Neural classification of internet gaming disorder and prediction of treatment response using a cue-reactivity fMRI task in young men.
Neural mechanisms underlying internet gaming disorder (IGD) are important for diagnostic considerations and treatment development. However, neurobiological underpinnings of IGD remain relatively poorly understood. We employed multi-voxel pattern analysis (MVPA), a machine-learning approach, to examine the potential of neural features to statistically predict IGD status and treatment outcome (percentage change in weekly gaming time) for IGD. Cue-reactivity fMRI-task data were collected from 40 male IGD subjects and 19 male healthy control (HC) subjects. 23 IGD subjects received 6 weeks of craving behavioral intervention (CBI) treatment. MVPA was applied to classify IGD subjects from HCs and statistically predict clinical outcomes. MVPA displayed a high (92.37%) accuracy (sensitivity of 90.00% and specificity of 94.74%) in the classification of IGD and HC subjects. The most discriminative brain regions that contribute to classification were the bilateral middle frontal gyrus, precuneus, and posterior lobe of the right cerebellum. MVPA statistically predicted clinical outcomes in the craving behavioral intervention (CBI) group (r = 0.48, p = 0.0032). The most strongly implicated brain regions in the prediction model were the right middle frontal gyrus, superior frontal gyrus, supramarginal gyrus, anterior/posterior lobes of the cerebellum and left postcentral gyrus. The findings about cue-reactivity neural correlates could help identify IGD subjects and predict CBI-related treatment outcomes provide mechanistic insight into IGD and its treatment and may help promote treatment development efforts.


Automated traffic incident detection with a smaller dataset based on generative adversarial networks.
An imbalanced and small training sample can cause an incident detection model to have a low detection rate and a high false alarm rate. To solve the scarcity of incident samples, a novel incident detection framework is proposed based on generative adversarial networks (GANs). First, spatial and temporal rules are presented to extract variables from traffic data, which is followed by the random forest algorithm to rank the importance of variables. Then, some new incident samples are generated using GANs. Finally, the support vector machine algorithm is applied as the incident detection model. Real traffic data, which were collected from a 69.5-mile section of the I-80 highway, are used to validate the proposed approach. A total of 140 detectors are installed on the section enabling traffic flow to be measured every 30s. During 14 days, 139 incident samples and 946 nonincident samples were extracted from the raw data. Five categories of experiments are designed to evaluate whether the proposed framework can solve the small sample size problem, imbalanced sample problem, and timeliness problem in the current incident detection system. The experimental results show that our proposed framework can considerably improve the detection rate and reduce the false alarm rate of traffic incident detection. The balance of the dataset can improve the detection rate from 87.48% to 90.68% and reduce the false alarm rate from 12.76% to 7.11%. This paper lends support to further studies on combining GANs with the machine learning model to address the imbalance and small sample size problems related to intelligent transportation systems.


Evaluation of a Machine Learning Model Based on Pretreatment Symptoms and Electroencephalographic Features to Predict Outcomes of Antidepressant Treatment in Adults With Depression: A Prespecified Secondary Analysis of a Randomized Clinical Trial.
Despite the high prevalence and potential outcomes of major depressive disorder, whether and how patients will respond to antidepressant medications is not easily predicted. To identify the extent to which a machine learning approach, using gradient-boosted decision trees, can predict acute improvement for individual depressive symptoms with antidepressants based on pretreatment symptom scores and electroencephalographic (EEG) measures. This prognostic study analyzed data collected as part of the International Study to Predict Optimized Treatment in Depression, a randomized, prospective open-label trial to identify clinically useful predictors and moderators of response to commonly used first-line antidepressant medications. Data collection was conducted at 20 sites spanning 5 countries and including 518 adult outpatients (18-65 years of age) from primary care or specialty care practices who received a diagnosis of current major depressive disorder between December 1, 2008, and September 30, 2013. Patients were antidepressant medication naive or willing to undergo a 1-week washout period of any nonprotocol antidepressant medication. Statistical analysis was conducted from January 5 to June 30, 2019. Participants with major depressive disorder were randomized in a 1:1:1 ratio to undergo 8 weeks of treatment with escitalopram oxalate (n = 162), sertraline hydrochloride (n = 176), or extended-release venlafaxine hydrochloride (n = 180). The primary objective was to predict improvement in individual symptoms, defined as the difference in score for each of the symptoms on the 21-item Hamilton Rating Scale for Depression from baseline to week 8, evaluated using the C index. The resulting data set contained 518 patients (274 women; mean [SD] age, 39.0 [12.6] years; mean [SD] 21-item Hamilton Rating Scale for Depression score improvement, 13.0 [7.0]). With the use of 5-fold cross-validation for evaluation, the machine learning model achieved C index scores of 0.8 or higher on 12 of 21 clinician-rated symptoms, with the highest C index score of 0.963 (95% CI, 0.939-1.000) for loss of insight. The importance of any single EEG feature was higher than 5% for prediction of 7 symptoms, with the most important EEG features being the absolute delta band power at the occipital electrode sites (O1, 18.8%; Oz, 6.7%) for loss of insight. Over and above the use of baseline symptom scores alone, the use of both EEG and baseline symptom features was associated with a significant increase in the C index for improvement in 4 symptoms: loss of insight (C index increase, 0.012 [95% CI, 0.001-0.020]), energy loss (C index increase, 0.035 [95% CI, 0.011-0.059]), appetite changes (C index increase, 0.017 [95% CI, 0.003-0.030]), and psychomotor retardation (C index increase, 0.020 [95% CI, 0.008-0.032]). This study suggests that machine learning may be used to identify independent associations of symptoms and EEG features to predict antidepressant-associated improvements in specific symptoms of depression. The approach should next be prospectively validated in clinical trials and settings. ClinicalTrials.gov Identifier: NCT00693849.


Atractylenolide III Enhances the Anti-Neoplastic Efficacy of Docetaxel in Gastric Cancer Cell by Inhibiting Fibroblast Growth Factor Receptors 1, -2, and -4 Expression.
Natural active components have been reported to serve as adjuvant medications in the clinical practice of cancer therapeutics. However, the antineoplastic roles of atractylenolide III (ATL) are rarely reported. In the present study, we assessed the functions of ATL combined with docetaxel in gastric cancer cells. Cell viability and cytotoxic activity were evaluated using CCK-8 and LDH-based cytotoxicity assays, respectively. Protein expression levels were measured by western blotting analysis. Annexin V-FITC/PI staining was used to evaluate cell apoptosis using flow cytometry. AGS and SGC-7901 cell viability was significantly inhibited in ATL combined with docetaxel group compared with docetaxel treatment alone. The levels of LDH, apoptosis rate, and the ratio of BAX to Bcl-2 were significantly elevated in combination treatment group compared to docetaxel treatment alone. Intriguingly, docetaxel combined with ATL resulted in a significant decrease in FGFR1, FGFR2, and FGFR4 protein expression compared with docetaxel treatment alone. Knockout of FGFR1, -2, and -4 exhibited a similar role of medications to inhibit growth and induce apoptosis in AGS and SGC-7901 cells. ATL and docetaxel treatment performed the synergistic effects on the inhibition of growth and induction of apoptosis in gastric cancer cells, and the underlying mechanism was mediated, at least partially, through the inhibition of FGFR1, -2, and -4.


The impact of inflammation on the pathogenesis and prognosis of ischemic stroke.
The inflammation plays a critical role in the stroke onset and even in the worsening of the lesions. Therefore, the investigation of inflammatory response in the acute stage may contribute to improve the treatment of ischemic stroke. High-sensitive CRP (hsCRP), IL-6 and TNFalpha were measured as inflammatory markers on admission and in the 28th day after the onset. Oxidized LDL was measured simultaneously, since it can be a marker of reactive oxygen species which reflect the activity of inflammation. Ischemic stroke patients within 24 h after the onset (n=105) were included in this study. All patients were classified into cardioembolism, large-artery atherosclerosis, lacunar infarction, branch atheromatous disease and arterial dissection groups based on the findings of MRI and MRA and clinical records. Oxidized LDL was significantly increased in the acute phase of all cases. The amplified level of IL-6 was related to the worse outcome. The increase of TNFalpha in lacunar infarction was statistically correlated to the neurological severity on admission. In conclusion, IL-6 may predict not only the severity of the stroke lesions but also the outcome of patients. TNFalpha may suggest the small arterial lesions.


Postdevelopmental effects of boron, fluoride, and their combination on dental caries activity in the rat.
Drinking water of rats aged 21 days was supplemented with 1, 10, 30, 50, 100, or 283 ppm of boron or 10 or 25 ppm of fluoride individually or in combination. All rats were fed a cariogenic diet. Boron did not reduce dental caries activity in erupted molars after eight weeks. When given in combination, it partially antagonized the cariostatic effect of fluoride.


CONCURRENT VALIDITY OF THE BRUNET-LÉZINE SCALE WITH THE BAYLEY SCALE FOR ASSESSMENT OF THE DEVELOPMENT OF PRETERM INFANTS UP TO TWO YEARS.
To verify the correlation between the areas evaluated by the Brunet-Lézine and the Bayley III scales of preterm infants up to two years. The study included 88 children who were divided into 3 groups: Group 1 (1 month to 5 months and 29 days of corrected chronological ages - CCA) with 32 children; Group 2 (6 months to 11 months and 29 days of CCA) with 36 participants; and Group 3 (18 -23 months and 23 days of CCA) with 20 children. The concurrent validity of the Brunet-Lézine scale and the Bayley III scale was calculated using the Pearson correlation or its non-parametric version, the Spearman correlation. Group 1 showed moderate correlation between the developmental quotient for hand-eye and fine motor coordination (DQE), and fine motor score (ρ=0.448; p=0.01). Group 2 had moderate correlation between the developmental quotient for posture and gross motor function (DQP), and the gross motor score (ρ=0.484; p=0.003, between the DQE and fine motor score (r=0.489; p=0.002), and between the developmental quotient for social reactions (DQS) and the socio emotional score (r=0.435; p=0.008). Group 3 showed moderate correlation between the DQP and the gross motor score (ρ=0.468; p=0.037) and strong correlation between developmental quotient for language (DQL) and the score of language (r=0.890; p<0.001). The Brunet-Lézine scale showed strong correlation with the Bayley III scale regarding the language domain in Group 3, suggesting its validity to assess the language of children aged between 18 and 24 months.


10-year follow-up of the Super-Seniors Study: compression of morbidity and genetic factors.
Super-Seniors are healthy, long-lived individuals who were recruited at age 85 years or older with no history of cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease. In a 10-year follow-up, we aimed to determine whether surviving Super-Seniors showed compression of morbidity, and to test whether the allele frequencies of longevity-associated variants in APOE and FOXO3 were more extreme in such long-term survivors. Super-Seniors who survived and were contactable were re-interviewed 10 years after initial characterization. Health and lifestyle were characterized via questionnaire. Geriatric tests including the Timed Up and Go (TUG), Geriatric Depression Scale (GDS), Instrumental Activities of Daily Living (IADL) and the Mini-Mental State Exam (MMSE) were administered, and data were compared to results from on average 10 years earlier. As well, genotype and allele frequencies for SNPs rs7412 and rs429358 in APOE, and rs2802292 in FOXO3 were compared to the frequencies in the original collection of Super-Seniors and mid-life controls. Of the 480 Super-Seniors recruited from 2004 to 2007, 13 were alive, contactable, and consented to re-interview (mean age = 100.1 ± 3.3). Eight of these 13 participants (62%) still met Super-Senior health criteria. Diseases that occurred in late life were cardiovascular (5 of 13; 38%) and lung disease (1 of 13; 8%). MMSE and IADL scores declined in the decade between interviews, and GDS and TUG scores increased. The surviving group of centenarians had a higher frequency of APOE and FOXO3 longevity-associated variants even when compared to the original long-lived Super-Senior cohort. Although physical and mental decline occurred in the decade between interviews, the majority of Super-Seniors re-interviewed still met the original health criteria. These observations are consistent with reports of compression of morbidity at extreme ages, particularly in centenarians. The increased frequency of longevity- associated variants in this small group of survivors is consistent with studies that reported genetics as a larger contributor to longevity in older age groups.


Disaccharide analysis of glycosaminoglycan mixtures by ultra-high-performance liquid chromatography-mass spectrometry.
Glycosaminoglycans are a family of polysaccharides widely distributed in all eukaryotic cells. These polyanionic, linear chain polysaccharides are composed of repeating disaccharide units that are often differentially substituted with sulfo groups. The diversity of glycosaminoglycan structures in cells, tissues and among different organisms reflect their functional an evolutionary importance. Glycosaminoglycan composition and structure also changes in development, aging and in disease progression, making their accurate and reliable analysis a critical, albeit, challenging endeavor. Quantitative disaccharide compositional analysis is one of the primary ways to characterize glycosaminoglycan composition and structure and has a direct relationship with glycosaminoglycan biological functions. In this study, glycosaminoglycan disaccharides, prepared from heparan sulfate/heparin, chondroitin sulfate/dermatan sulfate and neutral hyaluronic acid using multiple polysaccharide lyases, were fluorescently labeled with 2-aminoacridone, fractionated into 17 well-resolved components by reverse-phase ultra-performance liquid chromatography, and analyzed by electrospray ionization mass spectrometry. This analysis was successfully applied to cell, tissue, and biological fluid samples for the picomole level detection of glycosaminoglycan composition and structure.


Escape from inhibition of synaptic transmission during in vitro hypoxia and hypoglycemia in the hippocampus.
Electrophysiological recordings were made from rat hippocampal slices exposed to in vitro ischemic conditions in which the superfused medium is hypoxic and lacking glucose. Under these conditions, the evoked population spike recorded in CA1 is initially depressed and then transiently returns prior to an anoxic depolarization. This transient return in synaptic function under ischemic-like conditions also occurs if the population spike is inhibited by pretreatment with adenosinergic agonists or with the gamma-aminobutyric acid (GABA)B agonist, baclofen.


On a risk of inhalation exposure during visits in Chernobyl exclusion zone.
In recent years Chernobyl exclusion zone has become a very popular tourist destination. Many people visiting power plant, Pripyat city or surrounding villages use different types of personal dosimeters to control external exposure, however very small group of tourist have opportunity to control internal contamination of respiratory tract using dedicated, high sensitive whole body counters. In this study 11 anti-dust masks collected from CEZ visitors and filters from one military MP-5 mask were analyzed using alpha, beta and gamma spectrometry to determine doses from actinides and fission products which can be inhaled without proper protective equipment. Results showed, that average effective dose from inhalation of contaminated aerosol in case of single-day trip (avoided due to use of mask) was 1.3 μSv per person, which is much smaller than potential effective dose after exploration of highly contaminated areas like Jupiter complex, where combined dose from all measured nuclides collected on MP-5 mask filter was 1.4 mSv.


Quantifying the Digital Divide: Associations of Broadband Internet with Tele-mental Health Access Before and During the COVID-19 Pandemic.
During the COVID-19 pandemic, telemedicine quickly expanded. Broadband speeds may impact equitable access to video-based mental health (MH) services. To identify access disparities in Veterans Health Administration (VHA) MH services based on broadband speed availability. Instrumental variable difference-in-differences study using administrative data to identify MH visits prior to (October 1, 2015-February 28, 2020) and after COVID-19 pandemic onset (March 1, 2020-December 31, 2021) among 1176 VHA MH clinics. The exposure is broadband download and upload speeds categorized as inadequate (download ≤25 Megabits per second - Mbps; upload ≤3 Mbps), adequate (download ≥25 Mbps and <100 Mbps; upload ≥5 Mbps and <100 Mbps), or optimal (download and upload ≥100/100 Mbps) based on data reported to the Federal Communications Commission at the census block and spatially merged to each veteran's residential address. All veterans receiving VHA MH services during study period. MH visits were categorized as in-person or virtual (i.e., telephone or video). By patient, MH visits were counted quarterly by broadband category. Poisson models with Huber-White robust errors clustered at the census block estimated the association between a patient's broadband speed category and quarterly MH visit count by visit type, adjusted for patient demographics, residential rurality, and area deprivation index. Over the 6-year study period, 3,659,699 unique veterans were seen. Adjusted regression analyses estimated the change after pandemic onset versus pre-pandemic in patients' quarterly MH visit count; patients living in census blocks with optimal versus inadequate broadband increased video visit use (incidence rate ratio (IRR) = 1.52, 95% CI = 1.45-1.59; P < 0.001) and decreased in-person visits (IRR = 0.92, 95% CI = 0.90-0.94; P < 0.001). This study found patients with optimal versus inadequate broadband availability had more video-based and fewer in-person MH visits after pandemic onset, suggesting broadband availability is an important determinant of access-to-care during public health emergencies requiring remote care.


Basic proteins of rodent peripheral nerve myelin: immunochemical identification of the 21.5K, 18.5K, 17K, 14K, and P2 proteins.
Proteins in peripheral nervous system and central nervous system myelin and homogenates of sciatic nerve and brain from young and adult mice and rats were characterized with affinity-purified anti-P2 and anti-myelin basic protein sera after electrophoretic transfer from sodium dodecyl sulfate-polyacrylamide gels to nitrocellulose sheets. Using this method we have identified a component of rodent peripheral nervous system myelin as P2 protein. Peripheral nervous system myelin also showed the presence of four basic proteins in addition to P2 protein. These were found to be analogous to the 14, 17, 18.5, and 21.5K species found in the central nervous system myelin. A number of high-molecular-weight proteins were also detected with anti-myelin basic protein serum in peripheral nervous system, as well as central nervous system myelin. In addition, we report the presence of a high-molecular-weight P2 cross-reactive protein in rodent brain stem homogenates, but not in central nervous system myelin. Key Words: Basic proteins--PNS myelin--CNS myelin--Immunocharacterization. Greenfield S. et al. Basic proteins of rodent peripheral nerve myelin: Immunochemical identification of the 21.5K, 18.5K, 17K, 14K, and P2 proteins.


Expression of prolactin messenger ribonucleic acid in the mouse gonads during sexual maturation.
The pituitary hormone prolactin is known to be produced in various extrapituitary tissues as well. We examined the presence of prolactin mRNA in the mouse gonads by reverse transcription (RT)-PCR and nucleotide sequence analysis. Both ovary and testis were found to express small amounts of mRNA coding prolactin, identical to that in the pituitary gland. Next, we established a sensitive competitive RT-PCR method to estimate the amount of prolactin mRNA and then measured its expression in the gonads during sexual maturation (10-80 days of age). In the ovary, the amount of prolactin mRNA (copies/microg of total RNA) gradually decreased from day 10 to 40, and the lower level was maintained until day 80. Little difference in the amount was observed between the estrous and diestrous groups on day 80. Conversely, the amount of testicular prolactin mRNA gradually increased from day 10 to 80. These results suggest that prolactin is produced in the mouse gonads and that it acts as an autocrine/paracrine factor modulating gonadal functions.


Tricin inhibits proliferation of human hepatic stellate cells in vitro by blocking tyrosine phosphorylation of PDGF receptor and its signaling pathways.
4',5,7-Trihydroxy-3',5'-dimethoxyflavone (Tricin), a naturally occurring flavone, has anti-inflammatory potential and exhibits diverse biological activities including antigrowth activity in several human cancer cell lines and cancer chemopreventive effects in the gastrointestinal tract of mice. The present study aimed to investigate the biological actions of tricin on hepatic stellate cells (HSCs) in vitro, exploring its potential as a treatment of liver fibrosis, since HSC proliferation is closely related to the progression of hepatic fibrogenesis in chronic liver diseases leading to irreversible liver cirrhosis and hepatocellular carcinoma. Tricin inhibited platelet-derived growth factor (PDGF)-BB-induced cell proliferation by blocking cell cycle progression and cell migration in the human HSC line LI90 and culture-activated HSCs. It also reduced the phosphorylation of PDGF receptor β and the downstream signaling molecules ERK1/2 and Akt, which might be due to its tyrosine kinase inhibitor properties rather than inhibition of the direct binding between PDGF-BB and its receptor. Our findings suggest that tricin might be beneficial in HSC-targeting therapeutic or chemopreventive applications for hepatic fibrosis.


Response to re-challenge of a MEK inhibitor in a patient with recurrent low-grade serous carcinoma of the peritoneum.
Low-grade serous carcinoma of the ovary/peritoneum is a rare epithelial cancer subtype characterized by younger age at diagnosis, relative chemoresistance, and prolonged overall survival compared with high-grade serous carcinoma. In addition, alterations in the mitogen activated protein kinase pathway are frequent and play a major role in the pathogenesis of this tumor. MEK inhibitors have demonstrated promising activity in the treatment of recurrent low-grade serous carcinoma. Although prevailing wisdom in cancer therapy is that the re-treatment with a drug after emergence of resistance is futile, we report the initial case of a patient with recurrent low-grade serous carcinoma who experienced a partial response when re-challenged with a MEK inhibitor after previously having prolonged stable disease followed by disease progression on a MEK inhibitor.


A protocol for the combined sub-fractionation and delipidation of lipid binding proteins using hydrophobic interaction chromatography.
Cellular lipids frequently co-purify with lipid binding proteins isolated from tissue extracts or heterologous host systems and as such hinder in vitro ligand binding approaches for which the apo-protein is a prerequisite. Here we present a technique for the complete removal of unesterified fatty acids, phospholipids, steroids and other lipophilic ligands bound to soluble proteins, without protein denaturation. Peroxisome proliferator activated receptor gamma ligand binding domain and intracellular fatty acid binding proteins were expressed in an Escherichia coli host and completely delipidated by hydrophobic interaction chromatography using phenyl sepharose. The delipidation procedure operates at room temperature with complete removal of bound lipids in a single step, as ascertained by mass spectrometry analysis of organic solvent extracts from purified protein samples. The speed and capacity of this method makes it amenable to scale-up and high-throughput applications. The method can also easily be adapted for other lipid binding proteins that require delipidation under native conditions.


Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway as Survival Biomarkers in Colorectal Cancer.
Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRC.


Inducing effect of albendazole on rat liver drug-metabolizing enzymes and metabolite pharmacokinetics.
Albendazole (ABZ), methyl (5-(propylthio)-1H-benzimidazol-2-yl)carbamate, is a broad spectrum anthelmintic drug. S-oxidation to the sulfoxide (SO-ABZ) and the sulfone (SO2-ABZ) are the first steps of its bioconversion. SO-ABZ is pharmacologically active and embryotoxic in rats. In the present study, rat liver microsomal drug-metabolizing enzymes were assayed after 10 days oral administration with 40 mumol ABZ/kg per day. The activities of 4-nitroanisole O-demethylase, benzo[a]pyrene hydroxylase, 7-ethoxycoumarin O-deethylase, and 7-ethoxyresorufin O-deethylase increased 6-, 7-, 8-, and 30-fold, respectively. By immunoblotting an increase in cytochrome P-448 was observed. UDP-glucuronosyltransferase (GT) type 1 activities (1-naphthol, 7-hydroxycoumarin, 4-nitrophenol, and 4-methylumbelliferone) were significantly higher than in control microsomes (3- to 4-fold), while GT type 2 activities and bilirubin-GT remained unchanged. Microsomal epoxide hydrolase (benzo[a]pyrene oxide) increased 2-fold. Microsomal gamma-glutamyltransferase activity was unchanged. The in vivo SO-ABZ plasma level was decreased when the SO2-ABZ plasma level was increased. In vitro sulfoxidation and sulfonation were, however, unchanged. Although a range of imidazole derivatives, including benzimidazole itself, were commonly reported as inhibitors of monooxygenase activities, ABZ behaved as an inducer of cytochrome P-448, GT1, and epoxide hydrolase.


Biologic therapies in the metastatic colorectal cancer treatment continuum--applying current evidence to clinical practice.
More therapeutic options are now available than ever before for patients with metastatic colorectal cancer (mCRC) and, as such, treatment decisions have become more complex. A multidisciplinary approach is, therefore, required to effectively manage these patients. In the past few years, many trials have reported on the value of combining biological agents, such as those targeting vascular endothelial growth factor A and epidermal growth factor receptors, with chemotherapy. However, despite the plethora of information now available, the optimal treatment strategy for patients with mCRC remains unclear. Indeed, the propensity of investigators to conduct clinical trials utilising a variety of chemotherapy backbones combined with the increased complexity of retrospectively incorporating analyses of genetic mutation status (e.g. KRAS and BRAF) have led to conflicting results for seemingly similar endpoints, particularly overall survival. As a result, guidelines that have been developed, whilst having some similarities, have distinct differences in terms of suggested therapeutic combinations. Therefore, here, we review and distil the currently available data reported from phase III trials of biologic agents in the first-, second- and third-line mCRC settings.


Human intestinal spirochetosis, irritable bowel syndrome, and colonic polyps: A systematic review and meta-analysis.
Human colonic spirochetosis (CS) is usually due toBrachyspira pilosicolior Brachyspira aalborgiinfection. While traditionally considered to be commensal bacteria, there are scattered case reports and case series of gastrointestinal (GI) symptoms in CS and reports of colonic polyps with adherent spirochetes. We performed a systematic review and meta-analysis investigating the association between CS and GI symptoms and conditions including the irritable bowel syndrome (IBS) and colonic polyps. Following PRISMA 2020 guidelines, a systematic search of Medline, CINAHL, EMBASE, and Web of Science was performed using specific keywords for CS and GI disease. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Of 75 studies identified in the search, 8 case-control studies met the inclusion criteria for meta-analysis and 67 case series studies met the inclusion criteria for pooled prevalence analysis. CS was significantly associated with diarrhea (n = 141/127, cases/controls, OR: 4.19, 95% CI: 1.72-10.21, P = 0.002) and abdominal pain (n = 64/65, OR: 3.66, 95% CI: 1.43-9.35, P = 0.007). CS cases were significantly more likely to have Rome III-diagnosed IBS (n = 79/48, OR: 3.84, 95% CI: 1.44-10.20, P = 0.007), but not colonic polyps (n = 127/843, OR: 8.78, 95% CI: 0.75-103.36, P = 0.084). In conclusion, we found evidence of associations between CS and both diarrhea and IBS, but not colonic polyps. CS is likely underestimated due to suboptimal diagnostic methods and may be an overlooked risk factor for a subset of IBS patients with diarrhea.


Cumulative Inflammation Could Be a Risk Factor for Intestinal Failure in Crohn's Disease.
Intestinal failure is the most critical complication of Crohn's disease. Intestinal failure requires home parenteral nutrition, which worsens the quality of life of the patients and sometimes causes life-threatening complications. The purpose of this study was to investigate the incidence and risk factors for intestinal failure in Crohn's disease. We performed a retrospective analysis of Crohn's disease patients (162 cases) at Osaka University Hospital between January 2000 and December 2017. Kaplan-Meier analysis was used to investigate the cumulative incidence of intestinal failure. To identify the risk factors of intestinal failure, patient characteristics were analyzed by multivariate analysis, including disease classification, surgical history, medical treatment other than surgery, and cumulative inflammation was calculated using the average C-reactive protein value and disease duration. The cumulative incidence of intestinal failure 5, 10, and 15 years after Crohn's disease diagnosis was 2.6%, 3.4%, and 8.6%, respectively. Multivariate analysis identified the following as independent risk factors for intestinal failure in Crohn's disease: residual small intestinal length < 200 cm (odds ratio 7.51, 95% confidence interval 2.14-29.96), non-use of anti-tumor necrosis factor-alpha therapy (3.34, 1.22-10.74), and cumulative inflammation (1.01, 1.001-1.038). We created a new predictive nomogram consisting of these risk factors. Intestinal failure occasionally occurred during long-term treatment of Crohn's disease. Cumulative inflammation for the first time, in addition to short residual small intestinal length and non-use of anti-tumor necrosis factor-alpha therapy, was shown to be potential risk factors for intestinal failure in Crohn's disease.


A yeast small nuclear RNA is required for normal processing of pre-ribosomal RNA.
In Saccharomyces cerevisiae, seven snRNAs (snR3, 4, 5, 8, 9, 10 and 17) are retained in the nucleus under conditions in which nucleoplasmic RNAs are lost, and may be nucleolar. All of these snRNAs show properties consistent with hydrogen bonding to pre-ribosomal RNAs; snR5 and 8 with 20S pre-rRNA, snR3, 4, 10 and 17 with 35S pre-rRNA and snR9 with 20-35S RNA. Strains lacking snR10 are impaired in growth and specifically defective in the processing of 35S RNA. Processing is slowed, leading to 35S RNA accumulation and most cleavage occurs, not at the normal sites, but at sites which in wild-type strains are used for subsequent steps in rRNA maturation.


Does component axial rotational alignment affect clinical outcomes in Oxford unicompartmental knee arthroplasty?
Limited studies have examined the relationship between axial rotational alignment and functional outcome in mobile-bearing UKA. The aims of this study was to determine the correlation between component axial rotational alignment and functional outcomes, and to recommend a safety range for component rotation for Oxford UKA. A retrospective study of 83 Oxford UKA was performed in 67 patients. Postoperative CT scans and clinical assessments were performed at a mean follow up of 21 months. Functional outcomes were measured by the OKS, modified KSS and KFS scores. A moving threshold analysis was performed to evaluate the relationship between different rotational alignment cut-off values and functional outcome scores. The mean femoral and tibial components were positioned with a mean of 4.8° and 7.5° external rotation (ER), respectively. Increasing tibial external rotation was negatively correlated with clinical outcome scores while increasing femoral component rotation did not correlate with clinical outcomes. Better functional scores were observed at mean femoral and tibial rotation angles between 2-6° ER (1.2-6.6°) and 1-8° ER (0.5-8.8°), respectively; with the highest OKS, KSS and FKS observed at 3-4° ER for femoral component, and 4-5° ER for tibial component. Femoral component axial rotation between 2°- 6° ER, and tibial component axial rotation between 1° and 8° ER correlated with significantly better functional scores. Surgeons should be especially aware of the relatively high variability in tibial component rotation and its implications of functional outcomes.


Not so rigid capsids based on cyclodextrin complexes: Keys to design.
Membranes based on cyclodextrin complexes can be used as functional nanocarrier envelopers by chemical modifications of the cyclodextrin hydroxyl groups or by encapsulating different ligands in their cavities. Molecular dynamics simulations of monolayers and bilayers based on supramolecular complexes consisting of two α or β-cyclodextrin and one sodium dodecylsulfate or dodecane at 283 K and at 298 K were performed. It is shown that the structure and main interactions stabilizing the membranes, as well as their permeability to water and ions can be tuned by changing the cyclodextrin, the ligand, the number of layers or/and the temperature. These results provide new evidences about both their dynamic nature and the interactions responsible for the stabilization of the membranes and will facilitate the design of new functional capsides and applications based on cyclodextrin complexes.


Anomalous dominance in sibling stutterers: evidence from CT scan asymmetries, dichotic listening, neuropsychological testing, and handedness.
Two left-handed siblings with developmental stuttering are comprehensively described. The methods of study included speech and language evaluation, neurological and neuropsychological examinations, dichotic listening, auditory evoked responses, electroencephalogram, and CT scan asymmetry measurements. The data from each sibling showed evidence of anomalous cerebral dominance on many of the variables investigated. The CT scan measurements showed atypical asymmetries, especially in the occipital regions. These findings support the theory that stuttering may be related to anomalous cerebral dominance, both on functional as well as structural bases. Implications of anomalous dominance and the resultant effect of hemispheric rivalry on speech fluency are discussed.


Intracellular deoxyribonucleic acid--modifying activity of intermittent phototherapy.
Phototherapy is capable of damaging the genetic material of eukaryotic and prokaryotic cells at fluences considerably less than that received by irradiated infants. It has been suggested that intermittent phototherapy, with varying on-off cycles, may offer theoretical advantages since the total light dosage received by the exposed infant is reduced. The present study was undertaken to determine the effect of intermittent phototherapy on the genetic material of human cells in tissue culture. Intermittent illumination produced more DNA damage than a similar light dosage administered continuously. These results suggest that intermittent phototherapy regimens may prove more deleterious to irradiated infants than continuous phototherapy.


The use of amantadine in the prevention of progression and treatment of COVID-19 symptoms in patients infected with the SARS-CoV-2 virus (COV-PREVENT): Study rationale and design.
COVID-19, a disease caused by infection with the SARS-CoV-2 virus, is asymptomatic or mildly symptomatic in most cases. Some patients, usually burdened with risk factors develop acute respiratory failure and other organ dysfunction. In such cases, the mortality rate is very high despite the use of intensive therapy. Amantadine has complex activity including antiviral, antiinflammatory and dopaminergic effects. This clinical trial will assess the efficacy and safety of amantadine in the prevention of COVID-19 progression toward acute respiratory failure and neurological complications. The trial will enroll 200 patients who are positive for SARS-CoV-2 infection and have one or more risk factors for worsening the disease. These patients will be included as hospitalized or ambulatory subjects for early treatment of illness. The recruitment will take place in 8 centers covering different regions of Poland. For 14 days they will be given either 200 mg of amantadine a day or placebo. Our hypothesis is a considerable reduction in the number of patients with progression toward respiratory insufficiency or neurological complications thanks to the treatment of amantadine. Demonstrating the efficacy and safety of amantadine treatment in improving the clinical condition of patients diagnosed with COVID-19 is of great importance in combating the effects of the pandemic. It has potential to influence on the severity and course of neurological complications, which are very common and persist long after the infection as long-COVID syndrome. www. gov identification no. NCT04854759; Eudra CT number: 2021-001144-98 (dated 27 February 2021).


Parinaud's oculoglandular syndrome associated with Sporothrix schenckii.
The Parinaud oculoglandular syndrome is a rare eye disease caused by different etiologic agents, including bacteria, viruses and fungi. It is characterized by a granulomatous conjunctivitis, accompanied by adjacent preauricular lymphadenopathy and can bring consequences if not treated promptly. We present a case of Parinaud oculoglandular syndrome caused by Sporothrix schenckii from the sporotrichosis epidemic in its zoonotic form occurring in Rio de Janeiro, Brazil.


Combinatorial chemistry of hydantoins.
Access to combinatorial chemistry of hydantoins is provided by convenient and versatile methods for the solid phase synthesis of libraries of 3,5-, 1,3- and 1,3,5-substituted hydantoins. The preparation of trisubstituted hydantoins features a Mitsunobu reaction for introduction of the substituent on N-1.


ROCK1 expression is regulated by TGFbeta3 and ALK2 during valvuloseptal endocardial cushion formation.
During early heart development at the looped heart stage, endothelial cells in the outflow tract and atrioventricular (AV) regions transform into mesenchyme to generate endocardial cushion tissue. This endocardial epithelial-mesenchymal transition (EMT) is regulated by several regulatory pathways, including the transforming growth factor-beta (TGFbeta), bone morphogenetic protein (BMP), and Rho-ROCK pathways. Here, we investigated the spatiotemporal expression pattern of ROCK1 mRNA during EMT in chick and examined whether TGFbeta or BMP could induce the expression of ROCK1. At the onset of EMT, ROCK1 expression was up-regulated in endothelial/mesenchymal cells. A three-dimensional collagen gel assay was used to examine the mechanisms regulating the expression of ROCK1. In AV endocardium co-cultured with associated myocardium, ROCK1 expression was inhibited by either anti-TGFbeta3 antibody, anti-ALK2 antibody or noggin, but not SB431542 (ALK5 inhibitor). In cultured preactivated AV endocardium, TGFbeta3 protein induced the expression of ROCK1, but BMP did not. AV endothelial cells that were cultured in medium supplemented with TGFbeta3 plus anti-ALK2 antibody failed to express ROCK1. These results suggest that the expression of ROCK1 is up-regulated at the onset of EMT and that signaling mediated by TGFbeta3/ALK2 together with BMP is involved in the expression of ROCK1.


Modified Manouguian technique for aortic root enlargement: A case series.
Manouguian aortic root enlargement (ARE) has been a standard root enlargement procedure to assist in patients with a small annular size. We describe a modification to the Manouguian ARE similar to Yang et al. This approach could serve as an alternate technique for performing ARE; to date only case reports have defined this approach and no studies have evaluated its efficacy or safety. A retrospective case series was performed on patients who underwent ARE for surgical aortic valve replacement via the modified Manouguian procedure at a single institution. Thirteen patients were identified between 2015 and 2021, and all surgeries were performed by a single operator. Data were collected via the Society of Thoracic Surgeons database and chart review. The primary outcome was difference in valve size after the procedure. The most common indication for surgery was aortic stenosis (12, 92%), with the most common etiology being degenerative calcification (7, 54%). Congenital bicuspid or unicuspid valves were identified in five (38%) patients. The majority (10, 77%) of patients received a mechanical valve. This procedure was successfully performed in all 13 of the patients. Additionally, 13 of the 13 patients (100%) were upsized to a satisfactory valve size based on preoperative echocardiography sizing. The modified Manouguian aortic enlargement technique can be safely and effectively used as an aortic enlargement procedure in a broad sample of patients.


Multidisciplinary rehabilitation versus medical care: a meta-analysis.
Research studies in physical medicine have not demonstrated the effectiveness of inpatient rehabilitation services, primarily due to differences in methodological approaches which have led to inconsistent findings. Because of differing inclusion and outcome criteria, even meta-analyses have been inconclusive. To address this problem, research literature comparing the clinical effectiveness of rehabilitation programs with medical care was evaluated for three uniformly available outcome criteria: survival; functional ability; and discharge location. Published trials were obtained from citations in Index Medicus (Medicine) and Nursing and Allied Health Abstracts covering the recent 20 year period from 1974 to 1994. We used meta-analyses to test the hypotheses that specialized rehabilitative care (vs conventional medical care) improves health outcomes. Results of our meta-analyses indicated that rehabilitation services were significantly associated with better rates of survival and improved function during hospital stay (P < 0.01), but significance was not observed at follow-up. Also, rehabilitation patients returned to their homes and remained there more frequently than controls (P < 0.001). We concluded that patients who participate in inpatient rehabilitation programs function better at hospital discharge, have a better chance of short term survival, and return home more frequently than non-participants. However, long term survival and function were the same for experimental and control subjects. The sustaining benefit of returning home may suffice to justify the provision of inpatient rehabilitation. However, the lack of other long term benefits suggests that services may need to be continued at home or in subacute care settings to optimize their effectiveness.(ABSTRACT TRUNCATED AT 250 WORDS)


Lumbosacral stenosis and injury of the cauda equina.
Idiopathic (congenital) L/S stenosis, acquired (degenerative) L/S stenosis, and traumatic injury to the vertebral column caudal to L6 often produce signs of neurologic dysfunction attributed to compression, displacement, entrapment, or trauma of the cauda equina. Clinical signs vary from animal to animal and depend upon which roots of the cauda equina are involved and the nature of the compromise. An understanding of the anatomy of the area and an appreciation for the functional relationship between the cauda equina and structures innervated are essential for accurate evaluation, workup, diagnosis, treatment, and outcome.


Purification and characterization of bilirubin UDP-glucuronyltransferase from the liver of eel, Anguilla japonica.
1. The enzyme bilirubin uridine diphosphate glucuronyltransferase (UDPGT) was purified and characterized from the liver of eel, Anguilla japonica. 2. The molecular weight of the enzyme was 88,000. 3. The optimal working pH of the enzyme was 7.5-8.0. The optimal working temperature of the enzyme was around 46 degrees C. 4. The Km of bilirubin and uridine diphosphate glucuronic acid for this enzyme was 1.6 mM and 1.8 mM respectively. 5. The concentration of bilirubin did not show any significant effect of inhibition on this enzyme up to 3.3 mM. 6. Since this is the first time UDPGT has been purified and characterized from poikilothermic aquatic animals, it provided interesting information on evolution and adaptation of this enzyme when compared to that of mammals.


A multinational case-control study on childhood brain tumours, anthropogenic factors, birth characteristics and prenatal exposures: A validation of interview data.
Little is known about the aetiology of childhood brain tumours. We investigated anthropometric factors (birth weight, length, maternal age), birth characteristics (e.g. vacuum extraction, preterm delivery, birth order) and exposures during pregnancy (e.g. maternal: smoking, working, dietary supplement intake) in relation to risk of brain tumour diagnosis among 7-19 year olds. The multinational case-control study in Denmark, Sweden, Norway and Switzerland (CEFALO) included interviews with 352 (participation rate=83.2%) eligible cases and 646 (71.1%) population-based controls. Interview data were complemented with data from birth registries and validated by assessing agreement (Cohen's Kappa). We used conditional logistic regression models matched on age, sex and geographical region (adjusted for maternal age and parental education) to explore associations between birth factors and childhood brain tumour risk. Agreement between interview and birth registry data ranged from moderate (Kappa=0.54; worked during pregnancy) to almost perfect (Kappa=0.98; birth weight). Neither anthropogenic factors nor birth characteristics were associated with childhood brain tumour risk. Maternal vitamin intake during pregnancy was indicative of a protective effect (OR 0.75, 95%-CI: 0.56-1.01). No association was seen for maternal smoking during pregnancy or working during pregnancy. We found little evidence that the considered birth factors were related to brain tumour risk among children and adolescents.


[Research on heterocyclic compounds. VI. Imidazo(1,2-b)pyridazine derivatives].
The preparation of a group of imidazo[1,2-b]pyridazin-2-carboxylic and -2-acetic acids is reported. The ethyl esters of these acids were prepared by reaction of some 3-aminopyridazines with ethyl bromopyruvate or 4-bromoacetoacetate. The acids were obtained by hydrolysis of the corresponding esters, and their anti-inflammatory activity was tested.


Current Status of Metastatic Cardiophrenic Lymph Nodes (CPLNs) in Patients With Ovarian Cancer: A Review.
One of the most common sites of extra-abdominal disease spread of advanced stage ovarian cancer is the cardiophrenic lymph node (CPLN) region. The role and impact of extra-abdominal cytoreduction is not obvious in patients with cardiophrenic lymph node metastases. We examined the relevant and currently available literature to determine the prognostic value and management of enlarged CPLNs in ovarian cancer patients. Transdiaphragmatic excision of CPLNs or via video-assisted thoracoscopic surgery (VATS) is achievable without major complications. The most common postoperative complications were pleural effusion, pneumothorax and pneumonia. On preoperative CT scan, the cut-off size of suspicious CPLNs is not uniform and is indicated as 5 to 10 mm short-axis dimension. CPLNs were detected in up to 60% of patients and malignancy was pathologically confirmed in 45-95% of the cases. The presence of enlarged CPLNs was found to be a negative prognostic factor, although its impact on progression-free and overall survival is not yet clarified and needs further investigation.


Emerging therapies for obstructive sleep apnea.
Obstructive sleep apnea (OSA) is a prevalent disorder often associated with daytime sleepiness, cognitive dysfunction, and adverse cardiovascular consequences. Available therapies are limited by either lack of long-term adherence or low response rates. Two emerging therapies hold promise in providing alternatives to patients with OSA. The first stems from the importance of the upper-airway dilator muscles in maintaining pharyngeal stability. Electrical stimulation of the genioglossus muscle improves both upper-airway diameter and ameliorates pharyngeal obstruction. The results of phase I and II clinical trials hold promise, but the reported improvements in the apnea-hypopnea index vary between subjects and concerns about long-term safety await long-term studies. The second technology relies on creating an increased expiratory nasal resistance via a bidirectional valve designed to be worn just inside the nostrils. Initial findings of clinical trials suggest reduction in severity of sleep apnea and subjective daytime sleepiness. Considerable heterogeneity in response to the nasal device was noted despite the high adherence rates. It remains unclear which patients will likely benefit a priori from these devices.


5-hydroxytryptamine release in the anterior hypothalamic and the hippocampal areas of cholestatic rats.
Cholestasis contributes to the genesis of fatigue through several mechanisms. Among these mechanisms, affected serotonergic neurotransmission is important in the pathogenesis of central fatigue. Previously, elevated levels of 5-hydroxyindole acetic acid (5-HIAA), the metabolite of 5-hydroxytryptamine (5-HT) and increased 5-HT(2) receptor density were demonstrated in the anterior hypothalamus and in the hippocampus of bile duct resected rats (BDR), respectively. The aim of this paper is to demonstrate evoked 5-HT release in selected brain regions like anterior hypothalamus and hippocampal CA1 regions of cholestatic rats using BDR rats as an experimental model for cholestasis. In this study, we analyzed the K+ evoked 5-HT and its metabolite 5-HIAA levels by using HPLC with electrochemical detection in the microdialysis samples collected from anterior hypothalamic and hippocampal CA1 regions of sham-operated and BDR rats (n = 6). The ratios of [5-HIAA] to [5-HT] following perfusion with 100 mM K+ artificial cerebrospinal fluid was used for the comparison of the evoked release of 5-HT. Locomotor activity was used to assess the signs of cholestasis associated fatigue in the BDR rats. The vertical and horizontal activity counts within 15 min were found to be decreased in the BDR rats compared to sham-operated rats (p < 0.05). Besides, the number of fecal boli (an index of emotionality) was also significantly fewer in the cholestatic rats (p < 0.05). No significant difference between the sham-operated and the BDR rats was detected in the basal 5-HT and 5-HIAA levels of anterior hypothalamus. K+ stimulation yielded a more profound increase in the [5-HIAA]/[5-HT] in the BDR rats (p < 0.05). The basal levels of 5-HT in CA1 region of the BDR rats was found to be lower than that of sham-operated group (p < 0.05), but no significant difference was observed in terms of evoked 5-HT release in both sham-operated and BDR rats. These findings imply the presence of affected serotonergic system in cholestasis.


Evaluating heart function in patients with POEMS syndrome.
Our aim is to investigate the characterized echocardiographic cardiac measurements of POEMS syndrome and determine its relationship with clinical manifestations. The cross-sectional study included 27 treatment-naïve patients with newly diagnosed POEMS syndrome and 26 age- and sex-matched healthy volunteers. Information of clinical manifestations, serological tests, pulmonary function tests, and both conventional echocardiograph and tissue Doppler imaging (TDI) were collected and analyzed. Pearson's correlation coefficient was used for determining the related clinical and echocardiographic parameters. Compared to healthy people, left ventricular (LV) mass index (LVMI) was elevated in patients with POEMS syndrome (41.3 ± 11.0 g/m2.7 , P < .05). LV systolic dysfunction was found by decreased mitral S' (9.0 ± 2.2 m/sec, P < .01), and diastolic dysfunction by mitral E'/A' (1.10 ± 0.42, P < .05), E/E' (8.69 ± 4.06, P < .001) on lateral, and E/E' (7.90 ± 3.28, P = .133) on septal mitral annulus. The presence of decreased tricuspid annular plane systolic excursion (TAPSE) (22.2 ± 3.5 mm, P < .01) and lateral tricuspid S' (11.1 ± 1.8 m/sec, P < .05) suggested deterioration of right ventricular (RV) systolic function. Parameters obtained from standard echocardiograph (tricuspid E/A ratio and DT) and TDI ((lateral tricuspid annulus E'/A' and E/E') indicated reduced RV diastolic function. Pulmonary hypertension (PH) was presented in six patients. Correlation analysis suggested that PH was related to total lung capacity (TLC) and diffusion capacity of carbon monoxide (DLCO). Echocardiographic measurements found that there was elevation of LVMI, pulmonary artery hypertension, and subclinical impairment of systolic and diastolic functions of both the right and left heart in patients with POEMS syndrome.


Concentrations and sources of PAHs in surface sediments of the Fenhe reservoir and watershed, China.
Sixteen PAHs in surface sediments at 28 sites throughout Fenhe reservoir and watershed were measured. The ∑PAHs concentrations ranged from 539.0 to 6281.7 with the mean of 2214.8ng/g. The 2-3 rings PAHs, contributing 55 percent to ∑PAHs, were the dominant species. Twenty-eight sites were grouped into three segments: Fenhe principal stream, estuaries of main branch streams, and Fenhe reservoir. ∑PAHs was highest in the estuaries of main branch streams. The ecological risk assessment was studied by biological thresholds. The results showed levels of PAHs might cause mild but not acute adverse biological effects. In addition, PAHs ratios, PCA/MLR and hierarchical clustering analysis were applied to evaluate the possible sources. Coal combustion (35 percent), diesel and gasoline emissions (29 percent and 16 percent, respectively) might be the important sources. For sites in Fenhe reservoir, the major sources were complex, while other two segments were mainly influenced by coal combustion source.


Boxing injuries: neurologic, radiologic, and neuropsychologic evaluation.
Boxing is an endeavor that may have to be re-evaluated in the coming years as to whether it should be designated as a sport. It is the only "sport" in which victory is determined by the amount of physical damage done to the opponent. We have presented the largest number of professional and amateur boxers (58) evaluated by various modern diagnostic modalities and have unequivocally demonstrated the deleterious effects of boxing upon the brain. There have been few, if any, meaningful actions taken by the promoters of boxing to correct the conditions under which boxers are subjected to physical abuse. Recommendations regarding the creation of a National Board of Boxing to supervise this "sport" have not been heeded. Suggested safeguards for the boxer, including mandatory medical and boxing history records (passports), use of headgear and approved safe boxing gloves, avoiding blows to the head, improved boxing ring floors, mandatory neurologic examinations, and more competent physicians at ringsides making medical decisions, have essentially not been implemented. The suggestions that mandatory computed tomograms at various stages in a boxer's career be used to determine possible changes of atrophy have not been followed, even when the CT scans have been made available at no cost to the boxers. The effective use of neuropsychologic evaluation, even when offered at no cost, has also been denied. The established medical injuries due to boxing and the lack of any sustained and significant efforts on the part of organized boxing create an atmosphere that is conducive to following the call for the consideration of a ban of boxing.


G-Banded Karyotyping of Human Pluripotent Stem Cell Cultures.
Acquired chromosomal abnormalities may occur during the reprogramming and culture of human pluripotent stem cells (hPSCs). Therefore, it is required that regular testing of genetic integrity be conducted. G-banded karyotyping is a widely used genetic assay that is capable of detecting chromosomal abnormalities. Karyotyping of hPSC cultures can be a challenging undertaking for inexperienced investigators; here, we provide detailed procedures for karyotyping, including sample preparation and analysis, as well as the interpretation of hPSC karyotype results.


Impact of MR-safe headphones on PET attenuation in combined PET/MRI scans.
MR headphones are attenuation sources affecting PET quantification in hybrid PET/MRI. Despite potentially better patient communication, usage in PET/MRI scans is not approved by the vendor. This study aims to determine the impact of headphones on PET by means of phantom and patient scans. Additionally, the perceived benefit of using headphones was evaluated. A cylinder phantom was scanned without and with dedicated MR headphones in a PET/CT scanner. Headphone attenuation was additionally assessed in a clinical setup in 10 patients on a PET/MR scanner using F-18-fluoro-deoxy-glucose. The difference in tracer uptake with and without headset was determined for the various brain regions. Additionally, the patients were asked for differences in noise levels, patient comfort, communication quality, and preference. CT data revealed headphone attenuation values of 350-500 HU. Neglecting headphone attenuation leads to a decrease in PET values between the earcups of about 11 % when compared to the correctly reconstructed data. Regions further away from the headphones were less affected. Patient images demonstrated a decrease of 11 % on average in the cerebellum and temporal lobes, while other regions were less affected. No visual artefacts in the images were noticed. On average, no advantage in terms of noise and patient comfort and only slightly better quality of communication were imparted by the patients. Using headphones during PET/MR acquisition leads to a negative bias in brain uptake values without introducing obvious image artefacts. Since they lack benefits for the patients, they should be avoided if PET quantification of the brain is needed.


Enantioselective organocatalytic Michael addition of aldehydes to trifluoroethylidene malonates.
An efficient, highly enantioselective, organocatalytic Michael addition reaction of aldehydes with trifluoroethylidene malonates is described. The asymmetric reaction provided highly optically pure β-trifluoromethyl aldehydes which can be conveniently transformed into 4,4,4-trifluoromethyl butyric acid and trifluoromethyl substituted δ-lactones without loss in enantioselectivity.


Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2014 to 2018 in Japan: A large-scale multicenter retrospective study.
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. The aim of this study was to determine the recent prevalence and clinical characteristics of NAFLD in Japan. This study initially included 410 061 retrospectively enrolled adults from the medical health checkup registry for metabolic syndrome, chronic kidney disease, and fatty liver in Japan (MIRACLE-J; UMIN-CTR no. UMIN000049419), who were evaluated between 2014 and 2018 at 13 health centers in Japan. Individuals consuming >20 g of alcohol/day or with chronic liver disease were excluded. Fatty liver was diagnosed by ultrasonography. The probability of NAFLD with advanced fibrosis was estimated based on the fibrosis-4 index and NAFLD fibrosis score. A total of 71 254 participants were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, twofold difference in NAFLD prevalence between men (37.4%) and women (18.1%). Nonalcoholic fatty liver disease prevalence increased linearly with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even in the absence of obesity. Among patients with NAFLD, 14% had diabetes mellitus, 31% had hypertension, and 48% had dyslipidemia. The estimated prevalence of NAFLD with advanced fibrosis was 1.7% and 1.0% according to the fibrosis-4 index and NAFLD fibrosis score, respectively. The prevalence of NAFLD was approximately one-quarter of the general population in Japan. There was a linear relationship between NAFLD prevalence and various metabolic parameters, even in nonobese participants. The prevalence of NAFLD with advanced fibrosis was estimated to be 1%-2%.


Antipsychotic medication adherence in schizophrenia.
For individuals who have schizophrenia, adherence to medication is often poor, and stopping medication often has serious consequences. This article provides an update on recent literature regarding the frequency, clinical and social impact, and clinical correlates of nonadherence to antipsychotic medication in schizophrenia. The authors then review published trials of interventions to improve adherence in schizophrenia.


Weakness in patients with subacromial pain syndrome is local and more pronounced in females.
Subacromial pain syndrome is the predominant cause of shoulder pain, accounting for approximately half of all shoulder complaints. This population presents with weakness of the involved shoulder. However, there is a gap in our understanding of how pain contributes to this weakness, and whether there are sex related differences. Regional and global isometric strength was tested at the involved shoulder joint and remote joints (uninvolved shoulder and both knees) in patients with subacromial pain syndrome. Data were collected before and after acute pain reduction with a subacromial injection. Patients demonstrated weakness at the involved shoulder while remote joints demonstrated normal strength. When compared to healthy controls, male patients were shown to exhibit greater levels of weakness than female patients at the involved shoulder, based on comparisons with sex-matched controls using z-scores. Pain reduction (through an anesthetic injection) had no influence on strength in the short-term. Weakness in patients appears to be sex dependent and is not resolved with reduction of pain. This calls into question the assumptions of the physiological causes of this weakness.


Incomplete opening of an ALN-type inferior vena cava filter due to entanglement of the filter legs resulting in filter migration and inferior vena cava perforation.
Incomplete filter opening, causing filter migration and inferior vena cava (IVC) perforation, have often been observed with the Greenfield-type IVC filter, but reports of incomplete opening of the ALN-type IVC filter are extremely rare. We present herein the case of incomplete opening of an ALN-type IVC filter due to entanglement of the filter legs, which caused filter migration, IVC wall perforation, and penetration into the kidney and iliopsoas muscle. Successful percutaneous retrieval was performed without complications. Our experience provides guidance for similar situations in the future, including the need to check for complete filter opening.


Diagnostic accuracy of ultrasound and fine-needle aspiration in the study of thyroid nodule and multinodular goitre.
Ultrasonography and cytology obtained by fine-needle aspiration are part of the basic study of the thyroid nodule. Although they are not diagnostic in every case, they are cost-effective methods that inform surgical treatment and its extent. The purpose of this study was to evaluate the accuracy of ultrasonography associated with fine-needle aspiration to predict malignancy in nodular thyroid pathology. We collected prospective data from patients undergoing thyroidectomy by single nodule or multinodular goitre between 2006 and 2016. A total of 417 patients were included. Ultrasounds were classified as suspected of malignancy if they had 2 or more of the following characteristics: hypoechogenicity, microcalcifications, intranodular central hypervascularization, irregular margins and poorly defined edges. Ultrasound and fine-needle aspiration accuracy. In the postoperative study, 40% presented malignant pathology. 33% of patients with nonsuspicious ultrasound and 73% of those with suspicious ultrasound had malignant disease. Among patients with single nodule and suspicious ultrasound, the malignancy rate reached 80%. As for cytology, 100% of Bethesda VI patients, 88% of V, 63% of IV, 31% of III and 12% of II were found to have carcinoma. The combination of the 2 tests showed a high predictive value, particularly in cases of Bethesda IV cytology. Thyroid cytology provides high predictive value of the presence of carcinoma. The predictive value of ultrasound is also high, mainly in the study of isolated nodules. The combination of the 2 tests results in increased diagnostic accuracy.


A spectrum of morphologic lesions of focal segmental glomerulosclerosis by Columbia criteria in human immunodeficiency virus infection.
The Columbia working classification of focal segmental glomerulosclerosis (FSGS) identifies five types of glomerular lesions, designated collapsing (COLL), cellular (CELL), glomerular tip lesion (GTL), perihilar (PH), and not otherwise specified (NOS) variant lesions. FSGS COLL and non-collapsing variants of FSGS are described in human immunodeficiency virus (HIV)-associated kidney disease. This study examined the range and relationships of Columbia-type segmental sclerosing lesions in biopsies from patients with HIV infection. We identified 47 renal biopsies from 46 patients with HIV infection obtained over an 8-year period. Twenty-seven biopsies from 26 patients had FSGS. Sixteen biopsies had FSGS COLL (59.3%), 3 had CELL (11.1%), 5 had NOS (18.5%), 2 had PH (7.4%), and 1 had GTL (3.7%) by the Columbia classification. Biopsies had more than one type of Columbia FSGS lesion in 63% and one type in 37%. Single types of FSGS lesions were identified in eight of eight biopsies with ≤10 glomeruli. Combinations of lesions were observed in 17 of 19 (89.5%) with >10 glomeruli, and the coincidence of COLL, CELL, and NOS lesions was not random. NOS, COLL, and CELL morphologic lesions of FSGS frequently coexist in kidney biopsies from HIV+ patients. Combined patterns of FSGS suggest that lesions identified by Columbia criteria may be part of a spectrum of responses to injury in the setting of HIV infection.


Sulpiride antagonizes the biphasic locomotor effects of quinpirole in weanling rats.
Low doses of dopamine (DA) agonists such as the D2 receptor subfamily agonist quinpirole are thought to stimulate DA autoreceptors selectively, thereby inhibiting locomotor activity. High doses of quinpirole initially suppress and later activate locomotion during a single test-session; the activation is presumably due to stimulation of postsynaptic receptors. The aim of this study was to investigate whether pretreatment with a selective DA D2 receptor antagonist, sulpiride, could block the putative autoreceptor-mediated inhibition at a lower dose than was required to block the postsynaptically mediated activation. Male and female 30-day-old rats were injected SC with one of eight doses of sulpiride (0.313-40 mg/kg) or the vehicle. Sixty minutes later, rats were injected SC with 0.2 mg/kg quinpirole or the vehicle. Five minutes after the second injection, rats were placed in automated activity monitors which recorded locomotor behavior for 60 min at 5-min intervals. Quinpirole at this dose first suppressed and later increased locomotor activity. Sulpiride pretreatment dose-dependently reversed both the early inhibition and later activation of quinpirole-induced locomotion. However, sulpiride did not block the quinpirole-induced early suppression at a lower dose than was required to block the later activation. Thus, there was no evidence that the locomotor suppression elicited by quinpirole is mediated by a more sensitive subset of DA receptors.


Depressive symptoms are independently correlated with lipid peroxidation in a female population: comparison with vitamins and carotenoids.
Lipid peroxidation (LPO) is involved in oxidative tissue injuries. The present investigation examined the association between LPO and psychological depressive symptoms. A cross-sectional study was conducted on 66 female volunteers aged 38-70. Lipid peroxides (LOOH) in serum were evaluated by hemoglobin-methylene blue (Hb-MB) method; additionally, serum antioxidants were also detected. To assess depressive symptoms, the Center for Epidemiologic Studies Depression (CES-D) Scale and a subscale in the 28-item General Health Questionnaire (GHQ) were applied. LOOH concentration displayed a significant positive correlation with CES-D and GHQ depression scores. Multiple regression analysis was performed in which LOOH concentration served as a dependent variable and CES-D scores and antioxidants as independent variables. Consequently, CES-D scores demonstrated significant positive correlation with LOOH. The positive relationship between depressive symptoms and LPO in a female population may support the hypothesis that LPO may affect depressive symptoms.


The dendritic trees of Purkinje cells: a computer assisted analysis of HRP labeled neurons in organotypic cultures of kitten cerebellum.
Purkinje cell dendritic arborizations were studied in HRP intracellularly stained mature neurons grown during 30-50 days in organotypic cerebellar cultures from newborn kittens. The effects of afferent fiber depletions on the final dendritic topological parameters were investigated by computer assisted methods. Three differently deafferented models lacking both parallel and climbing fibers (PF and CF), only PF or only CF were thus studied. Qualitative data were found to be common to these 3 in vitro models and similar to those following other in vivo deafferenting procedures. Quantitative data obtained from 16 measurable parameters showed that all dendritic trees were markedly reduced in size as indicated by a decrease in total dendritic length and total number of segments although in all models individual segment lengths remained largely unaltered. A discriminant analysis permitted the recognition of 3 populations (100% well classified cells) based on 3 selected variables: dendritic field area, mean path length and total number of segments (with the lowest values for the model lacking only PF). These results are shown to lend further support to the role played in the final dendritic arrangement by both intrinsic (non-discriminant) and extrinsic (discriminant) factors and more precisely by the two distinct specific afferent systems (PF and CF).


Rapid evolutionary divergence of Gossypium barbadense and G. hirsutum mitochondrial genomes.
The mitochondrial genome from upland cotton, G. hirsutum, was previously sequenced. To elucidate the evolution of mitochondrial genomic diversity within a single genus, we sequenced the mitochondrial genome from Sea Island cotton (Gossypium barbadense L.). Mitochondrial DNA from week-old etiolated seedlings was extracted from isolated organelles using discontinuous sucrose density gradient method. Mitochondrial genome was sequenced with Solexa using paired-end, 90 bp read. The clean reads were assembled into contigs using ABySS and finished via additional fosmid and BAC sequencing. Finally, the genome was annotated and analyzed using different softwares. The G. barbadense (Sea Island cotton) mitochondrial genome was fully sequenced (677,434-bp) and compared to the mitogenome of upland cotton. The G. barbadense mitochondrial DNA contains seven more genes than that of upland cotton, with a total of 40 protein coding genes (excluding possible pseudogenes), 6 rRNA genes, and 29 tRNA genes. Of these 75 genes, atp1, mttB, nad4, nad9, rrn5, rrn18, and trnD(GTC)-cp were each represented by two identical copies. A single 64 kb repeat was largely responsible for the 9 % difference in genome size between the two mtDNAs. Comparison of genome structures between the two mitochondrial genomes revealed 8 rearranged syntenic regions and several large repeats. The largest repeat was missing from the master chromosome in G. hirsutum. Both mitochondrial genomes contain a duplicated copy of rps3 (rps3-2) in conjunction with a duplication of repeated sequences. Phylogenetic and divergence considerations suggest that a 544-bp fragment of rps3 was transferred to the nuclear genome shortly after divergence of the A- and D- genome diploid cottons. These results highlight the insights to the evolution of structural variation between Sea Island and upland cotton mitochondrial genomes.


A new feature of angiotensin-converting enzyme in the brain: hydrolysis of substance P.
Highly purified rat brain angiotensin-converting enzyme hydrolyzes substance P which contains a C-terminal amino acid with an amidated carboxyl group. The hydrolysis of substance P verified by amino-group fluorometry and by high-performance liquid chromatography is inhibited by captopril, but not by phosphoramidon. The presence of sodium chloride is essential for the hydrolysis. The analyses of cleavage products indicate that the enzyme hydrolyzes substance P between Phe7-Phe8 and Phe8-Gly9 by an endopeptidase action, followed by successive release of dipeptides by a dipeptidyl carboxypeptidase action.


The pathophysiology of falciparum malaria.
Falciparum malaria is a complex disease with no simple explanation, affecting organs where the parasite is rare as well as those organs where it is more common. We continue to argue that it can best be understood in terms of excessive stimulation of normally useful pathways mediated by inflammatory cytokines, the prototype being tumor necrosis factor (TNF). These pathways involve downstream mediators, such as nitric oxide (NO) that the host normally uses to control parasites, but which, when uncontrolled, have bioenergetic failure of patient tissues as their predictable end point. Falciparum malaria is no different from many other infectious diseases that are clinically confused with it. The sequestration of parasitized red blood cells, prominent in some tissues but absent in others with equal functional loss, exacerbates, but does not change, these overriding principles. Recent opportunities to stain a wide range of tissues from African pediatric cases of falciparum malaria and sepsis for the inducible NO synthase (iNOS) and migration inhibitory factor (MIF) have strengthened these arguments considerably. The recent demonstration of bioenergetic failure in tissue removed from sepsis patients being able to predict a fatal outcome fulfils a prediction of these principles, and it is plausible that this will be demonstrable in severe falciparum malaria. Understanding the disease caused by falciparum malaria at a molecular level requires an appreciation of the universality of poly(ADP-ribose) polymerase-1 (PARP-1) and Na(+)/K(+)-ATPase and the protean effects of activation by inflammation of the former that include inactivation of the latter.


Prospective randomized comparison of monthly fluorouracil and cisplatin versus weekly cisplatin concurrent with pelvic radiotherapy and high-dose rate brachytherapy for locally advanced cervical cancer.
To compare monthly fluorouracil (FU) plus cisplatin and weekly cisplatin concurrent with radiotherapy for locally advanced cervical cancer. A total of 158 patients (stages IIB through IVA) without para-aortic lymph nodes were randomized to receive 3 monthly cycles of FU (1000 mg/m2/day i.v.) plus cisplatin (20 mg/m2/day i.v.) for 5 days (group I, n=79) or 6 cycles of weekly cisplatin (30 mg/m2 i.v.) (group II, n=79), concurrent with definitive radiotherapy. Radiotherapy consisted of external irradiation to the whole pelvis of 41.4-50.4 Gy in 23-28 fractions plus high-dose rate (HDR) intracavitary brachytherapy (30-35 Gy in 6-7 fractions) to point A, together with a parametrial boost. Compliance with treatment, toxicity, response, and survival was analyzed and compared. Of the 158 women, 155 women were eligible for analysis; the median follow-up of surviving patients was 39 months. Full planned chemoradiotherapy was delivered to 47 (60%) and 55 (71%) patients in groups I and II, respectively. The incidence of acute grade 3/4 hematologic toxicity was 43% and 26% (p=0.037). The complete response rate of each group was 91%. Four-year overall and progression-free survival rates were 70% and 67%, respectively, in group I and 67% and 66%, respectively, in group II. The regimen of chemoradiation using weekly cisplatin significantly improves compliance with treatment and reduces acute hematologic toxicity, while not affecting response and survival rates.


Differences between porcine longissimus thoracis and semitendinosus intramuscular fat content and the regulation of their preadipocytes during adipogenic differentiation.
Intramuscular fat (IMF) plays an important role in pork quality. However, differences in the adipogenic regulation of IMF content between pig longissimus thoracis (LT) and semitendinosus (ST) remain unclear. Here, we found that IMF content of 180-day-old pig LT was greater than that of pig ST. Furthermore, lipid accumulation was earlier and greater in LT intramuscular preadipocytes (L-IMA) than in ST intramuscular preadipocytes (S-IMA) during differentiation. Interestingly, glucose consumption was lower in L-IMA than in S-IMA. Moreover, monounsaturated fatty acid content was greater in L-IMA than in S-IMA, whereas polyunsaturated fatty acid content was lower. Levels of the expression of key adipogenic genes were higher in L-IMA than S-IMA. Compared with S-IMA, adipogenic signals were more activated in L-IMA after adipogenic induction. In conclusion, IMF deposition differences between pig LT and ST were due to different glucose consumption, fatty acid composition, expression of key adipogenic genes and level of activating adipogenic signals between S-IMA and L-IMA during adipogenesis.


Mesenchymal stem cells derived from different perinatal tissues donated by same donors manifest variant performance on the acute liver failure model in mouse.
Mesenchymal stem cells (MSCs) derived from different tissues have variant biological characteristics, which may induce different performances in the treatment of diseases. At present, it is difficult to know which type of MSC is most suitable for acute liver failure (ALF), and there is no parallel study to compare MSCs from different tissues of the same donor. In this study, we derived MSCs from three different perinatal tissues of the same donor: cord lining (CL), cord-placenta junction (CPJ) and fetal placenta (FP), respectively, for compared gene expression profiles by transcriptome sequencing, and ability of proliferation and immune regulation in vitro. In addition, the therapeutic effects (e.g., survival rate, histological evaluation, biochemical analysis) of CL-MSCs, FP-MSCs and CPJ-MSCs on ALF mouse model were compared. The transcriptome analysis showed that FP-MSCs have significantly high expression of chemokines compared to CPJ-MSCs and CL-MSCs, similar to the q-PCR result. Of note, we found that CPJ-MSCs and FP-MSCs could improve the survival rate of mice with ALF induced by carbon tetrachloride, but CL-MSCs had no difference with Sham group. Moreover, we also found that biomarkers of ALF (e.g., MDA, SOD and GSH-px) significantly improved post-CPJ-MSCs and FP-MSCs treatment, but not CL-MSCs and Sham group. However, CL-MSCs treatment leads to inflammatory reaction in the early stage (day 3) of ALF treatment but not found with other groups. It is important to select the MSCs derived from different tissues with variant performance for therapeutic purpose, and the CPJ-MSCs and FP-MSCs cells can significantly improve the syndrome of ALF which is highly recommended for a potential therapeutic options for ALF.


Immunohistochemical localization of the cloned mu opioid receptor in the rat CNS.
Three opioid receptor types have recently been cloned that correspond to the pharmacologically defined mu, delta and kappa 1 receptors. In situ hybridization studies suggest that the opioid receptor mRNAs that encode these receptors have distinct distributions in the central nervous system that correlate well with their known functions. In the present study polyclonal antibodies were generated to the C terminal 63 amino acids of the cloned mu receptor (335-398) to examine the distribution of the mu receptor-like protein with immunohistochemical techniques. mu receptor-like immunoreactivity is widely distributed in the rat central nervous system with immunoreactive fibers and/or perikarya in such regions as the neocortex, the striatal patches and subcallosal streak, nucleus accumbens, lateral and medial septum, endopiriform nucleus, globus pallidus and ventral pallidum, amygdala, hippocampus, presubiculum, thalamic and hypothalamic nuclei, superior and inferior colliculi, central grey, substantia nigra, ventral tegmental area, interpeduncular nucleus, medial terminal nucleus of the accessory optic tract, raphe nuclei, nucleus of the solitary tract, spinal trigeminal nucleus, dorsal motor nucleus of vagus, the spinal cord and dorsal root ganglia. In addition, two major neuronal pathways, the fasciculus retroflexus and the stria terminalis, exhibit densely stained axonal fibers. While this distribution is in excellent agreement with the known mu receptor binding localization, a few regions, such as neocortex and cingulate cortex, basolateral amygdala, medial geniculate nucleus and the medial preoptic area fail to show a good correspondence. Several explanations are provided to interpret these results, and the anatomical and functional implications of these findings are discussed.


Oral fluid samples used for PRRSV acclimatization program and sow performance monitoring in endemic PRRS-positive farms.
An effective gilt acclimatization program is one of the most important management strategies for controlling porcine reproductive and respiratory syndrome virus (PRRSV) infection. Recently, oral fluid samples have been used as alternative diagnostic samples for various swine diseases. This study utilized oral fluids for PRRSV monitoring during the gilt acclimatization period in PRRSV endemic farms. The study was performed in two selected commercial breeding herds (farm A and farm B). PRRSV RNA and PRRSV-specific antibodies were monitored using oral fluid and serum samples. Sow performance parameters related to PRRSV infection were recorded and assessed. After PRRSV exposure during acclimatization, viral RNA was demonstrated in oral fluids from 1 to 10 weeks post-exposure (WPE). PRRSV RNA was detected in serum at 1 and 4 WPE in farm A and at 1, 4, 8, and 12 WPE in farm B. Prolonged viremia of gilts from farm B was possibly due to re-infection (within the herd) and later, reproductive problems were found in the breeding herd. The correlation of PRRSV RNA concentration in oral fluids and serum was evident. The S/P ratio values of PRRSV antibodies in oral fluid samples were higher and had similar patterns of antibody responses to the serum samples. The results suggest that the use of oral fluid samples for PRRSV monitoring during gilt acclimatization in endemic farms is effective, convenient, practical, and economical and would be most beneficial when used with other parameters.


In situ hybridization: alkaline phosphatase visualization of biotinylated probes in cryostat and paraffin sections.
Alkaline phosphatase immunochemical systems were evaluated for use in the demonstration of in situ hybridized biotin-labelled probes in frozen and fixed sections of tonsil. Three probes were used: total genomic DNA, pHY2.1, a human repetitive sequence which hybridizes to a 2.12 KB sequence on the Y chromosome (2000 repeats) and a 2.0 KB sequence on the autosomes (100-200 repeats), and human papilloma virus type II. Indirect, three- and five-stage detection methods were compared on cryostat sections. The indirect method involved the application of a streptavidin, biotinylated alkaline phosphatase sequence. The three-stage procedure comprised a mouse monoclonal anti-biotin, rabbit anti-(mouse immunoglobulin), mouse APAAP system. In the five-stage method the indirect and three-stage reagents were sequentially applied. Alkaline phosphatase was demonstrated using a Fast Red naphthol-capture method. The total genomic DNA probe was used initially to investigate hybridization conditions including the optimum temperature of denaturation, which was found to be higher than previously reported. The five-stage detection method gave the most sensitive results for the Y sequence probe, with intense demonstration of the Y body in male nuclei and autosomal sequences in female nuclei. This method was then applied to fixed tissue sections and gave Y body signals on Bouin's and Carnoy's fixed tissue. On the other hand tissue fixed using formalin-based solutions required proteolytic digestion as a pretreatment to hybridization for a Y body signal. The application of this methodology to viral diagnosis in routine fixed anogenital tissue and cytological preparations was also demonstrated.


Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate.
Luteinizing hormone-releasing hormone agonist therapy for prostate cancer is a new method of management for metastatic disease. During the initial 1 to 2-week period of administration an increase in serum testosterone concentration can lead to an exacerbation of clinical symptoms (flare phenomenon). Two patients are summarized who received luteinizing hormone-releasing hormone agonist therapy without flare blockade and died suddenly during month 1 of therapy. A review of 765 patients in 9 series found 10.9% who suffered disease flare and 15 who died during disease flare. Of these 17 patients 12 were similar to our 2. These data suggest that any patient placed on luteinizing hormone-releasing hormone agonist therapy for prostate cancer merits some form of flare blockade during the initial 1 or 2 months of therapy.


BRAIN AND EYE AS POTENTIAL TARGETS FOR IONIZING RADIATION IMPACT. PART III / FEATURES MORPHOMETRIC RETINAL PARAMETERS, AMPLITUDE AND LATENCY COMPONENTS OF VISUAL EVOKED POTENTIAL IN RADIATION EXPOSED IN UTERO.
One of the current problems of modern radiobiology is determine the characteristics of the manifestation of radiation-induced effects not only at different dose loads, but also at different stages of development of the organism. In previous reports, we have summarized available evidence that at certain ages there is a comparative acceleration of radiation-induced pathological changes in the eye and brain, and the study and assessment of the risk of possible ophthalmic and neurological pathology in remote periods after contamination of radioactive areas. Data of irradiated in utero individuals are possible on the basis of observation of the state of the visual analyzer in persons who underwent intrauterine irradiation in 1986. Therefore, a parallel study of retinal morphometric parameters, amplitude and latency of components of evoked visual potentials in irradiated in utero individuals was performed. to evaluate the retinal morphometric parameters, amplitude and latency components of the evoked visual potentials in intrauterine irradiated persons. The results of surveys of 16 people irradiated in utero in the aftermath of the Chornobyl disaster were used; the comparison group were residents of Kyiv of the corresponding age (25 people). Optical coherence tomography was performed on a Cirrus HD-OCT, Macular Cube 512x128 study technique was used. At the same time, the study of visual evoked potentials on the inverted pattern was performed, and occipital leads wereanalyzed. Visual evoked potentials were recorded on a reversible chess pattern (VEP) - an electrophysiological test, which is a visual response to a sharp change in image contrast when presenting a reversible image of a chessboard. In those irradiated in utero at the age of 22-25 years, there was a probable increase in retinal thickness in the fovea, there was a tendency to increase the thickness of the retina in the areas around the fovea. When recording visual evoked potentials on a reversible chess pattern in this group, there was a tendency to decrease the amplitudes of components (N75, P100, N145, P200) in the right and left parieto-occipital areas and asymmetric changes in latency of these components. Early changes of fovea recorded in OCT and decreasing amplitudes of components of visual evoked potentials on the reversible chess pattern at the age of 22 25 years may indicate a risk of development in patients irradiated in utero, early age-related macular degeneration, as well as increased risk and increased risk structures of the visual analyzer.


Correction: Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer.
A Correction to this paper has been published: https://doi.org/10.1038/s41419-020-03208-z.


Molecular properties and biogenesis of phytochrome I and II.
Previously, phytochrome was thought to consist of a single molecular species. However, physiological and spectrophotometric evidence has accumulated to indicate that there are two phytochrome pools in tissues, one of which is predominant in dark-grown tissues and rather unstable in the light, and the other present in very low concentrations but stable, even in the Pfr form, irrespective of light condition. Recently, two immunochemically distinct phytochromes I and II, PI and PII, were found in both dark- and light-grown tissues, and their comparative amino acid sequences shown to be 64% homologous. This is crucial evidence for the presence of chemically different phytochrome apoproteins in a single plant species. However, it is still an open question as to which phytochrome, PI or PII, is a component of the photolabile and photostable pools of phytochrome. Our understanding of the molecular structure of phytochrome has been greatly improved by recent, rapid progress in the cloning and characterization of phytochrome genes. The expression of PI genes is photoreversibly inhibited by the photostable Pfr pool, while that of several other genes, like Cab, appears to be induced by PI in the Pfr form. It is suggested that autoregulation of phytochrome gene expression is not so simply governed in plants as thought earlier. If there are two different phytochromes in a plant cell, the most important physiological problem to be solved is which phytochrome triggers the numerous red/far-red reversible reactions reported in the literature. Photomorphogenetic mutants and transgenic plants with engineered phytochrome genes will probably help to solve this problem in the future, and preliminary work along this line has already introduced in this article. A model of the molecular structure of pea PI dimer was proposed on the basis of small angle X-ray scattering analysis, and the model then confirmed by rotary shadowing electron microscopy. Important questions are still open, such as: what is the nature of phytochrome's partner compounds in cells (phytochrome receptor)? How is/are the phytochrome-induced signal(s) transmitted in the signal transduction chain?


A user's experience with a standard non-linear regression program (BMDP3R).
A study was made to test and compare the behavior of a standard non-linear regression program (BMDP3R) in fitting data from six classical least-squares problems. The use of three program control parameters is discussed and four measures of regression failure are utilized to give a quantitative reference of success. Recommendations are given to aid the user of packaged programs in the parameter estimation of non-linear regression models.


Mitral paravalvular leak closure by antegrade percutaneous approach: three-dimensional transesophageal echocardiographic guided multiple Amplatzer implantation by a modified sequential anchoring-based technique.
We describe the technical aspects and the possible advantages of a modified anchoring-based technique for the implantation of multiple Amplatzer devices, in a case of large anteroseptal mitral paravalvular leak causing massive regurgitation, which was manaed by antegrade transseptal, single-stage, percutaneous approach. Real-time three-dimensional transesophageal echocardiographic guidance was crucial to ensure successful recrossings of the target defect and the optimal anatomical closure.


A practical guide to multiple imputation of missing data in nephrology.
Health data are often plagued with missing values that can greatly reduce the sample size if only complete cases are considered for analysis. Furthermore, analyses that ignore missing data have the potential to introduce bias in the parameter estimates. Multiple imputation techniques have been developed to recover the information that would otherwise be lost when excluding observations with missing data and to help minimize bias. However, the validity of analyses using imputed data relies on the imputation model having been correctly specified. The aim of this guide is to aid the reader in the decision-making process when conducting an analysis with multiply imputed data in the context of nephrology research. We discuss (i) missing mechanism assumption, (ii) imputation method, (iii) imputation model, (iv) derived variables, (v) the number of imputed data sets, (vi) diagnostic checks, (vii) analysis and pooling of results, and (viii) reporting the results. This process is demonstrated using data from the National Health and Nutrition Examination Survey to explore the association between hypertension and kidney disease in adults from the general population. Example code is provided for SAS software and the mice package in R.


The enhancement of completely autotrophic nitrogen removal over nitrite (CANON) by N2H4 addition.
The long-term addition of N2H4 to completely autotrophic nitrogen removal over nitrite (CANON) sequencing batch reactors (SBRs) recovered and enhanced their autotrophic nitrogen removal capacity while simultaneously reducing their production of NO3(-). The total nitrogen (TN) removal rate and TN removal efficiency of the process increased from 0.202±0.011 to 0.370±0.016 kg N/m(3)/d and from 65.1±3.75% to 77.4±3.8%, respectively, and the molar ratio of NO3(-) production to NH4(+) removal (MRNN) decreased to 0.058. The most effective concentration of N2H4 addition was approximately 3.99 mg/L. N2H4 could increase the specific growth rate of anaerobic ammonium-oxidizing bacteria (AnAOB) and inhibit aerobic ammonia oxidation. The electrons released from the oxidation of additional N2H4 using hydrazine dehydrogenase (HDH), which substituted the electrons from NO2(-) oxidation to NO3(-), replenished the consumption of AnAOB anabolism and significantly reduced the consequent NO3(-) production.