A mathematical analysis of the mortality kinetics of Drosophila melanogaster exposed to gamma radiation.
A mathematical model with nonlinear time-varying characteristics has been developed which describes the relationship between the kinetics of natural aging and radiation-induced delayed mortality. Based on this model, it appears that there is an immediate effect of radiation which is continuously, but nonlinearly, increasing in severity. Two phases appear in this variation, corresponding to the two phases (plateau and dying phase) of the mortality curves for control populations. Accordingly, S/E (survival time post-irradiation/further expectation of life) can best be interpreted as an increasing function during the plateau phase of normal mortality curves, which levels off during the ensuing dying phase.


Remote delivery of a therapeutic intervention to court-mandated youths of Haitian descent during COVID-19.
The threat generated by the COVID-19 pandemic has triggered sudden institutional changes in an effort to reduce viral spread. Restrictions on group gatherings and in-person engagement have increased the demand for remote service delivery. These restrictions have also affected the delivery of court-mandated interventions. However, much of the literature has focused on populations that voluntarily seek out face-to-face medical care or mental health services, whereas insufficient attention has been paid to telehealth engagement of court-mandated populations. This article draws on data gathered on an NIH/NIDA-funded study intervention implemented with juvenile justice-involved youths of Haitian heritage in Miami-Dade County, Florida, during the COVID-19 public health crisis. We explore the process of obtaining consent, technological access issues, managing privacy, and other challenges associated with remote delivery of family-based therapy to juvenile justice-involved youth. Our aim is to provide some insights for consideration by therapists, healthcare workers, advocates, researchers, and policymakers tasked with finding alternative and safer ways to engage nontraditional populations in health services. The clinical trial registration number is NCT03876171.


Thymidylate synthase-catalyzed, tetrahydrofolate-dependent self-inactivation by 5-FdUMP.
In view of previous crystallographic studies, N4-hydroxy-dCMP, a slow-binding thymidylate synthase inhibitor apparently caused "uncoupling" of the two thymidylate synthase-catalyzed reactions, including the N5,10-methylenetetrahydrofolate one-carbon group transfer and reduction, suggesting the enzyme's capacity to use tetrahydrofolate as a cofactor reducing the pyrimidine ring C(5) in the absence of the 5-methylene group. Testing the latter interpretation, a possibility was examined of a TS-catalyzed covalent self-modification/self-inactivation with certain pyrimidine deoxynucleotides, including 5-fluoro-dUMP and N4-hydroxy-dCMP, that would be promoted by tetrahydrofolate and accompanied with its parallel oxidation to dihydrofolate. Electrophoretic analysis showed mouse recombinant TS protein to form, in the presence of tetrahydrofolate, a covalently bound, electrophoretically separable 5-fluoro-dUMP-thymidylate synthase complex, similar to that produced in the presence of N5,10-methylenetetrahydrofolate. Further studies of the mouse enzyme binding with 5-fluoro-dUMP/N4-hydroxy-dCMP by TCA precipitation of the complex on filter paper showed it to be tetrahydrofolate-promoted, as well as to depend on both time in the range of minutes and the enzyme molecular activity, indicating thymidylate synthase-catalyzed reaction to be responsible for it. Furthermore, the tetrahydrofolate- and time-dependent, covalent binding by thymidylate synthase of each 5-fluoro-dUMP and N4-hydroxy-dCMP was shown to be accompanied by the enzyme inactivation, as well as spectrophotometrically confirmed dihydrofolate production, the latter demonstrated to depend on the reaction time, thymidylate synthase activity and temperature of the incubation mixture, further documenting its catalytic character.


User involvement in the making: Positions and types of knowledge enacted in the interaction between service users and researchers in user panel meetings.
Numerous studies of user involvement in research have been conducted. However, there is a lack of studies applying observational methods and addressing the concrete practice of involvement. To determine what knowledge types and competences users apply when involved in the research process through user panel meetings. User panel meetings in a qualitative project in rehabilitation were sound-recorded and transcribed verbatim. Data analysis applied an abductive approach framed by positioning theory. Six rehabilitation service users and a similar number of researchers met 20 times during a six-year project period. They discussed various issues in the research process such as interview guides, analysis and dissemination of results. The service users combined their respective knowledge and competence into six positions enacted in the panel interactions. They engaged as co-researchers, based their contributions on their respective personal histories, represented an NGO and peers, applied their respective professional and educational backgrounds and, finally, engaged as concerned citizens. The findings add to the discussion of professionalization of user involvement by introducing a wider array of positions enacted than do the findings of previous studies. Researchers recruiting user panel members, as well as NGOs appointing candidates for user panels, are advised to consider a wide competence profile for possible candidates. A panel is also considered as a resource in confirming and elaborating on a study's findings. A service user panel contributed to the study.


cPKCγ Inhibits Caspase-9-Initiated Neuronal Apoptosis in an Ischemia Reperfusion Model In Vitro Through p38 MAPK-p90RSK-Bad Pathway.
Strokes are one of the leading causes of death and disability in the world. Previously we have found that conventional protein kinase Cγ (cPKCγ) plays neuroprotective role in ischemic strokes. Further, we found that cPKCγ knockdown increased the level of cleaved (cl)-Caspase-3. However, the precise mechanisms underlying cPKCγ-mediated neuronal death remain unclear. To this end, a model incorporating 1 h oxygen-glucose deprivation/24 h reoxygenation (1 h OGD/24 h R) was established in cortical neurons. We found that cPKCγ knockdown remarkably increased neuronal death after OGD. We also found that cPKCγ knockdown increased the level of cl-Caspase-3 through the upstream initiators Capsases-9 (not Caspase-8/12) in OGD-treated neurons. Overexpression of cPKCγ could decrease neuronal death and cl-Caspase-3 and -9 levels. Moreover, cPKCγ knockdown further reduced the phosphorylation levels of p38 MAPK, p90RSK, and Bad. In addition, the protein levels of Bcl-2 and Bcl-xl were decreased after cPKCγ knockdown, whereas that of Bax was increased. In conclusion, our results suggest that cPKCγ partly alleviates ischemic injury through activating the p38 MAPK-p90RSK-Bad pathway and inhibiting Caspase-9 initiated apoptosis. This may have potential as a therapeutic target for ischemic stroke.


Selection of Cells Defective in Pyrimidine (TK(-)) and Purine (APRT (-) and HPRT (-) Salvage : Development of Host Strains Appropriate for Transfection.
The usefulness of the purine and pyrimidine salvage pathways in the study of the mechanisms of mutation and in the selection of cell lines stably transformed by vectors expressing these genes is well documented. Unfortunately, many investigators are deterred from selecting new host strains deficient in these enzymes because of the difficulties inherent in isolating recessive mutations of autosomal genes. Furthermore, considerable suspicion was cast over somatic cell genetics by the so-called epigenetic nature of some phenotypic changes (1). However, given the clear molecular basis of the vast majority of mutant phenotypes, such apprehensions are largely unwarranted, provided that careful, clean selections are employed (e.g., see. 2).


Improving forecasts of individual ocean eddies using feature mapping.
Marine industries, war fighters, and world leaders demand accurate maps of ocean properties to underpin tactical and strategic decisions. Oceanographers have approached this challenge by borrowing mapping techniques from weather forecasters. However, compared to the atmosphere, the spatial scales of the ocean are small, and ocean properties are vastly under-sampled. Not surprisingly, despite decades of dedicated effort, the quality of maps of under-sea conditions remains poor. Feature mapping is a new approach to this problem that treats every ocean eddy individually. It strictly limits the influence of each observation to the oceanographic feature that it directly observes. Resulting maps are precise and realistic and may revolutionise ocean forecasting.


A study of SARS-CoV-2 epidemiology in Italy: from early days to secondary effects after social distancing.
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to 101,739 confirmed cases, in Italy, as of March 30th, 2020. While the analogous event in China appears to be under control at the moment, the outbreaks in western countries are still at an early stage of development. Italy, at present, is playing a major role in understanding the transmission dynamics of these new infections and evaluating the effectiveness of control measures in a western social context. We combined a quarantined model with early-stage development data in Italy (during the period February 20th-March 30th) to predict longer-term progression (from March 30th, till June 25th, 2020 in a long-term view) with different control measures. Due to significant variations in the control strategies, which have been changing over time, and thanks to the introduction of detection technologies leading to faster confirmation of the SARS-CoV-2 infections, we made use of time-dependent contact and diagnosis rates to estimate when the effective daily reproduction ratio can fall below 1. Within the same framework, we analyze the possible secondary infection event after relaxing the isolation measures. We study two simplified scenarios compatible with the observation data and the effects of two stringent measures on the evolution of the epidemic. On one side, the contact rate must be kept as low as possible, but it is also clear that, in a modern developed country, it cannot fall under certain minimum levels and for a long time. The complementary parameter tuned is the transition rate of the symptomatic infected individuals to the quarantined class, a parameter δI I connected with the time tI = 1/δI needed to perform diagnostic tests. Within the conditions of the outbreak in Italy, this time must fall under 12-8 h in order to make the reproduction number less than 1 to minimize the case numbers. Moreover, we show how the same parameter plays an even more important role in mitigating the effects of a possible secondary infection event.


Irinotecan-induced alterations in intestinal cell kinetics and extracellular matrix component expression in the Dark Agouti rat.
Chemotherapy-induced mucositis is characterized by damage of mucous membranes throughout the alimentary tract (AT). Extracellular matrix (ECM) components play a vital role in maintaining mucosal barrier integrity by regulating cellular apoptosis, proliferation and differentiation of overlying epithelial cells. The aims of this study were to characterize the changes in epithelial cell kinetics and to investigate the expression of the ECM components in the gastrointestinal tract following irinotecan administration. Female dark agouti rats were treated with single 200 mg/kg dose irinotecan and killed at various time points (1, 6, 24, 48, 72, 96 and 14 h) after treatment. Ki67 immunostaining and TUNEL were used to assess proliferation and apoptosis, respectively, in the jejunum and colon. Masson trichrome staining and picro-sirius red staining were used to determine the level of collagen, and immunohistochemistry was used to further assess collagen IV, fibronectin and laminin 1 and 2 expression in these tissues. Irinotecan halved cellular proliferation in the jejunum and colon at 48 and 24 h, respectively, while apoptosis peaked at 6 h (P < 0.05). There was a substantial increase in total collagen deposits around crypts from 24 h in both regions. However, collagen IV expression decreased significantly in the crypt region in a delayed fashion (P < 0.05). Fibronectin expression decreased significantly in jejunum and colon from 6 to 24 h following treatment (P < 0.05). Irinotecan induced a significant alteration in epithelial cell kinetics in both the jejunum and colon, and this correlated with changes in ECM component expression. Changes in ECM expression may have a direct impact on the loss of mucosal layer integrity evident in chemotherapy-induced mucositis.


Three-dimensional nasolabial changes after maxillary advancement osteotomy in class III individuals: a systematic review and meta-analysis.
Background Class III malocclusions with maxillary retrognathia are commonly treated with single jaw Le Fort I maxillary advancement. The three-dimensional (3D) effects of surgery on the nasolabial region varies among the clinical studies. Quantifying these changes is of great importance for surgical planning and obtaining valid consent. Objectives To investigate the 3D relationship between soft tissue and skeletal changes secondary to Le Fort I maxillary advancement surgery in skeletal class III patients.Search methods Comprehensive search of multiple electronic databases supplemented by a manual and grey literature search were undertaken from inception to 9 June 2020.Selection criteria Studies that evaluated the 3D soft tissue changes of patients before and after maxillary advancement surgery alone.Data collection and analysis Study selection, data extraction and risk of bias assessment were performed independently by two reviewers, with disputes resolved by a third reviewer. A quantitative synthesis of the data was pre-planned for pooling similar outcome measures.Results Four studies were included in the final review and meta-analysis, with a total of 105 patients (mean age 16.7 + 33.9 years). The mean maxillary advancement of the included studies was 5.58 mm (95% CI 5.20-5.96). The sagittal effects of surgery on nose tip projection and prominence were insignificant (P >0.05, two studies); however, subnasal projection (MD 1.7 mm, two studies) and upper lip projection (MD 2.90 mm, four studies) increased significantly in a forward direction after surgery (P <0.05). Le Fort I osteotomy widens the upper philtrum width (MD 0.84 mm, two studies) (P <0.05). Inconsistencies among the included studies were identified; therefore, the results should be interpreted with caution.Conclusions There is weak evidence based on quantitative assessments that Le Fort I maxillary advancement significantly affects the nasolabial soft tissue envelope mainly in a sagittal dimension. These changes are concentrated around the central zone of the nasolabial region. Future prospective studies on maxillary advancement osteotomy with a standardised method of assessment, taking into consideration the confounding factors, are required.


The response of rubrospinal neurons to axotomy in the adult opossum, Didelphis virginiana.
To provide endpoints for developmental studies of rubrospinal plasticity in the North American opossum, we have attempted to determine the degree to which rubrospinal neurons survive axotomy in the adult animal. Bilateral or unilateral injections of the long-lasting fluorescent marker fast blue were made into the T-10 or the T-11 segment of the spinal cord to label rubrospinal neurons, and 7 days later, the rubrospinal tract was cut unilaterally four segments rostral to the injection(s). In cases with unilateral injections, the lesion was made ipsilateral to the injection. The animals were allowed to survive for 30-60 days before being sacrificed and perfused so that sections through the red nuclei could be examined for labeled neurons. The results show that most axotomized neurons survived the lesion, suggesting that lesion-dependent cell death is not a major factor in the failure of the rubrospinal tract to regenerate in the adult animal.


A physiological pharmacokinetic model describing the disposition of lead in the absence and presence of L-ascorbic acid in rats.
The influence of L-ascorbic acid (As-Ac) on the multiple-tissue disposition of lead has been evaluated. Lead concentrations in femur, liver, kidney and plasma of rats were monitored over a 120h period after its intravenous bolus administration (1.0 mg/kg) in the absence and presence of As-Ac at steady state. The observed lead concentration-time data in different tissues of the rats, in the absence and presence of As-Ac, have been simulated using a physiological pharmacokinetic modelling technique. In both cases, the predicted lead concentrations in various tissues were in adequate agreement with the observed data. The model developed in the present investigation supports the previous finding that As-Ac may be useful as a prophylactic agent for lead poisoning.


The biosynthesis of 2-guanidinoethanol in intact mice and isolated perfused rabbit kidneys.
The metabolic pathway for the synthesis of 2-guanidinoethanol (GEt) was studied in intact mice and isolated perfused rabbit kidneys. GEt excretions in 24-hr urine increased after the intraperitoneal injection of ethanolamine (EA) into mice. Perfusion of isolated rabbit kidneys with EA and L-arginine (Arg) enhanced the GEt excretion from the ureter. This enhancement was observed in an EA concentration-dependent manner under the presence of Arg. When glycine (Gly) was added to the perfusion medium together with EA and Arg, the enhancement of GEt excretion was inhibited, whereas, guanidinoacetic acid excretion was increased to the same extent as during the perfusion with Gly and Arg. These results indicate that GEt is synthesized from Arg and EA in the kidney and that this synthesis is catalyzed by Arg:Gly amidinotransferase (EC 220.127.116.11.). We also described the guanidino compound excretion levels, including levels of GEt, in the rabbit, mouse, rat, and cat. The levels varied considerably with mammalian species.


Research advances in function and regulation mechanisms of plant small heat shock proteins (sHSPs) under environmental stresses.
Plants respond to various stresses by triggering the expression of genes that encode proteins involved in plant growth, fruit ripening, cellular protein homeostasis, and tolerance systems. sHSPs, a subfamily of heat shock proteins (HSPs), can be expressed in plants to inhibit abnormal aggregation of proteins and protect normal proteins by interacting with folding target proteins, protect cell integrity, and improve resistance under various adverse conditions. Thus, sHSPs have significant influences on seed germination and plant development. In this review, the classification, structure, and functions of sHSP family members in plants are systematically summarized, with emphasis on their roles in promoting fruit ripening and plant growth by reducing the accumulation of ROS, improving the survival rate of plants and the antioxidant activity, and protecting photosynthesis under biotic and abiotic stresses. Meanwhile, the production and regulatory mechanisms of sHSPs are described in detail. Heat shock factors, long non-coding RNA (lncRNAs), microRNA (miRNAs), and FK506 binding proteins are related to the production process of sHSPs. Molecular chaperone complex HSP70/100, plastidic proteins, and abscisic acid (ABA) are involved in the regulatory mechanisms of sHSPs. Besides, scientific efforts and practices for improving plant stress resistance have carried out the constitutive expression of sHSPs in transgenic plants in recent years. It is a powerful path for inducing the protective mechanisms of plants under various stresses. Therefore, exploring the role of sHSPs in the plant defense system paves a way for comprehensively unraveling plant tolerance in response to biotic and abiotic stress.


Effect of dietary fibre from cereal brans and legume seedcoats on serum lipids in rats.
The present investigation was carried out to study the hypolipidemic effect of dietary fibre from cornbran and blackgram seedcoat in rats. Isoproteinous diet having one percent cholesterol and ten percent dietary fibre from cornbran and blackgram seedcoat was fed to four groups of albino rats for six weeks. With consumption of both the grain husks, total lipids, cholesterol and tryglycerides were lowered while HDL-cholesterol was found to be significantly increased. However, serum phospholipids were not affected significantly by grain husks. Cornbran was observed to be more hypolipidemic than blackgram seedcoat.


DNA sequence, chromosomal localization, and tissue expression of the mouse proteasome subunit lmp10 (Psmb10) gene.
Proteasomes are nonlysosomal multicatalytic proteases involved in antigen processing. Three of the 10 mammalian proteasome beta subunits (LMP2, LMP7, and LMP10) are induced by IFN-gamma. Two of these (LMP2 and LMP7) are encoded in the major histocompatibility complex of both human (chromosome 6) and mouse (chromosome 17). However, the human homologue of Lmp10, MECL1, is found on chromosome 16. Here we show that in mice, Lmp10 is a single-copy gene localized to chromosome 8, in a region of conserved synteny with human chromosome 16. Sequencing of a 129/SvJ strain genomic clone revealed that the gene has eight exons spanning 2.3 kb. Characterization of a full-length mouse cDNA clone indicates that Lmp10 encodes a protein of 273 amino acids with a calculated molecular weight of 29 kDa and an isoelectric point of 6.86. Northern analysis of Lmp2, Lmp7, and Lmp10 showed expression in heart, liver, thymus, lung, and spleen, but not in brain, kidney, skeletal muscle, or testis.


Dry coating in a rotary fluid bed.
A highly efficient dry coating process was developed to obtain an enteric film avoiding completely the use of organic solvents and water. Using hydroxypropyl methylcellulose acetate succinate (HPMCAS) an enteric coat should be obtained without adding talc as anti-tacking agent because of problems arising from microbiological contamination. Further on, a method was developed preparing isolated films in order to determine the glass transition temperature (T(g)) and the required process temperature. The process was conducted in the rotary fluid bed with a gravimetric powder feeder achieving an exact dosage in contrast to volumetric powder feeder. A three way nozzle was aligned tangential to the pellet bed movement feeding simultaneously powder and plasticizer into the rotary fluid bed. The determined coating efficiency of the talc-free formulation was high with 94% and storage stability regarding tacking could be achieved using colloidal silicium dioxide as top powder. The T(g) of the enteric coat could be determined analyzing the T(g) of isolated films obtained by coating celluloid spheres instead of pellets using the dry coating process in rotary fluid bed. The dry coating process has been demonstrated to be a serious alternative to conventional solvent or water based coating processes.


Histologic differential diagnostic problems for oral discoid lupus erythematosus.
Biopsies of oral lesions from 21 patients with diagnostic skin lesions of discoid lupus erythematosus and from 21 patients with oral lichen planus and leukoplakia were examined blindly by light microscopy. The correct histologic diagnosis (DLE) was established in less than half of the cases. In one-third of the cases differentiation between DLE and lichen planus could not be made. In the rest of the cases histologic diagnoses other than DLE were stated. The study shows the need for better diagnostic methods for oral lesions.


Is there a future for direct renin inhibitors?
The renin-angiotensin-aldosterone system (RAAS) is a key regulator of blood pressure (BP), as well as volume and electrolytes, in both hypertensive and normotensive individuals. Inappropriate activation of the RAAS is important in hypertension-induced cardiovascular disease (CVD) and chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS cascade, which makes direct renin inhibitors (DRIs) an attractive target for RAAS suppression and treatment of hypertension. Current regimens using either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) result in feedback upregulation of renin and aldosterone breakthrough, which contribute to incomplete suppression of the RAAS. Thereby, aliskiren - alone or in combination - might offer a novel therapeutic intervention to improve suppression of the RAAS, with potential to translate to improved CVD and CKD outcomes. Herein, we present the current state of knowledge of DRIs in the preclinical and clinical realm and their antihypertensive efficacy in relation to cardiovascular and renal risk. Recent clinical trials (2007 - 2009) support the efficacy of aliskiren, and studies suggest the potential for improved CVD and CKD outcomes. An understanding of the mechanism of action of DRIs and a perspective of recent clinical trials. The DRI aliskiren is an effective antihypertensive agent that preliminary data suggests has a beneficial effect in CVD and CKD. Combination of aliskiren with an ACEi or ARB may be better tolerated than the ACEi-ARB combination. Future work is needed to further quantify aliskiren's impact on hard CVD and CKD end points.


Compensatory responses to nigrostriatal bundle injury. Studies with 6-hydroxydopamine in an animal model of parkinsonism.
Intracerebral injections of the neurotoxin 6-hydroxydopamine (6-HDA) can produce selective, near-total destruction of the dopamine (DA)-containing neurons of the nigrostriatal bundle. The dysfunctions in animals with these lesions show many parallels with those present in Parkinsonian patients. Among these are the extensive loss of DA neurons in the basal ganglia, neurological impairments including akinesia, paradoxical kinesia in response to activating conditions, and improved sensory-motor function after the administration of DOPA. Moreover, as with patients with preclinical Parkinsonism, 6-HDA-treated rats with less extensive lesions show few or no behavioral dysfunctions, but are unusually sensitive to the akinesia-inducing effects of stress and dopaminergic antagonists. In this review, we summarize the behavioral effects of 6-HDA-induced depletion of striatal DA in the rat and then focus on the compensatory changes that may underlie the preclinical stage of the disorder. These compensations appear to include an increase in the number of active DA neurons, an increase in the release of DA per impulse from residual terminals, and a decrease in the amount of DA inactivated by high affinity uptake. Collectively, these alterations permit a few residual DA neurons to maintain a normal level of control over cellular activity in the striatum.


Epithelioid sarcoma in association with total knee replacement. A case report.
A case is reported in which an epithelioid sarcoma developed in an apparently benign enchondroma or bone infarct at the site of a chrome-cobalt total knee replacement.


Computed tomography enterography-based multiregional radiomics model for differential diagnosis of Crohn's disease from intestinal tuberculosis.
To build computed tomography enterography (CTE)-based multiregional radiomics model for distinguishing Crohn's disease (CD) from intestinal tuberculosis (ITB). A total of 105 patients with CD and ITB who underwent CTE were retrospectively enrolled. Volume of interest segmentation were performed on CTE and radiomic features were obtained separately from the intestinal wall of lesion, the largest lymph node (LN), and region surrounding the lesion in the ileocecal region. The most valuable radiomic features was selected by the selection operator and least absolute shrinkage. We established nomogram combining clinical factors, endoscopy results, CTE features, and radiomic score through multivariate logistic regression analysis. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the prediction performance. DeLong test was applied to compare the performance of the models. The clinical-radiomic combined model comprised of four variables including one radiomic signature from intestinal wall, one radiomic signature from LN, involved bowel segments on CTE, and longitudinal ulcer on endoscopy. The combined model showed good diagnostic performance with an area under the ROC curve (AUC) of 0.975 (95% CI 0.953-0.998) in the training cohort and 0.958 (95% CI 0.925-0.991) in the validation cohort. The combined model showed higher AUC than that of the clinical model in cross-validation set (0.958 vs. 0.878, P = 0.004). The DCA showed the highest benefit for the combined model. Clinical-radiomic combined model constructed by combining CTE-based radiomics from the intestinal wall of lesion and LN, endoscopy results, and CTE features can accurately distinguish CD from ITB.


The carbon emissions related to the land-use changes from 2000 to 2015 in Shenzhen, China: Implication for exploring low-carbon development in megacities.
Megacities exploit enormous amounts of lands from outside of the city boundary. However, there is a large knowledge gap in the impact of socioeconomic activities associated land-use changes on carbon emissions of megacities during the urbanization. In the current work, we combined the material-flow analysis, environmental extended input-output model, and land matrix data to construct a hybrid network framework. Such a framework was used to estimate the carbon emissions driving from trade between sectors and associated land use changes during 2000-2015 in Shenzhen, China. Results indicated that the total carbon emissions of Shenzhen had a growth rate of 262.7% from 2000 to 2010 and a declining rate of 17.6% from 2010 to 2015. This pattern is associated with large declining rates in the overall energy and carbon intensities by 53.8% and 63.2% during the period of 2000-2015. Meanwhile, embodied carbon emissions of Shenzhen kept rising by approximately twofold, accompanied by the increasing trends in the land-use related carbon emissions both inside and outside of city boundary. The land uses per unit GDP showed a dramatical decline by 85.7% and with a large contribution of the transportation and industrial land, and this caused a gradual increase in overall land-use related emissions with average growth rate of 7.1%. In addition, the land-use change related carbon emissions of the transportation and industrial land had a cumulative growth of 85%. As for the embodied land-use related carbon emissions, the dominated contributor was the Agriculture sector which drove an average of 0.13 MtC yr-1 emissions via importing agricultural products from outside of Shenzhen. This study provides a scientific foundation for corporately mitigate carbon emissions between megacities and their surrounding regions.


Paradoxical hepatic tumor: Undifferentiated embryonal sarcoma of the liver.
Undifferentiated embryonal sarcoma (UES) is a rare primary malignant tumor of the liver that typically presents in late childhood. We report a case of primary UES, which had a typical paradoxical appearance on different imaging modalities.


The importance of social characteristics of communities for the medically based disability pension.
The aim of this study was to look for any possible contextual effect of deprivation at municipality level on the risk of being granted the medically based disability pension, controlled for compositional effects due to spatial concentration of people with a high risk of disability. The material consists of the residentiary part of a total Norwegian county population aged 20-54 years without disability pension at baseline, n=40,083. This study was performed as a 10-year follow-up study. The relative risk of being granted a disability pension was estimated by logistic regression analyses as odds ratios (OR) between people living in different municipalities according to a municipality deprivation index at three levels, adjusted for individual factors. The OR of disability pension was 1.36 (1.22, 1.51) for people residing in intermediate deprived municipalities and 1.48 (1.31, 1.67) for people residing in the most deprived municipalities compared to the most affluent municipalities, adjusted for gender and age. After adjustment for individual risk factors the OR was 1.26 (1.12, 1.41) and 1.18 (1.04, 1.35) respectively. Analyses stratified by gender showed that the increased risk of receiving a disability pension for men in the most deprived municipalities was explained by individual factors alone. Relative municipality deprivation seems to account for an increase in the incidence of disability pension. This effect contributes to marginalization of people living in less affluent areas out of employment and thus to widening socioeconomic inequalities in the population.


The human nucleoporin Tpr protects cells from RNA-mediated replication stress.
Although human nucleoporin Tpr is frequently deregulated in cancer, its roles are poorly understood. Here we show that Tpr depletion generates transcription-dependent replication stress, DNA breaks, and genomic instability. DNA fiber assays and electron microscopy visualization of replication intermediates show that Tpr deficient cells exhibit slow and asymmetric replication forks under replication stress. Tpr deficiency evokes enhanced levels of DNA-RNA hybrids. Additionally, complementary proteomic strategies identify a network of Tpr-interacting proteins mediating RNA processing, such as MATR3 and SUGP2, and functional experiments confirm that their depletion trigger cellular phenotypes shared with Tpr deficiency. Mechanistic studies reveal the interplay of Tpr with GANP, a component of the TREX-2 complex. The Tpr-GANP interaction is supported by their shared protein level alterations in a cohort of ovarian carcinomas. Our results reveal links between nucleoporins, DNA transcription and replication, and the existence of a network physically connecting replication forks with transcription, splicing, and mRNA export machinery.


Assessing effectiveness and patient perceptions of a novel electronic medical record for the management of inflammatory bowel disease.
There is an increasing prevalence of chronic disease worldwide, resulting in multiple management challenges. Inflammatory bowel disease (IBD) is an exemplar chronic disease requiring coordinated longitudinal care. We propose that Crohn's Colitis Care (CCCare), a novel IBD-specific, structured electronic medical record is effective at improving data capture and is acceptable to patients. A comparison was made between IBD-data completeness in usual records and CCCare. CCCare's acceptability to patients was assessed in two independent IBD patient cohorts and included:• Overall ratings of acceptability.• Factors associated with pre-exposure acceptability ratings.• Whether exposure and security concerns influenced acceptability ratings.• Direct patient feedback through CCCare's patient portal. In all cases reviewed, there was data gain using structured CCCare fields compared with IBD documentation in usual medical records. The overall acceptability in the combined cohort (n = 310) was very high. More than three-quarters of patients rated acceptability as >7 of 10. Self-reported information technology (IT) literacy positively associated with acceptability. Exposure had a small positive affect on acceptability, whereas security concerns had little impact on acceptability. Patient portal feedback revealed that most patients are very likely to recommend CCCare to others (8.56 ± 2.2 [out of 10]). CCCare is effective in supporting more complete IBD-specific data capture compared with usual medical records. It is highly acceptable to patients, especially those with reasonable IT literacy. Patient concerns about privacy and security of electronic medical records (EMRs) did not significantly affect acceptability.


Epigenetic targets for novel therapies of lung diseases.
In spite of substantial advances in defining the immunobiology and function of structural cells in lung diseases there is still insufficient knowledge to develop fundamentally new classes of drugs to treat many lung diseases. For example, there is a compelling need for new therapeutic approaches to address severe persistent asthma that is insensitive to inhaled corticosteroids. Although the prevalence of steroid-resistant asthma is 5-10%, severe asthmatics require a disproportionate level of health care spending and constitute a majority of fatal asthma episodes. None of the established drug therapies including long-acting beta agonists or inhaled corticosteroids reverse established airway remodeling. Obstructive airways remodeling in patients with chronic obstructive pulmonary disease (COPD), restrictive remodeling in idiopathic pulmonary fibrosis (IPF) and occlusive vascular remodeling in pulmonary hypertension are similarly unresponsive to current drug therapy. Therefore, drugs are needed to achieve long-acting suppression and reversal of pathological airway and vascular remodeling. Novel drug classes are emerging from advances in epigenetics. Novel mechanisms are emerging by which cells adapt to environmental cues, which include changes in DNA methylation, histone modifications and regulation of transcription and translation by noncoding RNAs. In this review we will summarize current epigenetic approaches being applied to preclinical drug development addressing important therapeutic challenges in lung diseases. These challenges are being addressed by advances in lung delivery of oligonucleotides and small molecules that modify the histone code, DNA methylation patterns and miRNA function.


Using agonists for iNKT cells in cancer therapy.
The capacity of α-galactosylceramide (α-GalCer) to act as an anti-cancer agent in mice through the specific stimulation of type I NKT (iNKT) cells has prompted extensive investigation to translate this finding to the clinic. However, low frequencies of iNKT cells in cancer patients and their hypo-responsiveness to repeated stimulation have been seen as barriers to its efficacy. Currently the most promising clinical application of α-GalCer, or its derivatives, is as stimuli for ex vivo expansion of iNKT cells for adoptive therapy, although some encouraging clinical results have recently been reported using α-GalCer pulsed onto large numbers of antigen presenting cells (APCs). In on-going preclinical studies, attempts to improve efficacy of injected iNKT cell agonists have focussed on optimising presentation in vivo, through encapsulation in particulate vectors, making structural changes that help binding to the presenting molecule CD1d, or injecting agonists covalently attached to recombinant CD1d. Variations on these same approaches are being used to enhance the APC-licencing function of iNKT cells in vivo to induce adaptive immune responses to associated tumour antigens. Looking ahead, a unique capacity of in vivo-activated iNKT cells to facilitate formation of resident memory CD8+ T cells is a new observation that could find a role in cancer therapy.


Accelerated myelination with motor system involvement in a neonate with immediate postnatal onset of seizures and hemimegalencephaly.
The timetable for normal myelination in the developing brain on MRI is well described. Beyond the genetically determined myelination process, environmental or other incidental factors may modulate the actual myelination, globally or regionally. Delayed myelination is well known in many pathological conditions interfering with adequate energy or myelin precursor supply. Rare but specific conditions where the normal process of myelination is accelerated are also known. We describe a case of early postnatal epilepsy demonstrating a striking degree of accelerated myelination both in the cerebral tissue adjacent to the presumed epileptic focus and along the ipsilateral pyramidal tract through the brainstem, a feature not previously described in the literature. This distal myelination highlights the peculiar system involvement pattern of function-induced myelination rather than simply regional myelination in response to an epileptic or other stimulus. This may have implications on our understanding of the development of function systems (visual, auditory, motor, sensory, etc.) or even the more complex interactive process of learning and may open new therapeutic opportunities in pathological functional conditions previously believed to be incurable.


5 year incidence of YAG capsulotomy and PCO after cataract surgery with single-piece monofocal intraocular lenses: a real-world evidence study of 20,763 eyes.
To evaluate the 3- and 5-year incidence of posterior capsule opacification (PCO) and neodymium-doped yttrium aluminium garnet (Nd:YAG) capsulotomy in patients following cataract surgery, comparing results for different single-piece acrylic hydrophilic and hydrophobic monofocal intraocular lens (IOL) models and other patient factors. Electronic medical record data collected from seven United Kingdom (UK) National Health Service (NHS) ophthalmology clinics for routine, age-related (≥65 years) cataract surgeries that implanted single-piece acrylic monofocal IOLs during 2010-2013 were used to calculate 3- and 5-year incidence of Nd:YAG and PCO. IOL models of Alcon Acrysof, AMO Tecnis, Bausch & Lomb (B & L) Akreos, LenStec Softec, and Rayner Flex were analyzed. Pairwise comparisons were conducted between AcrySof IOLs and other IOLs using Bonferroni adjustment for multiplicity. Multivariate analyses were conducted adjusting for known confounders. The incidence of Nd:YAG capsulotomy ranged between 2.4-12.6% at 3 years and 5.8-19.3% at 5 years post-cataract surgery. Similarly, the incidence of PCO ranged between 4.7-18.6% at 3 years and 7.1-22.6% at 5 years. When comparing all of the single-piece IOLs, AcrySof demonstrated the lowest incidence rates for both PCO and Nd:YAG (P < 0.001 for each comparison). From adjusted logistic regression analysis, AcrySof were associated with lower 3- and 5-year odds of Nd:YAG and PCO incidence. Following cataract surgery with single-piece monofocal IOLs different incidence rates of PCO were observed with different IOLs. AcrySof IOLs were associated with significantly lower incidence of PCO requiring Nd:YAG treatment over periods of 3 and 5 years.


Role of the N-terminal region of the skeletal muscle myosin light chain kinase target sequence in its interaction with calmodulin.
The binding of calmodulin (CaM) to four synthetic peptide analogues of the skeletal muscle myosin light chain kinase (sk-MLCK) target sequence has been studied using 1H-NMR. The 18-residue peptide WFF is anchored to CaM via the interaction of the Trp 4 side chain with the C-domain and the Phe 17 side chain with the N-domain of the protein. A peptide corresponding to the first 10 residues (WF10) does not provide the second anchoring residue and is not long enough to span both domains of CaM. 1H-NMR spectroscopy indicates that the WF10 peptide interacts specifically with the C-domain of CaM, and the chemical shifts of the bound Trp side chain are very similar in the CaM:WF10 and CaM:WFF complexes. Binding of the C-domain of CaM to the strongly basic region around Trp 4 of this MLCK sequence may be an important step in target recognition. Comparison of 1H-NMR spectra of CaM bound to WFF, a Trp 4-->Phe analogue (FFF), or a Trp 4-->Phe/Phe 17-->Trp analogue (FFW) suggests that all three peptides bind to CaM in the same orientation, i.e., with the peptide side chain in position 4 interacting with the C-domain and the side chain in position 17 interacting with the N-domain. This indicates that a Trp residue in position 4 is not an absolute requirement for binding this target sequence and that interchanging the Trp 4 and Phe 17 residues does not reverse the orientation of the bound peptide, in confirmation of the deduction from previous indirect studies using circular dichroism (Findlay WA, Martin SR, Beckingham K, Bayley PM, 1995, Biochemistry 34:2087-2094). Molecular modeling/energy minimization studies indicate that only minor local changes in the protein structure are required to accommodate binding of the bulkier Trp 17 side chain of the FFW peptide to the N-domain of CaM.


Prostaglandin E1 modifies porcine cerebral arterial tone through cyclooxygenase related eicosanoid(s) release.
The effects of prostaglandin E1 (PGE1) on porcine cerebral arteries were studied in the absence and presence of cyclooxygenase inhibitors, 5 x 10(-6) M indomethacin or 10(-4) M aspirin. In preparations placed at a resting tension, 3 x 10(-9) to 10(-6) M PGE1 caused dose-dependent contractions. In prostaglandin F2 alpha (PGF2 alpha)- contracted preparations, low concentrations of 10(-9) and 3 x 10(-9) M PGE1 did not modify arterial tone and higher concentrations of 10(-8) to 10(-6) M PGE1 further increased the arterial tone in all preparations tested. In contrast, in the presence of the cyclooxygenase inhibitors, low concentration of 10(-9) and 3 x 10(-9) M PGE1 markedly decreased the arterial tone induced by PGF2 alpha and higher dose of 10(-8) to 10(-6) M PGE1 increased the arterial tone in 15 of 18 preparations (83%). These findings suggest that PGE1 modifies porcine cerebral vascular tone at least partly through cyclooxygenase-related eicosanoid(s) production.


Association between ion shift index and prognosis in severe trauma patients without isolated head injury.
This study aimed to investigate the ion shift index (ISI) as a prognostic factor of severe trauma. We hypothesized that the initial ISI measured in the emergency department (ED) is associated with discharge survival in severe non-isolated head injury (IHI) patients. This retrospective observational study included severe trauma patients with available medical records from January 2017 to December 2018 but excluded those with IHI. Logistic regression analysis was conducted to identify the risk factors for mortality in non-IHI patients, and adjustments were performed for relevant covariates. An area under the receiver operating characteristics curve (AUROC) analysis was performed to examine the primary outcome of our study, which was mortality at hospital discharge in severe non-IHI trauma patients. Of the 483 severe non-IHI trauma patients included in the study, 86 patients (17.8 %) died. The multiple logistic regression analysis demonstrated ISI (odds ratio [OR], 2.300; 95% CI, 1.183-4.470) was significantly associated with mortality in the non-IHI group. Additionally, trauma and injury severity score (TRISS; OR, 0.538; 95% CI, 0.447-0.649), lactate (OR, 1.410; 95% CI, 1.252-1.588), creatinine (OR, 1.554; 95% CI, 1.221-1.979), and activated partial thromboplastin time (aPTT; OR, 1.050; 95% CI, 1.021-1.080) were independently associated with mortality at hospital discharge. The AUROC values for TRISS, lactate, aPTT, creatinine, and ISI were as follows: 0.892 (95% CI, 0.861-0.918), 0.838 (95% CI, 0.803-0.870), 0.754 (95% CI, 0.712-0.792), 0.650 (95% CI, 0.606-0.693), and 0.848 (95% CI, 0.813-0.879), respectively. The AUROC for the multiple logistic regression model with ISI was 0.942 (95% CI, 0.917-0.962). In a model in which TRISS was omitted, the addition of ISI to other predictors significantly improved the AUROC to 0.900 (95% CI, 0.869-0.925) (p=0.039). The initial ISI in the ED after trauma was associated with mortality in severe non-IHI trauma patients. In conjunction with other prognostic indicators, it could be used as an early prognostic marker, particularly if TRISS is unavailable.


Updates in diagnostics, treatments, and correlations between oral and ocular manifestations of Sjogren's syndrome.
Sjogren's syndrome (SS) is characterized as an autoimmune disorder targeting secretory glands, including the lacrimal and salivary glands, causing dry eye and dry mouth predominantly in women over the age of 40. In this review, we summarize recent advancements in SS diagnostics, treatments, and our understanding of correlations between oral and ocular manifestations of SS. Google Scholar and PubMed databases were utilized to search peer-reviewed papers since 2016 on SS diagnosis, treatment, and correlations between oral and ocular manifestations. For diagnostics, we discuss the updated SS classification criteria by the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR), new biomarkers, and compare studies of current diagnostic methods with alternative technologies. For treatments, we discuss topical, systemic, and surgical treatment developments in the management of oral and ocular symptoms of SS as there is still no cure for the disorder. Finally, we report studies that directly suggest correlations between the ocular surface disease and oral disease in SS, as well as shared abnormalities in the microbiome and cytokine expression that may be correlated. We conclude by stating limitations to our review as well as paths moving forward. Elucidating correlations between oral and ocular manifestations may be the key to furthering our understanding of SS pathogenesis as well as defining new standards for diagnosis and treatment.


Erratum to "What is open-access publishing and what it means for the forensic enterprise" [Forensic Sci. Int.: Synergy (2019) 290-293].
[This corrects the article DOI: 10.1016/j.fsisyn.2019.06.045.].


Liposomal incorporation changes the effect of 1.25-dihydroxyvitamin D3 on the phospholipase C signal transduction pathway and the eicosanoid cascade on keratinocytes in vitro.
1.25-dihydroxyvitamin D3 is of clinical importance (e.g. in the treatment of psoriasis) given its ability to regulate the proliferation and differentiation of human keratinocytes. 1.25-Dihydroxyvitamin D3 mediates its action via genomic and nongenomic pathways. The nongenomic actions begin with the activation of phospholipase C and the subsequent rapid rise in calcium within the cells. We incorporated 1.25-dihydroxyvitamin D3 in liposomes of varying compositions in an attempt to improve their effect/negative side effect ratio. The influence of empty liposomes (1 mM) and free and liposomally incorporated 1.25-dihydroxyvitamin D3 (10 nM) on the rapid release of sulfidoleucotrien and inositole 1,4,5 triphosphate was examined in keratinocytes in vitro. Free 10 nM 1.25-dihydroxyvitamin D3 provoked a rapid rise in sulfidoleucotriens within 30 seconds, followed by a swift decrease in sulfidoleucotrien and inositole 1,4,5-triphosphate concentration after 10 minutes. Empty liposomes and liposomal-incorporated 1.25-dihydroxyvitamin D3 did not show such a strong effect. These results suggest the occurrence of specific binding sites for 1.25-dihydroxyvitamin D3 on the membrane level that are incapable of recognizing 1.25-dihydroxyvitamin D3 trapped within liposomal membrane.


After-effects reported by women having follow-up cervical cytology tests in primary care: a cohort study within the TOMBOLA trial.
Although it is recognised that some women experience pain or bleeding during a cervical cytology test, few studies have quantified physical after-effects of these tests. To investigate the frequency, severity, and duration of after-effects in women undergoing follow-up cervical cytology tests, and to identify subgroups with higher frequencies in Grampian, Tayside, and Nottingham. Cohort study nested with a multi-centre individually randomised controlled trial. The cohort included 1120 women, aged 20-59 years, with low-grade abnormal cervical cytology who completed a baseline sociodemographic questionnaire and had a follow-up cervical cytology test in primary care 6 months later. Six weeks after this test, women completed a postal questionnaire on pain, bleeding, and discharge experienced after the test, including duration and severity. The adjusted prevalence of each after-effect was computed using logistic regression. A total of 884 women (79%) completed the after-effects questionnaire; 30% of women experienced one or more after-effect: 15% reported pain, 16% bleeding, and 7% discharge. The duration of discharge was ≤2 days for 66%, 3-6 days for 22%, and ≥7 days for 11% of women. Pain or bleeding lasted ≤2 days in more than 80% of women. Severe after-effects were reported by <1% of women. The prevalence of pain decreased with increasing age. Bleeding was more frequent among nulliparous women. Discharge was more common among oral contraceptive users. Pain, bleeding, and discharge are not uncommon in women having follow-up cervical cytology tests. Informing women about possible after-effects could better prepare them and provide reassurance, thereby minimising potential non-adherence with follow-up or non-participation with screening in the future.


Cerebral magnetic resonance imaging in a 2-year-old Caucasian girl, with hypomelanosis of Ito.
Hypomelanosis of Ito is a rare sporadic neurocutaneous disorder. CNS abnormalities are observed in more than 50% of the cases. A case of hypomelanosis in a 2 year old girl is reported. MRI is unusual in the fact that it shows symmetrical abnormalities: non-obstructive hydrocephalus, mega cisterna magna and multiple white matter lesions.


Genetic profile of primary plasma cell leukemia in Korea: comparison with plasma cell myeloma.
Plasma cell leukemia (PCL) is clinically and genetically distinct from multiple myeloma (MM), despite controversies regarding the disease definition. To determine the distinct features of PCL, the genetic property of primary PCL (pPCL) was compared with that of secondary PCL (sPCL) and MM. In patients with pPCL, Eighty-nine non-synonymous mutations were observed in 68 genes. The most frequently mutated genes were TP53, TSC2, and TYK2. In comparison with genetic abnormalities of sPCL and MM, 45 genes were present only in pPCL while 28 genes were only in sPCL and 22 genes only in MM. Among the common genes between pPCL and MM, a higher prevalence of TP53 was observed in pPCL, compared to MM (p < 0.05), while similar, compared to sPCL (p = 0.64). In summary, pPCL patients showed a higher level of genetic heterogeneity and distinctive genetic signature in their mutational profile compared to patients with MM and sPCL.


Extended half-life factor VIII concentrates in adults with hemophilia A: Comparative pharmacokinetics of two products.
The use of pharmacokinetic (PK) studies to help design personalized prophylaxis regimens for factor VIII (FVIII) concentrate in individuals with hemophilia A has been recognized for many years but only became practical for routine clinical use with the availability of web-accessible population PK applications based on Bayesian analysis. To compare PK variables using population PK studies done on 2 extended half-life recombinant FVIII concentrates in 23 individuals with hemophilia A after switching from one product to the other. We retrospectively analyzed PK parameters derived from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-HEMO) application on 23 individuals with severe or moderately severe hemophilia A who were required to switch from recombinant FVIII Fc (Eloctate; Biogen, Cambridge, MA, USA) to recombinant antihemophilic factor PEGylated (Adynovate; Takeda Pharmaceutical Company, Osaka, Japan) between 2016 and 2017. There were minor PK differences between Eloctate and Adynovate, but some parameters did reach statistical significance, namely in vivo recovery (mean, 2.73 IU/dL per IU/kg vs 2.41 IU/dL per IU/kg), clearance (mean, 0.163 mL/h vs 0.194 mL/h), and volume of distribution at steady state (mean, 42.5 ml/kg vs 49.8 mL/kg). Smaller nonsignificant trends toward higher values for Adynovate were seen in terminal half-life, area under the curve, and predicted times to 5% and 1% residual FVIII after infusion. Population PK analysis revealed differences between the two extended half-life FVIII concentrates, reaching significance for in vivo recovery, clearance, and volume of distribution.


Feedback moderates the effect of prevalence on perceptual decisions.
How does the prevalence of a target influence how it is perceived and categorized? A substantial body of work, mostly in visual search, shows that a higher proportion of targets are missed when prevalence is low. This classic low prevalence effect (LPE) involves a shift to a more conservative decision criterion that makes it less likely that observers will call an ambiguous item a target. In contrast, Levari et al. (Science, 360[6396], 1465-1467, 2018) recently reported the opposite effect in a simple categorization task. In their hands, at low prevalence, observers adopted a more liberal criterion, making observers more likely to label ambiguous dots on a blue-purple continuum "blue." They called this "prevalence-induced concept change" (PICC). Here, we report that the presence or absence of feedback is critical. With feedback, observers become more conservative at low prevalence, as in the LPE. Without feedback, they become more liberal, identifying a wider range of stimuli as targets, as in Levari's PICC studies. Stimuli from a shape continuum ranging from rounded ("Bouba") to bumpy ("Kiki") shapes produced similar results. Other variables: response type (2AFC vs. go/no-go), color (blue-purple vs. red-green), and stimuli type (solid color vs. texture) did not influence the criterion shifts. Understanding these effects of prevalence and ways they can be controlled illuminates the context-specific nature of perceptual decisions and may be useful in socially important, low prevalence tasks like cancer screening, airport security, and disease diagnosis in pathology.


Nutrition, aging, and the aged.
Nutrition plays a significant modulating role in the aging process and is an important component in the health care of the elderly. While considerable study of the nutritional needs of the elderly has been accomplished in recent years, we are as yet very limited in our knowledge and understanding of the nutrient requirements of the elderly, the methodology for assessing nutritional status, and the impact of disease on the nutritional status of the elderly. Clearly, the dynamic interrelationships of nutrition, aging, and the aged emerge as pressing and important aspects of modern medicine. To probe into the intricacies of these relationships is a monumental challenge. This challenge will certainly accelerate in the future.


Capillary morphogenesis gene (CMG)-1 is among the genes differentially expressed in mouse male germ line stem cells and embryonic stem cells.
We recently established a technique to expand male germ line stem (GS) cells in long-term culture without losing their spermatogenic capacity. To gain insight into the genetic program of these cells, we compared the mRNA expression profile of GS cells with that of embryonic stem (ES) cells using DNA microarrays. We found 79 genes that were upregulated in GS cells compared to ES cells, including synaptonemal complex protein-1, deleted in azoospermia-like, ubiquitin-conjugating enzyme E2B, and ubiquitin carboxy-terminal hydrolase L1, all of which are functionally important for spermatogenesis. In addition, we identified a cDNA encoding the mouse ortholog of capillary morphogenesis gene (CMG)-1. CMG-1 transcripts were predominantly produced in spermatogonia and spermatocytes in mouse testis. When CMG-1 expression was attenuated in a mouse spermatocyte-derived cell line, GC-2spd(ts), by a target-specific short interfering RNA, the morphology of the cells was changed and the expression of cyclin D2 was abrogated. A reporter assay using a genomic region upstream of the mouse cyclin D2 gene revealed that this downmodulation occurs at the transcriptional level. We detected FLAG-tagged CMG-1 protein in the nuclei of transfected COS7 cells, suggesting that CMG-1 may play a unique role in the transcriptional regulation of the cyclin D2 gene. The upregulated GS genes identified in this study will provide useful information for the future investigation of spermatogonial stem cells and the early phase of male germ cell differentiation.


Structural, electronic, and magnetic properties of the Fe-doped GaP nanotubes.
In this work we aimed to study the structural, electronic, and magnetic properties of the Fe-doped GaP nanotubes (GaPNTs). The method, utilized in this work is based on first-principle calculations that are applied to the case studies; (5,5) armchair, (8,0) zigzag GaPNTs, and Fe-doped GaPNTs. The results of simulation show that there is distortion around Fe impurity with respect to the pristine GaPNTs for Fe-doped (5,5) and (8,0) GaPNTs. The total density of states (DOS) indicates that Fe-doped GaPNTs show the metal behavior. Furthermore, it is perceived that both Fe-doped (5,5) and (8,0) GaPNTs are magnetic systems while pristine GaPNTs do not show magnetic behavior. The study suggests that such Fe-doped nanotubes may be useful in nanomagnets and spintronics.


Long-term outcome of fetal cell transplantation on postinfarction ventricular remodeling and function.
The purpose of this study was to determine the long-term outcome of fetal cell transplantation into myocardial infarction on left ventricular (LV) function and remodeling. While neonatal cell transplantation improved function for acute myocardial infarction, long-term data on the effects of cell-transplant therapy using a more primitive cell on ventricular remodeling and function are needed.Methods. - Therefore, we injected 4 x 10(6) Fischer 344 fetal cardiac cells or medium into 1-week old infarcts in adult female Fischer rats to assess long-term outcome. Ten months after transplantation histologic analysis showed that cell implants were readily visible within the infarct scar. Infarct wall thickness was greater in cell-treated at 0.69 +/- 0.05 mm (n = 11) vs. medium-treated hearts at 0.33 +/- 0.01 mm (n = 19; P = 0.0001). Postmortem LV volume was 0.41 +/- 0.04 ml in cell-treated vs. 0.51 +/- 0.03 ml in medium-treated hearts (P < 0.04). Ejection fraction assessed by LV angiography was 0.40 +/- 0.02 in cell-treated (n = 16) vs. 0.33 +/- 0.02 in medium-treated hearts (n = 24; P < 0.03) with trends towards smaller in vivo end-diastolic and end-systolic volumes in cell-treated vs. medium-treated hearts. Polymerase chain reaction analysis of the Sry gene of the Y chromosome was positive in four of five cell-treated and zero of five medium-treated hearts confirming viability of male cells in female donors. Over the course of 10 months, fetal cardiac cell transplantation into infarcted hearts increased infarct wall thickness, reduced LV dilatation, and improved LV ejection fraction. Thus, fetal cell-transplant therapy mitigated the longer-term adverse effects of LV remodeling following a myocardial infarction.


Expression of defense-related genes in mung bean varieties in response to Trichoderma virens alone and in the presence of Rhizoctonia solani infection.
Web blight/wet root rot caused by Rhizoctonia solani is one of the major constraints for mung bean (Vigna radiata) production. Growing of resistant varieties and use of biocontrol agents are the feasible options available to manage the disease. The present study was conducted to determine the variation in the expression of various defense-related genes in susceptible and resistant mung bean varieties in response to biocontrol agent Trichoderma virens and R. solani interactions. The primers were designed using sequences of defense-related genes, namely PR 10, epoxide hydrolase (EH), catalase and calmodulin available in NCBI database and evaluated against cDNA obtained from both susceptible and resistant mung bean plants at 1-4 days post-inoculation (dpi) with the test pathogen R. solani and biocontrol agent T. virens using conventional PCR and qPCR analyses. R. solani inoculation upregulated the mean expression of PR 10 and calmodulin in susceptible and resistant varieties, respectively, whereas downregulated in the rest of the treatments. Quantitative PCR analysis showed that except catalase in the susceptible variety, which is downregulated, the expression of PR 10, EH, catalase and calmodulin was upregulated in both resistant and susceptible varieties in response to T. virens alone and in the presence of R. solani. In general, the expression of PR 10 and calmodulin was highest at 1 dpi whereas EH and catalase expression were maximum at 4 dpi. The application of T. virens suppressed the development of disease in the presence of R. solani in both susceptible and resistant varieties with more pronounced effect in resistant variety. Thus, the application of biocontrol agent T. virens upregulated the expression of defense-related genes and reduced disease development.


Study of wetting of the animal retinas by Water and organic liquids and its Implications for ophthalmology.
Interfacial properties of the animal retinas are reported. Wetting of the retina-retinal pigment epithelium-choroid-sclera tissues of cow, sheep, and pig eyes by water, silicone and castor oil was explored experimentally. Both water and silicone oils demonstrated complete wetting of the retina, regardless of the viscosity of the silicone oil, whereas the castor oil demonstrated a partial wetting regime. Similar wetting regimes were observed for sheep, cow and pig retinas. The intact surface of animal retina was found to be both hydrophilic and oleophilic. Wetting experiments with double sandwich oil/water layers were performed. Water demonstrated stronger affinity to the retina than silicone and castor oils, and eventually replaced the oils at the liquid/retina interface. We conclude that aqueous solutions continuously secreted in the living eye may displace silicone oil from the retinal surface and contribute to retinal re-detachment. Study of dynamics of wetting of the animal retina by water and organic oils is reported. The exponent describing the dynamics of spreading of the castor oil is lower than that predicted by the Tanner law. Castor oil may provide more effective tamponade than silicone oil.


[Problems caused by the therapeutic interruption of pregnancy. Apropos of 120 cases observed from 1976 to 1983].
The authors present statistical data on 120 medical abortions performed at "Pavillon Victor Olivier" between April, 1976 and June, 1983. A precise study was performed on the maternal and fetal indications, the different techniques employed according to gestational age, and their follow-up since 1976. The principal purpose of this article is to arouse reflexion on the consequences of the law of 1975, as well as the appropriateness of the maternal and especially of the fetal indications. A major portion of these could be avoidable with prophylactic measures and adequate contraception.


The impact of anticancer activity upon Beta vulgaris extract mediated biosynthesized silver nanoparticles (ag-NPs) against human breast (MCF-7), lung (A549) and pharynx (Hep-2) cancer cell lines.
The present study tried for a phyto-synthetic method of producing silver nanoparticles (Ag-NPs) with size controlled as and eco-friendly route that can lead to their advanced production with decorative tranquil morphology. By inducing temperature fluctuation of the reaction mixture from 25 to 80°C the plasmon resonance band raised slowly which had an ultimate effect on size and shape of Ag-NPs as shown by UV-visible spectroscopy and TEM results. The biosynthesized nanoparticles showed good cytotoxic impact against MCF-7, A549 and Hep2 cells compared to normal cell lines. Compared to control plates, the percentage of cell growth inhibition was found to be high with as concentrations of Ag-NPs becomes more as determined by MTT assay. The AO/EtBr staining observations demonstrated that the mechanism of cell death induced by Ag-NPs was due to apoptosis in cancer cells. These present results propose that the silver nanoparticles (Ag-NPs) may be utilized as anticancer agents for the treatment of various cancer types. However, there is a need for study of in vivo examination of these nanoparticles to find their role and mechanism inside human body. Further, studies we plan to do biomarker fabrication from the green synthesized plant extract nanoparticles like silver, gold and copper nanoparticles with optimized shape and sizes and their enhancement of these noble nanoparticles.


Reconstruction of full-thickness loss skin wounds using skin collagen allografts.
Sheets of allogeneic dermal collagen measuring 20 X 15 mm and prepared by trypsin treatment of full-thickness skin were grafted under skin flaps in rats. After 2 to 5 weeks the protective recipient skin was excised and replaced by split-thickness skin isografts which remained viable on their supportive collagen beds. On average such composite grafts maintained 84 per cent of their original size over 3 to 28 weeks and in contrast with split-thickness skin grafts achieved full-thickness reconstruction of the excised skin.


More Frequent Premature Antibiotic Discontinuations and Acute Kidney Injury in the Outpatient Setting With Vancomycin Compared to Daptomycin.
Vancomycin and daptomycin are often used in outpatient parenteral antimicrobial therapy for gram-positive coverage. Vancomycin's narrow therapeutic window poses challenges. We retrospectively assessed acute kidney injury (AKI) and other adverse drug events in outpatient parenteral antimicrobial therapy patients receiving vancomycin or daptomycin at home after hospital discharge. Among 191 patients included, AKI was the most common adverse drug event. Early antibiotic discontinuation and AKI were more frequent in the vancomycin group. Vancomycin use (odds ratio [OR], 4.57; 95% confidence interval [CI], 1.02-20.51); p = 0.04], female sex (OR, 3.28; 95%CI, 1.41-7.67; P < .01), and longer hospitalization (OR, 1.06; 95%CI, 1.01-1.11; P = .02] independently predicted moderate-to-severe AKI. In the vancomycin group, trough concentrations increased after discharge, and were higher in female compared to male patients, and in those who developed moderate-to-severe AKI compared to those who did not. Female sex (OR, 8.37; 95%CI, 2.35-29.82; P < .01) and higher concentrations (OR, 1.12; 95%CI, 1.05-1.19; P < .01) predicted moderate-to-severe AKI in patients receiving vancomycin. In conclusion, premature antibiotic discontinuations and nephrotoxicity are more frequent in patients treated at home with vancomycin compared to daptomycin. Among patients receiving vancomycin, plasma concentrations increased after hospital discharge and predicted moderate-to-severe AKI. Women had higher vancomycin concentrations and higher risk for AKI.


Unintentional firearm mortality in African-American youths, 2010-2019.
There is a dearth of studies that have examined unintentional firearm-related mortality in African-American (AA) youths. The purpose of this article is to assess the epidemiology of unintentional firearm mortality in AA youth, examine the risk factors associated with unintentional AA youth firearm mortality, and explore the evidence for preventing unintentional firearm-mortality in AA youths. In this cross-sectional study, the Web-Based Injury Statistics Query and Reporting System (WISQARS) data from the Centers for Disease Control and Prevention (CDC) was used. Data were analyzed from the years 2010-2019 using descriptive statistics. Between the years 2010 and 2019, the AA youth unintentional firearm mortality rate increased by 48% while the rate for White youths declined by 29%. The decade from 2010 to 2019 saw almost 400 AA youths lose their lives to unintentional firearm trauma. AA male children averaged 87% of all AA unintentional firearm deaths during this time. The years of potential life lost due to unintentional firearm mortality ranged between 21,200 and 24,300 years. The risk factors for unintentional firearm mortality in AA youths include living in states with high rates of firearm ownership, living in a home with firearms, being an older adolescent, and being of lower socioeconomic status. Of all the strategies to prevent unintentional firearm mortality in youths, the most effective include strong (felony penalty) Child Access Prevention laws, the absence of Stand-Your-Ground laws, and physicians engaging in anticipatory guidance with patients regarding safe storage of firearms. Despite the limited scale of unintentional firearm mortality in AA youths, primary prevention dictates that public health professionals intervene to keep this public health problem from becoming an epidemic and a larger contributor to health disparities.


Exposures to 2,4-Dichlorophenoxyacetic acid with or without endotoxin upregulate small cell lung cancer pathway.
Pesticide residues in food and environment along with airborne contaminants such as endotoxins pose health risk. Although herbicide 2,4-Dichlorophenoxyacetic acid (2,4-D) has been associated with increased risk of lung cancers such as small cell lung cancer (SCLC) among agricultural workers, there are no data on the SCLC signaling pathway upon 2,4-D exposure without LPS or in combination with endotoxin. We exposed Swiss albino mice (N = 48) orally to high (9.58 mg kg- 1) and low (5.12 mg kg- 1) dosages of 2,4-D dissolved in corn oil for 90 days followed by E. coli lipopolysaccharide (LPS) or normal saline solution (80 μl/animal). Lung samples and broncho-alveolar fluid (BALF) were subjected to Total histological score (THS) and total leucocyte count (TLC) and differential leucocytes count (DLC) analyses, respectively. We used microarray and bioinformatics tools for transcriptomic analyses and differentially expressed genes were analyzed to predict the top canonical pathways followed by validation of selected genes by qRT-PCR and immunohistochemistry. Total histological score (THS) along with BALF analyses showed lung inflammation following long term dietary exposure to high or low doses of 2,4-D individually or in combination with LPS. Microarray analysis revealed exposure to high dose of 2,4-D without or with LPS upregulated 2178 and 2142 and downregulated 1965 and 1719 genes, respectively (p < 0.05; minimum cut off 1.5 log fold change). The low dose without or with LPS upregulated 2133 and 2054 and downregulated 1838 and 1625 genes, respectively. Bioinformatics analysis showed SCLC as topmost dysregulated pathway along with differential expression of Itgb1, NF-κB1, p53, Cdk6 and Apaf1. Immunohistological and quantitative real time PCR (qRT-PCR) analyses also supported the transcriptomic data. Taken together, the data show exposures to high and low dose of 2,4-D with/without LPS induced lung inflammation and altered pulmonary transcriptome profile with the involvement of the SCLC pathway. The data from the study provide the insights of the potential damage on lungs caused by 2,4-D and help to better understand the mechanism of this complex relation.


Risk and prevention of acute urinary retention after robotic prostatectomy.
Acute urinary retention after catheter removal is a recognized complication following open or robot-assisted radical prostatectomy. We evaluated patient and surgery related risk factors to determine whether acute urinary retention could be prevented. To our knowledge this has not previously been investigated for prostatectomy done by any technique. We reviewed a single surgeon, robot-assisted radical prostatectomy database of patients treated between February 2008 and June 2011 for acute urinary retention after catheter removal, which was routinely performed 3 to 7 days postoperatively. We compared the characteristics of patients with and without acute urinary retention. Of 1,026 patients 25 (2.4%) experienced acute urinary retention. There was no difference between patients with and without acute urinary retention in mean age, body mass index, blood loss or prostate size, and no difference in the frequency of bladder neck reconstruction or nerve sparing. The catheter was removed an average of 4.1 vs 5.7 days postoperatively in patients with vs without acute urinary retention. Of 25 patients with acute urinary retention 22 (88%) underwent catheter removal on postoperative day 3 or 4. Although only 3 of 381 patients (0.8%) had a leak on cystogram on postoperative day 3 or 4, the acute urinary retention rate when the catheter was removed on day 3 or 4 was 5.8% (22 of 381). This was several times higher than the rate in patients who retained the catheter for greater than 4 days (3 of 645 or 0.5%). Acute urinary retention develops infrequently after robotic prostatectomy. No patient related risk factors were identified beyond catheterization time. Although the catheter may be removed after 3 or 4 days with rare leaks, the acute urinary retention risk was much less when the catheter was left in place at least 5 days.


What's Known and What's Next: Contraceptive Counseling and Support for Adolescents and Young Adult Women.
The low rates of actual contraceptive failure and high rates of contraceptive use among young women highlight that choice of contraceptive method and patterns of contraceptive use greatly influence unintended pregnancy risk. Promoting contraceptive use among adolescent and young adult women requires supportive health systems and health providers who understand this population's evolving developmental needs. It also requires an awareness of effective tools for counseling patients, while being mindful of the power dynamics operational during clinical encounters to avoid inadvertently coercive interpersonal dynamics. Missed opportunities to provide such patient-centered care can lead to unplanned pregnancies and suboptimal health and social consequences for young women. Unfortunately, health providers often lack the tools and resources to appropriately identify and meet individual young women's contraceptive needs. This article summarizes the evidence supporting contraceptive counseling strategies linked with contraceptive initiation among young women, and evidence-based approaches for supporting contraceptive adherence and continuation after method initiation. It also orients readers to the unique neurodevelopmental factors that influence the shared decision-making process during contraception counseling sessions with young women. New and emerging approaches for supporting contraceptive initiation, adherence, and continuation are reviewed.


Integrating public health policies in the epidemiological modeling of hepatitis C with LEHC tool: application in Austria.
Eliminating hepatitis C requires addressing issues other than medicines or therapies. Public health policies focused on the hepatitis C virus (HCV) must be emphasized and worked to know the impacts on its epidemiologic dynamics. This research aims to provide a tool to evaluate and simulate alternatives by redefining policies meeting specific needs in each country towards the HCV elimination target by 2030. The development of a gamified model with 24 public health policies focused on HCV was conducted to evaluate the impact of measures in the disease epidemiologic dynamics. The Let's End HepC (LEHC) project encompassed key populations (people who inject drugs [PWID], prisoners, blood products and remnant population) in Austria and other countries, presenting prospects for every year from 2019 to 2030. The LEHC epidemiological model comprised an integrated solution for HCV, with adaptive conjoint analysis (ACA) and Markov chains constituting its main processes. Despite Austria's efforts towards achieving the HCV elimination goal by 2030, the LEHC model forecast quantitative analysis predicts that it is still not enough to meet the target; however, prospects are very optimistic if public health policies are adapted to the country's needs, being possible to achieve the goal as early as 2026. In Austria, the LEHC tool allowed to forecast the HCV elimination year anticipation to 2026, instead of being achieved after 2030. This target will only be valid if adequate management of the 24 public health policies focused on this pathology is further implemented.


Assessing Patients' Satisfaction With Hydrogen Peroxide Topical Solution, 40% for Treatment of Raised Seborrheic Keratoses.
Assess participants' satisfaction following treatment with a proprietary hydrogen peroxide topical solution 40%, w/w (HP40) for raised seborrheic keratoses (SKs). In this Phase 4, open-label study, eligible participants aged 30–75 years had clinically typical raised SKs including 2 target SKs (Physician's Lesion Assessment™ [PLA] grade of ≥2 [0 = clear; 1 = near clear; 2 = thin (≤1 mm); 3 = thick (>1 mm)]; 5–15 mm diameter) on the face and 1 target SK on the neck or décolletage. SKs received HP40 treatment on day 1. All SKs with PLA grade ≥1 were retreated on days 15 and 29. Endpoints included patients' satisfaction with their skin's appearance at day 113, relationships between patients' satisfaction and lesion PLA grade (evaluated by chi-square test), and patients' satisfaction with their treatment experience. Forty-one patients (mean [range] age, 62.4 [46–73] years) completed the study. 95% of patients were at least moderately satisfied with their skin's appearance and 90.2% of target lesions were clear. A statistically significant association was observed between the number of target lesions achieving clearance and patients' satisfaction with skin appearance level (χ2=22.03; P=0.001). 93% of patients were at least moderately satisfied with their HP40 treatment experience. Eight patients experienced treatment-emergent adverse events (TEAEs), most of which were mild or moderate; 4 experienced TEAEs considered treatment-related. Most patients with SKs on the face, neck, and décolletage were satisfied or very satisfied with both their skin's appearance and their treatment experience following HP40 treatment. These results support the use of HP40 for raised SKs. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.4974.


Oxidation of indometacin by ferrate (VI): kinetics, degradation pathways, and toxicity assessment.
The oxidation of indometacin (IDM) by ferrate(VI) (Fe(VI)) was investigated to determine the reaction kinetics, transformation products, and changes in toxicity. The reaction between IDM and Fe(VI) followed first-order kinetics with respect to each reactant. The apparent second-order rate constants (k app) decreased from 9.35 to 6.52 M-1 s-1, as the pH of the solution increased from 7.0 to 10.0. The pH dependence of k app might be well explained by considering the species-specific rate constants of the reactions of IDM with Fe(VI). Detailed product studies using liquid chromatography-tandem mass spectrometry (LC-MS/MS) indicated that the oxidation products were primarily derived from the hydrolysis of amide linkages, the addition of hydroxyl groups, and electrophilic oxidation. The toxicity of the oxidation products was evaluated using the Microtox test, which indicated that transformation products exhibited less toxicity to the Vibrio fischeri bacteria. Quantitative structure-activity relationship (QSAR) analysis calculated by the ecological structure activity relationship (ECOSAR) revealed that all of the identified products exhibited lower acute and chronic toxicity than the parent pharmaceutical for fish, daphnid, and green algae. Furthermore, Fe(VI) was effective in the degradation IDM in water containing carbonate ions or fulvic acid (FA), and in lake water samples; however, higher Fe(VI) dosages would be required to completely remove IDM in lake water in contrast to deionized water.


The question of futility and Roger C. Bone.
Medical futility, one of the most debated end-of-life issues in medical ethics, has been discussed among physicians and scholars for years but remained an unresolved question. Roger C. Bone (1941-1997), an outstanding pulmonologist and critical care specialist, devoted his last years to ethical issues of terminal care, while facing himself metastatic renal cancer. Criticising the abuse of technology in terminal care and the administrative and financial interference on medical decisions, he bequeathed important points on futility, bringing also patients' views into attention. He stressed the importance of physician-patient relationship and prompted physicians to remain honest with their patients and stand with them till their very last moments. Roger Bone's insight of futility, terminal care and physician-patient relationship remains an important legacy for health care professionals and for families and patients facing end-of-life issues.


Pediatric septorhinoplasty.
In the appropriately selected patient, septorhinoplasty can benefit a pediatric patient presenting with significant nasal trauma, abscess, or mass that will likely result in a progressive deformity in the growing nose or with negative functional or psychosocial effect. Clinical and experimental observations support a conservative approach to cartilage scoring and resection in pediatric patients in which septorhinoplasty is deemed necessary.


Uric acid metabolism in children.
The renal excretion of uric acid in children differs quantitatively, and perhaps qualitatively, from that in adult humans. The younger the child, the greater the renal clearance of uric acid and the greater the excretion of uric acid expressed as mg per kg body weight. During infancy, the reduced ability to maximally concentrate the urine may protect against precipitation of uric acid crystals within the kidney. Conversely, the extremely high urinary uric concentrations places the very small infant at jeopardy during sudden increases in the filtered load of uric acid. Understanding the pharmacologic and physiologic modulators of renal uric acid clearance will allow the pediatrician to minimize the risk of uric acid nephropathy, and to understand the implications of uric acid in the serum or urine in children with fluid and electrolyte disorders. Certainly evaluation of serum and urinary uric acid concentrations is essential in any child with acute renal failure.


Melatonin/nicotinamide mononucleotide/ubiquinol: a cocktail providing superior cardioprotection against ischemia/reperfusion injury in a common co-morbidities modelled rat.
The metabolic and intracellular abnormalities in aging and diabetes cause loss of cardioprotection by routine interventions against myocardial ischemia/reperfusion (I/R) injury. We aimed to evaluate the possible interaction of aging and type-2 diabetes mellitus with cardioprotection and the potential protective effect of a mitochondrial cocktail (melatonin/nicotinamide mononucleotide (NMN)/ubiquinol) on myocardial I/R injury in aged diabetic rats. Male Wistar rats (n = 108, 22-24 months old, 400-450 g) received high-fat diet/low dose of streptozotocin to induce type-2 diabetes, then were randomized into 9 groups of 12 rats each with/without I/R and/or melatonin, NMN, and ubiquinol, alone or in dual or triple combinations. Myocardial I/R was induced by LAD occlusion for 30 min followed by 24 h reperfusion. NMN (100 mg/kg/48 h, intraperitoneally) was administered for 28 days before I/R operation. Melatonin (10 mg/kg, intraperitoneally) and/or ubiquinol (30 mg/kg, intravenously) were administered at early reperfusion. Finally, hemodynamic index changes, infarct size, CK-MB levels, mitochondrial functional endpoints, and expression of mitochondrial biogenesis genes (SIRT-1/PGC-1α/NRF-2/TFAM) were assessed. The solo and dual applications of melatonin, NMN, and ubiquinol did not exert remarkable cardioprotective impacts. However, the triple combination improved myocardial function and decreased infarct size and CK-MB levels following myocardial I/R (P < .05 to P < .01). It also improved mitochondrial function and restored mitochondrial biogenesis genes (P < .01). Combination therapy with melatonin, NMN, and ubiquinol exerted significant cardioprotection and improved mitochondrial function and biogenesis via upregulation of SIRT-1/PGC-1α/NRF-2/TFAM profiles in aged diabetic rats and, thus, offers a promising strategy for providing noticeable cardioprotection against I/R injury also in aged diabetic patients.


Transcription factor E3 and transcription factor EB renal cell carcinomas: clinical features, biological behavior and prognostic factors.
Translocation renal cell carcinomas represent a distinct clinicopathological entity. Studying the natural history, biological behavior and potential prognostic factors are crucially warranted. We selected 54 patients with renal cell carcinoma with positive nuclear transcription factor E3 and transcription factor EB expression from the Juvenile RCC Network. Recurrence-free survival and overall survival were assessed. Median patient age was 24 years (range 1 to 64) and the male-to-female ratio was 1:1.4. At diagnosis 35 patients (65%) had local disease while 19 (35%) presented with distant metastases. The latter patients were older (median age 36 years) and predominantly male (male-to-female ratio 2) whereas the former group had a median age of 16 years and a male-to-female ratio of 1:2.5. Overall 36 patients underwent complete tumor resection and of these 8 had recurring cancer. On univariate analysis only lymph node involvement and American Joint Committee on Cancer stage were associated with poor recurrence-free survival. When stratified according to lymph node status age 25 years or older was found to predict relapse (p = 0.03). With a median followup of 19.2 months (range 1 to 58) 3-year overall survival was 14.3% in patients with distant metastasis and 70.6% in those without distant metastasis. Distant metastasis developed in the 2 patients with ASPSCR1-TFE3 fusion vs 1 of 11 with other fusion genes. Transcription factor E3 and transcription factor EB renal cell carcinoma display different clinical behavior according to gender and age. Lymph node involvement represents the only factor that predicts recurrence. ASPSCR1-TFE3 might be the most aggressive among the transcription factor E3 fusion genes.


Prognostic value and immune infiltration of a novel stromal/immune score-related P2RY12 in lung adenocarcinoma microenvironment.
Increasing evidence highlights the clinical implications of P2RY12 that belongs to the family of G-protein coupled receptors in carcinogenesis. Here, this study was designed to explore the associations between P2RY12 and tumor immune microenvironment of lung adenocarcinoma (LUAD). Based on 352 LUAD samples from The Cancer Genome Atlas (TCGA), stromal and immune scores of each sample were estimated by ESTIMATE algorithm. Differential expression analysis was presented between stromal/immune high- and low-score groups. Protein-protein interaction (PPI) was then constructed by STRING database. Univariate and multivariate Cox regression analysis was utilized to screen prognosis-related factors. Co-expressed genes of P2RY12 were analyzed, followed by functional enrichment analysis. Furthermore, the correlation between P2RY12 and immune cell infiltrations was estimated using the TIMER database. P2RY12 expression was validated between 37 pairs of LUAD and normal tissues using RT-qPCR and immunohistochemistry. After overexpressing P2RY12, the proliferation and migration of A549 cells was detected by CCK-8 and scratch test. 145 up- and 102 down-regulated stromal- and immune-related mRNAs were identified for LUAD. Based on 145 up-regulated mRNAs, a PPI network was conducted, consisting of 95 nodes and 210 relationship pairs. Ten hub genes were then identified. Among them, CCR8, CNR2, CXCR5, GPR18, GPR31 and P2RY12 were in association with overall survival of patients with LUAD. After adjusting other variables, P2RY12 expression was an independent prognostic factor for LUAD. 288 co-expressed genes of P2RY12 were determined and these co-expressed genes were primarily involved in immune-related biological processes or pathways. Moreover, P2RY12 was significantly correlated with M2 macrophage and dendritic cell infiltration. After validation, P2RY12 expression was significantly decreased in LUAD than normal tissues. Its overexpression distinctly suppressed proliferation and migration of A549 cells. Our findings suggest that P2RY12 is an immune infiltration-related prognostic marker for LUAD.


Treatment of acute monoblastic leukaemia by combination of recombinant human macrophage colony-stimulating factor and low dose of ara-C.
We present a patient with acute monoblastic leukaemia (AMoL) who achieved a complete remission on combination therapy with macrophage colony-stimulating factor (M-CSF) and low dose of cytosine arabinoside (ara-C). This 26-year-old man was admitted with a relapse of AMoL which proved refractory to several chemotherapeutic regimens. To kill dormant leukaemic cells, we administered 20 mg/m2 ara-C by continuous intravenous infusion and 800 x 10(4) unit M-CSF by 30 min drip intravenous infusion together for 14 d. The blasts disappeared, followed by a recovery of normal blood cells. The patient continued the complete remission for 5 months. This observation suggests that a combination M-CSF and a low dose of ara-C may be useful in treating some patients with AMoL.


Albumin as a blocking agent in studies of streptococcal adsorption to experimental salivary pellicles.
A procedure involving blocking with bovine albumin was useful for differentiating between streptococcal interactions with components of experimental salivary pellicles similar to those which form on teeth and potential interactions with uncoated areas of mineral.


A CRISPR toolbox to study virus-host interactions.
Viruses depend on their hosts to complete their replication cycles; they exploit cellular receptors for entry and hijack cellular functions to replicate their genome, assemble progeny virions and spread. Recently, genome-scale CRISPR-Cas screens have been used to identify host factors that are required for virus replication, including the replication of clinically relevant viruses such as Zika virus, West Nile virus, dengue virus and hepatitis C virus. In this Review, we discuss the technical aspects of genome-scale knockout screens using CRISPR-Cas technology, and we compare these screens with alternative genetic screening technologies. The relative ease of use and reproducibility of CRISPR-Cas make it a powerful tool for probing virus-host interactions and for identifying new antiviral targets.


Indigenous engagement in health: lessons from Brazil, Chile, Australia and New Zealand.
Given the persistence of Indigenous health inequities across national contexts, many countries have adopted strategies to improve the health of Indigenous peoples. Governmental recognition of the unique health needs of Indigenous populations is necessary for the development of targeted programs and policies to achieve universal health coverage. At the same time, the participation of Indigenous peoples in decision-making and program and policy design helps to ensure that barriers to health services are appropriately addressed and promotes the rights of Indigenous peoples to self-determination. Due to similar patterns of Indigenous health and health determinants across borders, there have been calls for greater global collaboration in this field. However, most international studies on Indigenous health policy link Anglo-settler democracies (Canada, Australia, Aotearoa/New Zealand and the United States), despite these countries representing a small fraction of the world's Indigenous people. This paper examines national-level policy in Australia, Brazil, Chile and New Zealand in relation to governmental recognition of differential Indigenous health needs and engagement with Indigenous peoples in health. The paper aims to examine how Indigenous health needs and engagement are addressed in national policy frameworks within each of the countries in order to contribute to the understanding of how to develop pro-equity policies within national health care systems. For each country, a review was undertaken of national policies and legislation to support engagement with, and participation of, Indigenous peoples in the identification of their health needs, development of programs and policies to address these needs and which demonstrate governmental recognition of differential Indigenous health needs. Government websites were searched as well as the following databases: Google, OpenGrey, CAB Direct, PubMed, Web of Science and WorldCat. Each of the four countries have adopted international agreements regarding the engagement of Indigenous peoples in health. However, there is significant variation in the extent to which the principles laid out in these agreements are reflected in national policy, legislation and practice. Brazil and New Zealand both have established national policies to facilitate engagement. In contrast, national policy to enable engagement is relatively lacking in Australia and Chile. Australia, Brazil and New Zealand each have significant initiatives and policy structures in place to address Indigenous health. However, in Brazil this is not necessarily reflected in practice and although New Zealand has national policies these have been recently reported as insufficient and, in fact, may be contributing to health inequity for Māori. In comparison to the other three countries, Chile has relatively few national initiatives or policies in place to support Indigenous engagement or recognise the distinct health needs of Indigenous communities. The adoption of international policy frameworks forms an important step in ensuring that Indigenous peoples are able to participate in the formation and implementation of health policy and programs. However, without the relevant principles being reflected in national legislature, international agreements hold little weight. At the same time, while a national legislative framework facilitates the engagement of Indigenous peoples, such policy may not necessarily translate into practice. Developing multi-level approaches that improve cohesion between international policy, national policy and practice in Indigenous engagement in health is therefore vital. Given that each of the four countries demonstrate strengths and weaknesses across this causal chain, cross-country policy examination provides guidance on strengthening these links.