the dimers of nucleosomes since 35% of their DNA could be hybridized to cytoplasmic RNA. The results of cDNA-DNA hybridizations indicate that the monomers and dimers of nucleosomes contain most of the DNA sequences which encode poly(A+) RNAs, however larger released fragments include some transcribed sequences, while the nuclease resistant chromatin is considerably impoverished in coding sites. These evidences are the finding that about 25% of the DNA from the dimers of nucleosomes are exclusively located in this class of fragments, tend to prove that the active chromatin regions are attacked in a non-random way by micrococcal nuclease. We have previously isolated, without using exogenous nuclease, an actively transcribed genomic fraction amounting to 1.5-2% of the total nuclear DNA, formed of single-stranded DNA. In the present study we show that all or nearly all the single-stranded DNA sequences could be reassociated with the DNA fragments present in the released monomers and dimers of nucleosomes. Our observations confirmed our previous finding that the greatest part of single-stranded DNA selectively originates from the coding strand of genomic DNA.


Kinetic studies of inhibition of estradiol 2- and 16 alpha-hydroxylases in rat liver microsomes with various cytochrome P-450 inhibitors.
Kinetic studies of inhibition of estradiol 2- and 16 alpha-hydroxylase activities in male rat liver microsomes with cytochrome P-450 inhibitors, alpha-naphthoflavone, DL-aminoglutethimide, SKF-525A and metyrapone, were extensively carried out. All of the inhibitors competitively blocked the two enzyme activities. The former three inhibitors preferentially inhibited the 16 alpha-hydroxylase activity while the reverse result was obtained in the case of metyrapone, and SKF-525A was the most potent inhibitors for the two enzyme among the four inhibitors. The kinetic data, the apparent Ki's for the four inhibitors and Km's for the substrate estradiol in the assays, along with the inhibition results with carbon monooxide suggest that different forms of cytochrome P-450 may be involved in the two hydroxylations. Kinetic parameters of the two hydroxylase activities in female rat liver microsomes were then determined to be an apparent Km of 23.0 and 158 microM and Vmax of 99.0 and 5.65 pmol/min/mg protein for the 2-hydroxylation and the 16 alpha-hydroxylation, respectively. The kinetic data show that the 2-hydroxylation may be quantitatively an exclusive hydroxylative pathway in estrogen metabolism in female.


Transient correction of genetic defects in cultured animal cells by introduction of functional proteins.
Material was introduced into cultures of cells by using the method of scrape loading, in which cells are simply rubbed from the surface of a plastic tissue culture dish by a rubber-tipped rod in the presence of a macromolecule of interest. The volume of solution introduced into cells was comparable to that generally injected in the direct microinjection method with glass capillaries, that is, about 50 to 100 fl per cell. Genetic defects (lack of hypoxanthine-guanine phosphoribosyltransferase and thymidine kinase) in several cell lines were transiently corrected by scraping the cells in the presence of crude cell extracts prepared from wild-type cells.


Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.
Hematopoietic growth factors have been shown to ameliorate the side effects of chemotherapy. Here we assess the ability of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to increase the dose-intensity and reduce the side effects of escalated methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. A prospective randomized trial to compare escalated MVAC versus escalated MVAC with rhGM-CSF was conducted. All patients were treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) and had a metastatic or unresectable urothelial tumor. Forty-eight patients were randomized (25 to MVAC with rhGM-CSF and 23 to escalated MVAC alone). The clinical characteristics of the study populations were similar (ie, degree of tumor dissemination and performance status). The dose-intensity in the two arms of the study did not differ significantly. No difference in the frequency of bacteriologically documented infections occurred between the two study arms. The use of the hematopoietic growth factor rhGM-CSF did not result in an increased dose-intensity of escalated MVAC. The inability to increase the dose-intensity of MVAC further was a result of nonhematologic side effects of the chemotherapy. Escalation of treatment delivered at its median-tolerated dose is unlikely to result in additional therapeutic benefit for patients with common solid tumors. Future development of therapy may require the development of new agents or concepts, rather than modification of existing therapies.


Uptake of lead by bacteria isolated from industrial effluents and their potential use in bioremediation of wastewater.
Due to rising populations and human activities, heavy metals (HM) toxicity has become a serious problem for all life forms. The present study deals with isolating and identifying lead-resistant bacteria from contaminated wastewater of tanneries effluents. Two isolated strains were identified as Bacillus cereus (ID1), and Bacillus sp. (ID3), and both strains resisted a 25 mM concentration of Lead nitrate (Pb (NO3)2). After four days of treatment, Bacillus cereus (ID1) showed 80% lead uptake, and Bacillus sp. (ID3) showed 88%. Lead uptake was confirmed by Energy dispersive X-Ray (EDX) analysis. Fourier transform infrared spectroscopy (FTIR) showed that structural alterations had occurred in functional groups of the treated samples compared to the controls. Our research indicates that these Bacillus strains may be useful in bioremediating heavy metals from polluted environments. Further investigation into the processes involved in the uptake and homeostasis of heavy metals by these strains is required, as is the identification of the genes and enzymes responsible for Pb-bioremediation.


The transmethylation cycle in the brain of Alzheimer patients.
Homocysteine accumulation, frequently observed in plasma of AD patients, may be a sign of a reduced activity of the brain methionine-homocysteine transmethylation cycle. S-Adenosylmethionine (SAM) is the main methyl donor in several transmethylation reactions. The demethylated product of SAM, S-adenosylhomocysteine (SAH), is hydrolyzed to yield homocysteine, which can be remethylated to methionine by transfer of a methyl group of 5-methyltetrahydrofolate (5-MTHF). A reduced activity of the transmethylation cycle in the brain may result in hypomethylation of the promoter of the presenilin 1 (PS1) gene, which will lead to overexpression of presenilin 1 and, consequently, to increased Abeta(1-42) (Abeta42) formation. Brain transmethylation was studied in 30 patients with 'probable' AD and 28 age-matched non-demented controls by measuring the cerebrospinal fluid (CSF) levels of SAM, SAH and 5-MTHF. 5-MTHF was determined by HPLC with electrochemical detection, while SAM and SAH were assayed by stable isotope dilution tandem mass spectrometry. We found no statistical differences between AD patients and controls for 5-MTHF, SAM and SAH levels, and the SAM/SAH-ratio in CSF. These findings argue against a possible change in methylation of the promoter and expression of PS1.


The median preoptic area in cardiovascular reflex activity.
Two examples are used to illustrate the flexibility within the central servocontrol system that regulates blood volume and blood pressure. The variations are seen in the modification of components directed both towards short-term and long-term control. The preferential circuit used in the servocontrol system can and does change. The interaction of baromechanisms with cerebellar-fastigial activation selectively engages sympathetic output to the kidney resulting in an enhanced release of renin that is disproportional to the rise in renal vascular resistance. The cerebellar component adds a feature to the reduction in vascular conductance that when fully developed increases vascular volume. The permissive role of sites in the anteroventral hypothalamus suggests a neural loop that, when absent, not only allows the sympathetic activity to run unabated but fails to prevent a tachycardia state or to develop a bradycardia in response to a rise in arterial pressure. The latter may be a transient feature not persisting for more than a day. However, when compared to the normal responses of the paired sham controls, such a change is taken as an example of dynamic shift in preferential pathways.


The 62-kb upstream region of Bombyx mori fibroin heavy chain gene is clustered of repetitive elements and candidate matrix association regions.
We sequenced an 80 kb DNA region containing the complete sequence of the silkworm Bombyx mori fibroin gene and its flanking, especially the upstream, regions (-62 kb). About 30% of the 62 kb upstream region is composed of repetitive elements including short interspersed elements Bm1, long interspersed elements L1Bm and mariner-like elements Bmmar1 which are widespread over the silkworm genome. This 62 kb region is also enriched of commonly considered matrix association region (MAR) motifs. A total of 25 individual MAR recognition signatures (MRSs) were identified, with 24 at the upstream and one at the downstream region. Combining two newly developed MAR prediction programs (MAR-finder and Chrclass), ten candidate MARs were predicted, with five containing MRS and seven related to the repetitive elements. The wide distribution of nested repetitive elements, candidate MARs, DNase I hypersensitive sites and other potential regulatory factors recognition sites indicates this region is probably a unique huge cis-acting element contributing to the regulation of the spatial and temporal specificity and efficiency of fibroin gene expression.


Vancomycin.
Vancomycin is an important antibiotic for the treatment of severe Gram-positive infection, especially in cases with resistant organisms or when the patient is allergic to penicillin. Because of its mode of action, pharmacokinetics and side effects, close liaison with the medical microbiologist is necessary.


Differences in the effects of medial and lateral preoptic lesions on thermoregulation and sleep in rats.
The effects of the destruction of the medial preoptic area and the lateral preoptic area with N-methyl-d-aspartic acid on sleep-wakefulness, brain temperature and thermoregulation were studied in two groups of male Wistar rats. Electroencephalogram, electrooculogram and electromyogram, along with brain temperature, were recorded for 3 days, prior to the destruction of the medial preoptic area and the lateral preoptic area, and on the 7th and 21st days after the destruction of these areas. The thermoregulatory capacity of the rats was assessed by recording their brain temperature when they were exposed to severe cold (5+/-1 degrees C) and heat (37+/-1 degrees C) before and after the lesion. Though sleep was decreased after the destruction of both the medial preoptic area and the lateral preoptic area, paradoxical sleep was reduced only by the destruction of the medial preoptic area. Decrease in sleep after the medial preoptic area lesion was brought about by a decrease in the duration of the slow wave sleep episodes and the frequency of paradoxical sleep episodes. Decrease in sleep after the lateral preoptic area lesion was brought about by a decrease in the frequency of slow wave sleep episodes. There was a significant increase in brain temperature after the medial preoptic area lesion but not after the lateral preoptic area lesion. The rats with lesion in the medial preoptic area showed deficits in thermoregulation on exposure to cold, while those with the lateral preoptic area lesion showed deficits in heat defense ability. The present findings suggest that the medial preoptic area and the lateral preoptic area regulate sleep by different modalities and that there is an anatomical segregation of heat and cold defense functions within the basal forebrain.


Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis.
Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat. We sought to investigate the immune pathways that underlie the pathogenesis of PPP. We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several TH2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4+ T cells of PPP patients were skewed toward a TH17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen-positive skin-homing cells. We also identified a subset of memory CD4+ T cells that expressed both TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 plasticity. Interestingly, the GATA3+/CD161+ cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy. PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.


Lonidamine transiently affects spermatogenesis in pubertal CD1 mice.
Lonidamine (LND) [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid], a well-known antispermatogenic drug, was studied for the first time in pubertal mice to assess its possible effects on spermatogenesis. Male CD1 mice were orally treated on Postnatal Day (PND) 28 with a single dose of LND (100 mg/kg body weight) and sacrificed on PND30, PND42, PND74 and PND123. On PND30 (48 h after dosing), severe testicular effects were evidenced in the treated animals: (a) reduction of the testicular sperm head concentration (approximately 50% of the control value); (b) changes in the spermatogenic cell type distribution (mild decrease of the elongated spermatids and S-phase cells fractions); and (c) morphological alterations of the Sertoli cell cytoplasm and germ cell exfoliation. These changes were recovered in adulthood, on PND74 and PND123. However, no effect on sperm chromatin structure was detected on the epididymal sperm of mature mice by sperm chromatin structure assay, suggesting that LND did not interfere with the process of chromatin reorganization and DNA packaging.


[Biomechanical studies of fibular movement as aspects of ligament injuries of the tarsal-tibia joint].
In 10 anatomical preparations of the ankle the relations between talar and fibular movements have been studied in stable and unstable joint. An average range of fibular rotation in uninjured joint amounted to 6 degrees increasing to 13 degrees after dissecting of the anterior tibiofibular ligament and to 31 degrees after subsequent deltoid dissection.


Prokaryotic expression of the chicken xanthine oxidase (XOD) subunit and its localization in liver and kidney.
Xanthine oxidase (XOD) is the members of the molybdenum hydroxylase flavoprotein family and it plays a vital role in the body's purine catabolism. In this study, we cloned the XOD 37kDa subunit protein by using RT-PCR and pMD-18-T clone vector based on the total RNA extracted from chicken liver. The cloning XOD subunit protein gene was ligated into the pET-32a to construct the recombinant plasmid pET-XOD. After the pET-XOD expression vector was transformed into host cells Rosetta (DE3), the recombinant XOD subunit proteins (54.8kDa) were successfully induced by isopropy1 β-d-thiogalactoside (IPTG). Rabbit antiserums were produced by using the purification of the recombinant XOD subunit protein as antigen. The titer of the antiserum was more than 1:102,400 determined by using ELISA. The result of Western blot demonstrated that the antiserum could specifically recognize the chicken liver XOD. Immunohistochemistry and immunofluorescence showed that the XOD mainly presented in the cytoplasm of chicken hepatocytes and proximal tubular epithelial cells. Our results indicated that the XOD subunit protein polyclonal antibody prepared by this method could be used for the further researches of the biological function of the XOD in the chicken.


Exosomes: A Source for New and Old Biomarkers in Cancer.
Clinical oncology needs reliable tumor biomarkers to allow a follow-up of tumor patients who do not necessarily need invasive approaches. To date, the existing biomarkers are not sufficiently reliable, and many of them have generated more problems than facilitating the commitment of clinical oncologists. Over the last decades, a broad family of extracellular vesicles, with size ranging between micro to nano, has been raised as a new hope for potential sources of new tumor biomarkers. However, while knowledge in the field is increasing, we do not currently have definitive information allowing a clinical use of extracellular vesicles in cancer clinics. Recent evidence provides new perspective in clinical oncology, based on data showing that circulating nanovesicles called exosomes may represent a valuable source of tumor biomarkers. In this review, we discuss the existing clinical data supporting a key role of exosomes as a source of tumor biomarkers, including proteins and miRNAs, but also discuss the importance of the expression of known tumor biomarkers when expressed on exosomes.