Metipranolol attenuates lipid peroxidation in rat brain: a comparative study with other antiglaucoma drugs.
Free radical production seems to be involved in the pathogenesis of a number of ocular diseases. Certain beta-adrenoceptor antagonists display antioxidant properties, but these have not been ascribed to any of the presently used ophthalmic beta-adrenoceptor antagonists. Therefore, we examined the influence of ophthalmic beta-adrenoceptor antagonists and other antiglaucoma drugs on stimulated lipid peroxidation in rat brain homogenates. Lipid peroxidation in rat brain homogenates was stimulated by iron/ascorbate or sodium nitroprusside. Lipid peroxidation was assessed by the formation of thiobarbituric acid reactive species (TBARS). Of the antiglaucoma drugs tested (brimonidine, carteolol, dorzolamide, latanoprost, levobetaxolol, levobunolol, metipranolol, pilocarpine, timolol, travoprost and unoprostone), only metipranolol and its active metabolite, desacetylmetipranolol, were found to significantly reduce iron/ascorbate-induced lipid peroxidation in rat brain homogenates with IC50 values of 6.9 and 1.1 microM, respectively. Metipranolol and desacetylmetipranolol also concentration-dependently inhibited sodium nitroprusside-stimulated lipid peroxidation in rat brain homogenates, displaying IC50 values of 25.1 and 2.6 microM, respectively. These data indicate that metipranolol and desacetylmetipranolol exhibit remarkable antioxidant properties, with an effect not dissimilar from the reference antioxidant trolox.


Transient neonatal hypothyroidism after gestational exposure to amiodarone: a follow-up of two cases.
Amiodarone (AMD) is an antiarrhythmic drug which contains 37% of iodine. It can reach the fetus by transplacental passage and induce fetal hypothyroidism. Since in some pregnant women AMD represents a cardinal therapeutic opportunity, it is necessary to establish not only the risk of teratogenicity linked to fetal AMD exposure but also to evaluate the psychomotor development of children with neonatal thyroid dysfunction related to fetal AMD exposure. We report on two cases involving children with an AMD gestational exposure and transient neonatal hypothyroidism, who were followed-up until the age of 4 years 8 months and 5 years 6 months, respectively. Denver's developmental milestone test and Whechsler Preschool and Primary Scale of Intelligence (WPPSI) were administered to the patients in accordance to their age. A normal psychomotor development was observed in both patients with full scale IQ score, verbal and performance IQ scores within normal range. In conclusion, if these data were validated by larger studies, it might not be obligatory to discontinue AMD administration in cardiopathic pregnant women, since mental impairment may not necessarily occur in children with transient neonatal hypothyroidism caused by fetal AMD exposure. However, the evaluation of the thyroid function of these children is imperative.


Investigation of the possible effect of the Chernobyl accident on Irish mortality rates.
RADIOACTIVE fallout from the Chernobyl accident reached Ireland in May 1986 and caused serious concern with regard to its possible effects on health. Reports of a large scale American study claim an almost immediate effect of Chernobyl fallout in terms of increased mortality rates. A study of Irish mortality rates reported a substantial increase in numbers of deaths during the three months immediately post-Chernobyl. The present study investigates whether there is a statistically significant basis for the reported increase in mortality in Ireland. No discernible evidence was found for increased mortality rates in Ireland during 1986, following the Chernobyl accident. The initial report of increased mortality rates was based on provisional mortality registration statistics and not on actual day by day data.


Characterizing property and treatability of dissolved effluent organic matter using size exclusion chromatography with an array of absorbance, fluorescence, organic nitrogen and organic carbon detectors.
In this study, size exclusion chromatography with an array of absorbance, fluorescence, organic nitrogen and organic carbon detectors was used for characterizing property and treatability of effluent organic matter (EfOM) from 12 wastewater treatment plants. According to their apparent molecular weight (AMW), EfOM fractions were assigned to biopolymers (>20 kDa), humic substances that comprise sub-fractions of humic-like acids (HA-I & HA-II, 2.3-7.0 kDa) and fulvic-like acids (FA, 1.5-2.3 kDa), building blocks (0.55-1.5 kDa) and low molecular weight neutral substances (<550 Da). The fractions of biopolymers and low molecular weight neutral substances didn't show humic-like fluorescence, while the fractions of HA-II, FA and building blocks usually had signatures of both humic-like and protein-like fluorescence. Humic substances generally contributed the largest proportion of dissolved organic carbon and nitrogen (DOC & DON) in effluents. Coagulation removed EfOM fractions following the order of biopolymers > HA subfraction > FA subfraction > building blocks, while little removal of protein-like fluorescence in HA-II and FA subfractions was detected. Anion exchange treatment could effectively reduce DOC and DON concentrations; the sequence of the treatment efficiency was humic substances > biopolymers > building blocks. Increasing O3 doses caused DOC and DON of EfOM to be gradually transformed from large AMW fractions into small AMW fractions, while chromophores and fluorophores in HA subfractions were relatively more refractory than those in the other fractions. Size exclusion chromatography with multiple detectors are suggested to be an informative technique for estimating treatability of EfOM by advanced wastewater treatment processes.


Overexpression of hexose transporter CsHT3 increases cellulose content in cucumber fruit peduncle.
Hexose transporters play many important roles in plant development. However, the role of hexose transporter in secondary cell wall growth has not been reported before. Here, we report that the hexose transporter gene CsHT3 is mainly expressed in cells with secondary cell walls in cucumber. Spatiotemporal expression analysis revealed that the transcript of CsHT3 mainly accumulates in the stem, petiole, tendril, and peduncle, all of which contain high cellulose levels. Immunolocalization results show that CsHT3 is localized at the sclereids in young peduncles, shifts to the phloem fiber cells during peduncle development, and then shifts again to the companion cells when the development of secondary cell walls is almost completed. Carboxyfluoresce unloading experiment indicated that carbohydrate unloading in the phloem follows an apoplastic pathway. Overexpression of CsHT3 in cucumber plant can improve the cellulose content and cell wall thickness of phloem fiber cells in the peduncle. The expression of cellulose synthase genes were increased in the CsHT3 overexpression plants. These results indicated that CsHT3 may play an important role in cellulose synthesis through promoting the expression of cellulose synthase genes.


Within-population variability in morphology and life history of Plantago major L. ssp. pleiosperma Pilger in relation to environmental heterogeneity.
An attempt was made to relate variation in life-history characteristics within a population of Plantago major ssp. pleiosperma to small-scale environmental variability. At a beach plain, embanked in 1966, a mosaic environment was distinguished with spatial variability in vegetation structure as well as in nutrient availability and water content of the soil. Differences between three subsites in comtemporary selection were demonstrated, e.g. in shoot morphology and allocation to reproductive tissue. The effects of nutrient supply and waterlogging on morphology and life history were studied on lines from the three subsites in a greenhouse. For most of the traits high levels of phenotypic plasticity were observed, covering almost entirely the observed phenotypic variability at the beach plain. In all treatments lines from the shrubs had, however, a higher leaf-area ratio as well as delayed flowering when compared to lines from more open subsites. In addition, in a reciprocal transplant experiment it was demonstrated that lines from the shrubs had larger shoots with e.g. broader leaves in the shady environment of the shrubs than other lines.From the experiments no indications were obtained that lines from any subsite were especially adapted to specific levels of nutrient supply or water content of the soil. With respect to these environmental factors P. major ssp. pleisoperma might occur and reproduce at all subsites by means of phenotypic plasticity, e.g. in plant form. However, it is suggested that spatial variability in vegetation structure caused a population subdivision in allocation patterns, leaf form and life history at the beach plain, over distances of about 15-25 m. This differentation occurred during primary succession over a period of twenty years.


Enhanced reactivity towards flunarizine in cerebrovascular bed of spontaneously hypertensive rats.
Cerebral blood flow (CBF) was measured and cerebrovascular resistance (CVR) was calculated in anesthetized spontaneously hypertensive rats (SHR) and normotensive rats (NR) following the administration of incremental dosages of i.v. flunarizine or papaverine. CBF and CVR changes following papaverine were the same in both groups of rats irrespective of the dose of the drug. The effect of flunarizine was much more pronounced in SHR than in NR. The results point out the greater dependency of basal cerebrovascular tone in SHR upon Ca2+ influx into vascular smooth muscle cells.


Comparison of safety and utilization outcomes in inpatient versus outpatient laparoscopic sleeve gastrectomy: a retrospective, cohort study.
Laparoscopic sleeve gastrectomy (LSG) is the most common type of bariatric surgery performed in the United States and may be performed on an outpatient basis. Limited literature exists comparing outcomes of outpatient and inpatient LSG, and study results are conflicting. To compare safety and utilization outcomes of outpatient versus inpatient LSG. Retrospective, multihospital database study (Optum Pan-Therapeutics Database). Patients 18 years of age and older who underwent LSG between October 1, 2015, and December 31, 2018, were identified from the Optum Pan-Therapeutics Database and classified as having undergone outpatient or inpatient surgery. Nearest neighbor propensity score matching and generalized estimating equations accounting for procedural physician-level clustering were used to compare the following outcomes between outpatient and inpatient LSG: all-cause 30-day patient morbidity, hospital readmission, readmission length of stay, bariatric reoperation. and mortality. We identified 22,945 patients (outpatient: 1542; inpatient: 21,403) meeting the study inclusion criteria. After propensity score matching, the inpatient and outpatient groups contained 1542 and 13,903 patients, respectively. Bariatric reoperation (n = 13) and mortality (n = 5) were rare events occurring in <.1% of all cases. Compared with the inpatient group, the outpatient group had a statistically significant lower readmission length of stay (4.63 versus 3.23 days; P = .0057). Otherwise, there was no significant association between procedure setting and 30-day overall morbidity (4.8% versus 5.3%; P = .5775) or hospital readmission (2.6% versus 2.1%; P = .1841). Safety and utilization outcomes were similar between outpatient and inpatient LSG, and outpatient LSG was associated with shorter hospital readmission length of stay.


Nonprogressive, histologically mild membranous glomerulonephritis appearing in all evolutionary phases as histologically "early" membranous glomerulonephritis.
Seven adult patients with idiopathic nephrotic syndrome and with a glomerular histology considered normal but with ultrastructurally provable membranous glomerulonephritis (MNG) were studied. The glomerular lesions were found to represent all ultrastructural evolutionary phases (A,B, and C) of MGN. In patients with serial biopsies, the membranous lesion seemed to have passed through all of its evolutionary phases towards healing (C) without developing spikes or thickening of the glomerular basement membrane (GBM), i.e., the traditional light microscopic characteristics of MGN. This evolution was associated with a benign clinical course. The membranous lesions were associated with a vacuolization visible in obliquely or tangentially cut segments of the GBM in silver-stained paraffin sections. This alteration seemed to be created by irregularities of the argyrophilic lamina densa of the GBM and not by subepithelial deposits, as suggested previously. All seven patients had a remission of the nephrotic syndrome which appeared to be spontaneous and not drug-induced. The amount of proteinuria correlated with the ultrastructural phase of MGN and with the intensity of immunofluorescent staining. In one patient, the latter became negative.


Analysis of a series of sixty soft tissue sarcomas in adults treated with a cyclophosphamide-vincristine-adriamycin-dacarbazine (CYVADIC) combination.
From 1976 to 1983, a group of 60 adult patients presenting with metastatic and/or locally advanced soft tissue sarcomas was treated with combination chemotherapy consisting in cyclophosphamide, vincristine, adriamycin, and DTIC (CYVADIC). A tumor response was obtained for 29 patients (48.3%), with 4 (6.7%) cases of complete regression. The median duration of the response was 10 months. Responses were noted in 14/22 patients receiving induction chemotherapy for advanced, and previously nonirradiated, primary tumors; among the patients with metastatic disease tumor regression was recorded in 17/32 patients with pulmonary metastases, but in none of the patients with metastases at other sites. Moreover, the attainment of a response was found to correlated with the patient's general condition, while response duration depended on the histoprognostic grade of the tumors.


Facile synthesis of Mn, Ce co-doped g-C3N4 composite for peroxymonosulfate activation towards organic contaminant degradation.
Peroxymonosulfate (PMS)-based advanced oxidation processes for wastewater treatment have received extensive attention in the past years. Here, a novel Mn, Ce co-modified g-C3N4 (MnCe-CN) composite was successfully synthesized by one-step pyrolysis for activating PMS. The physical and chemical characterization of MnCe-CN/PMS was conducted, indicating that Mn and Ce were evenly distributed on g-C3N4 and existed in the form of Mn-N structure and CeO2, respectively. The MnCe-CN/PMS system could effectively degrade pollutants such as acetaminophen (ACT), methylparaben (MeP), p-nitrophenol (PNP), and 2,4-dichlorophenol (2,4-DCP). Among them, 2,4-DCP could be rapidly degraded, reaching 100% within 30 min. The masking experiments and electrochemical testing results revealed that 2,4-DCP was degraded via superoxide radicals (O2˙-), singlet oxygen (1O2), and electron transfer path. The cyclic experiments and real water treatment experiments testified that the oxidative system had excellent stability and applicability. This study provides a facile synthetic method to fabricate bimetallic co-modified g-C3N4 for the enhancement of PMS activation.


Toxic and nontoxic components of botulinum neurotoxin complex are evolved from a common ancestral zinc protein.
Zinc atoms play an essential role in a number of enzymes. Botulinum neurotoxin (BoNT), the most potent toxin known in nature, is a zinc-dependent endopeptidase. Here we identify the nontoxic nonhemagglutinin (NTNHA), one of the BoNT-complex constituents, as a zinc-binding protein, along with BoNT. A protein structure classification database search indicated that BoNT and NTNHA share a similar domain architecture, comprising a zinc-dependent metalloproteinase-like, BoNT coiled-coil motif and concanavalin A-like domains. Inductively coupled plasma-mass spectrometry analysis demonstrated that every single NTNHA molecule contains a single zinc atom. This is the first demonstration of a zinc atom in this protein, as far as we know. However, the NTNHA molecule does not possess any known zinc-coordinating motif, whereas all BoNT serotypes possess the classical HEXXH motif. Homology modeling of the NTNHA structure implied that a consensus K-C-L-I-K-X(35)-D sequence common among all NTNHA serotype molecules appears to coordinate a single zinc atom. These findings lead us to propose that NTNHA and BoNT may have evolved distinct functional specializations following their branching out from a common ancestral zinc protein.


Transcatheter vs surgical aortic valve replacement in low to intermediate surgical risk aortic stenosis patients: A systematic review and meta-analysis of randomized controlled trials.
Transcatheter aortic valve replacement (TAVR) is regarded as the most superior alternative treatment approach for patients with aortic stenosis (AS) who are associated with high surgical risk, whereas the effectiveness of TAVR vs surgical aortic valve replacement (SAVR) in low to intermediate surgical risk patients remained inconclusive. This study aimed to determine the best treatment strategies for AS with low to intermediate surgical risk based on published randomized controlled trials (RCTs). RCTs that compared TAVR vs SAVR in AS patients with low to intermediate surgical risk were identified by PubMed, EmBase, and the Cochrane library from inception till April 2019. The pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated for the data collected using random-effects models. Seven RCTs with a total of 6929 AS patients were enrolled. We noted that TAVR significantly increased the risk of transient ischemic attack (TIA) (RR: 1.43; 95%CI: 1.04-1.96; P = .029), and permanent pacemaker implantation (RR: 3.00; 95%CI: 1.70-5.30; P < .001). However, TAVR was associated with lower risk of post-procedural bleeding (RR: 0.57; 95%CI: 0.33-0.98; P = .042), new-onset or worsening of atrial fibrillation (RR: 0.32; 95%CI: 0.23-0.45; P < .001), acute kidney injury (RR: 0.40; 95%CI: 0.25-0.63; P < .001), and cardiogenic shock (RR: 0.34; 95%CI: 0.19-0.59; P < .001). The risk of aortic-valve reintervention at 1- (RR: 2.63; 95%CI: 1.34-5.15; P = .005), and 2 years (RR: 3.19; 95%CI: 1.63-6.24; P = .001) in low to intermediate surgical risk patients who received TAVR was significantly increased than those who received SAVR. These findings indicated that low to intermediate surgical risk patients who received TAVR had low risk of complications, whereas the risk of TIA, permanent pacemaker implantation, and aortic-valve reintervention was increased.


A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.
Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.


Accuracy of fluoroscopic localization of the Crista terminalis documented by intracardiac echocardiography.
The crista terminalis is an important anatomic target for ablation of atrial arrhythmias. We determined the accuracy of catheter placement guided by fluoroscopy alone when directed to 24 sites along the crista terminalis in 6 patients. The sites selected included the most medial superior, most lateral superior, mid lateral, and most inferolateral sites along the crista terminalis in each patient. These sites were selected because of their recognized importance in sinus node and/or atrial tachycardia ablation and the importance of avoiding caval structures when targeting the most superior and/or inferior right atrium. The position of the catheter tip was documented using a catheter based ultrasound transducer in the right atrium or vena cava. The operator was blinded to the intracardiac echocardiographic (ICE) results until reviewing the images after the procedure in each patient. The catheter tip, guided by fluoroscopy alone, was identified by ICE to be within the right atrium and within 1cm of the crista terminalis at only 10 of the 24 sites (42%). Importantly, when targeting the most superior and inferior sites along the crista terminalis, the catheter tip, guided by fluoroscopy, was noted to be adjacent to the venous junction with the right atrium but actually located in the superior or inferior vena cava at 5 of the 18 such sites. The catheter was positioned appropriately (within 1 cm of the crista and within the right atrium) guided by fluoroscopy alone when targeting 1 of the 12 sites in the first 3 patients versus 9 of 12 sites in the last 3 patients, p<0.05. In conclusion, it appears that using fluoroscopic guidance alone: 1) localization of the crista terminalis is frequently inaccurate and 2) catheter positioning in the superior/inferior vena cava is commonly noted when targeting very superior and inferior sites along the crista terminalis. A learning curve, assisted by review of ICE recordings after each procedure, appears to improve the accuracy of catheter placement by fluoroscopy alone but still does not result in uniform success. ICE appears to facilitate and ensure accurate targeting of specific anatomic sites along the crista terminalis and thus may serve as an important adjunctive imaging technique in electrophysiology.


Molecular changes associated with chronic liver damage and neoplastic lesions in a murine model of hereditary tyrosinemia type 1.
Hereditary tyrosinemia type 1 (HT1) is the most severe inherited metabolic disease of the tyrosine catabolic pathway, with a progressive hepatic and renal injury and a fatal outcome if untreated. Toxic metabolites accumulating in HT1 have been shown to elicit endoplasmic reticulum (ER) stress response, and to induce chromosomal instability, cell cycle arrest and apoptosis perturbation. Although many studies have concentrated on elucidating these events, the molecular pathways responsible for development of hepatocellular carcinoma (HCC) still remain unclear. In this study the fah knockout murine model (fah(-/-)) was used to investigate the cellular signaling implicated in the pathogenesis of HT1. Fah(-/-) mice were subjected to drug therapy discontinuation (Nitisinone withdrawal), and livers were analyzed at different stages of the disease. Monitoring of mice revealed an increasing degeneration of the overall physiological conditions following drug withdrawal. Histological analysis unveiled diffuse hepatocellular damage, steatosis, oval-like cells proliferation and development of liver cell adenomas. Immunoblotting results revealed a progressive and chronic activation of stress pathways related to cell survival and proliferation, including several stress regulators such as Nrf2, eIF2α, CHOP, HO-1, and some members of the MAPK signaling cascade. Impairment of stress defensive mechanisms was also shown by microarray analysis in fah(-/-) mice following prolonged therapy interruption. These results suggest that a sustained activation of stress pathways in the chronic HT1 progression might play a central role in exacerbating liver degeneration.


Insecticidal and Antifeedant Activities of Malagasy Medicinal Plant (Cinnamosma sp.) Extracts and Drimane-Type Sesquiterpenes against Aedes aegypti Mosquitoes.
The overuse of insecticides with limited modes of action has led to resistance in mosquito vectors. Thus, insecticides with novel modes of action are needed. Secondary metabolites in Madagascan plants of the genus Cinnamosma (Canellaceae) are commonly used in traditional remedies and known to elicit antifeedant and toxic effects in insect pests. Here we test the hypothesis that extracts of Cinnamosma sp. enriched in drimane sesquiterpenes are toxic and/or antifeedant to the yellow fever mosquito Aedes aegypti. We show that the bark and root extracts, which contain a higher abundance of drimane sesquiterpenes compared to leaves, were the most efficacious. Screening isolated compounds revealed cinnamodial to be the primary driver of adulticidal activity, whereas cinnamodial, polygodial, cinnafragrin A, and capsicodendrin contributed to the larvicidal activity. Moreover, an abundant lactone (cinnamosmolide) in the root extract synergized the larvicidal effects of cinnamodial. The antifeedant activity of the extracts was primarily contributed to cinnamodial, polygodial, and cinnamolide. Parallel experiments with warburganal isolated from Warburgia ugandensis (Canellaceae) revealed that aldehydes are critical for-and a hydroxyl modulates-insecticidal activity. Our results indicate that plant drimane sesquiterpenes provide valuable chemical platforms for developing insecticides and repellents to control mosquito vectors.


Adipose tissue cells, lipotransfer and cancer: a challenge for scientists, oncologists and surgeons.
Despite recent evidence of the cancer-promoting role of adipose tissue-derived progenitor and differentiated cells, the use of lipotransfer for tissue/organ reconstruction after surgical removal of cancer is increasing worldwide. Here we discuss in a multidisciplinary fashion the preclinical data connecting obesity, adipose cells and cancer progression, as well as the clinical data concerning safety of lipotransfer procedures in cancer patients. A roadmap towards a more rationale use of lipotransfer in oncology is urgently needed and should include preclinical studies to dissect the roles of different adipose tissue-derived cells, the evaluation of drugs currently candidate to inhibit the interaction between adipose and tumor cells, and carefully designed clinical trials to investigate the safety of lipotransfer procedures in cancer patients.


Giant Splenic Artery Pseudoaneurysms: Two Case Reports and Cumulative Review of the Literature.
Giant splenic artery pseudoaneurysms (GSAPs) > 5 cm are a rare clinical entity. The aim of this study was to present our experience with 2 such patients successfully treated by coil embolization and surgery and review the pertinent literature. A 58-year-old woman and 57-year-old man with a history of chronic pancreatitis were diagnosed with GSAP based on computed tomography (CT) angiography. The first patient had a 6-cm pseudoaneurysm, which was successfully treated with transcatheter coil embolization using a sandwich exclusion method. The second patient had two 7-cm lesions, which were successfully treated with distal pancreatectomy and splenectomy. Postembolization CT angiography at 12 months showed remaining calcified pseudocyst without evidence of pseudoaneurysm in the first patient. Both patients remained well and symptom-free at 12 months. Combined with the experience of the previous literature, we believe that management of GSAP should be tailored for each individual case depending on the location and number of pseudoaneurysms, the underlying etiology, and the patient's hemodynamic status. Embolization should be considered as the first-line treatment for clinically stable patients with GSAP, whereas GSAPs with a pseudocyst are best treated with surgery.


'Biohyets': a method for displaying the extent and severity of environmental impacts.
Bioindicators are often more sensitive indicators of both biodiversity and environmental change than abiotic pollution parameters. The responses of selected plants and animals to anthropogenic insults can be used to assess environmental responses at a variety of spatial and temporal scales. This study maps the response of key reptile, mammal, bird and plant species to airborne contaminants around a large mine and mineral processing operation at Olympic Dam in arid Australia. The responses of different bioindicators should ideally be integrated in order to comprehend overall trends in biological integrity adjacent to pollution sources. Assimilation of different bioindicator responses allows greater precision and geographic coverage of the monitored region and reduces potential distortion from unrelated biological or monitoring responses of individual indicator groups. A single, integrated measure of ecosystem health that overlays the responses of otherwise incompatible datasets, is also of more value to industrial operators and environmental regulators than several disparate responses. Biohyets, which are the contours of bioindicator index values derived from multiple biotic measurements, are here used to map variability in ecosystem health and to identify regions, response variables and disturbance parameters for more rigorous analysis.


Synergistic drug combinations prediction by integrating pharmacological data.
There is compelling evidence that synergistic drug combinations have become promising strategies for combating complex diseases, and they have evident predominance comparing to traditional one drug - one disease approaches. In this paper, we develop a computational method, namely SyFFM, that takes pharmacological data into consideration and applies field-aware factorization machines to analyze and predict potential synergistic drug combinations. Firstly, features of drug pairs are constructed based on associations between drugs and target, and enzymes, and indication areas. Then, the synergistic scores of drug combinations are obtained by implementing field-aware factorization machines on latent vector space of these features. Finally, synergistic combinations can be predicted by introducing a threshold. We applied SyFFM to predict pairwise synergistic combinations and three-drug synergistic combinations, and the performance is good in terms of cross-validation. Besides, more than 90% combinations of the top ranked predictions are proved by literature and the analysis of parameters in model shows that our method can help to investigate and explain synergistic mechanisms underlying combinatorial therapy.


Neural entrainment underpins sensorimotor synchronization to dynamic rhythmic stimuli.
Neural entrainment, defined as unidirectional synchronization of neural oscillations to an external rhythmic stimulus, is a topic of major interest in the field of neuroscience. Despite broad scientific consensus on its existence, on its pivotal role in sensory and motor processes, and on its fundamental definition, empirical research struggles in quantifying it with non-invasive electrophysiology. To this date, broadly adopted state-of-the-art methods still fail to capture the dynamic underlying the phenomenon. Here, we present event-related frequency adjustment (ERFA) as a methodological framework to induce and to measure neural entrainment in human participants, optimized for multivariate EEG datasets. By applying dynamic phase and tempo perturbations to isochronous auditory metronomes during a finger-tapping task, we analyzed adaptive changes in instantaneous frequency of entrained oscillatory components during error correction. Spatial filter design allowed us to untangle, from the multivariate EEG signal, perceptual and sensorimotor oscillatory components attuned to the stimulation frequency. Both components dynamically adjusted their frequency in response to perturbations, tracking the stimulus dynamics by slowing down and speeding up the oscillation over time. Source separation revealed that sensorimotor processing enhanced the entrained response, supporting the notion that the active engagement of the motor system plays a critical role in processing rhythmic stimuli. In the case of phase shift, motor engagement was a necessary condition to observe any response, whereas sustained tempo changes induced frequency adjustment even in the perceptual oscillatory component. Although the magnitude of the perturbations was controlled across positive and negative direction, we observed a general bias in the frequency adjustments towards positive changes, which points at the effect of intrinsic dynamics constraining neural entrainment. We conclude that our findings provide compelling evidence for neural entrainment as mechanism underlying overt sensorimotor synchronization, and highlight that our methodology offers a paradigm and a measure for quantifying its oscillatory dynamics by means of non-invasive electrophysiology, rigorously informed by the fundamental definition of entrainment.


Quantitative genetic analysis of Cry1Ab tolerance in Ostrinia nubilalis Spanish populations.
Tolerance to Bacillus thuringiensis Cry1Ab toxin in Spanish Ostrinia nubilalis populations was analyzed by quantitative genetic techniques, using isolines established from field-derived insects. F1 offspring was tested for susceptibility to trypsin activated Cry1Ab using a concentration that caused a mean larval mortality of 87% (±17% SD). The progeny of the most tolerant isolines (that had shown mortalities lower than 60%) was crossed to obtain the F2 generation that was exposed to the same Cry1Ab concentration. A clear reduction in mortality (62±17% SD) was observed. The upper limit for heritability was estimated to range between 0.82 and 0.90, suggesting that a high part of phenotypic variation in tolerance to Cry1Ab was attributable to genetic differences. An estimate of the minimum number of segregating factors indicated that the loci involved in tolerance to Cry1Ab were at least two. The role of the cadherin gene, which is a B. thuringiensis resistance gene in Lepidoptera, was assessed in the most tolerant isolines by using an EPIC-PCR marker specifically developed for this study. Association between cadherin and tolerance was obtained in one tolerant isoline; however it could be not confirmed by segregation analysis in the F2 progeny because F2 offspring was not viable. Our results indicate that the tolerance trait is common in Spanish field populations. Quantitative genetic techniques may be helpful for estimating the influence of genetic factors to Cry1Ab tolerance in O. nubilalis.


Visualizing Staphylococcus aureus pathogenic membrane modification within the host infection environment by multimodal imaging mass spectrometry.
Bacterial pathogens have evolved virulence factors to colonize, replicate, and disseminate within the vertebrate host. Although there is an expanding body of literature describing how bacterial pathogens regulate their virulence repertoire in response to environmental signals, it is challenging to directly visualize virulence response within the host tissue microenvironment. Multimodal imaging approaches enable visualization of host-pathogen molecular interactions. Here we demonstrate multimodal integration of high spatial resolution imaging mass spectrometry and microscopy to visualize Staphylococcus aureus envelope modifications within infected murine and human tissues. Data-driven image fusion of fluorescent bacterial reporters and matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance imaging mass spectrometry uncovered S. aureus lysyl-phosphatidylglycerol lipids, localizing to select bacterial communities within infected tissue. Absence of lysyl-phosphatidylglycerols is associated with decreased pathogenicity during vertebrate colonization as these lipids provide protection against the innate immune system. The presence of distinct staphylococcal lysyl-phosphatidylglycerol distributions within murine and human infections suggests a heterogeneous, spatially oriented microbial response to host defenses.


Severe subtype of alopecia areata is highly associated with thyroid autoimmunity.
To assess the significance of thyroid autoimmune screening in alopecia areata (AA) patients in Saudi population, and to determine whether there is a difference in thyroid autoimmune susceptibility between mild and severe AA. In a prospective case-control study, we included 50 alopecia totalis (AT) and alopecia universalis (AU) patients, 50 age- and gender-matched patients with localized AA, and 50 age- and gender- matched healthy subjects between March 2015 and August 2015. Patients with AA were consecutively recruited from the hair disorders out-patient clinic of King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia. Thyroid autoantibodies (TAAs) were positive in AT/AU (40%), mild AA (14%), and healthy subjects (4%). The frequency of TAAs was significantly higher in patients with AT/AU than in mild AA (p=0.001) and healthy controls (p less than 0.001). The frequency of thyroid peroxidase antibody (TPO-Abs) was significantly higher in patients with AT/AU than in mild AA and healthy controls (p less than 0.001 for both). The frequency of TG-Abs was significantly higher in patients with AT/AU (p=0.003) and mild AA (p=0.043) than in healthy controls. Serum TSH level was significantly higher in AT/AU patients than in mild AA patients (p=0.006) and healthy controls (p=0.005). Severe subtype of AA is associated with a high risk of autoimmune thyroid disease. This highlights the significance of screening for thyroid abnormalities and TAAs in patients with AT/AU.


Pseudoexstrophy associated with congenital pouch colon.
Pseudoexstrophy or covered exstrophy is a rare exstrophy variant. The authors report a case of covered exstrophy that presented as a newborn with widely separated pubic bones and rectus muscles, a low-set umbilicus, and a subcutaneous bladder. The anal opening was absent, and there was a complex malformation of the external genitalia consisting of a small, laterally displaced penis and a right-sided ectopic hemiscrotum. Micturition and urinary continence were normal. The child also had a high anorectal malformation with a coexistent type IV congenital pouch colon (CPC) malformation. Both kidneys were normal. Preliminary surgery consisted of a divided sigmoid colostomy proximal to the colonic pouch. The literature is reviewed and the embryogenesis of pseudoexstrophy and its associated malformations are discussed.


Glossopharyngeal neuralgia as initial symptom in combined hyperactive dysfunction syndrome: case report.
Hyperactive dysfunction syndrome (HDS) is defined as symptoms arising from overactivities in cranial nerves, like trigeminal neuralgia (TN), hemifacial spasm (HFS), and glossopharyngeal neuralgia (GPN). A combination of these cranial nerve neuralgias, that might or might not occur in one or both sides, either synchronously, or metachronously is called combined hyperactive dysfunction syndrome (CHDS). We presented a 73 years-old male patient with CHDS presenting with GPN as the initial symptom, with total relief from GPN, TN, and HFS after microvascular decompression. Up to date, only nine patients have been reported in the literature with symptomatic. TN-HFS-GPN. Our case is the first case with GPN as the initial symptom. The combination of arterial and venous origin of the offending vessels makes the case picturesage.


Stimulation of cell proliferation by histamine H2 receptors in dimethylhdrazine-induced adenocarcinomata.
Cell proliferation in dimethylhydrazine-induced colonic carcinomata was stimulated by histamine and by the histamine H2 receptor agonist dimaprit and inhibited by the histamine H2 receptor antagonists Metiamide and Cimetidine but not by the histamine H1 receptor antagonist Mepyramine. In contrast histamine had no effect on colonic crypt cell proliferation in normal or dimethylhydrazine-treated rats.


Anatomical and temporal architecture of theory of mind: a MEG insight into the early stages.
Representation of others' actions and mental states leads to the activation of several brain networks: the mentalizing and the "mirror neuron" systems as well as a "low level" social perception component. However, respective activations of the regions belonging to these networks remain unknown with respect to chronometrical data when static drawing stimuli are presented. To determine anatomical and temporal characteristics of theory of mind processes, magnetic signals were measured in 21 subjects during a validated nonverbal attribution of intentions task. Minimum norm estimation provides chronometric and localization data showing that regions known to be involved in the mentalizing, "mirror neuron" and social perception networks have simultaneous activations between 100 and 700 ms post-stimulus, a period which may be thought as corresponding to early stages of social processes. Among some regions, different profiles as well as modulations regarding experimental conditions suggest functional distinctions between these structures, pleading for a cooperative nature of these networks. While the left temporo-parietal area and superior temporal sulcus seem more specialized in social cues coding, we demonstrate that their right homologues, as well as the right inferior parietal cortex, are preferentially recruited during attribution of intentions stimuli compared to scenarios based on physical causality from 200 to 600 ms.


Effect of environmental contaminants on nasal lysozyme secretions.
Human nasal secretions are comprised of lysozyme and albumin as their main protein components. Lysozyme, an anti-microbial substance, is produced by nasal serous cells while albumin is obtained, primarily, from increased nasal vasculature permeability. We measured lysozyme levels in nasal secretions following challenge by a variety of non-infectious environmental contaminants. The methodology given presents a simple and rapid method of collecting nasal secretions and determining their lysozyme content, a technique which can be used for a host of environmental irritants.


Patency of cryopreserved saphenous vein grafts as conduits for coronary artery bypass surgery.
To determine the angiographic patency of cryopreserved saphenous vein grafts used as conduits during coronary artery bypass surgery and whether this is affected by postoperative immunosuppressive therapy. A retrospective review of medical records and coronary angiograms of patients at a university hospital. Eleven patients undergoing 12 coronary artery bypass operations during which a total of 26 distal coronary anastomoses were created using cryopreserved vein grafts. Eight postoperative coronary angiograms were performed in 10 patients surviving longer than 1 week. All angiograms were performed on the basis of symptoms of suspected myocardial ischemia. Angiographic results, postoperative anticoagulation, and therapy with immunosuppressive agents were analyzed. Seventeen cryopreserved vein grafts were studied; one (6%) was patent, 12 (71%) were occluded, and 4 (23%) were stenosed. In patients treated with azathioprine, seven of the eight cryopreserved vein grafts were occluded. In patients not receiving immunosuppression, five were occluded, three were stenosed, and one was patent. All internal mammary grafts were widely patent. Cryopreserved vein grafts have a poor angiographic patency which did not appear to be affected by immunosuppressive therapy with azathioprine. The use of this graft should be restricted and alternative arterial conduits utilized.


Correlation between severity of carotid stenosis and vascular reserve measured by acetazolamide brain perfusion single photon emission computed tomography.
Few studies have investigated the relationship between the degree of stenosis of the internal carotid artery (ICA) and cerebrovascular reserve (CVR). This study examined that relationship. A total of 56 ICAs in 43 patients were included. Computed tomography scan or magnetic resonance imaging showed no evidence of infarction in any of these patients. Both iodine-123-N-isopropyl-p-iodoamphetamine ((123)IMP)-single photon emission computed tomography (SPECT) in the resting state and (123)IMP-SPECT with acetazolamide (ACZ) enhancement were performed. Quantitated cerebral blood flow (CBF) images were acquired with the (123)IMP autoradiography technique. The mean CBF without ACZ administration (resting CBF) and CVR in the middle cerebral artery territory were calculated using stereotactic extraction estimation (SEE) analysis software. The degree of stenosis in the origin of the ICA was calculated from intra-arterial digital subtraction angiography. Resting CBF was not correlated with the degree of ICA stenosis; however, nonlinear regression analysis (second-order equation) showed a moderate correlation between CVR and the degree of ICA stenosis. In 72% of the cases with a CVR <30%, ICA stenosis was >74%. Using the SEE method, CVR was moderately correlated with the degree of ICA stenosis. Our findings indicate that evaluating CVR by ACZ-enhanced (123)IMP-SPECT in patients with ICA stenosis is of clinical value.


Glucose utilization, pH reduction and density dependent inhibition in cultures of chick embryo fibroblasts.
The multiplication rate of sparse cultures of chick embryo cells is only slightly lower at pH 6.9 than at pH 7.4. There is, however, a marked reduction in the multiplication rate of the pH 6.9 cultures before they reach confluency. Cultures at pH 7.4 continue to multiply beyond confluency with only a slight decrease in the multiplication rate. Eighty to ninety percent of the glucose taken up by the cells growing at each pH is converted to lactic acid which is released into the medium. Metabolic reduction in pH of the medium is almost entirely accounted for by the amount of lactic acid produced by the cells. Neither the intracellular nor extracellular accumulation of lactic acid nor the accompanying reduction in pH is sufficient to explain density dependent inhibition of the rate of multiplication of chick cells. The rate of lactic acid production and the multiplication rate of chick cells are independent of glucose concentration in the range of 2--16 mM. In view of the kinetic parameters for the uptake of glucose, this shows that glycolysis is not limited by the rate of glucose uptake and that depletion of glucose from the medium cannot account for the onset of density dependent inhibition of multiplication. However, when cells reach very high population densities, conventional glucose concentrations of 5 mM can be depleted overnight by chick cells. Since the multiplication rate of cells is dependent on glucose concentration when it falls below 2 mM, depletion of glucose may cause some growth inhibition in crowded cultures supplied with conventional medium.


Polymorphisms in Toll-like receptors genes changes the host's immune response and is associated with cervical cancer.
Polymorphisms in Toll-like receptors (TLRs) genes have been associated with cervical cancer, but some inconsistencies were found in the results. The present study aimed to investigate the role of polymorphisms in the TLRs genes in cervical cancer, through meta-analysis and bioinformatics analysis. Searches were performed in PubMed, Science Direct, Scopus and Web of science online databases until November 2020. For bioinformatics analysis, we used SNP2TFBS, Raptor-X, MUpro, Gene Expression Profiling Interactive Analysis (GEPIA). The results of meta-analysis showed that the +1196T (rs4986791 TLR4), +7764T (rs1927911 TLR4), -1486C (rs187084 TRL9) +2848A (rs352140 TRL9) alleles carriers and -2604G/G (rs10759931 TLR4), -1237C/C (rs5743836 TRL9) genotypes were associated with an increased risk for cervical cancer. The bioinformatics analysis revealed that the -1237T>C (rs5743836) and -1486T>C (rs187084) polymorphisms can affect the transcription factors binding sites (RELA, NFKB1 and THAP1) in the TLR9 gene, and the +2848G>A (rs352140) polymorphism seems to alter the structure and stability of TLR4 protein. Additionally, using GEPIA, was observed a significantly high of IL-1β, IL-18 and TNF-α expression in cervical cancer tissues compared to normal tissues. These finds indicate that polymorphisms in the TLR4 and TLR9 genes can affect intracellular signaling and, consequently, change the patterns of the immune response, leading to an increased risk for cervical cancer.


One Health at gunpoint: Impact of wild boars as exotic species in Brazil - A review.
Wild boars have been listed among the 100 most invasive species worldwide, spreading impacts to all continents, with the exception of Antarctica. In Brazil, a major source of introduction was a commercial livestock importation for exotic meat market, followed by successive escapes and releases to natural ecosystems. Currently found in all six Brazilian biomes, with reports in 11 Brazilian states, wild boars have invaded natural and agricultural areas. Wild boars have been reportedly indicated as hosts and reservoirs of several zoonotic diseases in Brazil, including toxoplasmosis, salmonelosis, leptospirosis, brucellosis, tuberculosis, trichinellosis, and hepatitis E. Wild boars have been also associated with Brazilian spotted fever and rabies, infected while providing plentiful exotic blood supply for native ticks and hematophagous bats. Due to their phylogenetic proximity, wild boars may present ecological niche overlapping and direct disease risk to native white-lipped and collared peccaries. Moreover, wild boars may post an economical threat to Brazilian livestock industry due to restrictive diseases such as Aujeszky, enzootic pneumonia, neosporosis, hemoplasmosis, and classic swine fever. Finally, wild boars have directly impacted in environmentally protected areas, silting up water springs, rooting and wallowing native plants, decreasing native vegetal coverage, disbalancing of soil components, altering soil structure and composition. Wild boar hunting has failed as a control measure to date, according to the Brazilian Ministry of Environment, due to private hunting groups mostly targeting males, intentionally leaving females and piglets alive, disseminating wild boar populations nationwide. Meanwhile, non-government animal welfare organizations have pointed to animal cruelty of hunting dogs and wild boars (and native species) during hunting. Despite unanimous necessity of wild boar control, eradication and prevention, methods have been controversial and should focus on effective governmental measures instead occasional game hunting, which has negatively impacted native wildlife species while wild boars have continuously spread throughout Brazil.


Neuroprotective activity of proproten in rats with experimental local photothrombosis of the prefrontal cortex.
Proproten (ultralow doses of antibodies to S100 protein) exhibited neuroprotective activity in rats with experimental photochemical thrombosis of the prefrontal cortex. Proproten was more potent than standard neuroprotectors piracetam and vinpocetine in alleviating the signs of memory disorders produced by ischemic injury. Pathomorphological study of the damaged area confirmed the neuroprotective effect of Proproten.


Single-nucleus RNA sequencing of developing superior colliculus identifies neuronal diversity and candidate mediators of circuit assembly.
The superior colliculus (SC) is a sensorimotor structure in the midbrain that integrates input from multiple sensory modalities to initiate motor commands. It undergoes well-characterized steps of circuit assembly during development, rendering the mouse SC a popular model to study establishment of neural connectivity. Here we perform single-nucleus RNA-sequencing analysis of the mouse SC isolated at various developmental time points. Our study provides a transcriptomic landscape of the cell types that comprise the SC across murine development with particular emphasis on neuronal heterogeneity. We report a repertoire of genes differentially expressed across the different postnatal ages, many of which are known to regulate axon guidance and synapse formation. Using these data, we find that Pax7 expression is restricted to a subset of GABAergic neurons. Our data provide a valuable resource for interrogating the mechanisms of circuit development and identifying markers for manipulating specific SC neuronal populations and circuits.


Long-term clearance from small airways decreases with age.
The prevalence of respiratory symptoms increases with age. Age has been found to be negatively associated with large airway clearance. The small airways region is considered important for development of airway disease. Clearance after the first 24 h was studied in 46 healthy subjects with a wide age distribution, (mean 42, range 19-81 yrs). All subjects inhaled monodisperse 6 microm Teflon particles labelled with 111In, with an extremely slow inhalation flow (0.05 L.s-1). The particles were mainly deposited in the small conducting airways. Lung retention was measured at 0 and 24 h, and at 7, 14 and 21 days after inhalation. Significant relationships were found for the individual 24 h "large" airway clearance in per cent of initial lung deposition with age, forced expiratory volume in one second and forced vital capacity. Age was negatively associated with "small" airway clearance after 24 h as estimated at 2, 7, 14 and 21 days. Using stepwise linear regression only age remained significantly associated to clearance. In conclusion, small airway clearance over 21 days was found to decrease with age. This might be one factor associated with the high prevalence of respiratory symptoms associated among the elderly.


Quantitative analysis of 6,11-dihydro-11-oxo-dibenz[b,e] oxepin-2-acetic acid (isoxepac) in plasma and urine by gas--liquid chromatography.
A method is described for the quantitative analysis of 6,11-dihydro-11-oxo-dibenz[b,e]-oxepin-2-acetic acid (isoxepac) in plasma and urine. Isoxepac and internal standard was analysed by gas-liquid chromatography using a flame ionization detector. The method is accurate and precise over the range 0.1--30 microgram/ml. The method has been applied to the analysis of plasma and urine from both healthy volunteers and patients receiving therapeutic oral doses of isoxepac.


Evidence for clustered tumour suppressor gene loci on mouse chromosomes 2 and 4 in radiation-induced acute myeloid leukaemia.
To investigate the influence of genetic and epigenetic factors on allelic loss on chromosomes 2 and 4 in mouse radiation-induced acute myeloid leukaemia (r-AML). r-AML that arose in (CBA/HxC57BL/6)F1xCBA/H and F1xC57BL/6 mice were screened for transcription factor PU1 (also known as SPI-1) gene mutations and methylation of the paired box gene 5 (Pax5) gene promoter. We have increased the statistical significance of a genetic linkage analysis of affected F1xCBA/H mice to test for linkage to loci implicated directly or indirectly with r-AML-susceptibility. There was a statistically significant difference ( p < 10-4) in the frequency of PU1 gene mutations in F1xCBA/H and F1xC57BL/6 r-AML, implicating a second linked but genotype-dependent myeloid leukaemia suppressor gene on chromosome 2. A suggestive CBA/H r-AML-resistance locus maps within 10 cM of the minimally deleted region on chromosome 4. The Pax5 gene promoter is subject to ongoing subclonal promoter methylation in the r-AML, evidence that Pax5 gene silencing confers a selective advantage during clonal expansion in vivo. Allelic loss in mouse r-AML and subsequent tumour suppressor gene mutation (PU1) or silencing (Pax5) is strongly influenced by genetic background and/or epigenetic factors, and driven by in vivo clonal selection.


Guanosine tetraphosphate (ppGpp) dependence of the growth rate control of rrnB P1 promoter activity in Escherichia coli.
We have fused the ribosomal RNA promoter P1 from the rrnB gene of Escherichia coli to lacZ and examined its guanosine tetraphosphate (ppGpp)-dependent expression at different growth rates. The rrnB P1-lacZ fusion was constructed on plasmid vectors and then recombined into the chromosome of a delta lac relA1 strain close to the normal location of the rrnB locus and in the normal orientation, coincident with the direction of replication. A series of spoT strains differing in the severity of their SpoT defect were analyzed with respect to their growth characteristics and ppGpp metabolism. The spoT203 allele was introduced into the rrnB P1-lacZ fusion containing strain and used to manipulate the ppGpp concentration independently of the growth medium. 1) The levels of ppGpp during exponential growth are decreased in rich media due to a decreased activity of (p)ppGpp synthetase II (PSII). 2) The specific activity of rrn P1-directed beta-galactosidase was increased in a parabolic fashion with increasing growth rate. A theoretical analysis showed that this was to be expected since enzyme expression from a stringently controlled promoter is affected by changes in the growth rate both via the control of the promoter, and indirectly via the control of bulk mRNA synthesis. 3) The observer specific enzyme activities were converted into rrnB P1 promoter activities, given as lacZ transcription relative to the total rate of transcription. The rrn P1 promoter activity decreased exponentially with increasing cytoplasmic concentration of ppGpp, independent of whether a given level of ppGpp was achieved by using different growth media or by using a spoT allele. These results support two hypotheses: (i) that RNA polymerase is partitioned by ppGpp into two fractions with different abilities to initiate transcription at rrn P1 promoters; and (ii) that during exponential growth ppGpp is derived from ppGpp synthetase II (PSII). Together these hypotheses predict that the growth rate control of rRNA synthesis reflects a control of PSII activity which is regulated by the composition of the growth medium.


Glucose-resistant sporulation in Bacillus subtilis crsA47 mutants does not depend on promoter switching at the spo0A gene.
We have found that sporulation in Bacillus subtilis crsA47 mutants does not require the sigma(H)-dependent promoter of the spo0A gene. This implies that the glucose-resistant sporulation phenotype of this strain is not related to the switch from the vegetative-stage sigma(A)-dependent promoter to the sigma(H)-dependent promoter at the spo0A gene.


[Morphometric analysis of ultrastructure of human synovioma cells].
Under examination were two gigantic-cell benign synoviomas and seven synovial sarcomas, including two metastatic tumors. The most specific ultrastructural criterion allowing a judgement of the degree of malignancy of the neoplasm under study is a parameter characterizing the predominance of ergastoplasmic protein synthesis over polyribosomal one.


A novel crosslinked type of advanced glycation end-product derived from lactaldehyde.
Glycation of amino or guanidino groups of proteins with glucose and glucose-derived reactive aldehydes, such as α-hydroxyaldehydes, leads to accumulation of advanced glycation end-products (AGEs) in the body, resulting in diabetic complications and age-related pathology. Although molecular structures of glycolaldehyde- and glyceraldehyde-derived AGEs have been described in previous studies, little is known about lactaldehyde-derived AGEs of α-hydroxyaldehydes. Here, we report a novel crosslinked type of AGE, named as lactaldehyde-derived lysine dimer (LAK2), which is produced due to non-enzymatic glycation of N α-acetyl-L-lysine with lactaldehyde under physiological conditions. We have identified the molecular structure of LAK2 by extensive mass spectrometry and nuclear magnetic resonance analyses. Furthermore, we propose a reaction pathway to produce LAK2, in which it is formed through an intermediate common with the recently reported lactaldehyde-derived pyridinium-type lysine adduct (LAPL). Since lactaldehyde is known to be produced from L-threonine in a myeloperoxidase (MPO)-mediated reaction at sites of inflammation, LAK2 has the potential to be an oxidative stress marker of MPO-mediated reactions induced in inflammation.


Toxicity report of once weekly radiation therapy for low-risk prostate adenocarcinoma: preliminary results of a phase I/II trial.
Increasing clinical data supports a low α/β ratio for prostate adenocarcinoma, potentially lower than that of surrounding normal tissues. A hypofractionated, weekly radiation therapy (RT) schedule should result in improved tumour control, reduced acute toxicity, and similar or decreased late effects. We report the toxicity profile of such treatment. We conducted a multi-institution phase I/II trial of three-dimensional conformal radiation therapy (3D-CRT) for favourable-risk prostate cancer (T1a-T2a, Gleason ≤ 6 and PSA < 10 ng/ml). RT consisted of 45 Gy in nine 5 Gy fractions, once weekly. Primary end-points were feasibility and late gastrointestinal (GI) toxicity (RTOG scale), while secondary end-points included acute GI toxicity, acute and late genitourinary (GU) toxicity, biochemical control, and survival. Between 2006 and 2008, 80 patients were treated. No treatment interruptions occurred. The median follow-up is 33 months (range: 20-51). Maximal grade 1, 2, and 3 acute (< 3 months) GU toxicity was 29%, 31% and 5% respectively (no grade 4). Acute GI grade 1 toxicity was reported in 30% while grade 2 occurred in 14% (no grade 3 or 4). Crude late grade ≥ 3 toxicity rates at 31 months were 2% for both GU and GI toxicity. Cumulative late grade ≥ 3 GI toxicity at 3 years was 11%. Two patients had PSA failure according to the Phoenix definition. The three-year actuarial biochemical control rate is 97%. Weekly RT with 45 Gy in 9 fractions is feasible and results in comparable toxicity. Long term tumour control and survival remain to be assessed.


Use of alcohol vinegar in the inhibition of Candida spp. and its effect on the physical properties of acrylic resins.
Given the high prevalence of oral candidiasis and the restricted number of antifungal agents available to control infection, this study investigated the in vitro antifungal activity of alcohol vinegar on Candida spp. and its effect on the physical properties of acrylic resins. Tests to determine the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) of vinegar alcohol (0.04 g/ml of acetic acid) and nystatin (control) were performed. The antifungal activity of alcohol vinegar was assessed through microbial growth kinetic assays and inhibition of Candida albicans adhesion to acrylic resin at different intervals of time. Surface roughness and color of the acrylic resin were analyzed using a roughness meter and color analyzer device. Alcohol vinegar showed MIC75% and MFC62.5% of 2.5 mg/ml, with fungicidal effect from 120 min, differing from nystatin (p < 0.0001), which showed fungistatic effect. Alcohol vinegar caused greater inhibition of C. albicans adhesion to the acrylic resin (p ≤ 0.001) compared to nystatin and did not change the roughness and color parameters of the material. Alcohol vinegar showed antifungal properties against Candida strains and caused no physical changes to the acrylic resin.


C3 deposits worsens the prognosis in type iii extracapillary glomerulonephritis.
Type iii extracapillary glomerulonephritis (PEGN) is a common cause of rapidly progressive glomerulonephritis and it is usually associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Recent evidence points to complement activation as an important factor in the pathogenesis of PEGN. The aim of the present study was to assess the value of C3 deposits in the prognosis of PEGN. All patients diagnosed of PEGN from 1995 to 2015 (n=72) were included in this study. Progression of renal disease in patients with positive staining for C3 by immunofluorescence was compared with those with negative staining. Mean follow up was 73 months. Progression to end-stage renal disease in relation to clinical and histological variables was analyzed. Positive staining for C3 was observed in 22 out of the 72 patients (30.5%). At the time of diagnosis, patients with C3 deposits had higher serum creatinine concentration than those without C3 staining (5.00 vs. 3.85mg/dl, P=0.050). Renal survival at 10 years was 36.9% in patients with positive C3 staining vs. 64.4% in patients with negative staining (P=0.005). Mortality at 10 years was higher in patients with C3 deposits than in patients without deposits (77 vs. 49.3%). Thus, our study shows that PEGN with deposits of C3 is associated with worse renal prognosis and greater mortality. These results would support the hypothesis that activation of the alternative pathway complement may play an important role in the generation of renal injury associated with PEGN.


Efficacy of Dapoxetine in the Treatment of Patients With Lifelong Premature Ejaculation as an Alternative to Sertraline Therapy.
Before dapoxetine was approved for the treatment of lifelong premature ejaculation (LPE) in China, daily dosing with off-label sertraline was common. To investigate the efficacy of dapoxetine in the treatment of patients with LPE as an alternative to sertraline therapy. This prospective study included LPE patients who previously attempted treatment with sertraline and who agree to receive dapoxetine therapy in our hospital from January 2020 to March 2021. Patients who received any PE therapy in the two months prior to the dapoxetine therapy were excluded. All patients received dapoxetine 30 mg (taken 1-3 hours before sexual intercourse) for 12 weeks, and they were not taking sertraline during the trial. Data on their intravaginal ejaculatory latency time and premature ejaculation profile were recorded before and after the dapoxetine treatment. Clinical Global Impression of Change scores and data on Treatment-Emergent adverse events were collected after treatment. A total of 144 patients with LPE completed this study; including 64 patients who reported that previous sertraline treatment was satisfactory (group A) and 80 patients for whom previous sertraline therapy was unsatisfactory in treating PE (group B). Both groups experienced significantly increased intravaginal ejaculatory latency time. Dapoxetine therapy was reported satisfactory by 67.5% of patients with LPE in whom sertraline therapy unsatisfactory according to their Clinical Global Impression of Change score, which was not different from those who reported this result in group A (62.5%). Similar outcomes were also reported for premature ejaculation profile and treatment-emergent adverse events. Although both dapoxetine and sertraline are selective serotonin re-uptake inhibitors, dapoxetine therapy is satisfactory in 67.5% of patients with LPE in whom sertraline treatment unsatisfactory, and the effect of dapoxetine was independent of the effect of sertraline. Liu G, Yin Y, Zhang L. et al., Efficacy of Dapoxetine in the Treatment of Patients With Lifelong Premature Ejaculation as an Alternative to Sertraline Therapy. Sex Med 2021;10:100473.


Adsorption behavior and mechanism of chloramphenicols, sulfonamides, and non-antibiotic pharmaceuticals on multi-walled carbon nanotubes.
The adsorption behavior of different emerging contaminants (3 chloramphenicols, 7 sulfonamides, and 3 non-antibiotic pharmaceuticals) on five types of multi-walled carbon nanotubes (MWCNTs), and the underlying factors were studied. Adsorption equilibriums were reached within 12h for all compounds, and well fitted by the Freundlich isotherm model. The adsorption affinity of pharmaceuticals was positively related to the specific surface area of MWCNTs. The solution pH was an important parameter of pharmaceutical adsorption on MWCNTs, due to its impacts on the chemical speciation of pharmaceuticals and the surface electrical property of MWCNTs. The adsorption of ionizable pharmaceuticals decreased in varying degrees with the increased ionic strength. MWCNT-10 was found to be the strongest adsorbent in this study, and the Freundlich constant (KF) values were 353-2814mmol(1-n)L(n)/kg, 571-618mmol(1-n)L(n)/kg, and 317-1522mmol(1-n)L(n)/kg for sulfonamides, chloramphenicols, and non-antibiotic pharmaceuticals, respectively. The different adsorption affinity of sulfonamides might contribute to the different hydrophobic of heterocyclic substituents, while chloramphenicols adsorption was affected by the charge distribution in aromatic rings via substituent effects.


Current concepts on the management of tooth wear: part 4. An overview of the restorative techniques and dental materials commonly applied for the management of tooth wear.
This final article of the four part series on the current concepts of tooth wear will provide the reader with an evaluation of the data available in the contemporary literature with regards to the survival analysis of differing restorative materials, and their respective methods of application to treat tooth wear. It is vital that the dental operator is familiar with the role of differing materials which may be used to restore the worn dentition, some of which may prove to be more suitable for the management of particular patterns of tooth wear than others. The active management of tooth wear unfortunately commits the patient to a lifelong need for considerable maintenance, and it is imperative that this is understood from the outset.


A phenomenological cartography of misophonia and other forms of sound intolerance.
People with misophonia have strong aversive reactions to specific "trigger" sounds. Here we challenge this key idea of specificity. Machine learning was used to identify a misophonic profile from a multivariate sound-response pattern. Misophonia could be classified from most sounds (traditional triggers and non-triggers) and, moreover, cross-classification showed that the profile was largely transferable across sounds (rather than idiosyncratic for each sound). By splitting our participants in other ways, we were able to show-using the same approach-a differential diagnostic profile factoring in potential co-morbidities (autism, hyperacusis, ASMR). The broad autism phenotype was classified via aversions to repetitive sounds rather than the eating sounds most easily classified in misophonia. Within misophonia, the presence of hyperacusis and sound-induced pain had widespread effects across all sounds. Overall, we show that misophonia is characterized by a distinctive reaction to most sounds that ultimately becomes most noticeable for a sub-set of those sounds.


Activation of mitogen- and stress-activated kinase 1 is required for proliferation of breast cancer cells in response to estrogens or progestins.
Growth of breast cancers is often dependent on ovarian steroid hormones making the tumors responsive to antagonists of hormone receptors. However, eventually the tumors become hormone independent, raising the need to identify downstream targets for the inhibition of tumor growth. One possibility is to focus on the signaling mechanisms used by ovarian steroid hormones to induce breast cancer cell proliferation. Here we report that the mitogen- and stress-activated kinase 1 (MSK1) could be a potential druggable target. Using the breast cancer cell line T47D, we show that estrogens (E2) and progestins activate MSK1, which forms a complex with the corresponding hormone receptor. Inhibition of MSK1 activity with H89 or its depletion by MSK1 short hairpin RNAs (shRNAs) specifically abrogates cell proliferation in response to E2 or progestins without affecting serum-induced cell proliferation. MSK1 activity is required for the transition from the G1- to the S-phase of the cell cycle and inhibition of MSK1 compromises both estradiol- and progestin-dependent induction of cell cycle genes. ChIP-seq experiments identified binding of MSK1 to progesterone receptor-binding sites associated with hormone-responsive genes. MSK1 recruitment to epigenetically defined enhancer regions supports the need of MSK1 as a chromatin remodeler in hormone-dependent regulation of gene transcription. In agreement with this interpretation, expression of a histone H3 mutated at S10 eliminates the hormonal effect on cell proliferation and on induction of relevant target genes. Finally, we show that E2- or progestin-dependent growth of T47D cells xenografted in immunodefficient mice is inhibited by depletion of MSK1, indicating that our findings are not restricted to cultured cells, and that MSK1 plays an important role for hormone-dependent breast cancer growth in a more physiological context.


Effect of lanthanum on rooting of in vitro regenerated shoots of Saussurea involucrata Kar. et Kir.
In present study, the effect of lanthanum (La) on the rooting of regenerated shoots of Saussurea involucrata Kar. et Kir was analyzed. Rooting occurred from regenerated shoots inoculated on a medium supplemented with La, the plant rooting hormone indole-3-acetic acid (IAA), or both La and IAA together. The highest rooting efficiency (96%), root number/shoot (8.5), and root length (63 mm) were recorded in shoots cultured on medium containing 2.5 μM IAA combined with 100 μM La(3+). In order to elucidate the mechanism of rooting enhancement by La, we examined dynamic changes in antioxidant enzyme activities in plant tissue over time in culture. We found that the activities of peroxidase (POX) and superoxide dismutase (SOD) were significantly higher in plant tissue cultured in IAA plus La than in La or IAA alone. At the same time, the highest H(2)O(2) content was detected in plant tissue in the presence of 2.5 μM IAA plus 100 μM La(3+). In light of these data and previous results, we speculate that La enhanced IAA-induced rooting by acting as a mild abiotic stress to stimulate POX and SOD activities in plant cells. Then, IAA reacted with oxygen and POX to form the ternary complex enzyme-IAA-O(2) that dissociated into IAA radicals and O(2)(-). Subsequently, IAA-induced O(2)(-) readily converted to hydroxyl radical (HO·) via SOD-catalyzed dismutation. Finally, cell wall loosening and cell elongation occurred as a consequence of HO-dependent scission of wall components, leading to root growth. The treatment of IAA combined with La resulted in the highest plantlet survival (80%) compared to single treatments with IAA or La alone. These data suggest that rare earth elements enhance root morphogenesis and the growth of S. involucrata.


Diagnostic accuracy of a hyperbolic model in predicting digoxin concentrations based on glomerular filtration rates.
Inappropriate doses and high serum concentrations of digoxin are highly prevalent in patients with renal impairment, and the drug dosage adjustment according to the glomerular filtration rate (GFR) is recommended. The aim of our study was to evaluate the dependence degree of digoxin total clearance (CL) on GFR, and the diagnostic efficiency of a predictive model for serum digoxin steady-state concentrations (Css) from estimated GFR by Cockcroft-Gault formula. In 400 outpatients treated orally with digoxin, serum Css were determined (fluorescence polarization immunoassay from Abbott Laboratories), and total CL was calculated. The prediction of Css was carried out using a hyperbolic model developed by Konishi et al in Japan (J Clin Pharm Ther 2002;27:257), and the constants of the equation were modified for a Caucasian population. Only 26% of the digoxin CL interindividual variability may be explained by differences in GFR, and this fact is a serious limitation for the derived predictive models. A 65% diagnostic efficiency was obtained for original and modified hyperbolic models in the correct classification of predicted Css as subtherapeutic, therapeutic or supratherapeutic with respect to obtained Css concentrations. The diagnostic efficiency obtained in the prediction of serum digoxin concentrations from estimated GFR values is unacceptable for the drug dosage adjustment in clinical practice.


Sexual precocity induced by ovarian follicular cysts. Is autoimmunity involved?
A 2-year-old girl presented with gonadotrophin-independent precocious puberty due to ovarian follicles. Central precocious puberty was excluded by several GnRH-tests and overnight LH sampling. There were no signs of McCune-Albright syndrome. An ovarian tumour was excluded by laparotomy and biopsies. Abdominal sonography demonstrated follicles occurring mostly in the left, sometimes in the right, ovary. Immunoglobulin G (IgG) purified from the patient's serum was capable of stimulating DNA synthesis in granulosa cells of rat ovarian segments kept in organ culture. Since FSH had a similar in-vitro action it is hypothesized that this patient's IgG mimics the action of FSH.


A comparison of anaesthesia using remifentanil combined with either isoflurane, enflurane or propofol in patients undergoing gynaecological laparoscopy, varicose vein or arthroscopic surgery.
Anaesthesia comprising remifentanil plus isoflurane, enflurane or propofol was randomly evaluated in 285, 285 and 284 patients, respectively, undergoing short-procedure surgery. Anaesthesia was induced with propofol (0.5 mg x kg(-1) and 10 mg x 10 s(-1)), and a remifentanil bolus (1 microg x kg(-1)) and infusion at 0.5 microg x g(-1) x min(-1). Five minutes after intubation, remifentanil infusion was halved and 0.5 MAC of isoflurane or enflurane, or propofol at 100 microg x kg(-1) x min(-1) were started and titrated for maintenance. Patient demography and anaesthesia duration were similar between the groups. Surgery was performed as daycases (52%) or inpatients (48%). The median times (5-7 min) to extubation and postoperative recovery were similar between the groups. Responses to tracheal intubation (15% vs 8%) and skin incision (13% vs 7%) were significantly greater in the total intravenous anaesthesia (TIVA) group (P<0.05). Fewer patients given remifentanil and isoflurane (21%) or enflurane (19%) experienced > or =1 intraoperative stress response compared to the TIVA group (28%) (P<0.05). Median times to qualification for and actual recovery room discharge were 0.5-0.6 h and 1.1-1.2 h, respectively. The most common remifentanil-related symptoms were muscle rigidity (6-7%) at induction, hypotension (3-5%) and bradycardia (1-4%) intraoperatively and, shivering (6-7%), nausea and vomiting postoperatively. Nausea (7%) and vomiting (3%) were significantly lower with TIVA compared with inhaled anaesthetic groups (14-15% and 6-8%, respectively; P<0.05). Anaesthesia combining remifentanil with volatile hypnotics or TIVA with propofol was effective and well tolerated. Times of extubation, postanaesthesia recovery and recovery room discharge were rapid, consistent and similar for all three regimens.


First-generation inequality and college integration.
Institutional integration has long been an important focus in literatures on inequality, education and mobility. Building on this work and drawing from multi-wave survey and records data from a large public university, the analyses we offer in this article provide unique and systematic comparative tests of first- versus continuing-generation inequalities in integration, disaggregated by academic versus social types, and with attention to other potentially influential status attributes. Our findings reveal: (1) clear overall inequalities in campus integration for first-generation students that cut across gender and race/ethnic lines; (2) a higher likelihood of employment among first-generation students-employment that tends to detract from integration opportunities; and (3) especially pronounced inequalities when it comes to forms of academic and social integration that entail bureaucratic- and resource-related barriers. We discuss the implications for understanding inequality and the first-generation experience in higher education and for more general sociological conceptions of institutional integration and mobility.


[Sterility of non-preserved autologous serum drops for treatment of persistent corneal epithelial defects].
To investigate the sterility of non-preserved autologous serum drops in hospitalized patients with persistent corneal epithelial defects. Thirty patients with persistent corneal epithelial defects (aged between 28 and 85, mean 67+/-14 years) were treated with autologous serum drops in five different wards of a university eye hospital between October 2001 and March 2002. After centrifugation of freshly collected autologous blood, the serum was stored in sterile drop bottles at refrigerator temperature (7 degrees C) and applied undiluted every 1 or 2 h up to 7 days. Using blood, chocolate, endo, and Sabouraud agar media, we assessed the sterility of autologous serum drops on the day before application and on the 4th and 7th days. Examinations performed on the 1st and 4th days included 40 autologous serum drops each and on the 7th day 120 samples (40 serum drops, 40 bottle tops, and 40 bottle bottoms). The agar media for bacterial examination were read after 48 h of incubation time, and those for fungal examination were read after 21 days. All patients had received topical autologous serum therapy and prophylactic antibiotic drops for at least 7 days. The time period of autologous serum treatment ranged from 7 to 28 (10+/-5) days. On the 1st and 4th days autologous serum drops were sterile. On the 7th day, 3 of 40 (7.5%) samples were contaminated with Staphylococcus epidermidis. Two of these contaminations were due to a combined serum drop and bottle top contamination (5%). A third case resulted from additional bottle bottom contamination (2.5%). None of the samples examined showed signs of fungal infection. During application of autologous serum as well as during the follow-up period no patient showed any symptoms of ocular infection. The application of autologous serum has proven to be a practicable therapy in patients with persistent corneal epithelial defects. When the drops are applied by trained personnel, the absence of contamination can be ensured up to the 4th day. By additional application of prophylactic antibiotic drops, infections may be avoided even if refrigerated non-preserved autologous serum is used up to 7 days.


How experienced practitioners gain knowledge.
An evolution in nursing in the United Kingdom in the 1970s from rule-bound toward holistic, autonomous practice engendered an examination of nursing's body of knowledge and how it is incorporated into practice. This article describes Barbara Carper's (1978) Fundamental Patterns of Knowing in Nursing (empiric, ethical, aesthetic, and personal knowledge), and links it to three major worldviews of the way in which knowledge is sought (positivism, naturalism, and critical social theory). Carper's model was used in the United Kingdom as the basis for a curriculum of structured reflective practice using workshops, journaling, and clinical supervision. An example from a practitioner's diary demonstrates how Carper's model informs reflection on an interaction with a patient with newly diagnosed cancer.


Phage T4 DNA codes for two distinct 10-kDa proteins which strongly bind to RNA polymerase.
Radioactive proteins have been synthesized in vitro from a coupled transcription-translation system primed with bacteriophage T4 DNA. The labeled proteins were chromatographed on RNA polymerase-Sepharose affinity columns in order to identify a protein which comigrates with the 10-kDa anti-sigma subunit of T4-modified RNA polymerase. When we primed the in vitro system with specific restriction fragments of T4 DNA, we found that there seemed to be two widely separated genes which code for this protein. The products of these two genes were compared by two-dimensional electrophoresis; they were found to have different charges, even though they had the same molecular weight and strong affinity for RNA polymerase. One of these proteins exists in a form which has the same charge as the 10-kDa subunit isolated from purified T4-modified RNA polymerase. We report a preliminary mapping experiment within the 22.5-kb fragment harboring this gene.


Intracerebroventricular (i.c.v.) administration of mouse leptin in rats: behavioral specificity and effects on meal patterns.
Leptin is a protein that is produced primarily in fat tissue and is thought to be a lipostatic feedback signal for the regulation of body fat stores. The purpose of this study was to determine the behavioral specificity of i.c.v.-administered mouse leptin in rats and to assess the effects on meal patterns. Using a modified two-bottle paradigm we examined the putative aversive response to i.c.v. doses of 1, 5, 7, 10, and 30 microg of mouse leptin. Artificial CSF and intraperitoneal lithium chloride served as negative and positive controls, respectively. Saccharin consumption in all leptin treatments was not significantly different from the negative control. Following a recovery period, rats from the same group were used to assess the effects of a 30-microg i.c.v. dose on cumulative food intake and meal patterns using a computer-based system for acquisition of feeding data. Leptin (i.c.v.) significantly increased intermeal interval and decreased meal size. We, therefore, conclude that mouse leptin, at doses up to 30 microg i.c.v., is not aversive in the rat, and that leptin has a multiphasic effect on meal patterns.


An inter-domain regulatory mechanism controls toxic activities of PrPC.
The normal function of PrPC, the cellular prion protein, has remained mysterious since its first description over 30 years ago. Amazingly, although complete deletion of the gene encoding PrPC has little phenotypic consequence, expression in transgenic mice of PrP molecules carrying certain internal deletions produces dramatic neurodegenerative phenotypes. In our recent paper, 1 we have demonstrated that the flexible, N-terminal domain of PrPC possesses toxic effector functions, which are regulated by a docking interaction with the structured, C-terminal domain. Disruption of this inter-domain interaction, for example by deletions of the hinge region or by binding of antibodies to the C-terminal domain, results in abnormal ionic currents and degeneration of dendritic spines in cultured neuronal cells. This mechanism may contribute to the neurotoxicity of PrPSc and possibly other protein aggregates, and could play a role in the physiological activity of PrPC. These results also provide a warning about the potential toxic side effects of PrP-directed antibody therapies for prion and Alzheimer's diseases.


Transmission of the human immunodeficiency virus: an updated review.
Despite the inexorable spread of HIV infection and disease worldwide, only three routes of transmission (inoculation of blood, sexual and perinatal) still remain important. This article reviews current information related to the routes of transmission of HIV infection.


The immunohistochemical expression of von Willebrand factor, T-cadherin, and Caveolin-1 is increased in kidney allograft biopsies with antibody-mediated injury.
There are only a few reports evaluating the applicability of endothelial-damage markers analysis by immunohistochemistry (IHC) in kidney allograft samples. This study analyzed the expression of Caveolin-1 (Cav), von Willebrand factor (Vwf), and T-cadherin (Cad) in kidney biopsies and their association with antibody-mediated injury. In this retrospective study, 114 cases with antibody-mediated changes (Banff, 2020) and 72 with interstitial fibrosis/tubular atrophy were selected. IHC for Cav, Vwf and Cad was performed and evaluated according to their qualitative expression in peritubular capillaries. The cases were grouped according to the presence of microvascular inflammation (MVI), donor-specific antibodies (DSA), C4d positivity and antibody-mediated rejection (AMR). A level of significance < 0.05 was adopted. Vwf expression was associated with MVI (p < 0.001), DSA (p = 0.016), C4d (p < 0.001) and AMR (p < 0.001), and was higher in DSA+/C4d+ cases despite MVI (p < 0.001). The expression of Cad correlated with MVI (p = 0.015), C4d (p = 0.005) and AMR (p = < 0.001). Cad was more expressed in chronic AMR compared with acute/active cases (p = 0.001). Cav expression was associated with MVI (p = 0.029) and AMR (p = 0.016) and was also higher in chronic AMR (p = 0.049). A combined score of Vwf and Cad was higher in AMR when compared with C4d without rejection and IF/TA cases (p < 0.001). Vwf, Cad and Cav expression shows association with antibody-mediated injury and may be helpful to support AMR diagnosis.


Hepatoblastoma--an attempt of histological subtyping on fine-needle aspiration material.
Hepatoblastoma (HB) is classified into epithelial, mixed (epithelial/mesenchymal), and small-cell (anaplastic) type. Wnt/β-catenin pathway plays a key role in hepatic development, regeneration, and tumorigenesis, and HB is known to present β-catenin mutations (50-90%). The present study was undertaken to delineate the cytomorphologic features of HB and to evaluate the feasibility of subtyping of HB on fine-needle aspiration cytology (FNAC). The expression of β-catenin in these tumors was also evaluated both of histopathologic sections and on the aspirated material. Thirty-three cases with fine-needle aspirates of HB were retrieved over a period of 12 years. Cytologic diagnosis was reviewed in the light of clinicoradiological data, response to therapy, and subsequent histopathology. Immunochemistry for β-catenin was performed in 19 of 33 cases on histopathologic sections (n = 10)/cell blocks (n = 6)/cytosmears (n = 3). Based on the cytologic features, the cases were divided into fetal HB (n = 17), embryonal HB (n = 4), combined epithelial HB (n = 8), and mixed HB (n = 4). Four cases of histopathologically proven mixed HB were reported as pure epithelial HB on FNAC, as mesenchymal elements were not represented in the cytology smears. Cytoplasmic as well as nuclear staining for β-catenin was noted in a total of 10 of 19 cases. FNAC can accurately categorize epithelial HB; however, in mixed type, the accuracy depends on number of areas sampled. Cell block can be of help to perform ancillary investigations especially β-catenin for both diagnostic and therapeutic purposes.


Evaluation of WGA-Cre-dependent topological transgene expression in the rodent brain.
Novel neuromodulation techniques in the field of brain research, such as optogenetics, prompt to target specific cell populations. However, not every subpopulation can be distinguished based on brain area or activity of specific promoters, but rather on topology and connectivity. A fascinating tool to detect neuronal circuitry is based on the transsynaptic tracer, wheat germ agglutinin (WGA). When expressed in neurons, it is transported throughout the neuron, secreted, and taken up by synaptically connected neurons. Expression of a WGA and Cre recombinase fusion protein using a viral vector technology in Cre-dependent transgenic animals allows to trace neuronal network connections and to induce topological transgene expression. In this study, we applied and evaluated this technology in specific areas throughout the whole rodent brain, including the hippocampus, striatum, substantia nigra, and the motor cortex. Adeno-associated viral vectors (rAAV) encoding the WGA-Cre fusion protein under control of a CMV promoter were stereotactically injected in Rosa26-STOP-EYFP transgenic mice. After 6 weeks, both the number of transneuronally labeled YFP+/mCherry- cells and the transduced YFP+/mCherry+ cells were quantified in the connected regions. We were able to trace several connections using WGA-Cre transneuronal labeling; however, the labeling efficacy was region-dependent. The observed transneuronal labeling mostly occurred in the anterograde direction without the occurrence of multi-synaptic labeling. Furthermore, we were able to visualize a specific subset of newborn neurons derived from the subventricular zone based on their connectivity.


The role of vascular endothelial cells in tumor metastasis.
Vascular endothelial cells (VECs) are an integral component of the inner lining of blood vessels, and their functions are essential for the proper functioning of the vascular system. The tight junctions formed by VECs act as a significant barrier to the intravasation and extravasation of tumor cells (TCs). In addition to that, the proliferation, activation, and migration of VECs play a vital role in the growth of new blood vessels, a process known as tumor angiogenesis, which is closely related to the malignant progression of tumors. However, during tumor progression, VECs undergo endothelial-to-mesenchymal transition (EndMT), which further promotes tumor progression. Furthermore, VECs act as the first line of defense against effector immune cells and help prevent immune cells from infiltrating into tumor tissues. VECs also secrete various cytokines that can contribute to regulating the stemness of tumor stem cells. Thus, it has been increasingly recognized that dysfunction of VECs is one of the key driving forces behind tumor metastasis, and therapeutic strategies targeting VECs have the potential to be an effective means of antitumor therapy. This review aims to present a comprehensive overview of the role and mechanisms of VECs in regulating tumor progression and metastasis, providing insights into the possibilities for the development of novel antitumor therapies that target VECs.


Intracerebral grafting of fetal dorsal pons in genetically epilepsy-prone rats: effects on audiogenic-induced seizures.
The present experiments investigated if dorsal pontine tissue obtained from 16-day postconception rat fetuses and stereotaxically transplanted into the dorsal hippocampus or third ventricle of genetically epilepsy-prone rats (GEPRs) would alter the expression of audiogenic seizures. Of eight GEPR-9s receiving pontine-tissue grafts bilaterally into the dorsal hippocampus, none showed any reduction in AGS severity. In contrast, three of five GEPR-9s receiving grafts into the third ventricle eventually displayed a decreased seizure severity following transplantation. Of five GEPR-3s receiving transplants into the hippocampus, one animal showed a gradual and significant reduction in seizure severity after transplantation. Tyrosine-hydroxylase (TH) immunohistochemistry showed that transplanted tissue contained abundant TH-immunoreactive profiles including perikarya and fibers. The results of these preliminary studies suggest that the GEPR model of epilepsy may be useful in studying the corrective potential of neurotransplants.


Microplastics can affect soil properties and chemical speciation of metals in yellow-brown soil.
Although the influence of microplastics (MPs) in different soil environments has been investigated, their effects on the physiochemical properties and chemical speciation of heavy metals in yellow-brown soil remains unknown. This study aimed to determine the effects of various concentrations of linear low-density polyethylene (LLDPE), polyamide (PA), polyurethane (PU), polystyrene (PS), and low-density polyethylene (LDPE) MPs on the yellow-brown soil environment and chemical speciation of the heavy metals cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn). MPs influenced the physicochemical properties and chemical speciation of heavy metals in yellow-brown soil. The physicochemical properties of yellow-brown soil can be altered by changing the concentrations of LDPE MP. The relationship between changes in field capacity (FC) and LDPE concentrations was approximately linear. The physiochemical properties of yellow-brown soil containing added PA, PU, and LDPE MPs were substantially improved (control vs. MPs): FC, 39 % vs. 42.50 % for PU, cation exchange capacity (CEC) 45.77, 56.65, and 57.44 cmol.kg-1 for PA, PU, and LDPE respectively, and organic matter (OM) content, 40.16 vs. 51.68 g.kg-1 for PA. The LLDPE and PU MPs also simultaneously affected the chemical speciation of heavy metals in yellow-brown soil. The LLDPE MPs increased the acid-soluble (45.17-54.67 % (Cd-F1), 7.24-11.30 % (Cu-F1), 4.20-7.23 % (Pb-F1), 21.21-31.47 % (Zn-F1)) and reducible (24.02-29.41 % (Cd-F2), 25.69-34.95 % (Cu-F2), 74.29-81.07 % (Pb-F2), 28.77-34.19 % (Zn-F2)) fractions of heavy metals, which increased their bioavailability. However, PU MPs reduced the ecological risk of heavy metals in yellow-brown soil by increasing the content of the residual fraction (26.11-40.21 % (Cd-F4), 47.63-59.67 % (Cu-F4), 17.25-26.76 % (Pb-F4), 32.63-50.46 % (Zn-F4)). Changes in the properties of yellow-brown soil and the impact of MPs on heavy metals, might change the chemical speciation of heavy metals. The impact of MPs on heavy metals in yellow-brown soil requires further investigation.


Explaining US racial/ethnic disparities in health declines and mortality in late middle age: the roles of socioeconomic status, health behaviors, and health insurance.
Pervasive health disparities continue to exist among racial/ethnic minority groups, but the factors related to these disparities have not been fully elucidated. We undertook this prospective cohort study to determine the independent contributions of socioeconomic status (SES), health behaviors, and health insurance in explaining racial/ethnic disparities in mortality and health declines. Our study period was 1992-1998, and our study population consists of a US nationally representative sample of 6286 non-Hispanic whites (W), 1391 non-Hispanic blacks (B), 405 Hispanics interviewed in English (H/E), and 318 Hispanics interviewed in Spanish (H/S), ages 51-61 in 1992 in the Health and Retirement Study. The main outcome measures were death; major decline in self-reported overall health (SROH); and combined outcome of death or major decline in SROH. Crude mortality rates over the 6-year study period for W, B, H/E and H/S were 5.8%, 10.6%, 5.8%, and 4.4%, respectively. Rates of major decline in SROH were 14.6%, 23.2%, 22.1% and 39.4%, for W, B, H/E and H/S, respectively. Higher mortality rates for B versus W were mostly explained by worse baseline health. For major decline in SROH, education, income, and net worth independently explained more of the disparities for all three minority groups as compared to health behaviors and insurance, reducing the effect for B and H/E to non-significance, while leaving a significant elevated odds ratio for H/S. Without addressing the as-yet undetermined and pernicious effects of lower SES, public health initiatives that promote changing individual health behaviors and increasing rates of insurance coverage among blacks and Hispanics will not eliminate racial/ethnic health disparities.