Participants' experiences of the management of screen-detected complex polyps within a structured bowel cancer screening programme.
The Bowel Screening Wales complex polyp removal service was introduced to address variations in surgery rates for screen-detected complex benign colorectal polyps, to improve the quality of the screening service and to make management of these polyps more equitable across Wales. Little is known about patient experiences and the potential impact on quality of life when undergoing complex polyp removal. This study is part of a wider research programme evaluating the decision-making, pathways and outcomes from complex polyp removal. This study aimed to understand experiences of having a complex polyp removed and how this may influence quality of life. Semi-structured telephone interviews were conducted, and a thematic approach was used for data analysis. All participants had a complex polyp removed after a positive stool test and review by Bowel Screening Wales' Network Multi-Disciplinary Team. Twenty-one participants were interviewed. Most participants had their complex polyps removed endoscopically and reported no or minor problems or negative outcomes following their procedure. For a small minority, worse problems (e.g., pain, bowel dysfunction) and negative outcomes (e.g., cancer) followed their procedures. Most participants felt supported and reassured throughout their procedures. Any physical and emotional changes to quality of life were mainly linked to procedure outcomes. Experiences of complex polyp removal were generally positive, with minimal changes in quality of life. While most people had a positive experience of having a complex polyp removed, support initiatives, such as counselling or signposting to coping strategies, may be helpful to reduce any potential negative effects of procedures on quality of life. Four patient and public involvement partners provided feedback on participant materials.


Acute bilateral epidural hematomas. Report of two cases and review of the literature.
Two cases of acute postraumatic bilateral epidural hematomas with different clinical pictures are presented. In the review of the literature, acute, subacute and delayed bilateral epidural hematomas must be found. Clinical findings, results of CT scan and pathophysiology are discussed.


Unprecedented ipso aromatic nucleophilic substitution upon oxidative decarboxylation of tris(p-carboxyltetrathiaaryl)methyl (TAM) radicals: a new access to diversely substituted TAM radicals.
A new reaction of oxidative substitution of aromatic carboxyl groups on stable trityl radical derivatives (TAMs) by various nucleophiles is described; it leads to a wide variety of new persistent and diversely substituted TAM radicals.


[Ethnolinguistic map of Peru].
To provide adequate health care with an intercultural approach is necessary for the health care personnel know the Peruvian ethnolinguistic diversity, so we present 76 ethnic groups that belong to 16 ethnolinguistic families and their geographical distribution on a map of Peru.


LEVELS OF SMOKING AND PERI‑IMPLANT MARGINAL BONE LOSS: A SYSTEMATIC REVIEW AND META-ANALYSIS.
This systematic review and meta-analysis sought to determine if there was a significantly enhanced risk of peri‑implant marginal bone loss (MBL) due to the increased number of cigarettes smoked per day. Six databases, including Medline, Embase, Cochrane Library, Web of Science, Scopus, and ProQuest, were searched until February, 2021. The search terms "dental implant, oral implant, smoking, smoker, non-smoker, marginal bone loss and crestal bone loss" were used in combination to seek the articles providing data for MBL related to the smoking habit. Articles were excluded if the quantity of cigarettes smoked per day was not reported. Random-effects meta-analyses were used to pool the estimates of mean difference (MD) with 95% confidence intervals (CI). Eight studies were included for qualitative and 5 for quantitative synthesis. The meta-analyses revealed higher levels of MBL in patients who smoked <10 or >10 cigarettes/day than in non-smokers (<10: (MD -0.33, 95% CI -0.69-0.03 and >10: MD -0.58, 95% CI -0.96- -0.19). There was a significant risk of MBL between patients who smoked >10 and <10 cigarettes/day (MD -0.23, 95% CI -0.47-0.01). It seems the risk of MBL is steadily increasing as daily smoking increases.


Importance of the curve shape for interpretation of blood volume monitor changes during haemodiafiltration.
In children, the prescribed ultrafiltration needed to achieve the fixed end session dry weight can induce hypotensive episodes. A variety of on-line devices based on the direct measurement of the hematocrit are available, but these devices nearly always only measure the quantitative variation in the blood volume as the means of identifying a hypotensive occurrence risk. In February 2002, our unit began using an on-line hematocrit measurement available even with infants' blood lines. Since January 2004, this blood volume monitor (BVM) has been used routinely in all dialysis sessions, and 2240 BVM data sets have been recorded and analysed during the last 4 years. Based on our analysis of these data sets, we have determined that, in addition to the described threshold points, which provide a quantitative analysis of the BVM, the qualitative analysis of the BVM, the so-called curve shape, is also of clinical importance. In 91% of the sessions analysed, a very similar "symptom-free" curve shape was noted that consisted of an initial decrease, followed by the BV reaching a "stable" plateau. Additional curve shapes were identified: one with no BV decrease, presumably indicating an overload risk state, and one with a continuous BV decrease, presumably indicating an hypovolemic risk state. In our experience, only 2% of the patients had relevant clinical symptoms that were not visible by BVM.


An aqueous non-heme Fe(IV)oxo complex with a basic group in the second coordination sphere.
The Fe(IV)oxo complex of a coordinatively flexible multidentate mono-carboxylato ligand is obtained by the one electron oxidation of a low spin Fe(III) precursor in water.


The place of esophageal manometry in the diagnosis of dysphagia.
Esophageal manometry allows to quantify intraluminal pressure changes as the basis of normal or abnormal esophageal motility. It is a complementary diagnostic procedure which should only be performed after endoscopic and fluoroscopic examinations and may be helpful in the detection of various motility disorders like diffuse esophageal spasm, nutcracker esophagus and vigorous achalasia. Manometry is recommendable for therapy control after medical and surgical therapy, and mandatory prior to surgical reflux therapy.


A mutagenic metabolite synthesized by Salmonella typhimurium grown in the presence of azide is azidoalanine.
A mutagenic azide metabolite was purified from the medium in which Salmonella typhimurium cells were grown in the presence of azide. This metabolite was identified to be azidoalanine based on infrared and mass spectroscopy and elemental analysis. This compound appeared to be identical to the mutagenic compound synthesized in vitro from azide and O-acetylserine by partially purified O-acetylserine sulfhydrylase. The metabolite (azidoalanine) mutagenic efficiency and spectrum in S. typhimurium was similar to that of inorganic azide. The compounds 2-azidoethylamine, 2-bromoethylamine, 3-bromopropionic acid and N-(azidomethyl) phthalimide were also mutagenic with a similar spectrum to azide and azidoalanine, but with lower efficiency. The compounds 3-azidopropylamine, 4-azidobutylamine, 3-chloroalanine and ethylamine were only weakly or nonmutagenic. Numerous other chloro, bromo and azido phthalimide derivatives tested were nonmutagenic. It is suggested that the lack of azide mutagenicity (and perhaps carcinogenicity) in mammalian cells may be due to their inability to convert azide to azidoalanine.


A systematic review of the influence of occupational organophosphate pesticides exposure on neurological impairment.
The aim of this study was to conduct a systematic review of the published literature and to estimate whether or not there is a causal relationship between occupational exposure to organophosphate pesticides (OPs) and either neurological impairment or depressive symptoms. EMBASE, MEDLINE, Global Health and PsycINFO (1980 to April 2014). Observational studies (cross-sectional, cohort and case-control studies) with exposed and unexposed groups. People who occupationally use OPs for more than 1 month and their family. Results of neurological core test batteries or depressive symptoms such as headaches, anxiety and dizziness. After an extensive search of various literature databases, one author screened titles and abstracts, searched the relevant publications manually and conducted data extraction. All extracted data from the selected articles were synthesised for analysis. Quality appraisal was conducted using the Newcastle Ottawa Scale. Of the 1024 articles retrieved by database search, 24 studies that met the inclusion and exclusion criteria were selected for analysis. Of the selected studies, 17 were cross-sectional and the remaining 7 were cohort and nested case-control studies. The geographical areas included in the studies were the USA (10 studies), the UK (4 studies), Africa (4 studies), Asia (3 studies), Europe (2 studies) and South America (1 study). Each of the included studies used different exposure and outcome assessments such as neurological scores and depressive symptoms, making it difficult to compare the results exactly. Most studies showed that exposed groups had poorer results than unexposed groups; however, owing to the inconsistent neurological test batteries, there was not enough pooling evidence to conduct a meta-analysis. The findings of this literature review indicate that it is necessary to standardise the neurological or neuropsychological test battery and methods of measuring exposure to OPs.


Myocardial salvage after coronary stenting plus abciximab versus fibrinolysis plus abciximab in patients with acute myocardial infarction: a randomised trial.
Patients with acute myocardial infarction might benefit from the addition of glycoprotein IIb/IIIa inhibitors to fibrinolytic or mechanical reperfusion strategies. We compared two strategies, stenting and fibrinolysis, both combined with abciximab, in terms of their ability to salvage myocardium in patients with acute myocardial infarction. We enrolled 162 patients with acute myocardial infarction within 12 h of onset of symptoms, assigning 81 stenting plus abciximab and 81 alteplase plus abciximab. Technetium-99m sestamibi scintigraphy was done at admission and after a median of 11 days to calculate initial perfusion defect, final infarct size, and degree of myocardial salvage. The primary endpoint was the salvage index (the ratio of the degree of myocardial salvage to the initial perfusion defect). Major adverse clinical events within 6 months from randomisation were also compared between the two treatments. Paired scintigraphic measurements were available for 70 patients in the stent group and 71 in the alteplase group. Stenting was associated with greater myocardial salvage than alteplase (median 13.6% [IQR 5.9-23.9] vs 8.0% [2.5-16.0] of the left ventricle; p=0.007). Salvage index was greater in the stent group than in the alteplase group (median 0.60 [0.37-0.82] vs 0.41 [0.13-0.58]; p=0.001). The 6-month mortality rate was 5% (four deaths) in the stent group and 9% (seven deaths) in the alteplase group (relative risk 0.56 [95% CI 0.17-1.88]; p=0.35). In patients with acute myocardial infarction, a reperfusion strategy based on stenting with abciximab produced more myocardial salvage than the combination of fibrinolysis plus abciximab. Larger studies are needed to assess whether these effects translate into clinical benefit.


Quantitative bacteriology of closed-suction wound drainage in contaminated surgery.
This study was designed to evaluate the predictive value of quantitative bacteriology of closed-suction postoperative wound drainage in identifying the patient likely to develop wound infection as well as its subsequent flora. Forty-one patients undergoing major cancer surgery of the head and neck were studied. Postoperatively, closed-suction wound drainage was cultured, and anaerobic and aerobic bacterial isolates were quantitated. The wound infection rate was 20% (8/41). No trend toward increased rate of wound infection with increased numbers of bacteria colonizing the wound was observed. Additionally, there was no consistent correlation between species of bacteria isolated from closed-suction wound drainage and recovery from subsequent wound infection. Quantitative bacteriology of closed-suction wound drainage after contaminated head and neck cancer surgery does not accurately predict which patients were likely to become infected, or the probable bacteriology of subsequent wound infection.


The efficacy of 99mTc-HIG for sentinel lymph node mapping in breast cancer patients.
To evaluate the efficacy of Tc-HIG on SLN identification in patients with early-stage breast cancer. Seventeen women (18 tumours) with early-stage breast cancer were included. On the day of the operation, 111 MBq Tc-HIG was injected around the tumour or biopsy scar in all patients. Subsequently, dynamic lymphoscintigraphic images were taken for 30 min. After this, static images were recorded at 15-20 min intervals until the SLN was visualized. Patients were taken to the operating room 2-4 h after radiopharmaceutical injection. Before the incision, 5 ml of isosulfan blue dye solution was injected peritumourally in all subjects. Aided by blue dye and gamma probe SLN detection was done during the operation. In 17/18 tumours, SLN was detected with Tc-HIG lymphoscintigraphy. The mean visualization time for axillary SLNs was 49.94+/-11.25 min and for internal mammary SLNs was 52.50+/-10.60 min. In 15 of the tumours, only one SLN was detected in the axillary region. However, in two tumours, SLNs were found in both axillary and internal mammary regions. With blue dye mapping, axillary SLNs were found in 17/18 tumours. With the application of intraoperative gamma probe, all axillary and internal mammary SLNs were detected in 18 tumours. We conclude that Tc-HIG may be a suitable agent for SLN detection by lymphoscintigraphy and intraoperative gamma probe application in early-stage breast cancer patients.


Can scavenger receptor Class B Type I loaded ultrasound contrast agent be a new method for treating atherosclerosis?
Nowadays, Ultrasound contrast agent (UCA) is not only a good contrast agent for ultrasonic imaging, but also an important tool for drug delivery. As a kind of UCA, lipofectamine has the shell with positive charge. It can encapsulate genes and also be adhered to cells because genes and cells are all with negative charge. With this feature, it plays an important role in transfection. Scavenger Receptor Class B Type I(SR-BI) is a HDL receptor thought to be the first step in the progress of cholesterol transport. In this way, SR-BI loaded UCA has great possibility to cure atherosclerosis plaque.


RNA sequencing analysis of cortex and hippocampus in a kainic acid rat model of temporal lobe epilepsy to identify mechanisms and therapeutic targets related to inflammation, immunity and cognition.
Temporal lobe epilepsy (TLE) is the most common type of refractory epilepsy, in which inflammation is suggested to cause abnormal neuronal connections and neural networks. However, the expression of inflammatory genes in epilepsy remains incomplete, particularly in the context of the cortex, which is a hub of epileptic transmission but also is essential for mediating sensory, motor and cognitive function. Here, a rat model of epilepsy was established by kainic acid (KA) administration Gene transcriptome was explored in 4 signature phases in the hippocampus and cortex: acute damage (3 h), onset of epileptogenesis (3 d), spontaneous epilepsy (2 w) and cognitive impairment (9 w). Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis was applied to unravel the significantly altered pathways. We found, in both the hippocampus and cortex, the inflammatory gene was up-regulated in the acute phase, followed by a gradual decline; the phagocytosis and glial activation were remarkably increased since day 3; persistently down-regulated synaptic transmission and neuronal development started from the 3 h phase and lasted through the 9 w phase. While, the changed gene expression in the cortex fall into the same categories but were relatively lagging behind that in the hippocampus, also showing less number and distinct genes. Collectively, this study demonstrated the changes of gene transcriptome in the cortex and hippocampus in the signature phases after the KA administration, illustrating the association between epileptogenesis, inflammation genes and cognitive dysfunction, and may benefit identifying novel therapeutic targets for treating TLE and its comorbidities.


[Between symbol and symptom: pain and its meanings in classical antiquity].
According to semiotics, which may be defined as the doctrine of the essential nature and fundamental varieties of signs, objects, and interpretants, pain is considered to be a sign (significant) with very different meanings (significance) either as a naturalistic symptom (of disease) or as a symbol used in a metaphorical context. When following this methodological perspective it is possible to interpret medical as well as poetic writings on equal terms. In Graeco-Roman medical texts pain was mostly understood as a result and an indicator of disease, but nonetheless as a symptom which seemed to be actively produced by the affected body. Especially in the Corpus Hippocraticum dating from the 5th and 4th century B. C. this materialistic and at the same time psychosomatic attitude can be noticed. Aristotle (4th century B. C.), Celsus (1st century A. D.), and the famous experimental physiologist Galen (2nd century A. D.) agreed that pain was a sign of evil which should be fought without exception. It was Galen who added the disturbance of function (functio laesa) as the fifth cardinal sign of inflammation to the four well-known cardinal signs of Celsus (rubor, calor, tumor, dolor). He also coined the term [see text] to characterize an attack of migraine. In algotherapy, Galen used a complex pharmacological system which was based upon the four cardinal qualities of humoral pathology. On the other hand, pain was designed as a multi-dimensional symbol by the famous Graeco-Roman epic poets. In Homer's Odyssey (8th century B. C.), pain appears transformed into the shape of a scar which is visible and palpable on the hero's leg like an identification tag, whereas in Virgil's Aeneids (1st century B. C.) pain symbolizes weakness and defencelessness which can only be alleviated by the goddess Venus.


History of Gumboro (infectious bursal disease) in Pakistan.
Infectious Bursal Disease is the second important viral disease of poultry which affects the young growing pullets. The end fate appears in huge economic losses to poultry industry. Throughout the world, cheapest source of animal protein is chicken meat. It was initially reported in Europe; soon it spreads worldwide and causes drastic losses. In Pakistan, first of all this disease was reported in 1971. It is the first review to track the IBDV history in Pakistan. It provides comprehensive details of forty-six years researchers work in controlling this important disease. Different scientists worked to fill the gap areas to achieve the goal. Present review covers all the research aspects being explored in Pakistan since first report.


G-CSF filgrastim biosimilar-Sandoz reduces the incidence of febrile neutropenia in patients receiving chemotherapy regimens with rest periods not exceeding 14 days: A French, multicenter, prospective, non-interventional study.
The objective of this study was to describe filgrastim biosimilar-Sandoz modalities of use in patients receiving cytotoxic chemotherapy regimens with a rest period of ≤14 days and to investigate the incidence of febrile neutropenia (FN) in routine clinical practice. This was a French, multicenter, prospective and descriptive, non-interventional study including patients with breast, lung, gastrointestinal cancer or a lymphoma initiating filgrastim biosimilar-Sandoz treatment and in the context of cytotoxic chemotherapy with a rest period not exceeding 14 days. Data were collected during two routine clinical visits on the modalities of use of filgrastim biosimilar-Sandoz, on the incidence of neutropenia events and on adverse events. Between November 2015 and June 2018, 1080 patients were enrolled in the study in 129 centers. Overall, 941 patients were evaluable for efficacy and 937 for safety. Of the 941 patients, 84.8% had a solid tumor and 15.2% had a lymphoid hemopathy. Filgrastim biosimilar-Sandoz was prescribed as primary prophylaxis in 74.0% of the patients and as secondary prophylaxis in 22.4% of the patients. FN was reported in 1.5% of patients with a solid tumor and 12.6% of patients with a lymphoma. A chemotherapy relative dose intensity of over 85% with regard to the reference dose was achieved by more than 80% of the patients in all tumor localizations. The study showed that filgrastim biosimilar-Sandoz is safe to use and effective in preventing FN and in allowing to maintain the dose intensity of chemotherapy.


Risk of Uveitis in Patients With Inflammatory Bowel Disease on Immunosuppressive Drug Therapy.
Inflammatory bowel disease (IBD) patients may develop anterior uveitis. An observational cohort of IBD patients followed new users of (1) tumor necrosis factor inhibitor versus nonbiologic agents or (2) adalimumab versus infliximab until occurrence of anterior uveitis or treatment change/discontinuation. Cox-proportional hazards models estimated hazard ratios in propensity score-matched cohorts of Crohn disease or ulcerative colitis patients. No statistically significant differences in the risk of uveitis were observed between initiators of nonbiologics and tumor necrosis factor inhibitor. Effect estimates for adalimumab versus infliximab were highly imprecise due to limited outcomes. Uveitis risk was not different between IBD patients treated with immunosuppressives.


Effect of electrostatic forces on the dynamic rheological properties of injectable collagen biomaterials.
Injectable collagen is a concentrated dispersion of phase-separated collagen fibres in aqueous solution used to correct dermal contour defects through intradermal injection. The effect of electrostatic forces on the rheology of injectable collagen was studied by observation of the birefringence of collagen fibres through a polarizing microscope as well as by oscillatory rheological measurements on dispersions of varying ionic strengths (0.06-0.30). The birefringence of fibres progressively increased as ionic strength was reduced from 0.30 to 0.06. The linear viscoelastic measurements displayed a logarithmic relationship between storage (and loss) moduli and frequency over oscillation frequencies of 0.1-100 rad/s. The associated relaxation time spectra, interpreted using the theory of Kamphuis et al. for concentrated dispersions, show that collagen fibres become more flexible as ionic strength increases. This result was analysed at the molecular level from the perspective that collagen fibres are a liquid-crystalline phase of rigid rod collagen molecules which have phase-separated from solution. Electrostatic forces affect the volume fraction of water present in the collagen fibres which in turn alters the rigidity of the fibres. Flexible collagen fibre dispersions displayed emulsion-like flow properties whereas more rigid collagen fibre dispersions displayed suspension-like flow properties. Changes in fibre rigidity significantly alter the injectability of collagen dispersions which is critical in clinical performance.


Stevens-Johnson syndrome: a case report of possible cephalosporin-induced cutaneous adverse reaction.
A severe medical condition known as Stevens-Johnson syndrome (SJS) is marked by a cutaneous and mucosal reaction from the use of specific medications. The prodromal illness is followed by severe mucocutaneous symptoms in this immune-mediated disease. We describe the clinical history of a 55-year-old Caucasian woman who was exposed to cephalosporins. In resource-constrained countries and hospitals where cutaneous biopsy is not readily available, it is not easy to diagnose Steven Johnson Syndrome. This is particularly true in countries where the incidence of infectious diseases such as scarlet fever and measles is high and the early symptoms of SJS can be mistaken for these conditions. We used the Naronjo scale to confirm the probable association of the drug with the syndrome. Physicians while writing prescriptions for their patients need to warn them of potential side effects and they should keep in mind conditions like Stevens-Johnson syndrome. This case report highlights the need for improved knowledge and understanding of SJS among healthcare practitioners in resource-limited communities where the prevalence of infectious diseases is high.


The treatment of hepatic encephalopathy.
Current recommendations for the treatment of hepatic encephalopathy are based, to a large extent, on open or uncontrolled trials, undertaken in very small numbers of patients. In consequence, there is ongoing discussion as to whether the classical approach to the treatment of this condition, which aims at reducing ammonia production and absorption using either non-absorbable disaccharides and/or antibiotics, should be revisited, modified or even abandoned. Pros and cons of present therapeutic strategies and possible future developments were discussed at the fourth International Hannover Conference on Hepatic Encephalopathy held in Dresden in June 2006. The content of this discussion is summarized.


Laser light as a promising approach to improve the nutritional value, antioxidant capacity and anti-inflammatory activity of flavonoid-rich buckwheat sprouts.
Buckwheat sprouts are rich in several nutrients such as antioxidant flavonoids that have a positive impact on human health. Although there are several studies reported the positive impact of laser light on crop plants, no studies have applied laser light to enhance the nutritive values of buckwheat sprouts. Herein, the contents of health-promoting minerals, metabolites and enzymes as well as the antioxidant and anti-inflammatory activities were determined in laser-treated (He-Ne laser, 632 nm, 5 mW) common buckwheat (CBW) and tartarybuckwheat (TBW) sprouts. Out of 49 targeted minerals, vitamins, pigments and antioxidants, more than 35 parameters were significantly increased in CBW and/or TBW sprouts by laser light treatment. Also, laser light boosted the antioxidant capacity and anti-inflammatory activities through inhibiting cyclooxygenase-2 and lipoxygenase activities, particularly in TBW sprouts. Accordingly, laser light could be recommended as a promising method to improve the nutritional and health-promoting values of buckwheat sprouts.


Biodegradation of phenol in batch and continuous flow microbial fuel cells with rod and granular graphite electrodes.
Phenol biodegradation was evaluated in batch and continuous flow microbial fuel cells (MFCs). In batch-operated MFCs, biodegradation of 100-1000 mg L-1 phenol was four to six times faster when graphite granules were used instead of rods (3.5-4.8 mg L-1 h-1 vs 0.5-0.9 mg L-1 h-1). Similarly maximum phenol biodegradation rates in continuous MFCs with granular and single-rod electrodes were 11.5 and 0.8 mg L-1 h-1, respectively. This superior performance was also evident in terms of electrochemical outputs, whereby continuous flow MFCs with granular graphite electrodes achieved maximum current and power densities (3444.4 mA m-3 and 777.8 mW m-3) that were markedly higher than those with single-rod electrodes (37.3 mA m-3 and 0.8 mW m-3). Addition of neutral red enhanced the electrochemical outputs to 5714.3 mA m-3 and 1428.6 mW m-3. Using the data generated in the continuous flow MFC, biokinetic parameters including μm, KS, Y and Ke were determined as 0.03 h-1, 24.2 mg L-1, 0.25 mg cell (mg phenol)-1 and 3.7 × 10-4 h-1, respectively. Access to detailed kinetic information generated in MFC environmental conditions is critical in the design, operation and control of large-scale treatment systems utilizing MFC technology.


AMPK/mTOR/p70S6K axis prevents apoptosis of Porphyromonas gingivalis-infected gingival epithelial cells via BadSer136 phosphorylation.
Epithelial disruption is the initiation of most infectious disease. Regulation of epithelium apoptosis may play a key role in balance the survival competition between resident bacteria and host cells. The role of the mTOR/p70S6K pathway in preventing apoptosis of human gingival epithelial cells (hGECs) infected with Porphyromonas gingivalis (Pg) was investigated in order to further understand the survival strategy of the epithelial cells in during Pg infecting. hGECs was challenged with Pg for 4, 12, and 24 h. Additionally, hGECs was pretreated with LY294002 (PI3K signaling inhibitor) or Compound C (AMPK inhibitor) for 12 h and exposed them to Pg for 24 h. Subsequently, apoptosis was detected using flow cytometry, and expression and activity of Bcl-2, Bad, Bax, PI3K, AKT, AMPK, mTOR, and p70S6K proteins were analyzed using western blotting. Pg-infecting did not increase apoptosis of hGECs; but the expression ratio of Bad to Bcl-2 was increased after infecting. In contrast, BadSer136 phosphorylation was promoted, accompanied by a significant reduction of mTOR/p70S6K and PI3K/AKT signaling, along with the upregulation of AMPKThr172 signaling. Morrover, the PI3K inhibitor LY294002 promoted Pg-mediated reduction of mTOR/p70S6K expression, and the increase of AMPK signaling and BadSer136 phosphorylation rate, eventually decreasing apoptosis. While Compound C inhibited Pg-mediated activation of AMPK and downregulation of mTOR/p70S6K signaling, significantly reduced the BadSer136 phosphorylation rate, thereby increasing apoptosis. Thus, hGECs prevent apoptosis via an inherent cellular-homeostasis, pro-survival mechanism during Pg infection, the AMPK/mTOR/p70S6K pathway helps prevent apoptosis in hGECs infected with Pg by regulating BadSer136 phosphorylation.


Shenmai injection improves doxorubicin cardiotoxicity via miR-30a/Beclin 1.
Shenmai Injection (SMI) has been widely used in the treatment of cardiovascular diseases and can reduce side effects when combined with chemotherapy drugs. However, the potential protective mechanism of SMI on the cardiotoxicity caused by anthracyclines has not been clear. We used network pharmacology methods to collect the compound components in SMI and myocardial injury targets, constructed a 'drug-disease' target interaction network relationship diagram, and screened the core targets to predict the potential mechanism of SMI in treating cardiotoxicity of anthracyclines. In addition, the rat model of doxorubicin cardiotoxicity was induced by injecting doxorubicin through the tail vein. The rats were randomized in the model group, miR-30a agomir group, SMI low-dose group, SMI high-dose group,and the control group. The cardiac ultrasound was used to evaluate the structure and function of the rat heart. HE staining was used to observe the pathological changes of the rat myocardium. Transmission electron microscopy was used to observe myocardial autophagosomes. The expression of miR-30a and Beclin 1 mRNA in the rat myocardium was detected by RT-qPCR. Western Blot detected the expression of LC3-II/LC3-I and p62 protein. The network pharmacological analysis found that SMI could act synergistically through multiple targets and multiple pathways, which might exert a myocardial protective effect through PI3K-Akt signaling pathways and cancer microRNAs. In vivo, compared with the control group, the treatment group could improve the cardiac structure and function, and reduce myocardial pathological damage and the number of autophagosomes. The expression of miR-30a in the myocardium of rats in miR-30a agomir group and SMI group increased (P < 0.01),Beclin 1 mRNA was decreased (P < 0.01),LC3-Ⅱ/LC3-I protein was decreased (P < 0.01 or P < 0.05),and p62 protein was increased (P < 0.01 or P < 0.05). SMI has the characteristics of multi-component, multi-target, and multi-pathway. It can inhibit myocardial excessive autophagy by regulating the expression of miR-30a/Beclin 1 and alleviate the myocardial injury induced by doxorubicin.


Ten Years later: Assessments of the integrity of publications from one research group with multiple retractions.
When a research group has multiple retracted publications and/or research misconduct by a member is evident, there is a risk that its other publications are unreliable, so a comprehensive assessment of the group's publications is advisable. We analyzed the comprehensiveness of assessment of the integrity of 300 publications by a research group with numerous retractions and known research misconduct, for 292 of which we raised concerns to publishers and academic institutions between 3/2013 and 2/2020. By 4/2023, 91 (30%) publications had not been assessed by either publisher or academic institution. Publishers had assessed 185 (63%) publications. The 4 academic institutions had assessed 5/36 (14%), 56/216 (26%), 30/50 (60%) and 40/66 (61%) publications. Unprompted assessments, those undertaken without our notification of concerns, occurred for 24 (8%) publications, 3 (1%) by publishers and 21 (7%) by academic institutions. Among 32 journals with ≥2 affected publications, no unprompted assessments of the remaining publication(s) occurred after notification of concerns about the index publication(s). Publishers retracted 58/84 (69%) publications which institutions also assessed and decided needed no editorial action. These analyses demonstrate the failure of publishers and institutions to comprehensively and spontaneously determine the integrity of publications in a setting of known misconduct and multiple retractions.


Poly-ADP-ribosylated histones: potent DNA suppressors.
When rat liver nuclear chromatin was sonicated in buffer containing 0.35 M (NH4)2SO4 to release the engaged RNA polymerases, a potent inhibitor was also released. This inhibitor elicited dramatic inhibition of RNA synthesis regardless of whether the free or engaged RNA polymerase was used. On further analysis, it became apparent that the site of inhibition was on the DNA template, not on the enzyme. This inhibitor could be extracted into 0.25 N HCl by the standard procedure for the isolation of histones. This acid-soluble inhibitor, showing typical histone band on gel, was RNase A and DNase I resistant, but was sensitive to both pronase and snake venom phosphodiesterase digestion, as well as to 0.1 N KOH hydrolysis. Furthermore, when [14C]adenine labeled poly-ADP-ribosylated histones were digested by snake venom phosphodiesterase, the release of radioactivity was in parallel to the loss of inhibitor activity. We conclude that the inhibitor substances are poly-ADP-ribosylated histones and propose that the poly-ADP-ribosylated histones rather than the histones are the natural suppressors of the gene.


UK response was 'serious' error.
An authoritative report on the UK government's handling of the covid-19 pandemic has said that many thousands of deaths could have been avoided, reports Adam Vaughan.


Molecular-level comparison study on microwave irradiation-activated persulfate and hydrogen peroxide processes for the treatment of refractory organics in mature landfill leachate.
This study investigated the degradation of organics in mature leachate treated by microwave radiation-activated persulfate (MW/PS) and hydrogen peroxide (MW/H2O2) processes. Obvious synergistic effects existed in both the MW/PS and MW/H2O2 processes, but were significantly higher in the MW/PS process. Refractory organics were better degraded by the MW/PS process than the MW/H2O2 process due to the major contribution of SO4-. Moreover, according to Fourier transform-ion cyclotron resonance mass spectrometry coupled with electrospray ionization analysis results, the refractory organics (e.g. polycyclic aromatics (AI > 0.66), polyphenols (0.66 ≥ AI > 0.50)) were greatly degraded by both the MW/H2O2 and MW/PS processes, but the MW/PS process degraded dissolved organic matter (DOM) over a wider range than the MW/H2O2 process due to the different dominant radicals in the two processes. In addition, after reaction in the MW/PS process, the O/C ratio of DOM in the treated effluent showed an obvious increase, which can be mainly attributed to the reaction of sulfate radicals with the N- and S- containing compounds via single electron transfer.


Regulation of cyclic nucleotide phosphodiesterase activity in human lung fibroblasts.
Cyclic nucleotide phosphodiesterase activity (3', 5'-cyclic-nucleotide 5'-nucleotidohydrolase, 18.104.22.168) was studied in homogenates of WI-38 human lung fibroblasts using 0.1--200 microgram cyclic nucleotides. Activities were observed with low Km for cyclic AMP(2--5 micron) and low Km for cyclic GMP (1--2 micron) as well as with high Km values for cyclic AMP (100--125 micron) and cyclic GMP (75--100 micron). An increased low Km cyclic AMP phosphodiesterase activity was found upon exposure of intact fibroblasts to 3-isobutyl-1-methylxanthine, an inhibitor of phosphodiesterase activity in broken cell preparations, as well as to other agents which elevate cyclic AMP levels in these cells. The enhanced activity following exposure to 3-isobutyl-1-methylxanthine was selective for the low Km cyclic AMP phosphodiesterase since there was no change in activity of low Km cyclic GMP phosphodiesterase activity or in high Km phosphodiesterase activity with either nucleotide as substrate. The enhanced activity due to 3-isobutyl-1-methylxanthine appeared to involve de novo synthesis of a protein with short half-life (30 min), based on experiments involving cycloheximide and actinomycin D. This activity was also enhanced with increased cell density and by decreasing serum concentration. Studies of some biochemical properties and subcellular distribution of the enzyme indicated that the induced enzyme was similar to the non-induced (basal) low Km cyclic AMP phosphodiesterase.


Single session family therapy for beginners: what difference does it make to psychiatry registrars to participate in family sessions in front of and behind the screen?
Current competencies required for fellowship of the RANZCP require psychiatry registrars to have experience in working with clients across all age groups, as well as working with families and the client's wider network, however gaining this experience is not always easy for trainees. This paper reports on the experience of participating in Single Session Family Therapy (SSFT) during registrar training as a different modality for learning. An online survey was conducted with fourteen registrars who had participated in SSFT during their child and adolescent rotation. Qualitative and simple quantitative data were collected and analysed. Participating in SSFT during training was initially daunting, but had a positive effect on trainees, including influencing some towards focussing their future sub-specialisation in the child and youth area. Experience came through learning by doing, and seeing change. Registrars learnt about: understanding the role of the family; teamwork; technical skills; and gained confidence. Opportunities for trainees to participate in SSFT enables powerful learning beyond what can be taught in the classroom. Such opportunities may enhance registrars' perceptions of family work, and may positively influence decision about future sub-specialisation.


Cumulative Burden of Mental Health Factors and Engagement in HIV Care in Argentina.
Cumulative burden of multiple mental health conditions may worsen physical health outcomes in vulnerable populations. Accordingly, identifying cumulative burdens of mental health conditions that may affect HIV treatment and care can guide public health strategies to reduce their impact on HIV-related health outcomes. This study examined the relationship between the cumulative burden of mental health conditions and factors associated with engagement in HIV care in Argentina. Data for this study was obtained at baseline from Conexiones y Opciones Positivas en la Argentina 2 (COPA2). Participants (N = 360) were cisgender patients living with HIV who were lost to care, recruited from seven clinics serving people living with HIV in four Argentine urban centers. Cumulative burden of mental health conditions (i.e., depressive symptoms, problematic substance use, unhealthy alcohol use, and psychotic symptoms) was assessed. Every one-point increase in the number of mental health conditions present was associated with a decrement in patient-provider communication (b = - 0.22, p < .001), self-efficacy (b = - 0.13, p = .012), and motivation for adherence (b = - 0.11, p = .039). This study found cumulative burden of depression, problematic substance use, unhealthy alcohol use, and psychotic symptoms to be negatively associated with factors related to engagement in HIV care. Results highlight the importance of identification and treatment of challenges to mental health, in order to ameliorate their influence on engagement in HIV care.


MeCP2 prevents age-associated cognitive decline via restoring synaptic plasticity in a senescence-accelerated mouse model.
Age-related cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD), is associated with the deficits of synaptic plasticity. Therefore, exploring promising targets to enhance synaptic plasticity in neurodegenerative disorders is crucial. It has been demonstrated that methyl-CpG binding protein 2 (MeCP2) plays a vital role in neuronal development and MeCP2 malfunction causes various neurodevelopmental disorders. However, the role of MeCP2 in neurodegenerative diseases has been less reported. In the study, we found that MeCP2 expression in the hippocampus was reduced in the hippocampus of senescence-accelerated mice P8 (SAMP8) mice. Overexpression of hippocampal MeCP2 could elevate synaptic plasticity and cognitive function in SAMP8 mice, while knockdown of MeCP2 impaired synaptic plasticity and cognitive function in senescence accelerated-resistant 1 (SAMR1) mice. MeCP2-mediated regulation of synaptic plasticity may be associated with CREB1 pathway. These results suggest that MeCP2 plays a vital role in age-related cognitive decline by regulating synaptic plasticity and indicate that MeCP2 may be promising targets for the treatment of age-related cognitive decline in neurodegenerative diseases.


Synthesis of N-(2-pyridyl)indoles via Pd(II)-catalyzed oxidative coupling.
Readily available Pd(II) chloride catalysts can catalyze selective and efficient oxidative coupling between N-aryl-2-aminopyridines and internal alkynes to yield N-(2-pyridyl)indoles. This process involves the ortho C-H activation of N-aryl-2-aminopyridines, and CuCl(2) was used as an oxidant. Compared to our previously reported Rh(III)-catalyzed synthesis of this class of product, this method is advantageous with a wider scope of alkynes and cost-effective Pd(II) catalysts. Molecular oxygen can be used as a terminal oxidant.


Role of sodium azide in reducing nonspecific color development in enzyme immunoassays.
Improved enzyme immunoassay (EIA) procedures achieved by incorporating sodium azide during predilution of serum samples in a solid-phase EIA for the detection of anti-Toxoplasma antibody in swine using a peroxidase conjugate and in all washes of a bovine brucellosis rapid card test EIA using alkaline phosphatase conjugate are reported. Without this modification, substantial background interference was encountered that showed direct correlation with the degree of hemolysis of the serum samples. Anti-Toxoplasma gondii antibody-negative samples, separated by subjective groupings based on degree of hemolysis, into "clear", "slight", and "gross/total" samples, had a mean +/- standard deviation of 0.150 +/- 0.072, 0.187 +/- 0.105, and 0.232 +/- 0.108, respectively. The incorporation of sodium azide during the initial step of serum dilution dramatically eliminated the background, giving a mean +/- standard deviation of 0.079 +/- 0.029, 0.076 +/- 0.022, and 0.081 +/- 0.029, respectively. The level of endogenous peroxidase activity, a possible factor for this nonspecific interference, was considerably elevated in some of the swine sera. The clear, slight, and gross/total categories had relative levels of 1%, 2%, and 51% peroxidase activity compared to the conjugate peroxidase activity of 100%. Whereas sodium azide could be used only in sample predilution in the swine toxoplasmosis peroxidase-conjugate test, in the bovine brucellosis alkaline phosphatase-conjugate card test it could be used in all wash cycles. Many brucellosis card test results were visually uninterpretable because of significant background color when the manufacturer's wash reagent was used. The substitution of a wash reagent containing sodium azide eliminated background color, giving a visually unambiguous test.


The use of non-human primates for production of antisera to human tumor-associated antigens.
High-titered antisera against human melanoma- and leukemia-associated antigens have been produced in non-human primates. The data from this and from other studies suggest that this model may prove a valuable source of highly specific antisera against a variety of human tumor-associated antigens or alloantigens. Our methods for production and characterization of these antisera are reported.


The correlation between mid-brain serotonin transporter availability and intelligence quotient in healthy volunteers.
This study was performed to investigate the association between the mid-brain serotonin transporter (SERT) availability and intelligence quotient (IQ). One hundred and thirteen healthy participants, including 52 male and 61 female subjects, were recruited. We used SPECT with [(123)I]ADAM images to determine the SERT availability in the mid-brain, and measured the subjects' IQ using the WAIS-R. We found a significant positive correlation between the mid-brain SERT availability and the IQ of the participants. Even when controlling for age and sex, the significant association still existed. This result implied that the higher the SERT binding in the mid-brain, the better the IQ in healthy participants.


S100A4 plays a key role in TRPV3 ion channel expression and its electrophysiological function.
Transient receptor potential vanilloid 3 (TRPV3), a non-selective cation ion channel, is regulated by small molecules such as Ca2+ and calmodulin (CaM). Together with S100A4 (S100 calcium-binding protein family), is critical in cell proliferation and progression. Although TRPV3 has been proved to play a role in Ca2+ regulation and participate in Ca2+-related cellular processes, its molecular mechanism remains unclear. In this study, we found that TRPV3 and S100A4 were co-expressed in the same region of the cell, and surprisingly, the protein expression level of TRPV3 significantly increased with the overexpression of S100A4. Moreover, co-immunoprecipitation results showed that these two proteins could bind with each other. Functionally, we found that when S100A4 was simultaneously expressed in cells, more Ca2+ would be transferred into the cells through the TRPV3 ion channel. Consistent with Ca2+ regulation results, electrophysiological recordings demonstrated that S100A4 improved the function of TRPV3 in ions' flux, suggesting that the S100A4 could bind with TRPV3 and simultaneously promoted its expression, thus affecting its functions on related ions' flux. Our findings identified the link between S100A4 and TRPV3 and provided a novel molecular mechanism for TRPV3 regulation.


Effects of nitrogen deposition and soil fertility on cover and physiology of Cladonia foliacea (Huds.) Willd., a lichen of biological soil crusts from Mediterranean Spain.
We are fertilizing a thicket with 0, 10, 20 and 50 kg nitrogen (N) ha(-1) yr(-1) in central Spain. Here we report changes in cover, pigments, pigment ratios and FvFm of the N-tolerant, terricolous, lichen Cladonia foliacea after 1-2 y adding N in order to study its potential as biomarker of atmospheric pollution. Cover tended to increase. Pigments increased with fertilization independently of the dose supplied but only significantly with soil nitrate as covariate. β-carotene/chlorophylls increased with 20-50 kg N ha(-1) yr(-1) (over the background) and neoxanthin/chlorophylls also increased with N. (Neoxanthin+lutein)/carotene decreased with N when nitrate and pH seasonalities were used as covariates. Between 26 and 56 kg N ha(-1) yr(-1).Pinho et al. (2012) suggested that the critical Nload for Mediterranean epiphytic lichens (based on responses of functional groups) was lower than 26 kg N ha(-1) yr(-1) [corrected]. Water-stress, iron and copper also explained variables of lichen physiology. We conclude that this tolerant lichen could be used as biomarker and that responses to N are complex in heterogeneous Mediterranean-type landscapes.


Demographic characteristics and food choices of participants in the Special Diabetes Program for American Indians Diabetes Prevention Demonstration Project.
American Indians and Alaska Natives (AI/ANs) suffer a disproportionate burden of diabetes. Identifying food choices of AI/ANs at risk of type 2 diabetes, living in both rural and urban settings, is critical to the development of culturally relevant, evidence-based education strategies designed to reduce morbidity and mortality in this population. At baseline, 3135 AI/AN adults participating in the Special Diabetes Program for American Indians Diabetes Prevention Demonstration Project (SDPI-DP) completed a socio-demographic survey and a 27-item food frequency questionnaire (FFQ). The primary dietary behavior goal of SDPI-DP education sessions and lifestyle coaching is changes in food choices, i.e., increased fruits, vegetables and whole grains, decreased high sugar beverages, red meat, and processed foods. Subsequently, program assessment focuses on changes in food types. Foods were delineated using a 'healthy' and 'unhealthy' classification as defined by the educators advising participants. Urban and rural differences were examined using χ(2) tests and two sample t-tests. Multiple linear regressions and linear mixed models were used to assess the association between socio-demographic factors and food choice. Retired participants, those living in urban areas and with high income and education selected healthy foods most frequently. Young males, those with low income and education consumed unhealthy foods most frequently. Selection of unhealthy foods did not differ by urban and rural setting. The ubiquitous nature of unhealthy food choices makes them hard to avoid. Food choice differences by gender, age, income, and setting suggest that nutrition education should more effectively target and meets the needs of young AI/AN males.


Focally increased activity in the lateral aspect of the mid cervical spine on bone scintigraphy is almost always benign in nature.
Abnormal bone scan findings in the spine are often nonspecific. The confidence level for the differential diagnosis between metastases and benign or degenerative changes may vary depending on their appearance, location or intensity. The recognition of a specific pattern for certain benign conditions and its subcategorization will increase the credibility of bone scan interpretation while retaining a high level of sensitivity. We report one such finding, focally increased activity on the lateral side of the cervical spine on the posterior view, most common at the C3-C5 level ("mid-cervical-lateral-focus"). Of 481 patients with various cancers who had at least 2 whole-body bone scans, 6 months or more apart, 41 patients were judged to show this characteristic "mid-cervical-lateral-focus" on at least one scan. Final diagnosis (metastasis vs. benign) for each "mid-cervical-lateral-focus" was made based on clinical grounds and serial bone scans. The bone scan showed definite multiple metastases in 15 patients, and the differential diagnosis for the "mid-cervical-lateral-focus" was already clinically irrelevant in these patients. Nevertheless, the "mid-cervical-lateral-focus" was finally judged to be benign in 14 of these 15 patients and in all remaining 26 patients without other obvious metastases. The only "mid-cervical-lateral-focus" judged to be a metastatic focus was not only clinically redundant, but also the most intense among all the "mid-cervical-lateral-foci." in this series (too intense to be interpreted as benign). The typical "mid-cervical-lateral-focus" pattern is extremely unlikely to represent metastases (virtually 0% in patients without other obvious metastases). This knowledge helps exclude metastases on bone scans.


Evidence for presence of types A and B of beet necrotic yellow vein virus (BNYVV) in Iran.
Rhizomania a viral disease, caused by beet necrotic yellow vein benyvirus (BNYVV), is now widely spread, throughout the sugar beet growing areas of Iran. Genomes of BNYVV are composed of five RNA molecules with specific functions. In this study sequence analyses were conducted on the major coat protein gene (CP21), and parts of RNA3 and RNA4 of an Iranian strain of BNYVV from the Fars province. Sequence alignments of Iran Fars CP21 with other isolates showed closed similarities at nucleotide and amino acid levels with BNYVV pathotype A isolates; S from Japan, and YU2 from Yugoslavia. These results suggest that Iran-Fars isolate probably originated from Asia or neighboring European countries rather than from Germany or France.


Tinnitus: An Epidemiologic Perspective.
Tinnitus is commonly referred to as "ringing in the ears." Epidemiologic studies highlight challenges associated with clinical determination of tinnitus and ascertainment of its etiology, functional effects, temporal characteristics, psychoacoustic parameters, and risk factors. Because no standards exist for capturing these factors as measures, direct comparison of data between studies is not possible. This report suggests terminology and definitions to promote standardization, with a brief overview of findings from selected population-based epidemiologic studies. Tinnitus-specific data are presented from the Noise Outcomes in Servicemembers Epidemiology study. Further epidemiologic studies are needed to develop tinnitus treatment and a cure for this chronic condition.


Developing nursing clinical data models addressing delusion and hallucination with Meleis transitions theory as the theoretical reference model: A focus group study.
To build the final clinical data models regarding the nursing focuses "Delusion" and "Hallucination" with Meleis transitions theory as the theoretical reference model. A qualitative descriptive design was adopted, using two focus groups. The clinical data models obtained by this study recognize a perspective centered on the client's transition, which emphasizes the role of nursing in relation to a client suffering from delusion and hallucination. These clinical data models may contribute towards improving nursing clinical decision-making and nursing care quality regarding these areas.


The effect of an isovolumic left ventricle on the coronary vascular competence during reflow after global ischemia in the rat heart.
During global ischemia in isolated rat hearts, the development of contracture, due to irreversible myofilament sliding, causes reduction of left ventricle luminal volume. Also, a considerable area of the myocardium cannot be reperfused after 1 hour's global ischemia. The purpose of this study was to reduce myofilament sliding by placing a fluid-filled isovolumic balloon in the left ventricular cavity of isolated rat hearts and assess the extent of reflow, after 60 minutes' ischemia, by perfusion of a 1% fluorescein tracer solution. Light and electron microscopy was used to determine the state of the vasculature and myofibrillar apparatus. In hearts without the left ventricular balloon (control) the ischemia produced a no-reflow zone comprising 45% of the myocardial wall. In contrast, if an isovolumic balloon was in place during the ischemic period, only 6% of the wall was involved. The volume of the capillary bed in the subendocardium of the control hearts was about 60% of that in th isovolumic hearts. In the isovolumic ("isometric") mode, ischemic contracture was associated with more severe myocardial cell injury than in the corresponding control ("isotonic") mode. Our results support the concept that intramyocardial pressure generated by ischemic contracture plays a major role in the production of the no-reflow phenomenon in globally ischemic rat hearts, and indicate that it is the series elastic component of cardiac muscle which imparts the stiffness necessary to prevent reopening of coronary vessels after a severe ischemic insult.


Effect of salt loading in the rat on adenylate cyclase and phosphodiesterase activity in kidney cortex, medulla and papilla.
Adenylate cyclase (AC) and phosphodiesterase (PDE) activities were studied in the cortex, medulla and papilla of the rat kidney. Sodium loading in vivo for 14 days resulted in a decrease of AC activity in the cortex, a small increase in the medulla and a substantial increase of AC activity in the papilla. Sodium loading caused reciprocal effects on PDE activity: an increase in kidney cortex and a decrease in kidney papilla. Loading of glucose in vivo or chronic administration of antidiuretic hormone in vivo did not cause the changes in AC or PDE observed after sodium loading. The possible significance of these findings is discussed.


Bacterial community composition and fermentation patterns in the rumen of sika deer (Cervus nippon) fed three different diets.
Sika deer (Cervus nippon) rely on microorganisms living in the rumen to convert plant materials into chemical compounds, such as volatile fatty acids (VFAs), but how the rumen bacterial community is affected by different forages and adapt to altered diets remains poorly understood. The present study used 454-pyrosequencing of bacterial 16S ribosomal RNA (rRNA) genes to examine the relationship between rumen bacterial diversity and metabolic phenotypes using three sika deer in a 3 × 3 latin square design. Three sika deer were fed oak leaves (OL), corn stover (CS), or corn silage (CI), respectively. After a 7-day feeding period, when compared to the CS and CI groups, the OL group had a lower proportion of Prevotella spp. and a higher proportion of unclassified bacteria belonging to the families Succinivibrionaceae and Paraprevotellaceae (P<0.05). Meanwhile, the concentration of isobutyrate was significantly lower (P<0.05) in the OL group than in the CS and CI groups. There was no significant change of dominant bacterial genera in the OL group after 28 days of feeding. Conversely, total volatile fatty acids (TVFAs) showed an increase after 28 days of feeding, mainly due to the increasing of acetate, propionate, and valerate (P<0.05). The interplay between bacteria and metabolism in the OL group differed from that in the CS and CI groups, especially for the interaction of TVFAs and acetate/propionate. Overall, the current study suggested that Prevotella spp. played critical roles in the fermentation of feed in the rumen of sika deer. However, the differences in interplay patterns between rumen bacterial community composition and metabolic phenotypes were altered in the native and domesticated diets indicating the changed fermentation patterns in the rumen of sika deer.


Visual motion mechanisms under low retinal illuminance revealed by motion reversal.
The aim of this study is to determine what kinds of motion mechanisms operate at low luminance levels. We used a motion reversal phenomenon in which the perceived direction of motion is reversed when a blank inter-stimulus interval (ISI) frame is inserted between two image frames of similar mean luminance. At low luminance levels, we found that motion reversal was perceived when the moving pattern was presented in the retinal periphery, but no motion reversal was observed when the stimulus was presented in the central retina. When a large stimulus that covers both central and peripheral visual fields was presented, motion reversal did not occur. We conclude that as retinal illuminance decreases, the relative contribution of a feature-tracking mechanism in the central retina becomes larger, while motion perception in the peripheral retina continues to depend on a biphasic, first-order motion mechanism. When both central and peripheral visual fields are stimulated simultaneously, the motion mechanism that dominates in the central retina determines the perceived direction of motion at low luminance levels.


End-Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy.
The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes. We performed a gene-based collapsing test of rare protein-truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large-scale databases, gnomAD and TOPMed. Western blotting was used to investigate the functional consequences of variants. Clinical and magnetic resonance imaging features of mutated patients were characterized. We showed that LAMB1 truncating variants escaping nonsense-mediated messenger RNA decay are strongly overrepresented in CSVD patients, reaching genome-wide significance (p < 5 × 10-8 ). Using 2 antibodies recognizing the N- and C-terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in the endogenous fibroblasts of patients and trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy. These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. ANN NEUROL 2021;90:962-975.


Drug-drug interactions of non-steroidal anti-inflammatory drugs with other drugs in patients with rheumatic diseases.
To determine the prevalence of and identify drug-drug interactions (DDI) between non-steroidal anti-inflammatory drugs (NSAID) and other drugs in a prescription database of patients with rheumatic iseases. This is a cross-sectional study of a drug prescription database saving information on 35,000 individuals who benefited from a pre-paid medical system serving bank employees and their relatives. The analysis included one year period (from January to December 1998). NSAID-DDI were listed and classified into 3 levels (1: minor; 2: moderate, and 3: high health risk or death risk) according to DRUGDEX(r) as well as MEDLINE and EMBASE search. We analyzed 3,207 NSAID prescriptions (1.7±1.6 per patient) to 1,855 rheumatic patients (adults: 76.7%; geriatric: 20.2%, and pediatric: 3.0%; soft tissue rheumatism: 52%; osteoarthritis: 19%, and rheumatoid arthritis: 10%). There were 648 (20.20%) NSAID-DDI prescriptions: 594 (91.66%) corresponded to level 1; 46 (7.09%) to level 2, and 8 (1.23%) to level 3. In addition, 96 (2.99%) prescriptions included NSAID duplications. Interestingly, we found no NSAID-DDI with anticoagulants, anticonvulsants, and oral hypoglycemiants were found. The prevalence of NSAID-DDI prescriptions to 1,855 rheumatic patients was 20.20% in one year. NSAID-DDI was mostly (91.66%) level 1, and rarely (1.23%) level 3. NSAID duplications were found in 2.99%. These results provides information on the frequency of prescriptions with DDI, which might potentially produce harmful effects and data, which may help in the development of studies searching for the clinical relevance of NSAID-DDI.


Oligosaccharide attenuates aging-related liver dysfunction by activating Nrf2 antioxidant signaling.
Chitosan oligosaccharide (COS) is the depolymerized product of chitosan possessing various biological activities and protective effects against inflammation and oxidative injury. The aim of the present study was to investigate the antioxidant effects of COS supplements on aging-related liver dysfunction. We found that COS treatment significantly attenuated elevated liver function biomarkers and oxidative stress biomarkers and decreased antioxidative enzyme activities in liver tissues in D-galactose (D-gal)-treated mice. Furthermore, COS treatment significantly upregulated the expression of Nrf2 and its downstream target genes HO-1, NQO1, and CAT. Moreover, in vitro experiments showed that COS treatment played a vital role in protecting H2O2-exposed L02 cells against oxidative stress by activating Nrf2 antioxidant signaling. These data indicate that COS could protect against D-gal-induced hepatic aging by activating Nrf2 antioxidant signaling, which may provide novel applications for the prevention and treatment of aging-related hepatic dysfunction.


Mortality from infectious diseases among New Mexico's American Indians, Hispanic whites, and other whites, 1958-87.
To examine ethnic differences in infectious disease-related mortality in New Mexico's American Indian, Hispanic White and other White populations, we analyzed vital records data from 1958 to 1987. We found that for most infectious causes, American Indians had the highest mortality rates, followed by Hispanics. The state's minority populations remain at increased risk for infectious disease mortality.


Pharmacologic induction of fetal hemoglobin production.
Reactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in adult patients with hemoglobin disorders. The understanding of the developmental regulation of γ-globin gene expression was followed by the identification of a number of chemical compounds that can reactivate HbF synthesis in vitro and in vivo in patients with hemoglobin disorders. These HbF inducers can be grouped in several classes based on their mechanisms of action. This article focuses on pharmacologic agents that were tested in humans and discusses current knowledge about the mechanisms by which they induce HbF.


Evaluation of SARS-CoV-2 main protease and inhibitor interactions using dihedral angle distributions and radial distribution function.
In order to evaluate the interactions between a potential drug candidate like inhibitor N3 and the residues in substrate binding site of SARS-CoV-2 main protease ( M pro ), we used molecular docking and dynamics simulations. The structural features describing the degrees of folding states of M pro formed by beta-barrels and alpha-helices were analyzed by means of root mean square deviation, root mean square fluctuation, radius of gyration, residue velocity, H-bonding, dihedral angle distributions and radial distribution function. All of the residues forming ligand binding domain (LBD) of M pro lie within the allowed region of the dihedral angle distributions as observed from the equilibrating best pose of M pro -N3 system. Sharp peaks of radial distribution function (RDF) for H-bonding atom pairs (about 2 Å radial distance apart) describe the strong interactions between inhibitor and SARS-CoV-2 M pro . During MD simulations, HSE163 has the lowest residue speed offering a sharp RDF peak whereas GLN192 has the highest residue speed resulting a flat RDF peak for the H-bonding atom pairs of M pro -N3 system. Along with negative values of coulombic and Lenard-Jones energies, MM/PBSA free energy of binding contributed by the non-covalent interactions between M pro and N3 has been obtained to be -19.45 ± 3.6 kcal/mol. These physical parameters demonstrate the binding nature of an inhibitor in M pro -LBD. This study will be helpful in evaluating the drug candidates which are expected to inhibit the SARS-CoV-2 structural proteins.


Does small bite closure reduce the incidence of incisional hernia compared to standard mass closure for midline laparotomy?
A best evidence topic was constructed using a defined protocol. The three-part question addressed was: in closure of midline laparotomy, which technique had lower incidence of incisional hernia: small bite closure or mass closure? The best evidence demonstrated that small bite technique has lower incidence of hernia.


How information guides movement: intercepting curved free kicks in soccer.
Previous studies have shown that balls subjected to spin induce large errors in perceptual judgments (Craig, Berton, Rao, Fernandez, & Bootsma, 2006; Craig et al., 2009) due to the additional accelerative force that causes the ball's flight path to deviate from a standard parabolic trajectory. A recent review however, has suggested that the findings from such experiments may be imprecise due to the decoupling of perception and action and the reliance on the ventral system (van der Kamp, Rivas, van Doorn, & Savelsbergh, 2008). The aim of this study was to present the same curved free kick trajectory simulations from the perception only studies (Craig et al., 2006, 2009) but this time allow participants to move to intercept the ball. By using immersive, interactive virtual reality technology participants were asked to control the movement of a virtual effector presented in a virtual soccer stadium so that it would make contact with a virtual soccer ball as it crossed the goal-line. As in the perception only studies the direction of spin had a significant effect on the participants' responses with significantly fewer balls being intercepted in the spin conditions when compared to no-spin conditions. A significantly higher percentage of movement reversals for the spin conditions served to highlight the link between information specifying ball heading direction and subsequent movement. The coherence of the findings for both the perception and perception/action study are discussed in light of the dual systems model for visual processing.


Analysis of ARMPS2010 database with LaModel and an updated abutment angle equation.
The Analysis of Retreat Mining Pillar Stability (ARMPS) program was developed by the National Institute for Occupational Safety and Health (NIOSH) to help the United States coal mining industry to design safe retreat room-and-pillar panels. ARMPS calculates the magnitude of the in-situ and mining-induced loads by using geometrical computations and empirical rules. In particular, the program uses the "abutment angle" concept in calculating the magnitude of the abutment load on pillars adjacent to a gob. In this paper, stress measurements from United States and Australian mines with different overburden geologies with varying hard rock percentages were back analyzed. The results of the analyses indicated that for depths less than 200 m, the ARMPS empirical derivation of a 21° abutment angle was supported by the case histories; however, at depths greater than 200 m, the abutment angle was found to be significantly less than 21°. In this paper, a new equation employing the panel width to overburden depth ratio is constructed for the calculation of accurate abutment angles for deeper mining cases. The new abutment angle equation was tested using both ARMPS2010 and LaModel for the entire case history database of ARMPS2010. The new abutment angle equation to estimate the magnitude of the mining-induced loads used together with the LaModel program was found to give good classification accuracies compared to ARMPS2010 for deep cover cases.


Beneficial effect of autologous endometrial cell coculture in patients with repeated implantation failure.
To confirm the beneficial effect of endometrial coculture in patients with repeated failures with assisted reproductive techniques (ART). Patients with previous failures were offered a repetition of ART in conjunction with autologous endometrial coculture. Private fertility center. Sixty-eight couples who had attempted 92 cycles of IVF or intracytoplasmic sperm injection without obtaining an evolutive pregnancy. Patients repeated one cycle of ART with concomitant endometrial coculture of their embryos. Comparative pregnancy and delivery rates in conventional ART cycles vs. cycles with autologous endometrial coculture. In the previous 92 cycles (146 ETs, fresh plus frozen) only 8 pregnancies were initiated, and all ended in spontaneous abortion. Upon repeating 68 cycles (76 ETs) using coculture, 39 pregnancies were obtained, of which 19 resulted in live births, 10 are ongoing evolutive pregnancies, and 10 ended in spontaneous abortions. These results confirm the usefulness of autologous endometrial coculture for the treatment of patients with repeated implantation failure.


Crowns and extra-coronal restorations: endodontic considerations: the pulp, the root-treated tooth and the crown.
Endodontic considerations is the fourth in the series on crowns and other extra-coronal restorations. This article focuses strongly on contemporary biological principles, and is not intended to provide a comprehensive review of commercially available materials and techniques. Principles are illustrated in a variety of clinical case scenarios.


Influence of biofilm thickness on nitrous oxide (N2O) emissions from denitrifying fluidized bed bioreactors (DFBBRs).
Nitrous oxide (N2O) is a significant anthropogenic greenhouse gas emitted from biological nutrient removal (BNR) processes. This study tries to get a deeper insight into N2O emissions from denitrifying fluidized bed bioreactors (DFBBRs) and its relationship to the biofilm thickness, diffusivity, and reaction rates. The DFBBR was operated at two different organic and nitrogen loading rates of 5.9–7 kg COD/(m3 d) and 1.2–2 kg N/(m3 d), respectively. Results showed that the N2O conversion rate from the DFBBR at a biofilm thickness of 680 μm was 0.53% of the total influent nitrogen loading while at the limited COD and a biofilm thickness of 230 μm, the N2O conversion rate increased by 196–1.57% of the influent nitrogen loading concomitant with a sevenfold increase in liquid nitrite concentration. Comparing the N2O emissions at different biofilm thickness showed that the N2O emission decreased exponentially with biofilm thickness due to the retention of slow growth denitrifiers and the limited diffusivity of N2O.


Alpha, mu and pi glutathione S-transferases: species (Talpa europaea) differences in their expression.
1. Tissue cytosols from Talpa europaea were examined for their glutathione S-transferase isoenzyme content by chromatofocusing, inhibition and immunological techniques and the results compared with data from adult human tissue cytosols. 2. Two sets of glutathione S-transferase isoenzymes were found in liver cytosol of Talpa europaea, they demonstrated similar properties to human alpha and mu isoforms. 3. There was no evidence of expression of the pi isoenzyme set in any of the tissues studied and in this respect Talpa europaea differs from other mammalian species studied so far.


Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin.
Asbestos-associated diseases remain a social burden worldwide. Our previous studies identified asbestos-induced iron-rich milieu for mesothelial cells with ceaseless macrophage ferroptosis. However, molecular mechanisms how this mutagenic milieu influences mesothelial cells have not been elucidated yet. Here, we propose a novel mechanism that extracellular vesicles (EVs) mediate asbestos-associated mutagenic factors to mesothelial cells. In a mice model of intraperitoneal crocidolite injection, mutagenic milieu highly expressed CD63, an exosomal marker. We then used a GFP-CD63 labeled THP-1 macrophage model exposed to crocidolite/iron, which generated EVs under ferroptotic process. We observed that MeT-5A mesothelial cells can receive and internalize these EVs. Furthermore, we comprehensively analyzed the ferroptosis-dependent EVs (FedEVs) for transported proteins and identified ferritin heavy/light chains as major components. Therefore, we inferred that FedEVs transport iron from ferroptotic macrophages to mesothelial cells. RNA sequencing revealed that the mesothelial cells receiving higher amounts of the FedEVs were mitotic, especially at the S and G2/M phases, by the use of Fucci mesothelial cells. Nuclear 8-hydroxy-2'-deoxyguanosine and γ-H2AX were significantly increased in the recipient mesothelial cells after exposure to FedEVs. Collectively, we here demonstrate a novel mechanism that FedEVs act as a key mutagenic mediator by transporting iron, which contribute to asbestos-induced mesothelial carcinogenesis.


Tissue repair and stem cell renewal in carcinogenesis.
Cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem-cell-like properties and in its possible derivation from normal tissue stem cells. But stem cell activity is tightly controlled, raising the question of how normal regulation might be subverted in carcinogenesis. The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.


Mannose ameliorates experimental colitis by protecting intestinal barrier integrity.
Metabolite alteration has been associated with the pathogenesis of inflammatory bowel disease (IBD), including colitis. Mannose, a natural bioactive monosaccharide that is involved in metabolism and synthesis of glycoproteins, exhibits anti-inflammatory and anti-oxidative activities. We show here that the circulating level of mannose is increased in patients with IBD and mice with experimental colitis. Mannose treatment attenuates intestinal barrier damage in two mouse colitis models, dextran sodium sulfate (DSS)-induced colitis and spontaneous colitis in IL-10-deficient mice. We demonstrate that mannose treatment enhanced lysosomal integrity and limited the release of cathepsin B, preventing mitochondrial dysfunction and myosin light chain kinase (MLCK)-induced tight junction disruption in the context of intestinal epithelial damage. Mannose exerts a synergistic therapeutic effect with mesalamine on mouse colitis. Cumulatively, the results indicate that mannose supplementation may be an optional approach to the treatment of colitis and other diseases associated with intestinal barrier dysfunction.


Relationship between hardiness and risk of burnout in a sample of 92 nurses working in oncology and AIDS wards.
The present study tested the hypothesis that particular personality dispositions act as resistance resources in the encounter with stressful life events. The sample consisted of 100 student nurses working in critical areas (oncology and AIDS). At the beginning of the 2nd year course subjects were administered the Kobasa Hardiness Scale and at the end of the year the Maslach Burnout Inventory. Higher hardiness levels at the beginning of the course were associated with lower emotional exhaustion and higher personal achievement scores at the end. As predicted, findings show hardiness scores to be predictive of the risk of burnout. A screening of personality traits could be useful in preventing the risk of burnout in nurses working in critical areas.


Surgical site infection and risk factors following right lobe living donor liver transplantation in adults: A single-center prospective cohort study.
Surgical site infection (SSI) is an important cause of decreased graft survival, prolonged hospital stay, and higher costs following living donor liver transplantation. There are several risk factors for SSI. In this cohort study, we aimed to investigate the incidence of SSI at our center and the associated risk factors. Adult right lobe living donor liver transplantations were included in this prospective cohort. Patients who died postoperatively within 3 days; patients with infected ascites or open abdomen, cadaveric, or pediatric transplants; and patients with biologic or cryopreserved vascular grafts were excluded. Patients' demographic characteristics and perioperative surgical findings were recorded. SSI follow-up was continued for 90 days. CDC-2017 criteria were used to diagnose SSI. In the presence of superficial, deep, and organ/space SSI, only the organ in the poorest condition was included in SSI evaluation. The patients were administered similar to antibiotic prophylaxes and immunosuppressive protocols. A total of 101 patients were enrolled in this study, of which 30 (29.7%) were diagnosed with SSI. Organ/space, only deep, and only superficial SSI were noted in 90% (27/30), 6.7% (2/30), and 3.3% (1/30) of the patients, respectively. Twenty-five of 30 patients with SSI had a remote site infection. One or more bacteria observed in cultures were obtained from 28 patients. A donor-recipient age difference of >10 years, cold ischemia lasting for ≥150 minutes, surgical duration of ≥600 minutes, intraoperative hemorrhage of ≥1000 mL, intraoperative blood transfusion, biliary leak or stricture, prolonged mechanical ventilation, prolonged intensive care unit and hospital stay, remote site infection, and the need for reoperation were associated with increased SSI incidence. Preoperative and intraoperative levels of blood glucose, albumin, and hemoglobin were not associated with SSI. A donor-recipient age difference of >10 years, remote site infection, and biliary leak were found to be independent risk factors for SSI. Hospital mortality with and without SSIs was 6.7% vs 4.4%, P = .61. Organ/space SSIs were the essential part of SSIs following right lobe living donor liver transplantations. Donor-recipient age gap, prolonged cold ischemia time, complicated surgery, and postoperative biliary complications were the main causes of SSIs. Although they did not increase the perioperative mortality, they promote increased rate of reoperations, remote infections, prolonged intensive care unit, and hospital stays.


Differential binding of retinol analogs to two homologous cellular retinol-binding proteins.
A comparative study of the interactions of rat cellular retinol-binding protein (CRBP) and cellular retinol-binding protein II (CRBP II) with a number of synthetic phenyl-substituted analogs of all-trans-retinol was performed using fluorescence and nuclear magnetic resonance analysis. These studies indicate that CRBP II is more sensitive to modifications of the ring moiety than CRBP. Removal of the two methyl substituents on the ring which are ortho to the polyene chain abolishes binding to CRBP II. Conformational analysis of the ligands indicates that these two methyl groups influence the planarity of the ligand. The identification of monospecific ligands may prove useful for studying the physiological roles of these two proteins.


Identification of biogenic dimethyl selenodisulfide in the headspace gases above genetically modified Escherichia coli.
Escherichia coli JM109 cells were modified to express the genes encoded in a 3.8-kb chromosomal DNA fragment from a metalloid-resistant thermophile, Geobacillus stearothermophilus V. Manual headspace extraction was used to collect the gases for gas chromatography with fluorine-induced sulfur chemiluminescence analysis while solid-phase microextraction was used for sample collection in gas chromatography/mass spectrometry (GC/MS) analysis. When grown in the presence of selenate or selenite, these bacteria produced both organo-sulfur and organo-selenium in the headspace gases above the cultures. Organo-sulfur compounds detected were methanethiol, dimethyl sulfide, dimethyl disulfide, and dimethyl trisulfide. Organo-selenium compounds detected were dimethyl selenide and dimethyl diselenide. Two mixed sulfur-selenium compounds, dimethyl selenenyl sulfide and a chromatographically late-eluting compound, were detected. Dimethyl selenodisulfide, CH(3)SeSSCH(3), and dimethyl bis(thio)selenide, CH(3)SSeSCH(3), were synthesized and analyzed by GC/MS and fluorine-induced chemiluminescence to determine which corresponded to the late-eluting compound that was bacterially produced. CH(3)SeSSCH(3) was positively identified as the compound detected in bacterial headspace above Se-amended cultures. Using GC retention times, the boiling point of CH(3)SeSSCH(3) was estimated to be approximately 192 degrees C. This is the first report of CH(3)SeSSCH(3) produced by bacterial cultures.


Genetics of melanoma predisposition.
Predisposition to melanoma is genetically heterogeneous. Two high penetrance susceptibility genes, CDKN2A and CDK4, have so far been identified and mapping is ongoing to localize and identify others. With the advent of a catalogue of millions of potential DNA polymorphisms, attention is now also being focused on identification of genes that confer a more modest contribution to melanoma risk, such as those encoding proteins involved in pigmentation, DNA repair, cell growth and differentiation or detoxification of metabolites. One such pigmentation gene, MC1R, has not only been found to be a low penetrance melanoma gene but has also been shown to act as a genetic modifier of melanoma risk in individuals carrying CDKN2A mutations. Most recently, an environmental agent, ultraviolet radiation, has also been established as a modifier of melanoma risk in CDKN2A mutation carriers. Hence, melanoma is turning out to be an excellent paradigm for studying gene-gene and gene-environment interactions.


Early detection of acute rejection in renal allografts using radioiodinated autologous fibrinogen.
131I-labeled autologous fibrinogen was used to detect acute renal allograft rejection in the early postoperative period. Ratios of radioactive counts over transplanted kidneys to those over the heart increased with deposition of radioactive fibrinogen in kidneys undergoing rejection. The test was positive in all instances of acute rejection twelve to twenty-four hours prior to clinical ro biochemical changes. False-positive test results were noted in instances of perinephric hematoma, seroma, and wound abscess and in one patient with urinary tract infection. The test was negative in cases of renal failure secondary to acute tubular necrosis, uric acid nephropathy (in the absence of acute rejection), and chronic rejection. This test is simple, rapid, and practical. It can be performed at the bedside and is free from complications, particularly serum hepatitis.


Prolonged inhibition of nitric oxide synthesis in Yoshida hyperlipidemic rat: aorta functional and structural properties.
To test whether inhibition of nitric oxide synthesis, associated with high levels of plasmatic lipids, can induce atherosclerotic lesions and phenotypic changes in smooth muscle cell composition in the aortic wall of an atherosclerotic-resistant species such as the rat, an inbred strain of hyperlipidemic Pittsburgh Yoshida rat was subjected to prolonged treatment (2 months) with the nitric oxide-synthase inhibitor L omega-nitro-arginine-methyl ester or with L-arginine. The two types of in vivo treatments were not able to modify in vitro aortic endothelium-mediated relaxation induced by acetylcholine or calcium-ionophore A-23187, the endothelium-independent sodium nitrite relaxation and the contractile response to serotonin. Histology and lipid infiltration of vascular specimens showed that L omega-nitro-arginine-methyl ester in vivo treatment did not induce any significant change in the aortic wall. Monoclonal antibodies to myosin isoforms and immunofluorescence procedures revealed the presence of an immature smooth muscle cell subpopulation in aortic specimens from saline-treated Pittsburgh Yoshida rats, whose expansion has been related in other species to atherogenesis. This peculiar cell phenotype disappeared in our animal model after prolonged L omega-nitro-arginine-methyl ester treatment. These data indicate that, despite interference with endothelium-mediated nitric oxide synthesis, atherosclerosis does not develop in this animal model and furnish for the first time a biological justification for atherogenesis resistance of rat, i.e., the lack of activation of an immature aortic smooth muscle cell population which in atherosclerosis-prone species is involved in lesion formation.


Prediction of preterm birth using the cervical consistency index.
To assess the diagnostic power of a new cervical consistency index (CCI) obtained using transvaginal sonography for the prediction of spontaneous preterm birth (PTB) and to establish reference ranges for this new variable. Included in this prospective cross-sectional study were 1115 singleton pregnancies at 5-36 weeks of gestation. Anteroposterior cervical diameter was measured before (AP) and after (AP') application of pressure on the cervix using the transvaginal probe. The index was calculated using the formula: CCI=((AP'/AP) × 100). Cervical length was also measured. The outcomes evaluated were spontaneous PTB before 32, 34 and 37 weeks. Logistic regression and analysis of receiver-operating characteristics (ROC) curves were performed to evaluate the diagnostic power of CCI and cervical length (adjusted for gestational age). Intraclass correlation coefficients (ICCs) and Bland-Altman analysis were used to evaluate intra- and interobserver variability. In the 1031 women with follow-up, the rate of spontaneous PTB before 32 weeks was 0.87%, before 34 weeks was 2.13% and before 37 weeks was 7.76% (n=80). There were 31 (3.01%) iatrogenic PTBs before 37 weeks. An inverse linear correlation between gestational age and CCI was observed, with regression equation: CCI (in %)=89.8 - 1.35 × (GA in weeks); r(2)=0.66, P<0.001. Cervical length showed an inverse quadratic, though non-significant, relationship with gestational age: CL (in mm)=31.084 - 0.0278× (GA in weeks)(2) + 1.0772× (GA in weeks); r(2)=0.076, P<0.14. The intra- and interobserver ICCs for CCI were 0.99 (95% CI, 0.988-0.994) and 0.98 (95% CI, 0.973-0.987), respectively. The area under the ROC curve for CCI in the prediction of spontaneous PTB before 32 weeks was 0.947, for spontaneous PTB before 34 weeks it was 0.943 and for spontaneous PTB before 37 weeks it was 0.907. For a 5% screen-positive rate, CCI had a sensitivity of 67%, 64% and 45% for prediction of spontaneous PTB before 32, 34 and 37 weeks, respectively, with equivalent values of 11%, 9% and 11% for cervical length. CCI shows a clear inverse linear relationship with GA. Assessment of CCI is reproducible and is effective in the prediction of spontaneous PTB. This new variable appears to provide better prediction of spontaneous PTB than does cervical length.


A phantom based laser marking workflow to visually assess geometric image distortion in magnetic resonance guided radiotherapy.
Magnetic resonance (MR)-only workflows require quality assurance due to potential dosimetric impacts of using geometry distorted MR images in radiotherapy planning. MR-visible silicone-based fiducials were arranged in regular 3D structures to cover extended imaging volumes. The scanner's patient marking workflow with a 2-axes movable laser bridge allowed to visually check geometric distortions of each MR reconstructed fiducial against its true position in 3D space. A measurement resolution and uncertainty of the order of 0.5 mm in sagittal and coronal, and 1 mm in transversal direction was found. The proposed workflow required 1 min of evaluation time per fiducial position, and a 9 min 3D MR volume acquisition.


Association of G84A and C276T polymorphism in neuronal nitric oxide synthase (nNOS) gene with herpes simplex encephalitis in eastern Indian population.
In this study, a hypothesis that genetic variations in neuronal nitric oxide synthase (nNOS) could influence the susceptibility and outcome of herpes simplex encephalitis was investigated. Polymorphic loci of nNOS gene, G84A and C276T were genotyped in 132 HSE cases (Age 8.2 ± 1.3yr) and 143 in healthy individuals (Age-9.2 ± 1.6yr) of the same ethnic background from Odisha. A significantly increased risk for HSVE was associated with the AG genotype (OR = 1.73, 95%CI = 1.03-2.9, P = 0.03) and AA genotype (OR = 2.96, 95%CI = 1.04-8.4, P = 0.04) of nNOS 84G →A locus. In case of nNOS 276C→T variation, HSVE risk was linked to CT genotype (OR = 1.79, 95%CI = 1.07-3.0, P = 0.03) and TT genotype (OR = 3.6, 95%CI = 1.2-10.8, P = 0.02). Patients with poor outcome either had homo or heterozygous genotype for both SNPs, but separate genotype analysis could not show significance. But combined genotype analysis of both SNPs confirmed that GG + CC was a risk factor for development of poor outcome. (OR = 6.3, CI-1.9-20.7, P = 0.0033). Haplotype analysis of both SNP did show that "at" haplotype was significantly higher and associated with HSVE cases (OR = 2.322,CI: 1.43-3.77, P = 0.00070). The result observed in this study suggested that variation at these loci of nNOS may have decreased its expression and caused low production of NO, which have resulted in risk of HSVE but provided good outcome in these patients.


Aflibercept or bevacizumab in combination with FOLFIRI as second-line treatment of mRAS metastatic colorectal cancer patients: the ARBITRATION study protocol.
The intensive study of predictive factors has strongly ameliorated the therapeutic flow-chart of metastatic colorectal cancer (mCRC) by allowing the selection of patients who benefit from specific therapies. For instance, in mRAS (mutated RAS) mCRC patients, anti-EGFR drugs (cetuximab and panitumumab) are not recommended; in this group of patients, the use of anti-angiogenic drugs (bevacizumab and aflibercept) is predominant. However, at progression to standard bevacizumab-based first-line chemotherapy, still to date, there are no studies to guide oncologists in the choice of the best second-line anti-angiogenic drug (bevacizumab beyond progression versus aflibercept). ARBITRATION is a prospective, observational study assessing efficacy differences between second-line fluorouracil/irinotecan (FOLFIRI)/bevacizumab versus FOLFIRI/aflibercept at progression to fluoropyrimidines, oxaliplatin and bevacizumab in mRAS mCRC patients. A test power of 80%, a median survival of 9 months from second-line treatment start and a hazard ratio of 0.67 between the two schedules were the basis for statistical design. The final sample will be 220 patients (110 per treatment). The significance will be verified with a two-tailed log-rank test with an alpha value of the I-type error of 5%. Time-to-outcome will be described by Kaplan-Meier curves and prognostic factors studied through multivariable analyses based on the Cox model. Secondary objectives include safety, responses' duration and progression-free survival. A translational research will be conducted to measure several angiogenic proteins in patients' serum before starting the therapy in order to evidence any angiogenic factor patterns related to outcome. We present a large, prospective, observational study aiming to answer two scientific questions: (1) outcome differences between second-line treatments with FOLFIRI/bevacizumab beyond progression versus FOLFIRI/aflibercept in mRAS mCRC patients, (2) angiogenic factors' patterns that could associate with efficacy and help oncologists to apply best the therapeutic anti-angiogenic strategies. The ARBITRATION trial (version 0.0, 13 April 2020) has been registered into the clinicaltrials.gov registry on 20 May 2020 with identifier NCT04397601.


Nonlinear current-voltage relationship of the plasma membrane of single CHO cells.
The application of electric field pulses to Chinese Hamster Ovary (CHO) cells causes membrane electroporation (MEP). If a voltage or current ramp is applied to the cellular membrane of a single CHO cell, the membrane conductance increases nonlinearly with field strength reaching saturation. In particular, the kinetics of the induced conductance changes represents the data basis for the interpretation in terms of underlying structural changes. The current/voltage characteristic is found to be continuous, but displays occasionally a sharp increase in the conductance. The step-like increases are interpreted to reflect the formation of one (or more) larger pore(s). The analysis of current clamp data yields pores of radius (r(p)) in the range of 2.5< or =r(p)/nm< or =20; the pores of the voltage clamp data are in the range of 2.5< or =r(p)/nm< or =55. The larger pores occur predominantly during hyperpolarising and less frequently during depolarising conditions, respectively. The different kinetics of pore formation in the hyperpolarising condition, where the inward field increases, and the depolarising condition, where the inward field first decreases and then increases in the opposite direction, suggests structural asymmetry with respect to the direction of the electric membrane field. At the required higher voltage, the effect of the resting potential is negligibly small.


The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells.
The immunoregulatory cytokine interleukin 10 (IL-10) is expressed mainly by T helper type 2 (T(H)2) cells but also by T(H)1 cells during chronic infection. Here we observed plasticity in the expression of IL-10 and IL-13 after chronic T(H)1 stimulation; furthermore, the expression of Il10 and Il13 was regulated by the transcription factor E4BP4. Chronically stimulated E4BP4-deficient (Nfil3(-/-); called 'E4bp4(-/-)' here) T(H)1 cells, regulatory T cells (T(reg) cells) and natural killer T cells (NKT cells) had attenuated expression of IL-10 and IL-13. Enforced expression of E4bp4 initiated the production of IL-10 and IL-13 by conventional T(H)1 cells. E4bp4(-/-) T(H)2 cells showed impairment of IL-10 production with no effect on IL-13. Our results indicate that E4BP4 has multiple functions in controlling the plasticity of IL-13 in T(H)1 cells and IL-10 in T(H)1 cells, T(H)2 cells, T(reg) cells and NKT cells.