Challenges for base excision repair enzymes: Acquiring access to damaged DNA in chromatin.
Repair of damaged DNA plays a crucial role in maintaining genomic integrity and normal cell function. The base excision repair (BER) pathway is primarily responsible for removing modified nucleobases that would otherwise cause deleterious and mutagenic consequences and lead to disease. The BER process is initiated by a DNA glycosylase, which recognizes and excises the target nucleobase lesion, and is completed via downstream enzymes acting in a well-coordinated manner. A majority of our current understanding about how BER enzymes function comes from in vitro studies using free duplex DNA as a simplified model. In eukaryotes, however, BER is challenged by the packaging of genomic DNA into chromatin. The fundamental structural repeating unit of chromatin is the nucleosome, which presents a more complex substrate context than free duplex DNA for repair. In this chapter, we discuss how BER enzymes, particularly glycosylases, engage in the context of packaged DNA with insights obtained from both in vivo and in vitro studies. Furthermore, we review factors and mechanisms that can modify chromatin architecture and/or influence DNA accessibility to BER machinery, such as the geometric location of the damage site, nucleosomal DNA unwrapping, histone post-translational modifications, histone variant incorporation, and chromatin remodeling.


Traction Time, Force and Postoperative Nerve Block Significantly Influence the Development and Duration of Neuropathy Following Hip Arthroscopy.
To (1) evaluate the individual and combined effects of traction time and traction force on postoperative neuropathy following hip arthroscopy, (2) determine if perioperative fascia iliaca block has an effect on the risk of this neuropathy, and (3) identify if the these items had a significant association with the presence, location, and/or duration of postoperative numbness. Between February 2015 and December 2016, a consecutive cohort of hip arthroscopy patients was prospectively enrolled. Traction time, force, and postoperative nerve block administration were recorded. The location and duration of numbness were assessed at postoperative clinic visits. Numbness location was classified into regions: 1, groin; 2, lateral thigh; 3, medial thigh; 4, dorsal foot; and 5,preoperative thigh or radiculopathic numbness. A total of 156 primary hip arthroscopy patients were analyzed, 99 (63%) women and 57 (37%) men. Mean traction time was 46.5 ± 20.3 minutes. Seventy-four patients (47%) reported numbness with an average duration of 157.5 ± 116.2 days. Postoperative fascia iliaca nerve block was a significant predictor of medial thigh numbness (odds ratio, 3.36; 95% confidence interval, 1.46-7.76; P = .04). Neither traction time nor force were associated with generalized numbness (P = .85 and P = .40, respectively). However, among those who experienced numbness, traction time and force were greater in patients with combined groin and lateral thigh numbness compared with those with isolated lateral thigh or medial thigh numbness (P = .001 and P = .005, respectively). Postoperative neuropathy is a well-documented complication following hip arthroscopy. Concomitant pudendal and lateral femoral cutaneous nerve palsy may be related to increased traction force and time, even in the setting of low intraoperative traction time (<1 hour). Isolated medial thigh numbness is significantly associated with postoperative fascia iliaca blockade. IV, case series.


Analysis of risk factors for lateral lymph node metastasis in papillary thyroid carcinoma: A retrospective cohort study.
To investigate the risk factors for lateral lymph node metastasis (LLNM) in papillary thyroid carcinoma (PTC). A retrospective analysis of 209 patients with PTC who underwent primary surgery at the Beijing Friendship Hospital affiliated with Capital Medical University from November 2014 to November 2018 was performed. The patients were divided into the LLNM group and the non-LLNM group. The clinical and pathological characteristics of the patients were analysed. The risk factors for LLNM were analysed by univariate and multivariate analyses. The incidence of LLNM was 13.4% in PTC patients. Univariate analysis showed that the maximum diameter of the primary tumour > 2 cm (P < 0.001), bilateral primary tumour (P = 0.020), extrathyroidal extension (ETE) (P < 0.001), central lymph node metastasis (CLNM) (P < 0.001), and CLNM number ≥ 5 (P < 0.001) were significantly associated with LLNM. Multivariate logistic regression analysis showed that the maximum diameter of the primary tumour > 2 cm, ETE, and CLNM were independent risk factors for LLNM (OR values were 3.880, 5.202, and 4.474, respectively). There were 6 patients with skip lateral cervical lymph node metastasis, accounting for 21% of all LLNM patients. This study revealed several independent risk factors for predicting LLNM in PTC patients, such as the maximum diameter of the primary tumour > 2 cm, ETE and CLNM. Lateral neck dissection may be recommended in PTC patients with those risk factors. Paying attention to the occurrence of skip lateral cervical lymph node metastasis during the clinical diagnosis and treatment processes is necessary.


Orofaciodigital syndrome type I in a patient with severe CNS defects.
A female patient with orofaciodigital syndrome type I associated with pachygyria, heterotopic gray matter, interhemispheric cyst, agenesis of the corpus callosum, and a Dandy-Walker anomaly is reported. Because some of these defects have been described in patients with different types of orofaciodigital syndromes, we recommend caution when using neuroradiologic criteria to separate these syndromes. Given the severe spectrum of brain abnormalities displayed by our patient, and considering their similarity with the brain defects formerly described in other X-linked dominant conditions with male lethality localized to Xp22, the use of DNA probes from Xp22 is advised in identifying the gene(s) causing orofaciodigital syndrome type I.


Liver Elastography in Healthy Children Using Three Different Systems - How Many Measurements Are Necessary?
Liver elastography is increasingly being applied in screening for and follow-up of pediatric liver disease, and has been shown to correlate well with fibrosis staging through liver biopsy. Because time is of the essence when examining children, we wanted to evaluate if a reliable result can be achieved with fewer acquisitions. 243 healthy children aged 4-17 years were examined after three hours of fasting. Participants were divided into four age groups: 4-7 years; 8-11 years; 12-14 years and 15-17 years. Both two-dimensional shear wave elastography (2D-SWE; GE Logiq E9) and point shear wave elastography (pSWE; Samsung RS80A with Prestige) were performed in all participants, while transient elastography (TE, Fibroscan) was performed in a subset of 87 children aged 8-17 years. Median liver stiffness measurement (LSM) values of 3, 4, 5, 6, 7, and 8 acquisitions were compared with the median value of 10 acquisitions (reference standard). Comparison was performed for all participants together as well as within every specific age group. We investigated both the intraclass correlation coefficient (ICC) with absolute agreement and all outliers more than 10 %, 20 % or ≥ 0.5 or 1.0 kPa from the median of 10 acquisitions. For all three systems there was no significant difference between three and ten acquisitions, with ICCs ≥ 0.97. All systems needed 4 acquisitions to achieve no LSM deviating ≥ 1.0 kPa of a median of ten. To achieve no LSM deviating ≥ 20 % of a median of ten acquisitions, pSWE and TE needed 4 acquisitions, while 2D-SWE required 6 acquisitions. Our results contradict recommendations of 10 acquisitions for pSWE and TE and only 3 for 2D-SWE.


Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine.
18-Methoxyroconaridine (18-MC), a synthetic derivative of ibogaine, reduces morphine self-administration and alleviates several signs of acute opioid withdrawal in rats. Although there is already well documented evidence of the mechanism mediating 18-MC's action to reduce the rewarding effects of morphine, nothing is known about the mechanism responsible for 18-MC's attenuation of opioid withdrawal. In vitro studies have demonstrated that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors (IC50=0.75 microM), which are predominantly located in the medial habenula and interpeduncular nuclei. Previous work indicating that alpha3beta4 nicotinic receptors mediate 18-MC's effects on drug self-administration prompted us to assess whether brain areas having high or moderate densities of alpha3beta4 receptors might be involved in 18-MC's modulation of opioid withdrawal. To test this possibility, 18-MC was locally administered into the medial habenula, interpeduncular nucleus and locus coeruleus of morphine-dependent rats; this treatment was followed by naltrexone to precipitate a withdrawal syndrome. Pretreatment with various doses of 18-MC into the locus coeruleus significantly reduced wet-dog shakes, teeth chattering, burying and diarrhea, while pretreatment into the medial habenula attenuated teeth chattering, burying, and weight loss. Some doses of 18-MC administered into the interpeduncular nucleus significantly ameliorated rearing, teeth chattering, and burying, while other doses exacerbated diarrhea and teeth chattering. The present findings suggest that 18-MC may act in all three nuclei to suppress various signs of opioid withdrawal.


Differences in sensitivity to rocuronium among orbicularis oris muscles innervated by normal or damaged facial nerves and gastrocnemius muscle innervated by somatic nerve in rats: combined morphological and functional analyses.
To evaluate mechanisms of discrepant responses to the nondepolarizing muscle relaxant rocuronium among normal and injured facial nerve-innervated orbicularis oris and tibial nerve-innervated gastrocnemius, and to provide information for the proper use of muscle relaxants to balance evoked electromyography (EEMG) monitoring and immobility in general anesthesia. Randomized controlled study. Right-sided facial nerve injury was induced by crush axotomy in 18 Sprague-Dawley rats. At different rocuronium concentrations, muscular tension amplitude (MTA) was determined in vitro for normal and injured facial nerve-innervated orbicularis oris and gastrocnemius; the number of unsaturated acetylcholine receptors (AChRs) at end plates was determined by (125) I-α-bungarotoxin staining followed with gamma spectroscopy. The morphological composition of muscle fibers was determined by histological examination. Following rocuronium incubation, the percentage of MTA inhibition (MTAI%) of gastrocnemius was significantly higher than the corresponding values of orbicularis oris (P < .05), and the degree of saturation of AChR in gastrocnemius was significantly greater than that in orbicularis oris (P < .05). The baseline MTA and AChR density of injured-side orbicularis oris was significantly smaller than those of the normal side, whereas no significant difference was found regarding MTAI% and the degree of AChR saturation between the normal and injured side. The affinity of AChR at end plates and different number of AChR per unit fiber cross-sectional area may be the mechanisms for differential sensitivities to neuromuscular blockers between facial nerve-innervated muscles and somatic nerve-innervated muscles. The lower EEMG responses in the impaired facial nerve-innervated muscles may result from the lower AChR density at end plates compared with the normal facial nerve-innervated muscles.


Roxithromycin inhibits chemokine-induced chemotaxis of Th1 and Th2 cells but regulatory T cells.
Roxithromycin (RXM), a 14-member macrolide antibiotic, has a variety of bioregulatory functions such as anti-inflammatory effects, anti-oxidant effects, and modulation of immune responses. In this study, we analyzed the effect of RXM on chemokine-induced chemotaxis of Th1, Th2, and regulatory T (Treg) cells established from three normal human peripheral blood lymphocytes by the reported methods. Incubation with 10 microM RXM for 18 h did not alter the expression profile of CXCR3 on Th1 cells and CCR4 on Th2 and Treg cells. However, upon RXM preincubation, the migration of Th1 cells to IP-10 and Th2 cells to TARC was partially suppressed, although RXM did not influence Treg cell migration. Erythromycin and clarithromycin at the same concentration did not exert such effects. F-actin polymerization and Ca(++) influx induced by IP-10 and TARC in Th1 and Th2 cells, respectively, was down-regulated by RXM pretreatment. These results imply that RXM exhibits bioregulatory function by influencing chemotaxis of Th1 and Th2 cells while leaving Treg cell migration unaffected.


Identifying factors that shape whether digital food marketing appeals to children.
Children are frequently exposed to unhealthy food marketing on digital media. This marketing contains features that often appeal to children, such as cartoons or bold colours. Additional factors can also shape whether marketing appeals to children. In this study, in order to assess the most important predictors of child appeal in digital food marketing, we used machine learning to examine how marketing techniques and children's socio-demographic characteristics, weight, height, BMI, frequency of screen use and dietary intake influence whether marketing instances appeal to children. We conducted a pilot study with thirty-nine children. Children were divided into thirteen groups, in which they evaluated whether food marketing instances appealed to them. Children's agreement was measured using Fleiss' kappa and the S score. Text, labels, objects and logos extracted from the ads were combined with children's variables to build four machine-learning models to identify the most important predictors of child appeal. Households in Calgary, Alberta, Canada. 39 children aged 6-12 years. Agreement between children was low. The models indicated that the most important predictors of child appeal were the text and logos embedded in the food marketing instances. Other important predictors included children's consumption of vegetables and soda, sex and weekly hours of television. Text and logos embedded in the food marketing instances were the most important predictors of child appeal. The low agreement among children shows that the extent to which different marketing strategies appeal to children varies.


Who is quitting? An analysis of the dis-adoption of climate smart sorghum varieties in Tanzania.
New agricultural technologies are continuously generated and promoted for adoption by farmers with the expectation that they bring about higher benefits than older technologies. Yet, depending on the perceived benefits, the user of the technology may choose to stop using it. This paper aims to analyze what drives farmers to dis-adopt climate smart sorghum varieties in Tanzania. The study uses cross-sectional farm household level data collected in Tanzania from a sample of 767 households. The determinants of dis-adoption are explored using a bivariate probit with sample selection model. The authors find that while farmers switch between different sorghum varieties, most farmers actually quit sorghum production. Older farmers and those facing biotic stresses such attacks by birds are more likely to dis-adopt sorghum. These findings suggest that there is scope for improving and sustaining the adoption of sorghum varieties in Tanzania once extension services are strengthened. The findings also point to a well-founded theory on the role of markets in enhancing the overall sustainability of food systems. The study findings have broader implications for understanding the sustainability of improved technology adoption. Dis-adoption is also positively associated with the lack of access to markets underscoring the role of markets in enhancing the overall sustainability of technology adoption and food systems.


Effect of Yoga on Clinical Outcomes and Quality of Life in Patients With Vasovagal Syncope (LIVE-Yoga).
This study aims to determine the impact of yoga as an adjunct to standard therapy versus standard therapy alone on the symptomatic burden in patients with recurrent vasovagal syncope (VVS). There is a significant reduction in the quality of life (QoL) of patients with recurrent VVS. Existing management therapies have been largely ineffective. Recent trials have demonstrated the efficacy of yoga in diseases with autonomic imbalance, suggesting its possible utility in VVS. Patients with recurrent VVS were randomized to receive either a specialized yoga training program in addition to current guideline-based therapy (intervention arm, group 1) or current guideline-based therapy alone (control arm, group 2). The primary outcome was a composite of the number of episodes of syncope and presyncope at 12 months. Secondary outcomes included QoL assessment by World Health Organization Quality of Life Brief Field questionnaire (WHOQoL-BREF) scores and Syncope Functional Status Questionnaire scores at 12 months, head up tilt test, and heart rate variability at 6 weeks. A total of 55 patients underwent randomization. The mean number of syncopal or presyncopal events at 12 months was 0.7 ± 0.7 in the intervention arm compared to 2.52 ± 1.93 in the control arm (P < 0.01). In the intervention arm, 13 (43.3%) patients remained free of events versus 4 (16.0%) patients in the control arm (P = 0.02). QoL at 12 months showed significant improvement of all Syncope Functional Status Questionnaire scores and 2 domains of WHOQoL-BREF scores (P < 0.05). Yoga as adjunctive therapy is superior to standard therapy alone in reducing the symptomatic burden and improving QoL in patients with recurrent VVS.


Gene amplification and tumor grading in parosteal osteosarcoma.
Parosteal osteosarcoma (POS) is a unique low grade osteosarcoma. Two separate oncogenes, MDM2 and CDK4, are specifically amplified in POS. Its clinical behavior is usually indolent. In some occasions, it may progress to high grade and become fatal. Malignant transformation with high grade differentiation is the most reliable indicator to predict its aggressiveness and metastatic potential. This study is to discover the relationship between gene amplification and grading. Retrospective analysis of MDM2/CDK4 expression/amplification using immunostaining, multiplex quantitative polymerase chain reaction (MQPCR) and fluorescence in situ hybridization (FISH) were studied on 14 patients with recurrent POS. Forty tumor specimens in formalin-fixed paraffin-embedded blocks from 14 patients of POS were included in this study. Twenty-seven tumors are low-grade, 13 are high-grade. All POS showed increased expression of both MDM2 and CDK4 proteins, but not those from conventional osteosarcoma. Except some tumors were non-informative (poor DNA quality), the rest of POS had a marked increase of MDM2 and CDK4 genes copies by MQPCR, and confirmed by MDM2 FISH. Moreover, the folds of amplification increase as tumors progress. And, the amplification folds in high-grade POS are consistently higher than those of conventional ones. FISH and MQPCR are both useful assays for estimating oncogene amplification status in bone tumors. Amplification levels of MDM2 and CDK4 are related to tumor grading and progression. Molecular determination of gene amplification status can be a reliable alternative for predicting clinical behavior of POS at small biopsies.


Structure and thermotropic properties of hydrated N-stearoyl sphingomyelin bilayer membranes.
Hydrated multibilayers of N-stearoyl sphingomyelin were investigated as a function of hydration using differential scanning calorimetry (DSC) and X-ray diffraction. Anhydrous N-stearoyl sphingomyelin exhibits an endothermic transition at 75 degrees C (delta H = 3.8 kcal/mol); increasing hydration progressively lowers the transition temperature and increases the transition enthalpy, until limiting values (Tm = 45 degrees C, delta H = 6.7 kcal/mol) are observed for hydration values greater than 21.4% H2O. At low hydration levels, less than 20% H2O, an additional transition is observed at approx. 20 degrees C. X-ray diffraction studies at temperatures below (22 degrees C) and above (55 degrees C) the main endothermic transition confirm that the bilayer gel (sharp 4.2 A reflection)----bilayer liquid crystal (diffuse 4.5 A reflection) transition occurs at all hydration levels with limiting bilayer hydration occurring at approx. 31.5% H2O in the gel phase and at approx. 35% H2O in the liquid crystal phase. The thermotropic properties and metastability of this partial synthetic N-stearoyl sphingomyelin differ in some respects from that of the previously studied synthetic DL-erythro-N-stearoyl sphingomyelin (Estep, T.N., Calhoun, W.I., Barenholz, Y., Biltonen, R.L., Shipley, G.G. and Thompson, T.E. (1980) Biochemistry 19, 20-24), suggesting an influential role of the interfacial molecular conformation.


Reproductive biology of Heteropneustes fossilis in a wetland ecosystem (Gajner Beel, Bangladesh) in relation to eco-climatic factors: Suggesting a sustainable policy for aquaculture, management and conservation.
The stinging catfish, Heteropneustes fossilis (Bloch, 1974) is a commercially important fish species in Asia. This is an important food fish as is enriched with high amounts of protein, iron and calcium. The current research demonstrates the population structure, size at sexual maturity, spawning- and peak-spawning season and fecundity of H. fossilis in an important wetland ecosystem - Gajner Beel in northwestern Bangladesh with an aim of its sustainable conservation through induced breeding and aquaculture practices. A total of 426 stinging catfish captured from the Gajner Beel through monthly sampling from January to December 2019 used in the study. Total length (TL), standard length (SL) and body weight (BW) of individual fishes were measured. The size ranges were with 6.70-24.10 cm TL, 1.37-83.94 g BW. Gonads were removed carefully through ventral dissection and weighted. Lm was 14.02, 13.5, 13.0 and 15.0 cm based on maximum length (Lmax ), TL vs. GSI (%), TL vs. SL and logistic model, respectively. Monthly variations of GSI and maturation stages were confirmed in April to August as spawning season and June as peak spawning month. Fulton's condition factor (KF ) was found to be with significant relations with GSI values. Fecundity was 1,730 to 23,870 and significantly correlated with both TL and BW. Temperature has been increasing 0.029 °C/year with the falling of rainfall at 2.96 mm/year in the study area. Environmental factors -Temperature, rainfall, dissolved oxygen and pH were found to be significantly correlated with GSI. We found the optimal range of temperature (29-31 °C), rainfall (350-380 mm), dissolved oxygen (5.0-6.0 mg/l) and pH (7.1-7.5) for spawning of H. fossilis. The paper recommended the policy guidelines to pave the ways of the aquaculture, conservation and management of H. fossilis in the changing eco-climatic events through specific management measures.


Association between housing environment and depressive symptoms among older people: a multidimensional assessment.
Depression is a common mental disorder among older people. This study aimed to assess the association between housing environment factors and depressive symptoms among older people using a multidimensional assessment method. The study uses a population-based cross-sectional design. A total of 950 participants aged ≥ 60 years were selected using a complex multistage sampling design from 22 locations in China. All data were collected using questionnaires by face-to-face interviews. A total of 938 participants were included in the analysis, and 17.1% of males and 23.1% of females were identified as having depressive symptoms. The depressive symptoms were assessed using the 15-item Geriatric Depression Scale. The housing environment was assessed on the basis of four dimensions: physical, social, psychological, and cognition and physical function. Cumulative logistic regression analysis was used to evaluate the association between housing environment and depressive symptoms. The Cochran-Armitage trend test showed that the depressive symptom scores were linearly negatively associated with self-assessed housing environment, living arrangement, life satisfaction, and other physical environment factors and linearly positively associated with cognitive and physical function scores. The results of cumulative logistic regression analysis showed that the housing environment was significantly associated with depressive symptoms. The participants' self-assessed housing environment was strongly associated with the levels of depressive symptom scores, and the odds ratio was 3.47 (95% CI, 1.14-10.82, P = 0.003). The housing environment was significantly associated with depressive symptoms. Our results suggest that multi-dimensional assessment in the housing environment may be an effective way to develop intervention strategies of depressive symptoms among older people.


Toward the development of a color visual prosthesis.
Objective. All of the human prosthetic visual systems implanted so far have been achromatic. Schmidtet al(1996Brain119507-22) reported that at low stimulation intensities their subject reported that phosphenes usually had a specific hue, but when the stimulus intensity was increased, they desaturated to white. We speculate here that previous B/W prosthetic systems were unnecessarily over-stimulating the visual cortex to obtain white phosphenes, which may be why unexpected alterations in phosphenes and seizures were not an uncommon occurrence. A color prosthesis would have the advantage of being elicited by lower levels of stimulation, reducing the probability of causing epileptogenic responses.Approach.A 'hybrid' mode of stimulation is suggested, involving a combination of B/W and color stimulation, which could provide color information without reducing spatial resolution.Main results.Colors in the real world are spread along intensity and chromatic gradients.Significance.Software implementation strategies are discussed, as are the advantages and challenges for possible color prosthetic systems.


Hepatic artery pseudoaneurysm ligation after orthotopic liver transplantation--a report of 7 cases.
Pseudoaneurysm (PA) is a rare but life-threatening complication of liver transplantation. The authors present their experience on 7 patients treated by ligation of a post-OLT PA. Hepatic artery ligation or embolization was performed from 10 to 70 days after liver transplantation. Of the seven patients, four survived, one developed a biliary stricture, treated by percutaneous balloon dilatation, two died of a complication not related to treatment, and one died of multiple organ failure.


Uptake of biogenic amines by thyroid glands.
The biogenic amines, serotonin (5-HT) and norepinephrine, activate follicular cells and are endogenous thyroid constitutents. Both amines are taken up by throid lobes incubated in vitro. Uptake of 5-HT is temperature and concentration dependent, is inhibited by chlorimipramine more than by desmethylimipramine, and although it is inhibited by norepinephrine, 5-HT uptake is unaffected by chemical sympathetomy with 6-hydroxydopamine. Electron microscopic radioautography reveals that follicular cells are responsible for uptake of 5-HT and adrenergic nerves for uptake of norepinephrine. These data are consistent with the hypothesis that biogenic amines are intrathyroidal transmitters acting on follicular cells, and that uptake mechanisms may contribute to their inactivation.


Integrative study of microbial community dynamics and water quality along The Apatlaco River.
The increasing demand for clean water resources for human consumption, is raising concerning about the sustainable worldwide provisioning. In Mexico, rivers near to high-density urbanizations are subject to irrational exploitation where polluted water is a risk for human health. Therefore, the aims of this study are to analyze water quality parameters and bacterial community dynamics to understand the relation between them, in the Apatlaco river, which presents a clear environmental perturbance. Parameters such as total coliforms, chemical oxygen demand, harness, ammonium, nitrite, nitrate, total Kjeldahl nitrogen, dissolved oxygen, total phosphorus, total dissolved solids, and temperature were analyzed in 17 sampling points along the river. The high pollution level was registered in the sampling point 10 with 480 mg/L chemical oxygen demand, 7 mg/L nitrite, 34 mg/L nitrate, 2 mg/L dissolved oxygen, and 299 mg/L of total dissolved solids. From these sites, we selected four samples for DNA extraction and performed a metagenomic analysis using a whole metagenome shotgun approach, to compare the microbial communities between polluted and non-polluted sites. In general, Proteobacteria was the most representative phylum in all sites. However, the clean water reference point was enriched with microorganism from the Limnohabitans genus, a planktonic bacterium widespread in freshwater ecosystems. Nevertheless, in the polluted sampled sites, we found a high abundance of potential opportunistic pathogen genera such as Acinetobacter, Arcobacter, and Myroides, among others. This suggests that in addition to water contamination, an imminent human health risk due to pathogenic bacteria can potentially affect a population of ∼1.6 million people dwelling nearby. These results will contribute to the knowledge regarding anthropogenic pollution on the microbial population dynamic and how they affect human health and life quality.


Tumours of the fifth cranial nerve.
Tumours of the fifth cranial nerve are very rare, comprising only 0.2% of all intracranial neoplasms. The authors critically review the literature, and report on 12 personal cases of trigeminal tumours (nine neurinomas, one meningioma, one epidermoid, one osteochondroma). General pathology, symptoms, and signs are analyzed, and compared with cases from the literature. Because of their insidious onset and slow "illogical" progression of misleading symptoms, trigeminal tumours often prove to be a diagnostic challenge. As a consequence they usually reach a large size before causing sufficient symptoms to lead the patient to a neurosurgical clinic. The diagnosis is therefore likely to be made by radiological investigations. The typical radiological feature (on plain skull films, pneumoencephalography, and angiography) are described, and differential diagnosis is discussed. All the patients in the present series were operated on. Surgical procedures and postoperative results are discussed.


Proteases and variants: context matters for SARS-CoV-2 entry assays.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), like other coronaviruses, relies on a flexible array of entry mechanisms, driven by the spike (S) protein. Entry is dependent on proteolytic priming, activation, and receptor binding; all of which can be variable, dependent on context. Here we review the implications of the complexity of SARS-CoV-2 entry pathways on entry assays that then drive our understanding of humoral immunity, therapeutic efficacy, and tissue restriction. We focus especially on the proteolytic activation of SARS-CoV-2 spike and how this constellation of proteases lends deeper insight to our understanding of arising variants and their putative role transmission or variable pathogenicity in vivo. In this review, we argue for better universal standards to assay virus entry as well as suggest best practices for reporting viral passage number, the cell line used, and proteases present, among other important considerations.


Association of sleep problems with urinary concentrations of personal care and consumer product chemicals: a nationally representative, population-based study.
Sleep problems are common in modern society and may be related to environmental chemicals. The objective of this study is to investigate the association between exposure to personal care and consumer product chemicals (PCCPCs) and sleep-related disorders. Nationally representative data from the National Health and Nutrition Examination Survey (NHANES) were used in this study (N=2415). Sleep-related variables, including sleep duration, snoring, and self-reported sleep problems, were included as outcome variables to assess sleep quality. Urinary PCCPC concentrations were used to assess the association of PCCPCs with sleep problems and adjusted for variables similar to those used in related studies. PCCPC levels were analysed as quartiles. Multivariate logistic regression and weighted quantile sum (WQS) regression were used to analyse the association of urinary PCCPCs with sleep problems. Nine of the 12 kinds of PCCPCs with a detection rate greater than 50% were included in our study. Specifically, the concentrations of bisphenol A (BPA), bisphenol F (BPF), methyl paraben (MP) and triclosan (TCS) were significantly related to insufficient sleep. Based on the WQS model, combined exposure to PCCPCs was also significantly related to insufficient sleep; TCS, BPA, and MP were the compounds with the greatest impact regarding combined exposure. A variety of PCCPCs were associated with insufficient sleep in participants but were not significantly associated with the other sleep problems reported in the NHANES. As poor quality sleep is associated with multiple adverse health outcomes, our study provides insight into the health risks of PCCPC exposure.


Age-dependent requirements of sympathetic neurons in serum-free culture.
Neurons dissociated from chick sympathetic ganglia of different embryonic ages can be cultured equally well in serum containing or serum-free (N1) medium on collagen polyornithine, and polyornithine pretreated with neurite-promoting factor (PNPF), in the presence of nerve growth factor (NGF). Quantitative analysis of nerve cell survival is best achieved in serum-free conditions and on PNPF-pretreated polyornithine. Under such conditions, 11-day embryonic (E11) sympathetic neurons showed a specific requirement for insulin, selenium and transferrin. Similar analyses at E8 and E16 revealed that the requirement for transferrin is developmentally regulated since it is not expressed by E8 nerve cells until after 3 days in vitro. These data strongly suggest that, besides NGF, other specific molecules are involved in the control of neuronal survival and that specific requirements may be displayed at different embryonic stages.


The Association Between Sleep Disturbances and Erectile Dysfunction During the COVID-19 Pandemic.
There is increasing concern about the impact of the SARS-CoV-2 pandemic on mental and physical health. Among the many possible outcomes of COVID-19, reports of sleep disturbances, and erectile dysfunction are becoming prevalent worldwide. We sought to evaluate the recent literature on this subject to produce a narrative review of the topic. We performed an extensive literature search to identify recent scientific findings on this subject. To date, the precise mechanisms that trigger pandemic related sexual dysfunction are not completely understood, although it has been suggested that psychogenic effects play an important role, in addition to the direct effects of the disease itself on those infected. There is evidence that the stress induced by the pandemic has had a significant impact on sleep, and sleep disturbances are known to induce erectile dysfunction. Other mechanisms which trigger this phenomenon, such as hormonal changes and previous health conditions, have been suggested to be associated with SARS-CoV-2 infection, and these factors may have a potential link to sleep disturbance. The combined effect of COVID-19 and the psychogenic disorders triggered by isolation, grief, and anxiety might be associated with the increased prevalence of erectile dysfunction. This feature might be worsened by the onset of pre-existing or pandemic-induced sleep disorders. However, few studies explored this subject. Understanding this phenomenon is important for the strategic planning of treatments that could improve the quality of life of the population. Andersen ML and Tufik S. The Association Between Sleep Disturbances and Erectile Dysfunction During the COVID-19 Pandemic. Sex Med Rev 2022;10:263-270.


Plasma glucosylceramide and ceramide in type 1 Gaucher disease patients: correlations with disease severity and response to therapeutic intervention.
The concentrations of plasma glucosylceramide (GlcCer) and ceramide (Cer) were determined in a cohort of type 1 Gaucher disease patients. In plasma of untreated patients, GlcCer concentrations were on average 3-fold increased (median Gaucher: 17.5 nmol/ml, range: 6.5-45.5 (n=27); median control: 5.9 nmol/ml, range 4.0-8.6 (n=15)). Although plasma Cer concentrations were not significantly different between the two groups (median Gaucher: 7.2 nmol/ml, range: 4.2-10.9 (n=27); median control: 7.8 nmol/ml, range 5.7-11.9 (n=15)) in individual patients plasma GlcCer/Cer ratio yields slightly better discrimination between Gaucher disease patients and normal individuals than the GlcCer levels. Positive correlations were detected between plasma GlcCer concentration and GlcCer/Cer ratio and severity of disease, plasma chitotriosidase and CCL18, surrogate markers of storage cells. Gaucher disease is treated by enzyme replacement and substrate reduction therapy. Both therapies were found to result in decreases in plasma GlcCer already within 6 months, without causing abnormal plasma GlcCer or Cer concentrations. The corrections in plasma GlcCer were most robust in patients with a pronounced clinical response. In conclusion, plasma GlcCer concentration and GlcCer/Cer ratio is of value to monitor Gaucher disease manifestation and response to therapeutic intervention.


Evaluation of the efficacy of a new modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine (Fostera PRRS) against heterologous PRRSV challenge.
The objective of this study was to evaluate a new modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine (Fostera PRRS, Zoetis, Florham, NJ, USA) that was based on a virulent US PRRSV isolate (P129) attenuated using CD163-expressing cell lines. Sixty-four PRRSV-seronegative 3-week-old pigs were randomly divided into the following four groups: vaccinated challenged (group 1), vaccinated unchallenged (group 2), unvaccinated challenged (group 3), and unvaccinated unchallenged (group 4). The pigs in groups 1 and 2 were immunized with a 2.0 mL dose of modified live PRRSV vaccine at 21 days of age, according to the manufacturer's recommendations. At 56 days of age (0 days post-challenge), the pigs in groups 1 and 3 were inoculated intranasally with 3 mL of tissue culture fluid containing 10(5) 50% tissue culture infective dose (TCID50)/mL of PRRSV (SNUVR090851 strain, fourth passage in MARC-145 cells). Vaccinated challenged pigs exhibited significantly lower (P<0.05) respiratory scores, viremia, macroscopic and microscopic lung lesion scores, and PRRSV-antigen with interstitial pneumonia than unvaccinated challenged pigs. The induction of PRRSV-specific IFN-γ-SCs by the new modified live PRRSV vaccine produced a protective immune response, leading to the reduction of PRRSV viremia. Although the new modified live PRRSV vaccine is not effective against heterologous PRRSV challenge, the new modified live PRRSV vaccine was able to reduce the levels of viremia and nasal shedding, and severity of PRRSV-induced lesions after challenging virus under experimental conditions.


Diagnostic accuracy of point of care faecal immunochemical testing using a portable high-speed quantitative analyser for diagnosis in 2-week wait patients.
Laboratory-based faecal immunochemical testing (FIT) is the gold standard for detecting the presence of blood in the stool. The aim was to perform a diagnostic accuracy study to confirm if a point of care (POC) analyser for FIT could be safely used as an adjunct in the triage and management of 2-week wait (TWW) colorectal patients. The Point of Care Faecal Immunochemical Testing (POC FIT) prospective observational cohort study was designed for TWW patients at a regional referral centre. Between July 2019 and March 2020, patients were invited to perform and bring a FIT sample to clinic. FIT was completed within the clinic appointment using a POC quantitative analyser that has a 2-min processing time (QuikRead go®). Patients and clinicians were blinded to results within the clinic appointment. The results were compared with subsequent diagnostic outcomes. Faecal haemoglobin of <10 µg haemoglobin/g of faeces was considered a negative result. Sensitivities for colorectal cancer (CRC) and combined serious bowel disease (SBD) were calculated using this pre-determined cut-off. A total of 553 patients were included for analytical comparison with diagnostic outcomes. There were 14 (2.5%) patients with CRC and 52 (9.4%) with SBD. The sensitivities for CRC and SBD were 92.9% (95% CI 68.5%-98.7%) and 76.9% (95% CI 63.9%-86.3%) respectively. 379 (68.5%) patients had a negative FIT result (negative predictive value for CRC was 99.7%). This POC FIT device is a useful adjunct to better manage TWW patients. The high observed sensitivity for CRC offers opportunities, within a single consultation, for improved triage and rationalization of investigation for those with bowel symptoms.


Safety of deep sedation in an urban oral and maxillofacial surgery training program.
To study the safety of deep sedation in an urban-based oral maxillofacial surgery training program. Charts of patients undergoing an intravenous sedation from January 2005 through December 2009 were reviewed. Data recorded included age, gender, type of procedures performed, and intravenous medications. Patients were divided in 2 groups depending on whether they received a general anesthetic agent (propofol or ketamine) or not. Anesthesia complications and failures were recorded and categorized. In total, 1,167 intravenous sedations were recorded. Eight patients developed adverse reactions, 3 of which required further evaluation in the emergency department. In addition, 7 intravenous sedations needed to be aborted because of patient agitation and combativeness. No deaths or long-term morbidities were reported. The safety of deep sedation in an urban-based oral maxillofacial training program is similar to office-based anesthesia. Sedations failures may be attributed to paradoxical benzodiazepine reactions.


Long-term supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine for pressure ulcer in sedentary older adults: a retrospective matched case-control study.
Growing evidence suggests that beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln) positively affect wound recovery. This study investigated the effects of long-term administration of HMB/Arg/Gln on pressure ulcer (PU) healing in sedentary older adults admitted to geriatric and rehabilitation care facilities. This was a pilot retrospective case (standard of care and HMB/Arg/Gln)-control (standard of care alone) clinical study. Outcome measures were relative healing rates and Pressure Ulcer Scale for Healing (PUSH) scores (calculated after 4, 8, 12, 16, and 20 weeks) and time to healing. The study subpopulation was comprised of 14 participants (four males, 28.6%) with the median age of 85.5 years (interquartile range [IQR], 82.0-90.2 years). The control subpopulation was comprised of 31 participants (18 males, 58.1%) with the median age of 84.0 years (IQR, 78.0-90.0 years). At the beginning of follow-up, there were no statistically significant demographic (sex and age) and clinical (main diagnosis, baseline area, and PU perimeter) differences between the groups. During the study period, there were no significant differences in the relative healing rates and PUSH scores between the subpopulations. The median time to complete healing in the study and control populations was 170.0 days (95% confidence interval [CI], 85.7-254.3) and 218.0 days (95% CI, 149.2-286.7) (log-rank, chi-square=3.99; p<0.046), respectively. More than 20 weeks of HMB/Arg/Gln supplementation had a positive effect on difficult PU healing in older adults with multiple comorbidities.


Edaravone and benidipine protect myocardial damage by regulating mitochondrial stress, apoptosis signalling and cardiac biomarkers against doxorubicin-induced cardiotoxicity.
Background: Doxorubicin (DOX) is a potential chemotherapeutic agent but its use is restricted due to cardiotoxicity. Edaravone is a potent-free radical scavenging agent used in cerebral ischaemia. Benidipine is a triple calcium channel blocker.Objective: We investigated the potential cardioprotective effects of edaravone and benidipine alone and their combination against DOX-induced cardiotoxicity. Cardiotoxicity was induced by administering six equal injections of DOX (2.5 mg/kg) on alternative days for 2 weeks.Result: DOX-treated group showed significant increase level of lipid peroxide and decrease in antioxidant status along with mitochondrial enzymatic activity. Cardiotoxity effect of DOX illustrated by significantly increased the cardiac biomarkers such as Cardiac troponin-I, Brain natriuretic peptide, Creatine kinase-MB in serum. Significant increased activation of TNF-α, Caspase-3 activity and myocardial infarct size in DOX-treated group. Histopathological evaluation also confirmed the DOX-induced cardiotoxicity. Pretreated with edaravone and benidipine was significantly attenuated level of thiobarbituric acid reactive substance, endogenous enzymes, mitochondrial enzyme activities and cardiac biomarkers. Furthermore, pretreated group showed decreased activation of TNF-α, Caspase-3 activity along with reduction in the myocardial infarct size. Histopathological evaluation also strengthened the above results.Conclusion: Taken together these results suggest that the pretreated with edaravone and benidipine have potential protective effect against DOX-induced cardiotoxicity.


Increased cerebrospinal fluid interleukin-8 in bipolar disorder patients associated with lithium and antipsychotic treatment.
Inflammation has been linked to the pathophysiology of bipolar disorder based on studies of inflammation markers, such as cytokine concentrations, in plasma and serum samples from cases and controls. However, peripheral measurements of cytokines do not readily translate to immunological activity in the brain. The aim of the present study was to study brain immune and inflammatory activity. To this end, we analyzed cytokines in cerebrospinal fluid from 121 euthymic bipolar disorder patients and 71 age and sex matched control subjects. Concentrations of 11 different cytokines were determined using immunoassays. Cerebrospinal fluid IL-8 concentrations were significantly higher in patients as compared to controls. The other cytokines measured were only detectable in part of the sample. IL-8 concentrations were positively associated to lithium- and antipsychotic treatment. The findings might reflect immune aberrations in bipolar disorder, or be due to the effects of medication.


Brachial plexus anesthesia for outpatient surgical procedures on an upper extremity.
We retrospectively reviewed 543 brachial plexus blocks performed on 526 outpatients. Most (98%) of the blocks were performed by means of the axillary approach. Various techniques were used, including paresthesia, transarterial fixation, nerve stimulation, or a combination of techniques; a high success rate was achieved with each of them. Only 7% of the blocks were incomplete and thus necessitated either general anesthesia or block supplementation with thiopental sodium and nitrous oxide. No persistent neurologic deficit was ascribed to the anesthetic technique. This review indicates that brachial plexus block, especially with use of the axillary approach, is a safe and effective option for outpatient surgical procedures on an upper extremity.


Cell Therapy in Myology: Dynamics of Muscle Precursor Cell Death after Intramuscular Administration in Non-human Primates.
Cell therapy could be useful for the treatment of myopathies. A problem observed in mice, with different results and interpretations, is a significant death among the transplanted cells. We analyzed this problem in non-human primates, the animal model more similar to humans. Autologous or allogeneic myoblasts (with or without a reporter gene) were proliferated in vitro, labeled with [14C]thymidine, and intramuscularly injected in macaques. Some monkeys were immunosuppressed for long-term follow-up. Cell-grafted regions were biopsied at different intervals and analyzed by radiolabel quantification and histology. Most radiolabel was lost during the first week after injection, regardless of whether the cells were allogeneic or autologous, the culture conditions, and the use or not of immunosuppression. There was no significant difference between 1 hr and 1 day post-transplantation, a significant decrease between days 1 and 3 (45% to 83%), a significant decrease between days 3 and 7 (80% to 92%), and no significant differences between 7 days and 3 weeks. Our results confirmed in non-human primates a progressive and significant death of the grafted myoblasts during the first week after administration, relatively similar to some observations in mice but with different kinetics.


Binding of diphosphoglycerate and ATP to oxyhemoglobin dimers.
The relative affinity of diphosphoglycerate and ATP for hemoglobin dimers and tetramers can be measured under conditions where the protein is in large molar excess over the polyphosphate. Binding of both compounds to dimers was about 25 times stronger than to tetramers in the case of the three low-spin hemoglobins, oxyhemoglobin, carboxyhemoglobin and cyanomethemoglobin. The mutation in hemoglobin Kansas leads to an increased dissociation into alpha beta dimers. The increase in diphosphoglycerate binding by this hemoglobin was in good agreement with that expected from the dimer-tetramer dissociation constant over a wide range of hemoglobin concentrations. In contrast to the liganded hemoglobins, both deoxyhemoglobin and aquomethemoglobin bind the two polyanions as tetramers.


Hip aspiration: verification of needle position by air arthrography.
A new method is described for verification of needle placement during hip aspiration or hip arthrography using suction air arthrography. The method is safe, rapid, reliable, and reproducible, and it eliminates problems with obscuring pathology by incorrect injection of dye or air, reactions to dye, or air embolism.


Power analysis as a tool to identify statistically informative indicators for monitoring coral reef disturbances.
Extensive biological field surveys are costly and time consuming. To optimize sampling and ensure regular monitoring on the long term, identifying informative indicators of anthropogenic disturbances is a priority. In this study, we used 1800 candidate indicators by combining metrics measured from coral, fish, and macro-invertebrate assemblages surveyed from 2006 to 2012 in the vicinity of an ongoing mining project in the Voh-Koné-Pouembout lagoon, New Caledonia. We performed a power analysis to identify a subset of indicators which would best discriminate temporal changes due to a simulated chronic anthropogenic impact. Only 4% of tested indicators were likely to detect a 10% annual decrease of values with sufficient power (>0.80). Corals generally exerted higher statistical power than macro-invertebrates and fishes because of lower natural variability and higher occurrence. For the same reasons, higher taxonomic ranks provided higher power than lower taxonomic ranks. Nevertheless, a number of families of common sedentary or sessile macro-invertebrates and fishes also performed well in detecting changes: Echinometridae, Isognomidae, Muricidae, Tridacninae, Arcidae, and Turbinidae for macro-invertebrates and Pomacentridae, Labridae, and Chaetodontidae for fishes. Interestingly, these families did not provide high power in all geomorphological strata, suggesting that the ability of indicators in detecting anthropogenic impacts was closely linked to reef geomorphology. This study provides a first operational step toward identifying statistically relevant indicators of anthropogenic disturbances in New Caledonia's coral reefs, which can be useful in similar tropical reef ecosystems where little information is available regarding the responses of ecological indicators to anthropogenic disturbances.


'Racial' differences in genetic effects for complex diseases.
'Racial' differences are frequently debated in clinical, epidemiological and molecular research and beyond. In particular, there is considerable controversy regarding the existence and importance of 'racial' differences in genetic effects for complex diseases influenced by a large number of genes. An important question is whether ancestry influences the impact of each gene variant on the disease risk. Here, we addressed this question by examining the genetic effects for 43 validated gene-disease associations across 697 study populations of various descents. The frequencies of the genetic marker of interest in the control populations often (58%) showed large heterogeneity (statistical variability) between 'races'. Conversely, we saw large heterogeneity in the genetic effects (odds ratios) between 'races' in only 14% of cases. Genetic markers for proposed gene-disease associations vary in frequency across populations, but their biological impact on the risk for common diseases may usually be consistent across traditional 'racial' boundaries.


Trends of sulfur and nitrogen deposition from 2003 to 2017 in Japanese remote areas.
Emissions of sulfur (S) and nitrogen (N) compounds in East Asia has drastically changed over the last two decades. To assess the influence of the drastic changes in air pollution on ecosystems in Japan, we investigated the trends of S and N deposition during 2003-2017 at remote sites of Acid Deposition Monitoring Network in East Asia (EANET). We measured wet deposition and inferentially estimated dry deposition of S and N using monitoring data from 2003 to 2017 at eight sites. We estimated dry deposition using the inferential method with an updated parameterization for gaseous surface resistance. The linear regression method and nonparametric Mann-Kendall test was used to analyze the temporal trends based on the monthly data sets. High S and N deposition amounts over 10 kg ha-1 year-1 were frequently found at most sites. There were significant increase trends in N deposition to S deposition (N/S) ratio at all sites throughout the 15-year period. Some trends were significantly found when the 15-year period was divided into three: 2003-2007, 2008-2012, and 2013-2017. S deposition had significantly decreased over a wide area in Japan, especially at Sado-seki, Happo, Oki, Hedo, and Ogasawara, in 2013-2017. Significant decreases in oxidized N deposition at Sado-seki and Oki were also found in 2013-2017. Because of almost flat N deposition mainly contributed by reduced N deposition, the N/S ratio clearly increased. These trends were associated with the recent reductions in SO2 and NOx emissions in China. The NOx emission reduction of China has not caught up with that of SO2, and NH3 emissions have not been reduced. This caused the significant increases in the N/S ratio not only in 2013-2017 but also in 2003-2017.


ICI-based therapies: A new strategy for oral potentially malignant disorders.
Oral potentially malignant disorders (OPMDs) are linked with an escalated risk of developing cancers, particularly oral squamous cell carcinoma (OSCC). Since prevailing therapies cannot effectively forestall the exacerbation and recurrence of OPMDs, halting their malignant progression is paramount. The immune checkpoint serves as a cardinal regulator of the immune response and the primary cause of adaptive immunological resistance. Although the exact mechanism remains elusive, elevated expression of multiple immune checkpoints in OPMDs and OSCC relative to healthy oral mucosa has been ascertained. This review delves into the immunosuppressive microenvironment of OPMDs, the expression of diverse immune checkpoints such as programmed death receptor-1 (PD-1) and programmed death receptor-1 ligand (PD-L1) in OPMDs, and the potential application of corresponding inhibitors. In addition, synergistic strategies incorporating combined immune checkpoint inhibitors, such as cGAS-STING, costimulatory molecules, cancer vaccines, and hydrogels, are discussed to gain a more comprehensive understanding of the role and application of immune checkpoint inhibitors (ICIs) in oral carcinogenesis.


Adenylate kinase 2, a mitochondrial enzyme.
The subcellular compartmentalization of the isoenzymes of ATP:AMP phosphotransferase (adenylate kinase) was analyzed in HeLa cells, RAG cells, and RAG-human hybrids that express human AK-2. In HeLa cells and in the hybrids, human AK-2 was present in a mitochemical fraction prepared from cell extracts and in mitochondria purified by density gradient centrifugation. Human AK-1 was, as expected, distributed in the soluble cytoplasmic fraction of the cells. The rodent isozymes which are homologous to human AK-1 and AK-2 have been determined.


Adaptive surrogate modeling for expedited estimation of nonlinear tissue properties through inverse finite element analysis.
Simulation-based prediction of specimen-specific biomechanical behavior commonly requires inverse analysis using geometrically consistent finite element (FE) models. Optimization drives such analyses but previous studies have highlighted a large computational cost dictated by iterative use of nonlinear FE models. The goal of this study was to evaluate the performance of a local regression-based adaptive surrogate modeling approach to decrease computational cost for both global and local optimization approaches using an inverse FE application. Nonlinear elastic material parameters for patient-specific heel-pad tissue were found, both with and without the surrogate model. Surrogate prediction replaced a FE simulation using local regression of previous simulations when the corresponding error estimate was less than a given tolerance. Performance depended on optimization type and tolerance value. The surrogate reduced local optimization expense up to 68%, but achieved accurate results for only 1 of 20 initial conditions. Conversely, up to a tolerance value of 20 N(2), global optimization with the surrogate yielded consistent parameter predictions with a concurrent decrease in computational cost (up to 77%). However, the local optimization method without the surrogate, although sensitive to the initial conditions, was still on average seven times faster than the global approach. Our results help establish guidelines for setting acceptable tolerance values while using an adaptive surrogate model for inverse FE analysis. Most important, the study demonstrates the benefits of a surrogate modeling approach for intensive FE-based iterative analysis.


Tibiopedal and distal femoral retrograde vascular access for challenging chronic total occlusions: predictors for technical success, and complication rates in a large single-center cohort.
To evaluate the safety and effectiveness of tibiopedal and distal femoral access for retrograde crossing of chronic total occlusion (CTO) in Rutherford stage III to VI peripheral arterial occlusive disease, and to determine factors that correlate with technical success. One hundred seventy-one consecutive patients were included in this retrospective study. Rutherford stages were III, IV, and V/VI in 24%, 8%, and 67% of patients. Inclusion criteria were CTO at the superficial femoral (SFA), popliteal (PA), and/or below-the-knee (BTK) level, and a failed antegrade treatment followed by a distal retrograde approach. The numbers of occluded vascular levels (OVL), lesion length, degree of calcification, technical success rate, complications, and clinical outcome were noted. OVL were 1 in 72%, 2 in 20%, and 3 in 8% of patients. CTOs were longer than 20 cm in 45.6% of cases and showed severe calcifications in 50.3%. Target vessels for distal access were the distal SFA/PA in 17% and BTK in 83%. The overall technical success rate was 82%. Severe calcification decreased technical success (p = 0.01) despite lesion length and Rutherford stage. Clinical outcome improved in 123/152 patients with a significant increase of the median ABI (N = 158) from 0.53 (interquartile range 0.39 to 0.61) to 0.85 (0.59 to 1.03; p < 0.001). Complications were reported in 7.6% cases with 2.3% related to the distal vascular access. The tibiopedal and distal femoral retrograde access presents a safe and effective treatment option of CTOs at the thigh and/or BTK after a failed antegrade attempt improving clinical outcome. Technical success decreased with lesion's degree of calcification. • Safety and effectiveness of the tibiopedal and distal femoral access for retrograde crossing of chronic total occlusion. • Target lesion's degree of calcification decreases technical success. • Complications related to the distal vascular access were rare.


CDX2 can be regulated through the signalling pathways activated by IL-6 in gastric cells.
The inflammatory infiltrate of the gastric mucosa associated with Helicobacter pylori infection increases the presence of the pro-inflammatory cytokine IL-6 that activates both the SHP-2/ERK/MAPK and the JAK/STAT signalling pathways. Furthermore, the ectopic expression of CDX2 is detected in pre-neoplasic lesions associated with decreased levels of SOX2, and we found that in gastric adenocarcinomas their expression is inversely correlated. To determine the role of IL-6 in the regulation of CDX2, MKN45 that constitutively expresses p-STAT3, and NUGC-4 gastric cancer cell lines were treated with IL-6, which induced the CDX2 up-regulation and SOX2 down-regulation. ChIP assays determined that in IL-6-treated cells, c-JUN and p-STAT3 bound to CDX2 promoter in MKN45 cells whereas in NUGC-4 cells, p-STAT3 binds to and c-JUN releases from the CDX2 promoter. Specific inhibition of STAT3 and ERK1/2 phosphorylation through AG490 and U0126, respectively, and STAT3 down-regulation using shRNA verified that the SHP-2/ERK/MAPK pathway regulates the expression of CDX2 in basal conditions, and the CDX2 up-regulation by IL-6 is through the JAK/STAT pathway in NUGC-4 cells whereas in MKN45 cells both pathways contribute to the CDX2 up-regulation. In conclusion, the signalling pathways activated by IL-6 have a crucial role in the regulation of CDX2 that is a key factor in the process of gastric carcinogenesis, suggesting that the inflammatory infiltrate in the gastric mucosa is relevant in this process and a potential target for new therapeutic approaches.


Adenosine administration during hybrid atrial fibrillation ablation to test dormant pulmonary vein conduction.
Adenosine administration after initial pulmonary vein isolation (PVI) reveals dormant conduction and predicts atrial fibrillation (AF) recurrence. Elimination of dormant conduction when present may increase a long-term success rate of AF ablation procedures. There are no studies till date using adenosine to reveal acute reconduction of pulmonary veins (PVs) after epicardial PVI during a hybrid AF ablation procedure. We included 24 patients (21 male, 55 ± 9 years) undergoing hybrid ablation for symptomatic paroxysmal (n = 12) and persistent (n = 12) AF, using an epicardial bipolar radiofrequency clamp to perform PVI. All antiarrhythmic medications were discontinued 5 days prior to the procedure, except for patients on amiodarone. Thirty minutes after PVI and once sinus rhythm was obtained, a bolus of adenosine (12 to 36 mg) was administered intravenously. The subsequent response was assessed for each PV (n = 96) using an in situ circular mapping catheter. Dormant conduction (i.e., the reappearance of PV potentials during at least one beat) was seen in 1 out of 96 PVs (1%). If reconduction was seen, further endocardial ablation using a 3.5-mm irrigated tip catheter was performed until no more reconduction occurred after repeating the adenosine bolus. Adenosine administration after PVI with the use of an epicardial bipolar radiofrequency clamp in the setting of hybrid AF ablation reveals acute reconduction in 1% of the PVs.


Genome-wide mRNA profiling and multiplex quantitative RT-PCR for forensic body fluid identification.
In forensic science, identifying a tissue where a forensic specimen was originated is one of the principal challenges. Messenger RNA (mRNA) profile clearly reveals tissue-specific gene expression patterns that many attempts have been made to use RNA for forensic tissue identification. To systematically investigate the body-fluid-specific expression of mRNAs and find novel mRNA markers for forensic body fluid identification, we performed DNA microarray experiment with 24 Korean body fluid samples. Shannon entropy and Q-values were calculated for each gene, and 137 body-fluid-specific candidate genes were selected. By applying more stringent criteria, we further selected 28 candidate genes and validated them by RT-PCR and qRT-PCR. As a result, we suggest a novel combination of four body-fluid-specific mRNA makers: PPBP for blood, FDCSP for saliva, MSMB for semen and MSLN for vaginal secretion. Multiplex qRT-PCR assay was designed using the four mRNA markers and DNA/RNA co-extraction method was tested for forensic use. This study will provide a thorough examination of body-fluid-specifically expressed mRNAs, which will enlarge the possibility of practical use of RNA for forensic purpose.


Bleeding outcomes and factor utilization after switching to an extended half-life product for prophylaxis in haemophilia A in Austria.
To prevent bleeding in severe haemophilia A [SHA, defined as factor VIII (FVIII) activity < 1%] regular prophylactic FVIII replacement therapy is required, and the benefits of factor products with extended half-life (EHL) over traditional standard half-life (SHL) are still being debated. We performed a multi-centre, retrospective cohort study of persons with SHA in Austria aiming to compare clinical outcomes and factor utilization in patients with SHA, who switched from prophylaxis with SHL to an EHL. Data were collected from haemophilia-specific patient diaries and medical records. Twenty male persons with SHA (median age: 32.5 years) were included. The most common reason for switching to the EHL was a high bleeding rate with SHL. Switch to rFVIII-Fc resulted in a significantly decreased annualized bleeding rate (ABR; median difference (IQR): - 0.3 (- 4.5-0); Wilcoxon signed-rank test for matched pairs: Z = - 2.7, p = 0.008) and number of prophylactic infusions per week (- 0.75 (- 1.0-0.0); Z = - 2.7, p = 0.007). Factor utilization was comparable to prior prophylaxis with SHL (0.0 (- 15.8-24.8) IU/kg/week; Z = - 0.4, p = 0.691). In summary, switch to EHL (rFVIII-Fc) was associated with an improved clinical outcome, reflected by ABR reduction, and less frequent infusions, without significantly higher factor usage.


Echo-tracking technology assessment of carotid artery stiffness in patients with coronary slow flow.
Coronary slow flow (CSF) in coronary angiography (CAG) is a well-recognized clinical entity. Previous studies have suggested that microvascular abnormalities and endothelial dysfunction are responsible for CSF. Accordingly, we hypothesized that the CSF phenomenon is a form of atherosclerosis including both small vessels and epicardial coronary arteries. The echo-tracking (ET) technique is a non-invasive detection method for early prediction of arterial atherosclerosis. Therefore, we investigated carotid elasticity with the ET technique in patients with CSF. Fifty patients with CSF and 50 patients with normal coronary artery blood flow, as determined by CAG, with a similar distribution of risk factors were recruited. The stiffness parameter (β), pressure-strain elastic modulus (Ep), arterial compliance (AC), augmentation index (AIx) and local pulse-wave velocity (PWV) were determined at the level of the bilateral common carotid artery (CCA) with using the ET technique. Levels of serum high-sensitivity C-reactive protein (hs-HSCRP) were determined for the two groups. β, Ep and PWV were significantly higher in the CSF group than in the control group (β: 11.4 ± 3.76 vs. 9.22 ± 3.28, p < 0.01; Ep: 153.44 ± 47.85 vs. 126.40 ± 43.32, p < 0.01; PWV: 7.26 ± 1.10 vs. 6.55 ± 1.02, p < 0.01), but AC was lower in the CSF group than in the control group (0.62 ± 0.20 vs. 0.74 ± 0.24, p < 0.01). The elasticity parameters of the bilateral common carotid artery did not significantly differ. The level of hs-HSCRP was correlated positively with β (r = 0.306, p = 0.015), Ep (r = 0.358, p = 0.005) and PWV (r = 0.306, p = 0.015), but negatively with AC (r = -0.236, p = 0.049). In conclusion, the ET technique is a simple practical method for evaluating carotid artery elasticity, and there is a significant correlation between carotid artery stiffness and level of hs-HSCRP in patients with CSF.


Examination of the role of the pituitary-adrenocortical axis, counterregulatory hormones, and insulin clearance in variable nocturnal insulin requirements in insulin-dependent diabetes.
In insulin-dependent diabetics, insulin requirements increase significantly after 0600 h, resulting in prebreakfast hyperglycemia with either conventional insulin therapy or constant insulin infusions with insulin infusion devices. In order to clarify the role of the pituitary-adrenocortical axis and further examine the mechanisms of the phenomenon of nocturnal variability in insulin requirements, we studied five IDDs using a closed-loop insulin infusion device (Biostator, GCIIS). The subjects were given saline (SAL) or dexamethasone (DEX) i.v. from 1800 to 0900 h on successive nights. From 2400-0300 to 0600-0900 h, mean insulin infusion rates required to maintain blood glucose values between 109 and 120 mg/dl increased by 0.21 +/- 0.05 mU/kg/min during the SAL infusion, and 0.16 +/- 0.04 mU/kg/min during the DEX infusion, when plasma cortisols were suppressed to less than or equal to 2 micrograms/dl. Mean free insulin concentrations did not increase and remained constant throughout both study nights in spite of the significantly higher 0600-0900-h insulin infusion rates. Growth hormone, glucagon, epinephrine, and norepinephrine concentrations showed normal nocturnal and early morning patterns during both study nights. We conclude that the nocturnal variability in insulin requirements persists despite suppression of the pituitary-adrenocortical axis, and that increased free insulin clearance or degradation may contribute to the "dawn phenomenon" of rising prebreakfast glucose despite constant insulin infusion.


Real-time diagnostic accuracy of blue light imaging, linked color imaging and white-light endoscopy for colorectal polyp characterization.
Background and study aims Fujifilm has developed a novel ELUXEO 7000 endoscope system that employs light-emitting diodes (LEDs) at four different wavelengths as light sources that enable blue light imaging (BLI), linked color imaging (LCI), and high-definition white-light endoscopy (HD-WLE). The aim of this study was to address the diagnostic accuracy of real-time polyp characterization using BLI, LCI and HD-WLE (ELUXEO 7000 endoscopy system). Patients methods This is a prespecified post-hoc analysis of a prospective study in which 22 experienced endoscopists (> 2,000 colonoscopies) from eight international centers participated. Using a combination of BLI, LCI, and HD-WLE, lesions were endoscopically characterized including a high- or low-confidence statement. Per protocol, digital images were created from all three imaging modalities. Histopathology was the reference standard. Endoscopists were familiar with polyp characterization, but did not take dedicated training for purposes of this study. Results Overall, 341 lesions were detected in 332 patients. Of the lesions, 269 histologically confirmed polyps with an optical diagnosis were included for analysis (165 adenomas, 27 sessile serrated lesions, and 77 hyperplastic polyps). Overall, polyp characterization was performed with high confidence in 82.9 %. The overall accuracy for polyp characterization was 75.1 % (95 % confidence interval [CI] 69.5-80.1 %), compared with an accuracy of 78.0 % (95 % CI 72.0-83.2 %) for high confidence assignments. The accuracy for endoscopic characterization for diminutive polyps was 74.7 % (95 %CI 68.4-80.3 %), compared with an accuracy of 78.2 % (95 % CI 71.4-84.0 %) for high-confidence assignments. Conclusions The diagnostic accuracy of BLI, LCI, and HD-WLE by experienced endoscopist for real-time polyp characterization seems limited (NCT03344289).


Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming.
Cofactors contribute to the elicitation of anaphylaxis. β-Blockers and angiotensin-converting enzyme (ACE) inhibitors are widely used cardiovascular drugs. We specially designed a mouse model to further analyze the cofactor potential of these drugs. We sought to test the hypothesis that β-blockers and ACE inhibitors alter the risk for severe anaphylaxis and to pinpoint the associated mechanism. The risk factor potency of cardiovascular drugs on the severity of anaphylaxis in patients from German-speaking countries was analyzed. In vivo interaction of the cardiovascular drugs metoprolol (β-blocker) and ramipril (ACE inhibitor) with the anaphylactic response was determined. Mast cell (MC) mediators (histamine, serotonin, leukotriene C₄, prostaglandin D2, and mouse mast cell protease 1) were quantified in serum. Bone marrow-derived cultured MCs served to identify whether the therapeutics targeted MCs directly. Our anaphylaxis database indicated a higher risk of severe anaphylaxis after monotherapy with β-blockers or ACE inhibitors, which was more pronounced when both drugs were combined. This was confirmed in our mouse model. While single therapeutics had either no significant (ramipril) or a modestly aggravating (metoprolol) effect, their combined administration exacerbated anaphylactic symptoms potently and simultaneously enhanced MC mediators, hinting at MCs as direct targets. In fact, FcεRI-mediated MC histamine release was synergistically increased by metoprolol/ramipril or metoprolol/bradykinin (the latter increased after ACE inhibitor intake), whereas the substances had no significant effect on their own. MC priming was particularly pronounced when FcεRI aggregation was in the suboptimal range, reflecting common clinical settings. β-Blockers and ACE inhibitors synergistically aggravate anaphylaxis at least partly by decreasing the threshold of MC activation.


Glutathione (GSH) and superoxide dismutase (SOD) levels among junior high school students induced by indoor particulate matter 2.5 (PM2.5) and nitrogen dioxide (NO2) exposure.
Indoor air pollution has globally known as the risk factor of acute respiratory infection in young children. The exposure to indoor particulate matter 2.5 (PM2.5) and nitrogen dioxide (NO2) at house or school can be a potential risk to children's health. This study aimed to examine the association between indoor PM2.5 and NO2 with oxidative stress markers in junior high school students. This study was conducted using a cross sectional study with 75 students collected randomly from four junior high schools in Jakarta. PM2.5 and NO2 were measured in classrooms and school yards. The schools were categorized based on the exposure level of PM2.5 and NO2 in classrooms. Superoxide dismutase (SOD) and reduced glutathione (GSH) were examined from the blood sample. All students were interviewed with questionnaires to determine upper respiratory tract infection, smoking family members, mosquito repellent usage, and dietary supplement consumption. Mean concentration of indoor PM2.5 and NO2 were 0.125±0.036 mg m-3 and 36.37±22.33 µg m-3, respectively. The schools which located near to highway showed lower PM2.5 and higher NO2 level indicated the emission of traffic activity. Mean activity of SOD was 96.36±50.94 U mL-1 and mean concentration of GSH was of 0.62±0.09 µg mL-1. Most of the students reported upper respiratory tract infection history, smoking family member, use mosquito repellent at home, and do not consume dietary supplement. The level of oxidative stress markers and the exposure categories of classroom PM2.5 and NO2 was not significantly different, however there were significant correlation with cigarette smoke and mosquito repellent at home. Nevertheless, the exposure of indoor PM2.5 and NO2 increased the risk of the exposure to cigarette smoke and mosquito repellent at home. Further study on the air pollution at school and home is needed to affirm association towards student's health and to design strategic control efforts.


Development of a computer-aided detection system for colonoscopy and a publicly accessible large colonoscopy video database (with video).
Artificial intelligence (AI)-assisted polyp detection systems for colonoscopic use are currently attracting attention because they may reduce the possibility of missed adenomas. However, few systems have the necessary regulatory approval for use in clinical practice. We aimed to develop an AI-assisted polyp detection system and to validate its performance using a large colonoscopy video database designed to be publicly accessible. To develop the deep learning-based AI system, 56,668 independent colonoscopy images were obtained from 5 centers for use as training images. To validate the trained AI system, consecutive colonoscopy videos taken at a university hospital between October 2018 and January 2019 were searched to construct a database containing polyps with unbiased variance. All images were annotated by endoscopists according to the presence or absence of polyps and the polyps' locations with bounding boxes. A total of 1405 videos acquired during the study period were identified for the validation database, 797 of which contained at least 1 polyp. Of these, 100 videos containing 100 independent polyps and 13 videos negative for polyps were randomly extracted, resulting in 152,560 frames (49,799 positive frames and 102,761 negative frames) for the database. The AI showed 90.5% sensitivity and 93.7% specificity for frame-based analysis. The per-polyp sensitivities for all, diminutive, protruded, and flat polyps were 98.0%, 98.3%, 98.5%, and 97.0%, respectively. Our trained AI system was validated with a new large publicly accessible colonoscopy database and could identify colorectal lesions with high sensitivity and specificity. (Clinical trial registration number: UMIN 000037064.).


Intrathoracic impedance and ultrasound lung comets in heart failure deterioration monitoring.
Echographic examination of the lung surface may reveal multiple ultrasound lung comets (ULCs) originating from water-thickened interlobular septa. These images were demonstrated to be useful for noninvasive assessment of interstitial pulmonary edema. Similarly, the correlation between implantable defibrillator-measured intrathoracic impedance and pulmonary capillary wedge pressure (PCWP) was demonstrated in heart failure (HF) patients. The aims of this analysis were to assess the agreement between defibrillator-detected impedance decrease and the presence of ULCs, as well as to compare the performance of the impedance-detection algorithm and the ULCs assessment in predicting HF worsening. We studied 23 HF patients implanted with a defibrillator capable of intrathoracic impedance measurement and alerting for fluid accumulation diagnosis. At regular follow-up and at visits for HF decompensation or device alert, clinical status was assessed, chest ultrasound was performed, and PCWP was noninvasively estimated with Doppler echocardiography. During 23 ± 11 months of follow-up, 45 paired assessments of defibrillator-measured intrathoracic impedance and ULCs were performed. The number of ULCs resulted significantly correlated to the paired PCWP estimations (r = 0.917, P < 0.001) and to the impedance fluid index (r = 0.669, P < 0.001). During follow-up, 12 episodes of HF decompensation were reported in 12 patients. The impedance alert detected clinical HF deterioration with 92% sensitivity and 69% positive predictive value. The presence of ≥5 ULCs showed 83% sensitivity and 91% positive predictive value. These data demonstrate the correlation between intrathoracic impedance and the number of ULCs at chest ultrasound, and a good agreement between the defibrillator warning for fluid index and the detection of multiple ULCs.


[Distribution of Aspidogaster conchicola (Aspidogastrea, Aspidogastridae) in the organism of Colletopterum spp. (Bivalvia, Unionidae) of different age from the Chivyrkuiski Gulf of Lake Baikal].
Distribution of Aspidogaster conchicola Baer, 1827 in the organisms of its hosts Colletopterum spp. from the Chivyrkuiski Gulf of Lake Baikal was investigated. The number of A. conchicola in the organism of Colletopterum spp. was found to decrease along the row pericardial cavity-mantle cavity-gills-kidney. The pericardial cavity of Colletopterum spp. is the most favorable habitat for A. conchicola with 72% of the helminthes parasitizing in it. In the pericardial cavity the largest number (61%) of A. conchicola was found in its posterior part.


Treatment of adult Class III malocclusions with orthodontic therapy or orthognathic surgery: receiver operating characteristic analysis.
The aim of this study was to distinguish between orthodontic patients with skeletal Class III malocclusions requiring surgery and those not requiring surgery by conducting a receiver operating characteristic analysis of cephalometric variables. We used lateral cephalometric radiographs of 80 subjects (40 nonsurgical and 40 surgical patients) with Class III malocclusions and obtain 25 cephalometric measurements using computerized cephalometry. Of these, 14 measurements showed statistically significant differences between the 2 groups. Receiver operating characteristic analysis was used to determine the ability of the 14 cephalometric measurements in distinguishing between the 2 groups. Six statistically validated and clinically relevant measurements were used to obtain the optimum discriminant effectiveness. For a Class III malocclusion patient with any 4 of these 6 measurement criteria, the sensitivity was 88% and the specificity was 90% in determining the need for surgical treatment: overjet, ≤-4.73 mm; Wits appraisal, ≤-11.18 mm; L1-MP angle, ≤80.8°; Mx/Mn ratio, ≤65.9%; overbite, ≤-0.18 mm; and gonial angle, ≥120.8°. We selected 6 cephalometric measurements as the minimum number of discriminators required to obtain the optimum discriminant effectiveness of diagnosis between surgical and nonsurgical treatment of skeletal Class III malocclusions.


Pediatric bronchography performed through the flexible bronchoscope.
Ten children, ranging in age from 2 months to 16 years, were evaluated by bronchograms performed during bronchoscopy. Nine of the ten children had significant pathology demonstrated by the bronchogram that elucidated findings unclear from other imaging procedures at the time of bronchoscopy. Despite the generally negative opinions about the utility of bronchograms in children, information obtained by bronchography can be quite useful. Bronchography during bronchoscopy proved to be quick, simple, and safe.


Protein kinase C promotes the phosphorylation of immunoprecipitated middle T antigen from polyoma-transformed cells.
Stimulation of protein kinase C in polyoma virus-transformed cells increased the phosphorylation of tyrosine residues of the viral middle T (mT) antigen in mT:pp60c-src complexes precipitated by anti-mT antibodies. This increase might have been due to a stimulation of the complex's pp60c-src tyrosine kinase activity or to an increased ability of the mT protein to be phosphorylated by pp60c-src. These observations suggest that cellular protein kinase C might control the ability of polyoma virus to transform its host cell.


Effect of photoinitiator concentration on marginal and internal adaptation of experimental composite blends photocured by modulated methods.
The aim of this study was to evaluate the influence of photoinitiator concentration on marginal and internal adaptation of composites photocured by modulated methods. Composites based on BisGMA/triethylene glycol dimethacrylate and 65 wt% of filler were prepared with different concentrations of camphorquinone/amine (C1-0.5%, C2-1%, C3-1.5%). Cavities were prepared (3 mm × 3 mm × 2 mm) on the buccal surface of 120 bovine incisors and the adhesive system Adper Single Bond 2 was applied following manufactures instruction. Specimens were then distributed according to type of composite (C1, C2, C3) and photoactivation method (high-intensity - 750 mW/cm(2) for 40 s; low intensity - 150 mW/cm(2) for 200 s; soft-start - 150 mW/cm(2) for 10 s + 750 mW/cm(2) for 38 s; pulse-delay - 150 mW/cm(2) for 10 s + 3 min dark + 750 mW/cm(2) for 38 s). Superficial and internal margins were analyzed by scanning electron microscopy, using the epoxy replica technique. The length of gaps was expressed as a percentage of the total length of the margins. Data were submitted to two-way analysis of variance and Tukey's test (α =0.05). Modulated curing methods did not influence gap formation regarding both superficial and internal adaptation. The composite with the lower initiator concentration (C1) presented higher gap formation when compared with those with higher concentrations (C2 and C3). Modulated photoactivation methods did not reduce gap formation for the experimental composite restorations evaluated. However, higher photoinitiator concentrations promote better marginal seal.


Examining a pathway for hormone mediated maternal effects--yolk testosterone affects androgen receptor expression and endogenous testosterone production in young chicks (Gallus gallus domesticus).
In vertebrates maternal androgens can substantially influence developing offspring, inducing both short and long term changes in physiology and behavior, including androgen sensitive traits. However, how the effects of maternal hormones are mediated remains unknown. Two possible pathways are that maternal androgens affect parts of the hypothalamus-pituitary-gonadal axis (HPG axis) or the sensitivity to androgens by affecting androgen receptor (AR) densities within the brain. To investigate both pathways, testosterone within the physiological range or vehicle only was injected into the egg yolk of unincubated chicken eggs and AR mRNA expression in different brain nuclei as well as plasma testosterone levels were measured in two week old male and female chicks that had hatched from these eggs. Our results showed a significant sex difference in plasma testosterone levels with males showing higher levels than females. Furthermore, AR mRNA expression as well as plasma testosterone levels were significantly lower in chicks hatched from testosterone treated eggs. These results suggest a compensatory mechanism for avoiding potential detrimental effects of high testosterone levels.


[The influence of medicated serum with root of Crataegus cuneata on human sperm motility parameters in vitro].
To study the influence of root of medicated serum with the root of Crataegus cuneata on human sperm motility in vitro. Sperm specimens of 16 asthenospermia patients were co-incubated with the medicated serum in vitro. The sperm motility characteristics were evaluated by computer-assisted semen analysis (CASA) at 5, 15, 30, 60 min and 120 min. Compared with the control group, the medicated serum significantly increased the sperm progressive motility in 5 and 15 min (P < 0.05), and the motility and progressive motility were both increased significantly in 60 and 120 min (P < 0.01). The excitatory effect of the medicated serum on the sperm motility exhibited in a time-dependent manner. Root of C. cuneata medicated serum can improve sperm motility of asthenospermia patients in vitro.


The triple procedure: combined penetrating keratoplasty, extracapsular cataract extraction and lens implantation. An expanded experience.
The results of 177 triple procedures are presented from a continuous series of 197 cases recorded from 1973 to 1982. Eighty-nine percent achieved a visual acuity of 20/40 or better within a minimum followup period of six months. The complication rate was low, and usually managed medically. Subsequent major surgical procedures were required in only twelve (7%) of these cases (eight repeat keratoplasty, two retina repair, one resuture of graft incision, and one peripheral iridectomy). Subsequent minor surgical procedures were for discission of the posterior lens capsule in 50% of the medallion-style lens cases, and in 7% of the posterior chamber lens cases.


Development of thermoregulation in the newborn lesser bushbaby (Galago senegalensis moholi, Smith 1839).
The temperature-regulating system in bushbabies operates from the 1st day of life. The postnatal metabolism decreases from the 5th (2.9 ml O2/g-h) to the 140th day (0.7 ml O2/g-h) to the level of the adults.


Nitrogen single breath test, flow-volume curves and spirometry in healthy children, 7-18 years of age.
One hundred and forty school children, 75 boys and 65 girls, aged 7-18 years, underwent the following lung function tests: closing volume, slope of the alveolar plateau, maximal expiratory and inspiratory flows at 75, 50 and 25% of vital capacity, static and dynamic lung volumes. Lung volumes and maximal flows increase with height in an exponential way, the exponents varying between 2.6 and 3.1, while closing volume in per cent of vital capacity and the slope of the alveolar plateau decrease linearily with increasing height. Regression equations are given for each sex with height as determinant.


Prognostic of Yield of Potatoes of Promising Domestic Varieties under the Impact of Stress Abiotic Factors.
Twenty-four potato (Solanum tuberosum L.) varieties differing in ripening groups (early, middle-early, and mid-season-ripening) were studied. Potatoes were grown under the conditions of the Middle Volga region of Russia in 2019-2021. It was found statistically that the yield (t/ha) of the early and mid-season-ripening varieties was negatively correlated with the increase in average temperatures during the growing season from May to August (R = -0.97, p = 0.04). Soil moisture content at a depth of 20 cm was positively correlated with the yield of middle-early varieties (R = 0.97, p = 0.04). The average tuber weight in the early varieties was sensitive to the increase in average temperatures (R = -0.95, p = 0.04). An increase in soil moisture content was beneficial to the average tuber weight (R = 0.98, p = 0.04), though only in the middle-early and mid-season-ripening groups. However, the soil moisture content and the tuber numbers in the mid-season-ripening varieties were negatively correlated (R = -0.96, p = 0.05).


The challenge of developing adenosine A2A antagonists for Parkinson disease: Istradefylline, preladenant, and tozadenant.
Laboratory and clinical experience have pointed to the value of targeting motor pathways emerging from the striatum to treat problems arising in advanced Parkinson's disease (PD). These pathways are selectively populated with a subtype of adenosine binding sites (A2A receptors) that offer a target for improving PD symptomatology. Several compounds were developed that possess high selectivity and potency for blocking this receptor. Three of these compounds - istradefylline, preladenant, and tozadenant - were chosen for clinical development programs that culminated in Phase 3 multicenter randomized clinical trials. Each of these drugs exert virtually no off-target neurochemical effects. Clinical trials with these drugs focused upon reducing OFF time when administered adjunctly to levodopa and other antiparkinsonian medications. Despite promising Phase 2 data, preladenant did not show efficacy when tested in a randomized placebo-controlled Phase 3 clinical trial. Reports of hematological toxicity necessitated ceasing an ongoing Phase 3 investigation of tozadenant. Following a challenging approval process, based on the results of randomized clinical trials carried out in the U.S. and Japan, istradefylline received approval in these countries for treatment of OFF episodes.


Structure-activity relationship studies on 3,5-dinitrophenyl tetrazoles as antitubercular agents.
In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily accessible compounds possessed high in vitro antimycobacterial activities against Mycobacterium tuberculosis, including clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with submicromolar minimum inhibitory concentrations (MICs). The most promising compounds showed low in vitro cytotoxicity and negligible antibacterial and antifungal activities, highlighting their highly selective antimycobacterial effects. 2-Substituted 5-(3,5-dinitrophenyl)-2H-tetrazole regioisomers, which are the dominant products of 5-(3,5-dinitrophenyl)-1H-tetrazole alkylation, showed better properties with respect to antimycobacterial activity and cytotoxicity than their 1-substituted counterparts. The 2-substituent of 5-(3,5-dinitrophenyl)-2H-tetrazole can be easily modified and can thus be used for the structure optimization of these promising antitubercular agents. The introduction of a tetrazole-5-thioalkyl moiety at position 2 of the tetrazole further increased the antimycobacterial activity. These compounds showed outstanding in vitro activity against M. tuberculosis (MIC values as low as 0.03 μM) and high activity against non-tuberculous mycobacterial strains.


Knockdown of PNO1 inhibits esophageal cancer progression.
The present study aimed to investigate the role of partner of NOB1 homolog (PNO1) in esophageal cancer (EC). The expression levels of PNO1 in EC were primarily analyzed using data obtained from databases. PNO1 expression was also knocked down in EC cells (Eca‑109 and TE1) to determine the biological effects of PNO1 on tumorigenesis in vitro and in vivo. In addition, possible downstream targets of PNO1 in EC were identified. The expression levels of PNO1 were upregulated in the tumor tissues compared with that noted in normal tissues. Moreover, the knockdown (KD) of PNO1 suppressed cell proliferation, migration and invasion, and promoted cell apoptosis (P < 0.05). Furthermore, the protein expression levels of AKT1, Twist, Myc, mTOR, matrix metalloproteinase 2 (MMP2), nuclear factor (NF)‑κB p65 and β‑catenin 1 (CTNNB1) were downregulated following the KD of PNO1 in Eca‑109 cells (P < 0.05). In addition, the overexpression of CTNNB1 reversed the effects of PNO1 KD in Eca‑109 cells (P < 0.05). In conclusion, the findings of the present study suggest that PNO1 promotes EC progression by regulating AKT1, Twist, Myc, mTOR, MMP2, NF‑κB p65 and CTNNB1 expression.


Preparation, characterization, molecular modeling and in vitro activity of paclitaxel-cyclodextrin complexes.
Paclitaxel (PTX) was complexed with beta-cyclodextrin (1), 2,6-dimethyl-beta-cyclodextrin (2) and 2,3,6-trimethyl-beta-cyclodextrin (3). PTX-CYD complexes were characterized both at the solid and liquid states. Experimental findings are in agreement with molecular modeling analysis, which showed different PTX-CYD interaction as a function of macrocyle methylation. The complexation of PTX within the CYD cavity preserved its antitumoral activity.


Occurrence, identification, and bacterial mutagenicity of heterocyclic amines in cooked food.
Potent mutagenic activity in Salmonella bacteria has been reported in cooked foods in numerous laboratories worldwide. Determining the human risk from exposure to these biologically active compounds in our diet requires genotoxic and carcinogenic evaluation of the chemicals coupled with determination of the dose consumed. Thus, knowledge of the exact structure of the mutagens present in the food and enough synthesized material for biological assessment are essential for this evaluation. To reach this goal, isolation of these compounds requires the Ames/Salmonella assay to guide the purification and identification process. Mass and NMR spectrometry are used to identify the isolated compounds. Finally, these findings are followed by synthesis of the exact isomer. The predominant class of mutagens found in cooked foods of the western diet are amino-imidazo-quinoxalines, amino-imidazo-pyridines and amino-imidazo-quinolines, collectively called amino-imidazoazaarenes (AIAs). Mass amounts of these specific compounds range from less than 1 to 70 ng/g of meat. The mutagens are formed from the heating of natural precursors (creatinine, amino acids, and possibly sugars) in the food. These AIAs are some of the most potent mutagens ever tested in Salmonella bacteria with the number and position of methyl groups having an important influence on the mutagenic activity.