A Strong Evidence Outbreak of Salmonella Enteritidis in Central Italy Linked to the Consumption of Contaminated Raw Sheep Milk Cheese.
Salmonellosis is the second most commonly reported gastrointestinal infection in humans after campylobacteriosis, and an important cause of foodborne outbreaks in the EU/EEA. The vast majority (72.4%) of the salmonellosis foodborne outbreaks reported in EU in 2019 were caused by Salmonella Enteritidis, even if their total number due to this serovar decreased. In spring 2020, a foodborne outbreak of S. Enteritidis occurred in the Marche region (Central Italy), involving 85 people. The common exposure source was a cheese, pecorino "primo sale", produced with raw sheep milk. The cheese batches were produced by two local dairies, with a livestock production facility, also including a sheep farm, being part of one dairy. Bacteriological analysis of samples collected allowed the detection of S. Enteritidis in animal faeces, environmental samples, raw-milk bulk tanks and milk taken from single animals. These data confirm that, despite the scarce scientific evidence, S. Enteritidis can infect sheep and be shed into the animals' milk. Hence, this is a real risk for public health when unpasteurized milk is used in production of such cheese. The present paper describes the results of the investigations conducted to clarify this outbreak.


Systematic review with meta-analysis: Significant histological changes among treatment-naïve chronic hepatitis B patients with normal alanine aminotransferase levels by different criteria.
The upper limits of normal (ULNs) of ALT are not consistent across the major international guidelines which may affect the eligibility for antiviral therapy for chronic hepatitis B (CHB). To estimate the proportions of histological changes among treatment-naïve patients with CHB within differently defined ALT ULNs. We searched PubMed and Embase up to May 15th, 2023, to identify studies of treatment-naïve CHB patients with liver biopsies. We pooled proportions of moderate to severe necroinflammation, significant fibrosis, and cirrhosis in those patients within different ALT ULNs by using random-effect models. We included 23 studies with 4010 participants. Within ALT ULN at 40 IU/L, the pooled proportions of moderate to severe necroinflammation, significant fibrosis, and cirrhosis were 33% (95% CI: 26%-42%), 32% (95% CI: 27%-38%), and 3% (95% CI: 1%-5%), respectively. Within ALT ULN at 30 IU/L for men and 19 IU/L for women, the pooled proportion of significant fibrosis remained at 30% (95% CI: 25%-34%; 432 participants). However, it was 21% (95% CI: 11%-37%; 361 participants) even in those within ALT ULN at 20 IU/L. Subgroup analyses suggested a significantly higher proportion of significant fibrosis among studies with prospective design or enrolled patients' mean age >35 or >40 years. Significant histological changes occurred in approximately 1/3 of treatment-naïve CHB patients within ALT ULN at 40 IU/L, whereas the proportion of significant fibrosis was approximately 1/5 even in those within ALT ULN at 20 IU/L.


A rapid method for assessing the suitability of quenching agents for individual biocides as well as combinations.
To develop a novel, rapid method for testing the ability of quenching agents to neutralize disinfectants. Tests were performed to determine the suitability of different neutralizers for a range of disinfectants, using a new method based on the Bioscreen optical density analyser. Results showed that during disinfection tests, efficacy could be over-estimated due to poor, or no, neutralization of the disinfectant after a specified time of exposure to the bacteria. The failure to distinguish adequately between bacteriostatic and bactericidal effects can lead to false results during disinfectant testing. Experiments also showed that dilution of the disinfectant, following exposure to the bacteria, was not always sufficient to stop the activity of the disinfectant for chemicals with low dilution coefficients. The quench test proved to be very quick and easy to perform, with results being available within 18 h. Using the Bioscreen, the test is automated and determines whether dilution into a particular neutralizer is able to inactivate a disinfectant within 30 s. This new approach allows the efficacy of quenching agents to be determined, prior to undertaking each disinfection study, and can help in the development of more suitable quenching solutions. The test has also been used to find suitable neutralizers for mixtures of disinfectants which might be used during studies on synergistic biocide combinations.


Research Note: Integrated proteomic analyses of chicken egg yolk granule.
Chicken egg yolk granules (EYG) were the precipitated component of egg yolk after water dilution and centrifugation. Compared with egg yolk, EYG are rich in proteins, phospholipids, and minerals. In this study, an integrated proteomic analysis was carried out to in-depth mapping of the proteome, phosphoproteome, and N-glycoproteome of EYGs. After hydrolysis of the EYG total protein, the hydrolyzed peptides or the enriched phosphopeptides/glycopeptides were identified by liquid chromatography-tandem mass spectrometry. A total of 125 phosphorylation sites from 36 phosphoproteins and 244 N-glycosylation sites from 100 N-glycoproteins were identified in EYG. All 3 vitellogenins (precursors of egg yolk high-density lipoprotein) were heavily phosphorylated and N-glycosylated, of which 37 phosphorylation sites and 32 N-glycosylation sites were identified on vitellogenins-2. A Total of 30 N-glycosylation sites were identified on apolipoprotein-B (precursor of egg yolk low-density lipoprotein), but no phosphorylation site was identified. These phosphorylation and N-glycosylation of EYG proteins provide new insights for understanding the assembly structure and functional characteristics of EYG, thus contributing to its development and utilization.


Radiation and third-generation chemotherapy.
All of the third-generation chemotherapeutic agents reviewed in this article are independently active against NSCLC, although the agents differ significantly in their cellular and molecular mechanisms of cytotoxicity. All have also been shown to potentiate radiation effects, and thus are promising in exerting further cytotoxicity when used in combination chemoradiation therapy for locally advanced NSCLC. Although the toxicity to normal tissue varies among these agents when used alone, phase I/II clinical results consistently demonstrated higher risk and severity of esophagitis and pneumonitis when these agents were administered concurrently with thoracic radiation. These results were consistent with the radiosensitization properties of all these agents. Nonetheless, most chemoradiation combinations have been made feasible through careful phase I studies that establish safe doses of these agents given concurrently with radiation. Indeed, phase I outcomes consistently have demonstrated the need for dose reduction compared with doses applied in the stage IV, metastatic disease setting (see Tables 1 and 2). There have been many different dose schedules in phase I/II studies for stage III NSCLC, and most have yielded improved response rates with these agents. For all these agents discussed, multiagent chemoradiation increased toxicity when compared with single agent chemoradiation, particularly in the risk of neutropenia, and the tumor response rates were no better than single-agent chemoradiation. Most studies have not reached an adequate interval for survival endpoint to assess the impact on survival using multiagent chemoradiation. A few earlier studies using paclitaxel chemoradiation, in fact, showed that the significant improvement in tumor response rate resulted in only a small gain in survival outcome. Despite much preclinical research conducted with these agents, the optimal sequence and dose of drug and the optimal schedule for combining the two modalities remain unknown. Optimal sequencing of the chemoradiation regimens may improve distant disease control and primary tumor control, as was seen in studies that administered both full-dose induction chemotherapy and concurrent chemoradiation at reduced drug dose and in studies that administered consolidative, full-dose chemotherapy after chemoradiation. Strategically altering the treatment schedule may also enhance the radiosensitizing effects while keeping toxicity low, such as was seen in the pulsed low-dose paclitaxel chemoradiation reported by Chen et al . This pulsed low-dose schedule resulted in superior tumor response (100%) and durable primary tumor control while keeping the toxicity low. Other methods to minimize normal tissue injury and to deliver higher radiation doses, such as conformal three-dimensional radiotherapy that excludes nontarget tissues from the radiation field, are under investigation. Marks and colleagues were able to deliver radiation to 80 Gy using accelerated hyperfractionation radiation after induction chemotherapy. Intensity-modulated radiotherapy is expected to revolutionize the targeting of tumor and exclusion of normal tissues from the high-dose radiation volume in the future. Integrating biologic response modifiers, radioprotectors, and molecular targeting strategies also are being investigated. It remains unclear which agent among the third-generation drugs performs better for combination chemoradiation. The CALGB 9431 study reported by Vokes et al provided some preliminary information, in that it was a randomized phase II study of a three-arm comparison of cisplatin-containing, two-drug combination chemoradiation with one of the third-generation agents. Although direct statistical comparison between the treatment arms was not valid for a phase II setting, such an analysis did indeed reveal similar overall response rates for these three arms. Chemoradiation using third-generation chemotherapeutic agents has improved local tumor response rates, with enhanced radiation toxicity such as esophagitis and pneumonitis. The challenge of targeting distant disease control for locally advanced NSCLC continues.


Expression profile and bioinformatics analysis of circular RNAs in acute ischemic stroke in a South Chinese Han population.
Recent studies have found that circular RNAs (circRNAs) play crucial roles not only in the normal growth and the development of different tissues and organs but also in the pathogenesis and progression of various disorders. However, the expression patterns and the function of circRNAs in acute ischemic stroke (AIS) in the South Chinese Han population are unclear. In the present study, RNA sequencing (RNA-seq) data was generated from 3 AIS patients and 3 healthy controls. The circRNAs were detected and identified by CIRI2 and Find_circ software. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were used to detect the expression of circRNAs. Meanwhile, the potential diagnostic value of the selected circRNAs for AIS was assessed by generating receiver operating characteristic (ROC) curve with area under curve (AUC). The bioinformatic analysis of the host genes of differentially expressed (DE) circRNAs was performed by gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, KOBAS for pathway analysis and regulatory network analysis. miRNA-circRNA and miRNA-mRNA interactions were predicted by using TargetScan, miRanda and starBase. CircRNA-miRNA-mRNA interaction networks were created with Cytoscape. Our result showed that there were 2270 DE circRNAs between AIS patients and healthy controls. Among them, 659 were found upregulated and 1611 were downregulated. Bioinformatic analysis showed that the DE circRNAs were related to the following biological processes: endocytosis, energy metabolism, apoptosis, FoxO signaling pathway, platelet activation, neurotrophin signaling pathway and VEGF signaling pathway, which may be associated with the pathological of AIS. Three randomly selected circRNAs were successfully validated by qRT-PCR. The results show that hsa_circ_0005548 was significantly upregulated, while hsa_circ_0000607 and hsa_circ_0002465 were significantly downregulated in AIS. Furthermore, the AUC values for hsa_circ_005548, hsa_circ_0000607 and hsa_circ_0002465 were 0.51, 0.75 and 0.69, respectively, suggesting that hsa_circ_0000607 and hsa_circ_0002465 could be potential biomarkers for AIS. In addition, Bcl2 was predicted to be a direct target of miR-337-3p, and hsa_circRNA_0000607 was predicted to act as a sponge for miR-337-3p. Thus, hsa_circ_0000607 may be involved in AIS by regulating the miR-337-3p/Bcl2 axis. Collectively, our findings indicate that numerous dysregulated circRNAs may play pivotal functional roles in AIS and hsa_circ_0000607 may play a crucial role in the pathogenesis and progression of AIS by regulating the miR-337-3p/Bcl2 axis.


Preliminary study of elastic-tension digital neoprene orthoses for proximal interphalangeal joint flexion contracture.
Flexion contracture of the proximal interphalangeal joint (PIPJ) is one of the most frequent complications in finger trauma. Orthoses are the most widely used method to optimize total end-range time (TERT). No previous studies showed that an elastic tension orthosis could be applied for longer than 12 h. We aimed to demonstrate that the elastic-tension digital neoprene orthosis (ETDNO) can achieve higher TERT and therefore better range of motion than other elastic-tension orthoses (ETO) described in the literature. A prospective study of treatment of PIPJ flexion contracture included 10 PIP joints in 8 patients who met the selection criteria. They were instructed to use the ETDNO for around 23 h per day as far as possible, during a period of 3 weeks. Patients reported a mean TERT of 20.6 h a day. PIPJ contracture improved by a mean Torque Range of Motion (TROM) of 23.5° at 500 g and 22.9° at 800 g of passive extension force during the 3-week treatment. Based on the results of this study, the ETDNO appears to offer a highly effective approach for improving PIPJ flexion contracture, increasing range of motion in extension. ETDNO's efficacy probably lies in the significantly improved comfort and low-profile design, enabling excellent compliance and thus optimizing TERT. LEVEL OF EVIDENCE: Level III.


Trends, Extreme Events and Long-term Health Impacts of Particulate Matter in a Southern Indian Industrial Area.
The present study uses various statistical tools to understand the behaviour of PM2.5 and PM10 in the Kanjikode industrial area of Southern India. Annual PM2.5 and PM10 average concentrations in 2018-2020 were three times more than the World Health Organization-specified standards (5 and 15 µg m-3). The statistical distribution analysis suggested well-fitted lognormal and gamma distributions of 24-h average PM2.5 concentrations and gamma distributions of 24-h average PM10 concentrations. Trend analysis observed a notable monotonic increasing trend for 24-h average PM2.5 concentrations with an increasing magnitude of 0.43 µg m-3 per annum. A downward trend was found for 24-h average PM10 concentrations, with a decreasing magnitude of 0.2 µg m-3 per year. Extreme event analysis of PM2.5 and PM10 has provided the highest concentration levels expected in the coming 10 years, 193 and 165 µg m-3, respectively, higher than the Indian National Ambient Air Quality Standards and considered a public health threat. The health risk assessment by AirQ + emphasized that more than 15, 34, and 27 premature deaths caused by total mortality in 2018, 2019, and 2020 could have been prevented if PM2.5 concentrations in the Kanjikode industrial area did not exceed 10 μg m-3. Statistical analysis and health risk assessment suggested adopting various constructive and multipronged approaches to reduce pollution levels and develop a health risk management plan in the industrial region. The online version contains supplementary material available at 10.1007/s11270-023-06302-y.


Increased apoptosis and hypomyelination in cerebral white matter of macular mutant mouse brain.
Hypomyelination in developing brain is often accompanied by congenital metabolic disorders. Menkes kinky hair disease is an X-linked neurodegenerative disease of impaired copper transport, resulting from a mutation of the Menkes disease gene, a transmembrane copper-transporting p-type ATPase gene (ATP7A). In a macular mutant mouse model, the murine ortholog of Menkes gene (mottled gene) is mutated, and widespread neurodegeneration and subsequent death are observed. Although some biochemical analysis of myelin protein in macular mouse has been reported, detailed histological study of myelination in this mouse model is currently lacking. Since myelin abnormality is one of the neuropathologic findings of human Menkes disease, in this study early myelination in macular mouse brain was evaluated by immunohistochemistry. Two-week-old macular mice and normal littermates were perfused with 4% paraformaldehyde. Immunohistochemical staining of paraffin embedded and vibratome sections was performed using antibodies against either CNPase, cleaved caspase-3 or O4 (marker of immature oligodendrocytes). This staining showed that cerebral myelination in macular mouse was generally hypoplastic and that hypomyelination was remarkable in internal capsule, corpus callosum, and cingulate cortex. In addition, an increased number of cleaved caspase-3 positive cells were observed in corpus callosum and internal capsule. Copper deficiency induced by low copper diet has been reported to induce oligodendrocyte dysfunction and leads to hypomyelination in this mouse model. Taken together, hypomyelination observed in this study in a mouse model of Menkes disease is assumed to be induced by increased apoptosis of immature oligodendrocytes in developing cerebrum, through deficient intracellular copper metabolism.


Demystifying Bretton Woods Institutions' Rhetoric on Public Services.
This article reviews Bretton Woods Institutions' approach to public services, including during the recent COVID-19 crisis. Drawing on the specific case of IMF and World Bank's response to the multiple crisis triggered by the pandemic, it shows that there is a discourse-practice disjuncture in the institutions approach to public services as they continue to favour austerity and market-oriented solutions for the delivery of public services. The article therefore seeks to demystify the Bretton Woods institutions rhetoric and demand the adoption of a different way of understanding public services, and social policy more broadly.


Superoxide dismutase activity, caeruloplasmin activity and lipoperoxide levels in tumour and host tissues of mice bearing the Lewis lung carcinoma.
Superoxide dismutase (SOD) activity, plasma caeruloplasmin activity and the level of whole tissue and subcellular lipoperoxides have been determined in normal and neoplastic tissues from control and tumour-bearing mice, measurements being made nine, twelve and fifteen days after the inoculation of Lewis lung carcinoma cells. SOD activity of host liver and lung tissues did not vary significantly from those of the control animals. Blood SOD activity of the tumoured animals was markedly elevated on the ninth and twelfth days after inoculation, decreasing to control levels on the fifteenth day. Tumor SOD diminished from activity on the ninth day which was greater than that for control lung to a level significantly lower than that for control lung on the twelfth and fifteenth days after inoculation. The presence of a tumor did not appear to affect plasma caeruloplasmin oxidase levels. The lipoperoxide level of hepatic tissue rose significantly as the tumour progressed. In the lung tissue the lipoperoxides decreased from a level four times higher on the ninth day to one not significantly different from that of the controls. Tumour lipoperoxides were about twice the level of hepatic tissue and of the order of ten-fold greater than those of lung. The level of lipoperoxide in the plasma of tumoured mice did not differ markedly from that of control mice. Assays of lipoperoxide in subcellular fractions of liver, lung and tumour tissue revealed that the elevated lipoperoxide was principally synthesized in the endoplasmic reticulum.


Genetic Contribution of Paleopolyploidy to Adaptive Evolution in Angiosperms.
Ancient whole-genome duplications (WGDs or polyploidy) are prevalent in plants, and some WGDs occurred during the timing of severe global environmental changes. It has been suggested that WGDs may have contributed to plant adaptation. However, this still lacks empirical evidence at the genetic level to support the hypothesis. Here, we investigated the survivors of gene duplicates from multiple ancient WGD events on the major branches of angiosperm phylogeny, and aimed to explore genetic evidence supporting the significance of polyploidy. Duplicated genes co-retained from three waves of independent WGDs (∼120 million years ago [Ma], ∼66, and <20 Ma) were investigated in 25 selected species. Gene families functioning in low temperature and darkness were commonly retained gene duplicates after the eight independently occurring WGDs in many lineages around the Cretaceous-Paleocene boundary, when the global cooling and darkness were the two main stresses. Moreover, the commonly retained duplicates could be key factors which may have contributed to the robustness of the critical stress-related pathways. In addition, genome-wide transcription factors (TFs) functioning in stresses tend to retain duplicates after waves of WGDs, and the coselected gene duplicates in many lineages may play critical roles during severe environmental stresses. Collectively, these results shed new light on the significant contribution of paleopolyploidy to plant adaptation during global environmental changes in the evolutionary history of angiosperms.


[Biliary lithiasis].
We have reviewed our experience with 2,430 cases of lithiasis of the biliary tract, 500 of them located in the common bile duct and 104 corresponding to residual lithiasis. We have made a general reflexion on the problems aroused by this very common al condition, which has an imprevisible, some times severe, outcome. The recent acquisition of new conservative methods, as disolvents and lithotrix, and the diagnostic and therapeutic role of endoscopy have revolutionated the state of the art and have introduced controversial points still unsolved. As it is common in clinical practice, biliary lithiasis should be approached in a multidisciplinary fashion, employing the most convenient diagnostic procedure for the clinical situation of the patient; a priori no accredited procedure should be disregarded.


Adapting the US Institute for Safe Medication Practices' Medication Safety Self Assessment tool for community pharmacies in Finland.
To adapt a US Institute for Safe Medication Practices' Medication Safety Self Assessment (MSSA) tool to, and test its usefulness in, Finnish community pharmacies. A three-round Delphi survey was used to adapt self-assessment characteristics of the US MSSA tool to Finnish requirements, and to obtain a consensus on the feasibility and significance of these characteristics in assessing the safety of medication practices in community pharmacies. The Delphi modified self-assessment tool was piloted in 18 community pharmacies in order to refine the tool, using a questionnaire containing structured and open-ended questions. A total of 211 self-assessment characteristics were accepted to the self-assessment tool for pilot use by expert panellists in the Delphi rounds. Most pilot users considered the tool as useful in: identifying medication safety targets for development; medication safety assessment; and identifying the strengths of medication safety. The substance of the self-assessment tool was considered as comprehensive and essential for medication safety. Most criticism was regarding: the multiplicity of self-assessment characteristics; interpretation of some characteristics; and that all the characteristics were not yet available. After the modification, according to the pilot users' comments, the final Finnish tool consisted of 230 medication safety characteristics. The study indicated the feasibility of adapting a US medication safety self-assessment tool for use in community pharmacy practice in Finland. More efforts should be made to familiarise Finnish community pharmacists with the self-assessment tool and its benefits, and get them to use the tool as part of their long-term quality improvement.


1H, 13C and 15N NMR assignments of a calcium-binding protein from Entamoeba histolytica.
We report almost complete sequence specific (1)H, (13)C and (15)N NMR assignments of a 150-residue long calmodulin-like calcium-binding protein from Entamoeba histolytica (EhCaBP6), as a prelude to its structural and functional characterization.


Decreased echogenicity of the embryo is correlated with absence of cardiac activity.
The purpose of this study was to investigate whether the sonographic echogenicity of embryos is associated with cardiac activity in utero. The present study reviewed a total of 164 embryos having a gestational age between 6 and 8 weeks. These embryos were examined by transvaginal ultrasonography and a comparison of their echogenicity was made with respect to those of the placenta and the myometrium. Grade II embryos were less echogenic than the placenta or had similar echogenicity with the myometrium, whereas grade I embryos shared the same echogenicity as the placenta. In contrast, grade III embryos were less echogenic than the myometrium. Most of the embryos with cardiac activity were detected to have grade II echogenicity (78/130, 60.0%), whereas the remaining embryos had grade I echogenicity (52/130, 40.0%). In contrast, most of the embryos without cardiac activity had grade III echogenicity (20/34, 58.8%), whereas the remaining embryos had either grade II (8/34, 23.5%) or grade I (6/34, 17.7%) echogenicity. Decreased echogenicity of embryos on grayscale ultrasound in the early first trimester is correlated with an absence of cardiac activity.


Trends in hospitalization among asthmatic children in Finland from 1972 to 1986.
Trends in hospitalization among asthmatic children were examined over a period of 15 years on the basis of a hospital discharge register covering all hospitals in Finland. The annual mean population under 15 years of age, 992,994, had a total of 37,965 hospitalization periods on account of asthma during the interval studied. Examination in 5 year age groups showed treatment periods for boys under 5 years to have increased by 1.8% annually relative to the total population (95% confidence interval +0.6(-)+3.1) and those for girls by 22% (95% CI +0.7(-)+3.7), whereas the changes in the older age groups were insignificant. First admissions decreased annually in all age groups in the case of both boys and girls. The numbers of hospitalization periods due to asthma were significantly higher for boys than for girls. The use of hospital services by asthmatic children was appropriate during the period concerned, which may partly be explained by the fact that child health care is well organized in Finland and the treatment of childhood asthma entirely in the hands of paediatricians.


Bed nucleus of the stria terminalis alpha(1)-adrenoceptor modulates baroreflex cardiac component in unanesthetized rats.
The bed nucleus of stria terminalis (BST) has a tonic modulating role on the baroreflex parasympathetic component. In the present study, we verified that local BST-adrenoceptors modulate baroreflex-evoked bradycardiac responses in unanesthetized rats. Bilateral microinjection of the selective alpha(1)-adrenoceptor antagonist WB4101 (15 nmol/100 nL) into the BST increased the gain of reflex bradycardia in response to mean arterial pressure increases caused by intravenous (i.v.) infusion of phenylephrine, suggesting that BST alpha(1)-adrenoceptors modulate baroreflex bradycardiac response. Bilateral microinjection of either the selective alpha(2)-adrenoceptor antagonist RX821002 (15 nmol/100 nL) or the non-selective beta-adrenoceptor antagonist propranolol (15 nmol/100 nL) into the BST had not affected baroreflex bradycardia. Animals were pretreated intravenously with the cholinergic muscarinic receptor antagonist homatropine methyl bromide (HMB, 1.5 mg/Kg) to test the hypothesis that activation of alpha(1)-adrenoceptors in the BST would modulate the baroreflex parasympathetic component. Baroreflex bradycardiac responses evoked before and after BST treatment with WB4101 were no longer different when rats were pretreated with HMB. These results suggest that parasympathetic activation accounts for the effects saw after BST pharmacological manipulation and ruling out the possibility of a sympathetic withdraw. In conclusion, our data point out that local alpha(1)-adrenoceptors mediate the BST tonic influence on the baroreflex bradycardiac response modulating parasympathetic cardiac activity.


Amelioration of oxidative stress in differentiated neuronal cells by rutin regulated by a concentration switch.
Increasing studies have implicated superfluous production of reactive oxygen species (ROS) as a significant factor in the progress of neurodegenerative disorders ranging from ischemic stroke to amyotrophic lateral sclerosis. The possible mechanisms relating to oxidative stress and neurodegeneration are yet to be thoroughly understood. Rutin, a flavonoid, has been well documented for its beneficial and pharmacological activities against diverse targets. However, the mechanism involved in the beneficial effects of rutin against neurodegeneration still remains unclear. Our study investigates the concentration switch effects of rutin on differentiated human neuroblastoma cells (IMR32) in vitro to unveil the possible mechanism of its action. IMR32 cells were differentiated using retinoic acid and challenged with different doses of rutin for 24 h duration to study the influence of ROS on differentiated neuronal cells and ROS-mediated apoptosis. The study showed that the high (100 μM) and low (100 nM and 10μM) rutin concentrations significantly avert ROS generation by two different mechanisms, by enhancing apoptosis through the modulation of levels of Bcl2, Caspase-3, survivin and its antioxidant activity via stress-related proteins, JNK and p38 MAPK. Our study suggests that rutin is a multi-targeted therapeutic and preventive agent that may act as an adjuvant complementary therapeutic molecule to treat oxidative stress-mediated neurodegeneration.


Overexpression of MRP1/ABCC1, Survivin and BCRP/ABCC2 Predicts the Resistance of Diffuse Large B-Cell Lymphoma to R-CHOP Treatment.
Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment resistance to the first-line R-CHOP regimen. ATP binding cassette (ABC) transporters and survivin might play a role in multidrug resistance (MDR) in various tumors. The aim was to investigate if the coexpression of ABC transporters and survivin was associated with R-CHOP treatment response. The expression of Bcl-2, survivin, P-glycoprotein/ABCB1, MRP1/ABCC1, and BCRP/ABCC2 was analyzed using immunohistochemistry in tumor specimens obtained from patients with DLBCL, and classified according to the treatment response as Remission, Relapsed, and (primary) Refractory groups. All patients received R-CHOP or equivalent treatment. Bcl-2 was in strong positive correlation with clinical parameters and all biomarkers except P-gp/ABCB1. The overexpression of MRP1/ABCC1, survivin, and BCRP/ABCC2 presented as high immunoreactive scores (IRSs) was detected in the Refractory and Relapsed groups (p < 0.05 vs. Remission), respectively, whereas the IRS of P-gp/ABCB1 was low. Significant correlations were found among either MRP1/ABCC1 and survivin or BCRP/ABCC2 in the Refractory and Relapsed groups, respectively. In multiple linear regression analysis, ECOG status along with MRP1/ABCC1 or survivin and BRCP/ABCG2 was significantly associated with the prediction of the R-CHOP treatment response. DLBCL might harbor certain molecular signatures such as MRP1/ABCC1, survivin, and BCRP/ABCC2 overexpression that can predict resistance to R-CHOP.


A scheme to detect the intensity of dusty weather by applying microwave radars and lidar.
Detection of the intensity of dusty weather is critical for weather forecasting. In this paper, the effective detection ranges of microwave radars and lidar in dusty weather of different intensities were theoretically calculated, which are validated by the microwave radar and lidar detection data in real dusty weather. Further, the excess charges carried by suspended dust and relative humidity can significantly enhance the echo power but have little effect on the effective detection ranges in dusty weather. Based on the effective detection ranges of microwave radars and lidar, a scheme of combined microwave radars and lidar to detect the intensity of dusty weather is proposed, that is to detect the severe dust storm by using the longer wavelength radar, while to detect the blowing dust/floating dust by using lidar. It will be a cost-saving way by using the existing meteorological radars to establish the detection scheme, which will make the precaution against disastrous weather promising.


The construction of a new integrative vector with a new selective marker of copper resistance for glycerol producer Candida glycerinogenes.
Candida glycerinogenes WL2002-5 has been used for industrial-scale fermentation of glycerol and may be a promising genetic host due to its tolerance to high osmotic pressure and fast growth. It resists many kinds of drugs, such as G418/hygromycin/cycloheximide. In previous studies, only Zeocin was used as a drug-resistant marker. But Zeocin is so expensive that it largely limits the genetic and molecular study. Here, we constructed a eukaryotic integrative vector pGAPZU, based on pGAPZB, to gain a new selectable marker of copper resistance for this strain. The results showed that the CUP1 gene of Saccharomyces cerevisiae elevated copper resistance of C. glycerinogenes. The C. glycerinogenes transformed with recombinant vector pGUC, obtained from introducing CUP1 gene into plasmid pGAPZU, could resist 21 mM copper, while the minimum inhibitory concentration (MIC) of wild type was 18 mM in solid YEPD medium. With copper resistance as a selective marker, research cost was largely reduced from 114.0 $/L with Zeocin as selective marker to 0.1 $/L. The new expression vector pGUC and selective marker of copper resistance gene establish a good foundation for further study on this industrial strain.


Effects of serum and insulin-like growth factors on human neuroblastoma cell growth.
Insulin-like growth factors (IGF-I and IGF-II) are mitogenic polypeptides expressed in both developing and adult tissues. To examine the effects of IGFs on neuronal growth, we used SH-SY5Y neuroblastoma cells as an in vitro model of nervous system development. In the current study, we found that either IGF-I (0.1 to 10 nM), insulin (0.1 to 5 micrograms/ml) or calf serum (0.1 to 3%) increased SH-SY5Y proliferation over a 3 day period in a dose dependent manner. In each case, treatment with anti-IGF-I receptor antibodies blocked cell proliferation. IGF-II mRNA levels correlated with SH-SY5Y cell density; subconfluent cells expressed high levels of IGF-II mRNA while low levels of IGF-II mRNA were present in confluent cells. Similarly, serum deprivation increased IGF-I receptor mRNA by 4-fold. Collectively, these results support the concept that an IGF/IGF-I receptor system at least partially mediates SH-SY5Y cell proliferation and suggests the importance of IGFs in regulating neuronal growth.


Childhood family disruption and adult height: is there a mediating role of puberty?
Childhood family background is known to be associated with child growth and development, including the onset of puberty, but less is known about the influence of childhood family disruption on outcomes in later life. Given the associations between early family disruption and childhood development, we predicted that there may be long-term health-relevant consequences of childhood disruption. Using data from a large US interview sample (n = 16 207), we test if death or divorce of parents, at different childhood periods, was associated with adult stature, and whether age at puberty mediated this relationship, for men and women. RESULTS MEN: : parental death and divorce during early childhood was associated with shorter adult height, and later puberty. Later puberty was associated with shorter adult height. Path analyses demonstrated that the relationship between parental divorce and height was completely mediated by age at puberty; although parental death was only partially mediated by age at puberty. WOMEN: the father's death during early childhood was associated with earlier puberty, which was in turn associated with shorter adult stature. The relationship between paternal death and height is entirely mediated by age at puberty; no evidence of a direct relationship between childhood family disruption and adult height. Early childhood familial disruption is associated with shorter height for men, and is partially mediated by later puberty. For women, the relationship between father's death, and height was completely mediated by earlier puberty. These findings indicate that disruption during childhood can have long-reaching health repercussions, particularly for boys.


Long-term outcomes of juvenile-onset recurrent respiratory papillomatosis.
To investigate the adult outcomes of children with juvenile-onset recurrent respiratory papillomatosis via long-term follow-up. Retrospective study. Beijing Tongren Hospital. The study includes 121 patients with recurrent respiratory papillomatosis. We followed up respiratory papillomatosis patients aged least 14 years and analysed their clinical features based on recurrence-free time. In total, 112 (92.6%) patients underwent three or more operations. The age at initial operation was 4.3 ± 2.9 years; 47.9% (58/121) experienced recurrence and underwent surgical treatment after age 14. At follow-up, 5% (6/121) had died, 41.3% (50/121) had been recurrence-free for 5 years or more (cured group), and 53.7% (65/121) had recurrence in the past 5 years (recurrent group). The age at the last operation was 9.2 ± 4.6 years in the cured group. The overall operation frequency was higher in the recurrence group than in the cured group (17.8 ± 11.9 vs 8.7 ± 6.5). Additionally, the human papillomavirus (HPV) infection and tracheal dissemination rates were higher in the recurrence group than in the cured group (90.8% [59/65] vs 54.0% [27/50] and 26.2% [17/65] vs 10% [5/50], respectively). The mortality rate for juvenile-onset recurrent respiratory papillomatosis is 5%. Approximately 50% of children experience recurrence and require repeated operations in adulthood. No significant difference in sex, age at initial operation or adjuvant therapy between the cured and recurrent groups was observed; however, significant between-group differences were found in overall operation frequency, aggressive disease, tracheal dissemination of papilloma, and HPV infection.


Pharmacological profile of natural and synthetic compounds with rigid adamantane-based scaffolds as potential agents for the treatment of neurodegenerative diseases.
This review is dedicated to the comparative analysis of structure-activity relationships for more than 75 natural and synthetic derivatives of adamantane. Some of these compounds, such as amantadine and memantine, are currently used to treat dementia, Alzheimer's and Parkinson's diseases and other neurodegenerative diseases. The data presented show that the pharmacological potential of 1-fluoro- and 1-phosphonic acid adamantane derivatives against Alzheimer's and Parkinson's diseases and other neurodegenerative diseases exceeds those of well-known amantadine and memantine. The information presented in this review highlights the promising directions of studies for biochemists, pharmacologists, medicinal chemists, physiologists, and neurologists, as well as to the pharmaceutical industry.


Surgery and the release of a neutrophil Fc gamma receptor.
The fact that the incidence and mortality from postsurgical sepsis have remained unchanged over the past 15 years raises the possibility that some patients possess an idiosyncratic predisposition to the development of a postoperative sepsis response. Genetic polymorphisms of the neutrophil receptor for immunoglobulin G, CD16, are known, and their inheritance is associated with functional differences in neutrophil phagocytosis. The present studies were designed to provide preliminary data on the effects of surgery on the level of expression of CD16 and its metabolism preparatory to detailed examination of the relationship of these polymorphisms to sepsis responses. Neutrophil CD16 expression was measured by flow cytometry before and after operation in patients undergoing major resectional surgery of the digestive tract. Assays were performed on whole blood preparations as well as on isolated and activated neutrophil preparations from these patients. Neutrophil CD16 expression was constitutively higher both before and after surgery in patients who developed a postoperative sepsis response than in those who did not. Surgery had no effect on the level of surface neutrophil CD16 expression in either group. Surgery depleted intracellular CD16 stores despite the maintenance of a constant level of CD16 on the neutrophil surface, membrane-bound CD16 being more readily cleaved by physiological neutrophil activators after surgery than before surgery. The intrinsic level of expression and postsurgical metabolism of neutrophil CD16 may be an important component of the predisposition of some patients to develop infection or sepsis after injury. Further studies of the distribution of CD16 allotypes and neutrophil function among surgical patients are warranted.


Aryl-, halogenated- and alkyl- organophosphate esters induced oxidative stress, endoplasmic reticulum stress and NLRP3 inflammasome activation in HepG2 cells.
Organophosphate esters (OPEs) are a group of extensively used man-made chemicals with diverse substituents that are ubiquitously detected in human-related samples including serum, breastmilk, food and house dust. The understanding of their toxicological effects and potential mechanisms on hepatocytes is still limited. In this study, nine most frequently detected OPEs were selected and divided into three subgroups (aryl-, halogenated- and alkyl-OPEs) based on their substituents. The cytotoxicity, apoptosis, oxidative stress, endoplasmic reticulum (ER) stress and NLRP3 inflammasome activation induced by OPEs were evaluated in human hepatocellular carcinomas HepG2 cells. All OPEs induced apoptosis likely through a caspase-dependent apoptotic pathway. The activities of anti-oxidative enzyme SOD and CAT exhibited sensitive responses after OPEs treatment for 6 h. The OPEs induced ROS overproduction, DNA damage, endoplasmic reticulum (ER) stress and NLRP3 inflammasome activation varied among aryl-, halogenated- and alkyl-OPEs. Halogenated- and alkyl- OPEs induced overproduction of ROS and DNA damage, and elevated ER stress and NLRP3 inflammasome activation are observed aryl-OPEs induced cytotoxicity.


New method to improve the quality of vision in cataractous keratoconus eyes.
To analyze using optical simulations if the proper use of a segmented intraocular lens (IOL) can improve the visual outcomes compared to the implantation of a spherical monofocal IOL. The wavefront profile of the Mplus (Oculentis) and a monofocal IOLs with the phase transformation introduced by each IOL were calculated using a Hartmann-Shack wavefront sensor. In addition, the wavefront profile of schematic eye models of various keratoconus conditions was obtained and was propagated to the IOLs. The optical performance of such combination was obtained after combining ray tracing and Fourier optics. A pre-clinical validation was also evaluated incorporating clinical data from three different keratoconus eyes of three patients. The implantation of the Mplus IOL can compensate or reduce the overall coma of the eye with keratoconus improving the quality of vision compared with a spherical monofocal IOL due to lower displacements of the retinal image or tilting in keratoconus. All theoretical simulations were confirmed afterwards by mean of a preclinical validation. The use of a standard toric segmented IOL with a proper orientation and selection of the addition can improve the optical quality of the keratoconus eye compared to the use of a monofocal spherical IOL.


Least squares fit of data to hyperbolic dose-response curves using a programmed minicalculator (TI-59).
Equations of the Michaelis-Menten form are frequently encountered in a number of areas of biochemical and pharmacological research. A program is presented for use on the programmable TI-59 calculator with added printer which performs an iterative least-squares fit of up to 80 data pairs to this equation and estimates the standard deviations and standard errors of the determined parameters. The program assigns equal weights to errors over the entire data range and is thus appropriate for situations in which data precision is independent of amplitude.


Hypoxia pretreatment of bone marrow-derived mesenchymal stem cells seeded in a collagen-chitosan sponge scaffold promotes skin wound healing in diabetic rats with hindlimb ischemia.
Bone marrow-derived mesenchymal stem cells (BM-MSCs) have properties that make them promising for the treatment of chronic nonhealing wounds. The major challenge is ensuring an efficient, safe, and painless delivery of BM-MSCs. Tissue-engineered skin substitutes have considerable benefits in skin damage resulting from chronic nonhealing wounds. Here, we have constructed a three-dimensional biomimetic scaffold known as collagen-chitosan sponge scaffolds (CCSS) using the cross-linking and freeze-drying method. Scanning electron microscopy images showed that CCSS had an interconnected network pore configuration about 100 μm and exhibited a suitable swelling ratio for maintaining morphological stability and appropriate biodegradability to improve biostability using swelling and degradation assays. Furthermore, BM-MSCs were seeded in CCSS using the two-step seeding method to construct tissue-engineered skin substitutes. In addition, in this three-dimensional biomimetic CCSS, BM-MSCs secreted their own collagen and maintain favorable survival ability and viability. Importantly, BM-MSCs exhibited a significant upregulated expression of proangiogenesis factors, including HIF-1α, VEGF, and PDGF following hypoxia pretreatment. In vivo, hypoxia pretreatment of the skin substitute observably accelerated wound closure via the reduction of inflammation and enhanced angiogenesis in diabetic rats with hindlimb ischemia. Thus, hypoxia pretreatment of the skin substitutes can serve as ideal bioengineering skin substitutes to promote optimal diabetic skin wound healing.


Motion artifacts reduction in DWI using navigator echoes: a robust and simple correction scheme.
NMR signal phase variation caused by macroscopic motion of an object during application of the diffusion gradient is a well-known effect in diffusion-weighted imaging (DWI) using the standard pulsed gradient spin-echo sequence (PGSE). This phase error causes severe ghost artifacts in the output image when phase encoding techniques, such as two dimensional Fourier transform (2DFT) imaging, are used. One possible way to eliminate the motion effects is the navigator echo technique. The method is based on estimating the phase error from the navigator echo and using it for the correction of the image echo. The phase errors (zero and first order) for the phase correction of the image echo are usually evaluated from the navigator echo after Fourier transform (FT) in the readout direction, correcting for both translation and rotation. We present here a simple algorithm which enables evaluation and correction in the time domain of phase errors induced by motion. This approach has the advantage of improved correction of motional artifacts and minimized sensitivity to noise and inaccurate setting up of the experiment.


Use of touch preps for intraoperative diagnosis of sentinel lymph node metastases in breast cancer.
Intraoperative touch prep (TP) is highly accurate for determining positive breast cancer margins and thereby reducing the need for second surgeries. It also may be useful in determining the status of the sentinel lymph node (SLN) during the initial surgical resection. The objective of this study was to test the ability of intraoperative TP to predict metastatic disease and, thus, the necessity for axillary lymph node dissection (ALND) at the time of SLN biopsy. Fifty-five patients with invasive breast cancer were entered in the SLN biopsy protocol. The SLN was identified by gamma probe, dissected, and sent to pathology for TP and permanent sections. Level I and II ALND was then performed. Any radiolabeled LN in the lymphadenectomy specimen also was sent for TP and permanent sections. A total of 124 radiolabeled lymph nodes (LNs) were submitted for TP; of these, 93 (75%) were SLNs. Pathologic diagnosis by TP was correct compared with permanent sections for 99.2% of the nodes. There were no false positives. There was one (0.8%) false negative. The positive predictive value was 100% and the negative predictive value was 99%. Sensitivity was 95.7% and specificity was 100%. TP is a simple, quick, and accurate method for detecting metastatic disease in the SLN and, when used intraoperatively, enables the surgeon to determine whether or not an ALND is necessary at the time of the initial surgery.


Photosynthesis in phosphoenolpyruvate carboxykinase-type C4 plants: pathways of C4 acid decarboxylation in bundle sheath cells of Urochloa panicoides.
The mechanism of C4 acid decarboxylation was studied in bundle sheath cell strands from Urochloa panicoides, a phosphoenolpyruvate carboxykinase (PCK)-type C4 plant. Added malate was decarboxylated to give pyruvate and this activity was often increased by adding ADP. Added oxaloacetate or aspartate plus 2-oxoglutarate (which produce oxaloacetate via aspartate aminotransferase) gave little metabolic decarboxylation alone but with added ATP there was a rapid production of PEP. For this activity ADP could replace ATP but only when added in combination with malate. In addition, the inclusion of aspartate plus 2-oxoglutarate with malate plus ADP often increased the rate of pyruvate production from malate by more than twofold. Experiments with respiratory chain inhibitors showed that the malate-dependent stimulation of oxaloacetate decarboxylation (PEP production) was probably due to ATP generated during the oxidation of malate in mitochondria. We could provide no evidence that photophosphorylation could serve as an alternative source of ATP for the PEP carboxykinase reaction. We concluded that both PEP carboxykinase and mitochondrial NAD-malic enzyme contribute to C4 acid decarboxylation in these cells, with the required ATP being derived from oxidation-linked phosphorylation in mitochondria.


Horizon Scanning for pharmaceuticals and effective health care programming: 2 years' experience at the Italian Medicines Agency.
The Italian Medicines Agency (AIFA) developed Horizon Scanning (HS) methodology to address programming and sustainability challenges posed by accelerating pharmaceutical innovation and increasing costs. From July 2018 to June 2020, 563 new potential treatments (new medicines and new indications of existing medicines) with an expected impact in 2020-2022 were identified. In this review, we assess and discuss these HS results, including medicine characteristics related to higher prioritization scores, such as clinical areas of major development. After exclusions because of the selection process, 213 (40.6%) new potential treatments were included in the prioritization tool; 25 (11.7%) were shown to be possibly associated with a major impact on healthcare systems (HCSs) according to overall prioritization criteria. Lessons learned from the process led to HS system improvements.


Binding of an antibody against a noncompact myelin protein to presumptive glial cells in the visual system of the crab Ucides cordatus.
Glial cells, in both vertebrate and invertebrate nervous systems, provide an essential environment for developmental, supportive, and physiological functions. However, information on glial cells themselves and on glial cell markers, with the exception of those of Drosophila and other insects, is not abundant in invertebrate organisms. A common ultrastructural feature of invertebrate nervous systems is that layers of glial cell cytoplasm-rich processes ensheath axons and neuronal and glial somata. In the present study, we have examined the binding of a monoclonal antibody to 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) in the compound eye and optic lobe of the crab Ucides cordatus using both light and electron microscopy. CNPase is a noncompact myelin protein that is a phenotypic marker of oligodendroglial and Schwann cells, is apparently involved in the ensheathment step prior to myelin compaction, and is also expressed by the potentially myelinating olfactory ensheathing glia. CNPase has raised much interest, first by virtue of its unusual enzymatic activity and more recently by its membrane-skeletal features and possible involvement in migration or expansion of membranes. We have found CNPase-like immunoreactivity in most cells of the compound eye basement membrane and both in optic cartridges of the synaptic layer and cells of the outer sublayer of the lamina ganglionaris. The results suggest that in the crab visual system some, but not all, glial cells, including some adaxonal glia, may express the noncompact myelin protein CNPase or a related protein.


Determinants of gastric cancer screening attendance in Korea: a multi-level analysis.
We aimed to assess individual and area-level determinants of gastric cancer screening participation. Data on gastric cancer screening and individual-level characteristics were obtained from the 2007-2009 Fourth Korea National Health and Nutrition Examination Survey. The area-level variables were collected from the 2005 National Population Census, 2008 Korea Medical Association, and 2010 National Health Insurance Corporation. The data were analyzed using multilevel logistic regression models. The estimated participation rate in gastric cancer screening adhered to the Korea National Cancer Screening Program guidelines was 44.0% among 10,658 individuals aged over 40 years who were included in the analysis. Among the individual-level variables, the highest income quartile, a college or higher education level, living with spouse, having a private health insurance, limited general activity, previous history of gastric or duodenal ulcer, and not currently smoking were associated with a higher participation rate in gastric cancer screening. Urbanization showed a significant negative association with gastric cancer screening attendance among the area-level factors (odds ratio (OR) = 0.73; 95% confidence interval (CI) = 0.57-0.93 for the most urbanized quartile vs. least urbanized quartile). There are differences in gastric cancer screening attendance according to both individual and regional area characteristics.


In vivo 1H NMR spectroscopy of an intracerebral glioma in the rat.
High-resolution 1H surface coil NMR spectroscopy (MRS) was used to evaluate in vivo the cerebral metabolism changes in rat brain induced by a glial tumor growing in situ. Tumor cells (C6 glioma cells) were stereotaxically placed in the right hemisphere superficially. 1H MRS was performed using 5-mm surface coils implanted over the right hemisphere and the water was suppressed using a binomial sequence. As the intracerebral tumor size increased, there was a marked decrease in the N-acetyl aspartate level and an increase in the 1.3 ppm peak. Edition of this peak showed that lactate increased but lipids increased much more than lactate. Moreover the ratio between the choline-phosphocholine and creatine-phosphocreatine peaks changed. This study demonstrates that high-resolution surface coil 1H MRS can be used to monitor changes in metabolism associated with growth of an experimentally induced rat brain tumor in situ.


Engineered allosteric ribozymes as biosensor components.
RNA and DNA molecules can be engineered to function as molecular switches that trigger catalytic events when a specific target molecule becomes bound. Recent studies on the underlying biochemical properties of these constructs indicate that a significant untapped potential exists for the practical application of allosteric nucleic acids. Engineered molecular switches can be used to report the presence of specific analytes in complex mixtures, making possible the creation of new types of biosensor devices and genetic control elements.


miR-181b-5p inhibits endothelial-mesenchymal transition in monocrotaline-induced pulmonary arterial hypertension by targeting endocan and TGFBR1.
Endothelial-mesenchymal transition (EndMT) is a frequent event in endothelial dysfunction, which is associated with pulmonary arterial hypertension (PAH). MiR-181 family members exert diverse effects in multiple biological processes. However, the relationships between miR-181b-5p (miR-181b) and EndMT in PAH are not well understood. In this study, Sprague-Dawley (SD) rats were injected with monocrotaline (MCT) to establish PAH model, and primary rat pulmonary arterial endothelial cells (rPAECs) were treated with TNF-α, TGFβ1 and IL-1β in combination to induce EndMT (I-EndMT). Then we explored miR-181b expression and examined its functional role in PAH. Our data showed that miR-181b was down-expressed in PAH, and its overexpression attenuated the hemodynamics, pulmonary vascular hypertrophy, right ventricular remodeling and EndMT process in MCT-induced PAH rats. In I-EndMT rPAECs, we observed that inducing miR-181b reversed the decrease of endothelial markers and increase of mesenchymal markers. However, knockdown of miR-181b induced similar effects to EndMT. In addition, endocan and TGFBR1 levels were also increased in EndMT, which were negatively regulated by miR-181b. Luciferase activity results indicated that endocan and TGFBR1 were direct target genes of miR-181b. In summary, our findings firstly demonstrate that the beneficial effect of miR-181b on PAH may be associated with endocan/TGFBR1-mediated EndMT, providing a new insight into the diagnosis and treatment of PAH.


The distribution of inside-out and right-side-out erythrocyte membrane vesicles in Duchenne progressive muscular dystrophy.
In ten cases of Duchenne muscular dystrophy, the distribution of erythrocyte ghost vesicles in dextran 110 gradient was examined. When compared with controls a greater number of inside-out vesicles was observed. It is suggested that the tendency to form abnormally oriented vesicles could result from structural abnormalities of the erythrocyte membranes.


Slow growth of Empetrum nigrum in industrial barrens: combined effect of pollution and age of extant plants.
We studied the impact of industrial pollution on population demography (age structure), growth and reproduction of crowberry, Empetrum nigrum L. Crowberry growing in severely polluted sites near non-ferrous smelters (at Harjavalta, Monchegorsk and Nikel) was on average twice as old as in unpolluted habitats, as indicated by the number of annual rings at root collar. Shoot length decreased both with plant ageing and due to pollution impact, while neither the proportion of generative plants nor berry production was affected by pollution or plant age. Our results suggest that death of the extant individuals of E. nigrum near the non-ferrous smelters is to a large extent explained by age-related damage of the main stem accelerated by pollution. Since vegetative propagation, seed germination and seedling establishment are hampered by soil toxicity, E. nigrum populations near the smelters continue to decline with ageing in spite of the gradual decline of emissions.


Mycotoxin fumonisin B1 selectively down-regulates the basal IL-8 expression in pig intestine: in vivo and in vitro studies.
Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium verticillioides and F. proliferatum, common contaminants of maize. FB(1) causes toxicological effects in laboratory and domestic animals including pigs. The gastrointestinal tract represents a barrier encountered by exogenous food compounds. The purpose of our study was to determine FB(1) effects on intestinal immune response. Nine recently weaned piglets orally received 0.5 mg of purified toxin/kg of body weight/day for 7 days, while eight other animals were kept as controls. After necropsy, ileal samples were analyzed for five pro-inflammatory cytokines mRNA expression by RT-PCR. No difference was observed for IL-1beta, IL-6, IL-12 and TNF-beta mRNA levels between control and FB(1)-treated animals. In contrast, FB(1) treatment induced a significant down-regulation of the expression of IL-8 mRNA in the pig ilea. The effect of FB(1) on the IL-8 expression was also examined in the porcine intestinal epithelial cell line IPEC-1. FB(1) decreases the expression of IL-8, both at the mRNA and protein levels, in a dose-dependant manner. Taken together, our data demonstrate that FB(1) alters the intestinal immune response by decreasing the level of IL-8. This may contribute to the increased intestinal colonization by pathogenic Escherichia coli that was observed in FB(1)-treated pigs and may have implications for humans/animals consuming FB(1)-contaminated food/feed.


The genotoxicity of lead.
Lead has been tested for genotoxic potential in a range of mutagenicity assays. Such studies report varying effects, and the results are equivocal. The reasons for this may be related to problems of the solubility of many lead compounds, their inability to dissolve in biological fluids, chemical interferences resulting in conflicting observations, the nonspecificity of the assays used, the delivery of toxic doses to specific genetic processes or the mediation of genotoxicity through indirect mechanisms. Occupational and environmental exposures to lead have also been associated with increases in chromosomal damage in humans at moderate to high exposures, although this evidence is contradictory. Where positive findings have been reported, many are related to exposure. The possibility that lead is genotoxic is by no means clear, but evidence is still accumulating.


Histochemistry and morphology of erector spinae muscle in lumbar disc herniation.
The purpose of this study was to detect any changes in the erector spinae muscles in patients undergoing surgery for lumbar disc herniation (LDH) and to analyze which factors (sex, age, the level and site of disc protrusion, and duration of symptoms) would be related to these changes. The percentage of mean area of the type I fibers was significantly larger in males and in the older age group (P less than 0.05), due to the decreasing size of type IIa and IIb fibers. Patients with LDH have: 1) angulated and selective atrophy of type II fibers with a higher type IIb/IIa ratio; 2) with increasing age and duration of symptoms, more marked atrophy of type II fibers; and 3) other unspecific pathologic changes.


Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
Interactome maps are valuable resources to elucidate protein function and disease mechanisms. Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions. This network reveals interconnectivity across diseases and links many known ND-causing proteins, such as α-synuclein, TDP-43, and ATXN1, to a host of proteins previously unrelated to NDs. It facilitates the identification of interacting proteins that significantly influence mutant TDP-43 and HTT toxicity in transgenic flies, as well as of ARF-GEP100 that controls misfolding and aggregation of multiple ND-causing proteins in experimental model systems. Furthermore, it enables the prediction of ND-specific subnetworks and the identification of proteins, such as ATXN1 and MKL1, that are abnormally aggregated in postmortem brains of Alzheimer's disease patients, suggesting widespread protein aggregation in NDs.


Stable HEV IgG seroprevalence in Belgium between 2006 and 2014.
Recent European studies suggest an emergence of hepatitis E virus (HEV) infection. We evaluated trends in birth cohort-specific HEV seroprevalence and regional differences in Belgium. HEV IgG seroprevalence was analysed on national serum banks (1579 and 2087 samples for 2006 and 2014, respectively. Hepatitis E virus antigen was tested on positive samples. Observed data were modelled using a generalized additive model with a complementary log-log link. No significant differences between birth cohorts or sexes were found. Modelling identified the individual's age and province as relevant factors. The probability of HEV seropositivity increases significantly with age. An estimated total of 434 819 (yearly rate of 54,352) (sero-)infections were found between 2006 and 2014. Overall, HEV IgG seroprevalences were 4.1% (64/1579, 95% CI 3.1-5.1) and 5.8% (121/2087, CI 4.8-6.9) in 2006 and 2014, respectively. Observed HEV antigen seroprevalence was 0.027% (1/3666) for the entire cohort. These results show stable HEV IgG seroprevalence in Belgium.


Correlation between sodium, potassium, hemoglobin, hematocrit, and glucose values as measured by a laboratory autoanalyzer and a blood gas analyzer.
Blood gas analyzers can be alternatives to laboratory autoanalyzers for obtaining test results in just a few minutes. We aimed to find out whether the results from blood gas analyzers are reliable when compared to results of core laboratory autoanalyzers. This retrospective, single-centered study examined the electronic records of patients admitted to the emergency department of a tertiary care teaching hospital between May 2014 and December 2017. Excluded from the study were patients under 18 years old, those lacking data, those who had any treatment before the laboratory tests, those whose venous gas results were reported more than 30 minutes after the blood sample was taken and for whom any of the laboratory tests were performed at a different time, and recurrent laboratory results from a single patient. Laboratory results were analyzed from a total of 31,060 patients. The correlation coefficients for sodium, potassium, hemoglobin, hematocrit, and glucose levels measured by a blood gas analyzer and a laboratory autoanalyzer were 0.725, 0.593, 0.982, 0.958, and 0.984, respectively; however, there were no good, acceptable agreement limits for any of the parameters. In addition, these results did not change according to the different pH stages (acidosis, normal pH and alkalosis). The two types of measurements showed a moderate correlation for sodium and potassium levels and a strong correlation for glucose, hemoglobin, and hematocrit levels, but none of the levels had acceptable agreement limits. Clinicians should be aware of the limitations of blood gas analyzer results.


Activity of blood coagulation factor XIII as a prognostic indicator in patients with Henoch-Schönlein purpura. Efficacy of factor XIII substitution.
Determination of coagulation Factor XIII (F XIII)-related parameters in 21 patients with Henoch-Schönlein purpura documented a significant decrease of F XIII activity as well as of the F XIII-related antigenic determinants. Subgroup analysis with regard to the clinical symptoms showed an even further decrease of these parameters in patients with gastrointestinal complications. Stimulated by these findings a substitution therapy with a F XIII concentrate was initiated in those patients whose F XIII activity in plasma remained low and who developed severe abdominal pain accompanied by persisting gastrointestinal bleeding. This therapeutic approach not only corrected the laboratory data, but more important led to a cessation of pain and bleeding. A rapid decrease of F XIII levels after transfusion below 40 U/ml was indicative of relapse of abdominal symptoms, while increasing values were associated with the recovery of the patients. F XIII activity determinations appear to have a predictive value in patients with Henoch-Schönlein purpura, and the administration of F XIII concentrates may contribute to the improvement of gastrointestinal complications.


An improved method of using two-dimensional model to evaluate the carrying capacity of regional water resource in Inner Mongolia of China.
The evaluation of regional water resource carrying capacity has been repeatedly conducted to provide a scientific basis for the local water resource management and the sustainable development, in particular in the water-limited regions. However, the definition of regional water resource carrying capacity and its evaluation method are still arguable. Through a case study of Inner Mongolia, located in the arid and semi-arid northern China, this paper developed an improved method to calculate regional water resource carrying capacity by the combination of the water supply-demand analysis and the S-shaped curve threshold analysis. The spatial and temporal patterns of the regional water resource carrying capacity in Inner Mongolia during 2000-2019 was evaluated at three scales, namely the province scale, the basin scale and the city scale. The results showed that the average regional water resource carrying capacity of the whole province was 0.25 (the full mark is 1.00); at the basin scale, the Yellow River Basin had the lowest regional water resource carrying capacity (0.17) among all the basins, showing that the utilization of the water resources was unreasonable; at the city scale, the average regional water resource carrying capacities in Hulunbuir and Xilingol were both over 0.25, while those in Alxa, BayanNur and Wuhai were below 0.1; Hulunbuir had 25.48 billion m3 water surplus, while BayanNur suffered from an average water deficit of 4.51 billion m3 from 2000 to 2019. This paper has provided a reasonable way to measure the regional water resource carrying capacity using an improved method by incorporating S-shaped curve threshold analysis, which may have a wider application for the clustering and optimization of regional water management. In addition, the spatial and temporal patterns of regional water carrying capacity are beneficial for policymakers in the implementation of the effective water usage.


Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats.
Impairments in the function of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced glucocorticoid receptor (GR) activity in the central amygdala (CeA) are critical mechanisms in the pathogenesis of alcohol use disorder (AUD). The GR antagonist mifepristone attenuates craving in AUD patients, alcohol consumption in AUD models, and decreases CeA γ-aminobutyric acid (GABA) transmission in alcohol-dependent rats. Previous studies suggest elevated GR activity in the CeA of male alcohol-preferring Marchigian-Sardinian (msP) rats, but its contribution to heightened CeA GABA transmission driving their characteristic post-dependent phenotype is largely unknown. We determined Nr3c1 (the gene encoding GR) gene transcription in the CeA in male and female msP and Wistar rats using in situ hybridization and studied acute effects of mifepristone (10 μM) and its interaction with ethanol (44 mM) on pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSCs) and electrically evoked inhibitory postsynaptic potentials (eIPSPs) in the CeA using ex vivo slice electrophysiology. Female rats of both genotypes expressed more CeA GRs than males, suggesting a sexually dimorphic GR regulation of CeA activity. Mifepristone reduced sIPSC frequencies (GABA release) and eIPSP amplitudes in msP rats of both sexes, but not in their Wistar counterparts; however, it did not prevent acute ethanol-induced increase in CeA GABA transmission in male rats. In msP rats, GR regulates CeA GABAergic signaling under basal conditions, indicative of intrinsically active GR. Thus, enhanced GR function in the CeA represents a key mechanism contributing to maladaptive behaviors associated with AUD.


Genetic control of the bypass of mono-adducts and of the repair of cross-links photoinduced by 8-methoxypsoralen in yeast.
A large UVA dose by itself induces lethal damage revealed in some repair-deficient strains of Saccharomyces cerevisiae. Following photoaddition of a monofunctional psoralen derivative, 3-carbethoxypsoralen, an extra killing effect is observed by applying a second high UVA dose, in conditions where a fraction of 8-methoxypsoralen (8-MOP) plus UVA-induced monoadducts are transformed into DNA cross-links. In an excision-repair-deficient context, the bypass of 8-MOP plus UVA-induced monoadducts is under the control of the RAD6+ gene product. However, when other steps of the mutagenic pathway are blocked by the rad18-2 or the pso1-1 mutations, bypass occurs. This is also true when in excision-deficient strains the recombinogenic pathway is blocked by the rad52-1 mutation. The recombinogenic pathway may be an alternative to the mutagenic pathway for bypass of monoadducts. The repair of the lesions induced by a second UVA dose applied after a first treatment by 8-MOP plus UVA [i.e. cross-links and other putative lesion(s)] is controlled by at least the RAD2+, RAD6+, RAD52+, PSO2+ and PSO1+ gene products. The role of the pathways involved is discussed according to the nature of the secondarily induced lesions.


Revisiting the Intriguing Electronic Features of the BeOBeC Carbyne and Some Isomers: A Quantum-Chemical Assessment.
Extensive high-level quantum-chemical calculations reveal that the rod-shaped molecule BeOBeC, which was recently generated in matrix experiments, exists in two nearly isoenergetic states, the 5 Σ quintet (5 6) and the 3 Σ triplet (3 6). Their IR features are hardly distinguishable at finite temperature. The major difference concerns the mode of spin coupling between the terminal beryllium and carbon atoms. Further, the ground-state potential-energy surface of the [2Be,C,O] system at 4 K is presented and differences between the photochemical and thermal behaviors are highlighted. Finally, a previously not considered, so far unknown C2v -symmetric rhombus-like four-membered ring 3 [Be(O)(C)Be] (3 5) is predicted to represent the global minimum on the potential-energy surface.


Nano-scaling law: geometric foundation of thiolated gold nanomolecules.
Thiolated gold nanomolecules show a power correlation between the number of gold atoms and the thiolate ligands with a 2/3 scaling similar to Platonic and Archimedean solids. Nanomolecule stability is influenced by a universal geometric factor that is foundational to its stability through the Euclidean surface rule, in addition to the electronic shell closing factor and staple motif requirements.


The role of the T-cell receptor (TCR) in alpha beta/gamma delta lineage commitment: clues from intracellular TCR staining.
T cells belong to two mutually exclusive lineages expressing either alpha beta or gamma delta T-cell receptors (TCR). Although alpha beta and gamma delta cells are known to share a common precursor the role of TCR rearrangement and specificity in the lineage commitment process is controversial. Instructive lineage commitment models endow the alpha beta or gamma delta TCR with a deterministic role in lineage choice, whereas separate lineage models invoke TCR-independent lineage commitment followed by TCR-dependent selection and maturation of alpha beta and gamma delta cells. Here we review the published data pertaining to the role of the TCR in alpha beta/gamma delta lineage commitment and provide some additional information obtained from recent intracellular TCR staining studies. We conclude that a variant of the separate lineage model is best able to accommodate all of the available experimental results.


Hepatocellular carcinoma vascularization: from the most common to the lesser known arteries.
Hepatocellular carcinoma is the sixth most common cancer throughout the world. It is almost exclusively arterially vascularized, unlike the vascularization of the liver, which has a dual supply with a portal component of 75 to 80% and an arterial component of 20 to 25%. The reference treatment for intermediary stages of the Barcelona (B) classification is hepatic artery chemoembolization. The aim of chemoembolization is to inject the tumor chemotherapy into the artery and then to embolize the artery (or arteries), which supply the tumor. For this, knowledge of the anatomy of the hepatic artery is essential. Approximately 55% of the patients belong to the modal distribution, although numerous anatomical variants exist and must be recognized. In addition, primarily non-hepatic arteries may contribute to the vascularization of some hepatocellular carcinomas. Furthermore, new arterial supplies can be recruited by tumors after surgical or chemoembolization treatments. The aim of this article is to describe the different arteries, which may vascularize hepatocellular carcinomas. These arteries must be looked for, recognized, and reported by the radiologist on cross-section examinations in the pre-treatment assessment.


Simulated distributions from negative experiments highlight the importance of the body mass index distribution in explaining depression-body mass index genetic risk score interactions.
Depression and obesity are complex global health problems. Recent studies suggest that a genetic predisposition to obesity might be accentuated in people with depression, but these analyses are prone to bias. Here, we tested the hypothesis that depression accentuates genetic susceptibility to obesity and applied negative control experiments to test whether any observed interactions were real or driven by confounding and statistical biases. We used data from up to 378 000 Europeans in UK Biobank, a 73 variant body mass index (BMI) genetic risk score, two depression measures [depression symptoms (DS), major depression (MD)] and an antidepressant usage variable available. We tested whether (i) depression and (ii) antidepressant treatment accentuated genetic susceptibility to obesity. Finally, we performed negative control experiments by sampling individuals at random so that they had BMI distributions identical to depression cases and controls. Depression was associated with an accentuation of an individual's genetic risk of obesity with evidence of interactions for both DS and MD (Pinteraction = 7 × 10-4 and 7 × 10-5 respectively). Antidepressant usage within DS cases accentuated genetic obesity risk (Pinteraction = 9 × 10-4), but not for MD (Pinteraction = 0.13). Negative control experiments suggested that the observed interactions for MD (empirical-P = 0.067) may be driven by statistical biases or confounding factors but were not possible with the larger DS groups. Antidepressant usage interaction also appears to be driven by statistical artefacts (empirical-P = 0.510 using MD and 0.162 using DS). We have highlighted the importance of running negative experiments to confirm putative interactions in gene-environment studies. We provide some tentative evidence that depression accentuates an individual's genetic susceptibility to higher BMI but demonstrated that the BMI distributions within cases and controls might drive these interactions.


Anti-IgE-and ConA-induced histamine release from human basophilic leukocytes: the existence of differences in relative responses within individuals.
Histamine release was induced from human blood leukocytes with Concanavalin A (ConA) and two different preparations of anti-IgE. A dose-response curve was constructed for each cell population and secretagogue. No qualitative difference in response pattern was observed with the two anti-IgEs; however, the relative release-inducing efficacy of ConA and anti-IgE seemed to vary with the individual providing the cells. These findings indicate that release induced by ConA is not completely equivalent to that induced by anti-IgE.


Relational caring and contact after treatment. An evaluation study on criminal recidivism.
Criminal recidivism within two years after discharge from secure Forensic Psychiatric Hospitals (FPHs) is high, that is, over 36% for short-term judicial measures. It is assumed that relational care during treatment and continued voluntary contact and informal care after discharge, are factors that contribute to the reduction of criminal recidivism. To examine whether the provision of relational care and continued contact after treatment can be effective in reducing criminal recidivism two years after discharge (prevalence and time to re-offense) in patients who received treatment according to article 37 of the Dutch Penal Law (i.e., a hospital order for one year) compared to patients with the same order receiving Care As Usual. An evaluation study of criminal recidivism in adult patients (N = 111) residing in 4 FPHs in the Netherlands two years after discharge. The intervention 'relational care' group was compared with a historical control group from the same hospital before the new approach had been introduced, and a concurrent control group from three other FPHs in the Netherlands. In the intervention group 15,6% of the participants reoffended within two years following discharge, which was significantly lower than recidivism in the historical (46,5%) and concurrent (47,8%) control group. The odds-ratio for recidivism in the intervention group was 0.245 (95% CI: 0.076-0.797) which was significant at p = .019. Patients who received relational care and subsequently were provided with voluntary contact after treatment recidivated later and at a lower rate than patients from two control groups receiving CAU. Relational care and the voluntary continuation of contact and informal (after)care, which was build up during the treatment period, may bridge the difficult period that patients face when they have left the forensic psychiatric hospital.


Clinical and imaging analysis to evaluate the response of patients with anti-DPPX encephalitis to immunotherapy.
To report the main spectrum and new clinical and imaging characteristics of dipeptidyl-peptidase-like protein 6 (DPPX) antibody-associated encephalitis, and to evaluate the effect of immunotherapy. A retrospective analysis of nine patients with anti-DPPX encephalitis was performed, and all previously reported cases in the literature were reviewed. A cell-based indirect immunofluorescence assay using human embryonic kidney 293 cells transfected with DPPX was used. Nine patients were identified (median age, 51 years; range, 14-65 years) with prodromal fever, diarrhea, or weight loss, followed by rapid progressive encephalopathy characterized by cognitive disorder. One patient who received methylprednisolone therapy and a trial of tacrolimus showed substantial improvement and had no relapse by the 6-month follow-up. Our comprehensive literature review demonstrated that 53 cases were reported, of which more than half had prodromal weight loss (52.8%) and gastrointestinal disorders (58.5%). Cognitive disorders (74.6%) and brainstem/spinal cord disorders (75.5%) were the most common major symptoms. A greater proportion of Chinese patients than non-Chinese patients had abnormalities on brain magnetic resonance imaging specific for encephalitis (70.0% vs. 23.3%, P < 0.001). Our study is the first to report three patients with anti-DPPX encephalitis who had sleep disorders with rapid eye movement sleep behavior disorder, limb paralysis (two), severe pleocytosis, elevated protein levels (two) in the cerebrospinal fluid, and increased T2/FLAIR signal abnormalities in the bilateral hippocampus, temporal lobe, amygdala, basal ganglia, thalamus, centrum semiovale, and frontal and parietal lobes in seven patients (77.8%). Our study expands the clinical and imaging phenotypes of anti-DPPX encephalitis. Further studies elucidating the entire clinical spectrum of anti-DPPX encephalitis, its pathogenic mechanisms, and prognosis under long-term immunosuppressive therapy are warranted.


Traditional Chinese Medicine Constitution Identification Based on Objective Facial and Tongue Features: A Delphi Study and a Diagnostic Nomogram for Blood Stasis Constitution.
The aim of this study was to systematically summarize and form an expert consensus on the theoretical experience of tongue and facial features for the identification of nine types of traditional Chinese medicine (TCM) constitution. Additionally, we sought to explore the feasibility of TCM constitution identification through objective tongue and facial features. We used Delphi method to investigate the opinions of experts on facial and tongue feature items for identifying TCM constitution. We developed and validated a diagnostic nomogram for blood stasis constitution (BSC) based on objective facial and tongue features to demonstrate the reliability of expert consultation. Eleven experts participated in two rounds of expert consultation. The recovery rates of the two rounds of expert consultation were 100.0% and 90.9%. After the first round, 39 items were screened out from 147 initial items, and 2 items were supplemented by experts. In the second round, 7 items were eliminated, leaving 34 items for 8 types of TCM constitution. The coefficient of variation in the first round was 0.11-0.49 for the 147 items and 0.11-0.29 for the included items. The coefficient of variation in the second round was 0.10-0.27 for the 41 items and 0.10-0.20 for the included items. The W value was 0.548 (P < 0.001) in the first round and 0.240 (P < 0.001) in the second round. Based on expert consultation, we selected BSC as an example and developed and validated a diagnostic nomogram consisting of six indicators: sex, hair volume, lip color-dark purple, susceptibility-facial pigmentation/chloasma/ecchymosis, zygomatic texture-red blood streaks, and sublingual vein-varicose and dark purple. The nomogram showed good discrimination (AUC: 0.917 [95% confidence interval [CI], 0.877-0.956] for the primary dataset, 0.902 [95% CI, 0.828-0.976] for the validation dataset) and good calibration. Decision curve analysis demonstrated that the nomogram was clinically useful. This is the first study to systematically summarize the existing knowledge and clinical experience to form an expert consensus on the tongue and facial features of nine types of TCM constitution. Our results will provide important prior knowledge and expert experience for future constitution identification research. Based on expert consultation, this study presents a nomogram for BSC that incorporates objective facial and tongue features, which can be conveniently used to facilitate the individualized identification of BSC.


Determination of serum iron and the total iron-binding capacity with a new chromogen, 4-aminophenazone.
A colorimetric procedure is described for the determination of serum iron and TIBC, utilizing the action of the iron on the oxidation reaction of 4-aminophenazone with H2O2. The chromogen oxidized has maximum absorption at 540 nm. The method is interesting because it has important advantages over other methods: no deproteinization is needed, microsamples are used, it is simple, gives adequate precision, and the results correlate well with those obtained with the standard bathophenanthroline method.


Metal swap between Zn7-metallothionein-3 and amyloid-beta-Cu protects against amyloid-beta toxicity.
Aberrant interactions of copper and zinc ions with the amyloid-beta peptide (Abeta) potentiate Alzheimer's disease (AD) by participating in the aggregation process of Abeta and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Abeta are associated with copper binding. Metallothionein-3 (Zn(7)MT-3), an intra- and extracellularly occurring metalloprotein, is highly expressed in the brain and downregulated in AD. This protein protects, by an unknown mechanism, cultured neurons from the toxicity of Abeta. Here, we show that a metal swap between Zn(7)MT-3 and soluble and aggregated Abeta(1-40)-Cu(II) abolishes the ROS production and the related cellular toxicity. In this process, copper is reduced by the protein thiolates forming Cu(I)(4)Zn(4)MT-3, in which an air-stable Cu(I)(4)-thiolate cluster and two disulfide bonds are present. The discovered protective effect of Zn(7)MT-3 from the copper-mediated Abeta(1-40) toxicity may lead to new therapeutic strategies for treating AD.


Prevention of stroke in high risk patients undergoing general anaesthesia.
The anaesthesiologist is primarly involved in the management of the stroke prone patient undergoing surgery. Preoperative assessments, per and post-operative management of such patients are discussed.


Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid.
Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC), is an antitumor agent effective in the treatment of several solid tumors but its use is hampered by short plasma half-life, rapid metabolism and low selectivity towards tumor tissue. To overcome these limits, bioconjugates of gemcitabine were studied using poly(ethylene glycol) as polymeric carrier. Two types of conjugates were prepared, non-targeted and folic acid targeted conjugates. The formers were obtained starting from mPEG-OH of 5 and 20 kDa with linear or branched structure. The folic acid targeted conjugates, differing for the drug loading, were prepared exploiting a heterobifunctional PEG that allowed a consecutive coupling of the targeting agent and the drug. Folic acid was chosen as targeting agent because its receptor is often over-expressed in many tumors. To increase the polymer drug payload, the bicarboxylic amino acid, aminoadipic acid, was used. All conjugates were able to release the drug in a pH-dependent manner with no role of enzymes. The pharmacokinetic profiles are strictly related to the polymer molecular weight and the folic acid targeting increased 2-3 times the affinity towards the cells over-expressing folic acid receptors. These results are promising and encourage in vivo studies on these conjugates that act as polymeric prodrugs.


Deep vein thrombosis in noncritically ill patients with coronavirus disease 2019 pneumonia: deep vein thrombosis in nonintensive care unit patients.
Venous thromboembolic events have been one of the main causes of mortality among hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia. The aim of our study was to describe the prevalence of deep vein thrombosis (DVT) in noncritically ill patients with COVID-19 pneumonia and correlate such observations with the thromboprophylaxis received. We performed a prospective cohort study of 67 patients admitted to the hospital for COVID-19 pneumonia. The diagnosis was confirmed using polymerase chain reaction testing of nasopharyngeal specimens. The deep veins were examined using compression duplex ultrasonography with the transducer on B-mode. The patients were separated into two groups for statistical analysis: those receiving low-molecular-weight heparin prophylaxis and those receiving intermediate or complete anticoagulation treatment. Risk analysis and logistic regression were performed. Of the 67 patients, 57 were included in the present study after applying the inclusion and exclusion criteria; 49.1% were women, and the patient mean age was 71.3 years. All 57 patients had undergone compression duplex ultrasonography. Of these 57 patients, 6 were diagnosed with DVT, for an in-hospital rate of DVT in patients with COVID-19 pneumonia of 10.5%. All the patients who had presented with DVT had been receiving low-molecular-weight heparin prophylaxis. The patients receiving prophylactic anticoagulation treatment had a greater risk of DVT (16.21%; 95% confidence interval, 0.04-0.28; P = .056) compared with those receiving intermediate or complete anticoagulation treatment. We also found a protective factor for DVT in the intermediate or complete anticoagulation treatment group (odds ratio, 0.19; 95% confidence interval, 0.08-0.46; P < .05). Noncritically ill, hospitalized patients with COVID-19 pneumonia have a high risk of DVT despite receipt of correct, standard thromboprophylaxis.


Characteristics of the brain tissue disialoganglioside G2a.
Disialoganglioside G2a was separated by one dimensional two-step TLC between the two ganglioside fractions using long plate precoated with silica H+ florisil in the particular solvent system. Behaviour of this fraction to the enzyme effect and molecule percentages of its components showed the characteristics of the ganglioside containing two N-acetylneuraminic acids. Synthesis dynamics of this fraction in rat brain was very intensive in the myelination period and it practically ended in 40th day. In mutant "Jimpy" mice brain ganglioside G2a served as an indicator of the normal ganglioside synthesis in relation to the changes in myelin sphingolipid molecular structure. Comparative brain studies undertaken in various species, intracellular rat brain fractions, various structures of Torpedo ocellata electric fish, emphasized the importance of this ganglioside in cell membrane formation where it is obligatory component. Quantitative determination of this fraction in Astrocytoma with various malignancy degree offers great help in differential diagnosis.


Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism.
Mammalian apurinic/apyrimidinic endonuclease 1 is a DNA repair enzyme involved in genome stability and expression of genes involved in oxidative stress responses, tumor progression and chemoresistance. However, the molecular mechanisms underlying the role of apurinic/apyrimidinic endonuclease 1 in these processes are still unclear. Recent findings point to a novel role of apurinic/apyrimidinic endonuclease 1 in RNA metabolism. Through the characterization of the interactomes of apurinic/apyrimidinic endonuclease 1 with RNA and other proteins, we demonstrate here a role for apurinic/apyrimidinic endonuclease 1 in pri-miRNA processing and stability via association with the DROSHA-processing complex during genotoxic stress. We also show that endonuclease activity of apurinic/apyrimidinic endonuclease 1 is required for the processing of miR-221/222 in regulating expression of the tumor suppressor PTEN. Analysis of a cohort of different cancers supports the relevance of our findings for tumor biology. We also show that apurinic/apyrimidinic endonuclease 1 participates in RNA-interactomes and protein-interactomes involved in cancer development, thus indicating an unsuspected post-transcriptional effect on cancer genes.APE1 plays an important role in the cellular response to oxidative stress, and mutations are linked to tumor progression and chemoresistance. Here, the authors characterize the interactions of APE1 with RNA and demonstrate a role in microRNA processing.


Hidden foreign body as a cause of recurrent hemoptysis in a teenage girl.
Hemoptysis in a teenage girl caused by a foreign body located in the posterior segment of the left lower lobe is described. The patient was seen four years after the initial inhalation. The importance of taking a meticulous history and the use of computed tomography in the localization of the lesion are emphasized, and the use of the fiberoptic bronchoscope in peripheral lesions and in the investigation of hemoptysis is discussed.


Five new species in the predaceous midge genus Macrurohelea Ingram amp; Macfie from Argentina, and descriptions of the previously unknown males of M. kuscheli Wirth and M. monotheca Spinelli amp; Grogan (Diptera: Ceratopogonidae).
Five new Neotropical species in the predaceous midge genus Macrurohelea Ingram Macfie are described: M. bassoi, M. donatoi, M. morenoi, M. sirii, and M. ventanensis, n. spp. and the previously unknown males of M. kuscheli Wirth and M. monotheca Spinelli Grogan are described from specimens collected in several localities of Argentina and Chile. Illustrations and photomicrographs of key features of both sexes are provided as well as a key to all Neotropical species of Macrurohelea.


A cross-sectional study of cardiovascular disease risk clustering at different socio-geographic levels in India.
Despite its importance for the targeting of interventions, little is known about the degree to which cardiovascular disease (CVD) risk factors cluster within different socio-geographic levels in South Asia. Using two jointly nationally representative household surveys, which sampled 1,082,100 adults across India, we compute the intra-cluster correlation coefficients (ICCs) of five major CVD risk factors (raised blood glucose, raised blood pressure, smoking, overweight, and obesity) at the household, community, district, and state level. Here we show that except for smoking, the level of clustering is generally highest for households, followed by communities, districts, and then states. On average, more economically developed districts have a higher household ICC in rural areas. These findings provide critical information for sample size calculations of cluster-randomized trials and household surveys, and inform the targeting of policies and prevention programming aimed at reducing CVD in India.