Malignant pyoderma.
Malignant pyoderma is a destructive, ulcerating skin disease that occurs chiefly in young adults. Only eight cases of this rare disease have been reported. The head and neck have been involved in all cases, and a predilection for the periauricular region has been noted in several of the cases. Although the disease is progressive and chronic, responses to high-dose systemic corticosteroids have been noted, but usually a flare is associated with a reduction in dose. An additional case is described in which therapy with isotretinoin and sulfapyridine led to complete remission.


Surface tension and cloud point changes of polyoxyethylenic non-ionic surfactants during autoxidation.
Changes in the surface tension-concentration curves of the non-ionic surfactant cetomacrogol, a polyoxyethylenic (POE) hexadecyl ether containing about 24 ethylene oxide (EO) groups, have been examined during autoxidation of aqueous solutions. The curves exhibit decreases in cmc values and changes in the slopes below and above the cmc which lead to the loss of the sharp break characteristic of micelle-formation. There is also a progressive decrease in the cloud point during autoxidation. Surface tensions and cloud points of a series of known POE hexadecyl ethers containing from 10 to 60 EO units have been measured and related to the number of EO units present. From these data, it is apparent that autoxidation of cetomacrogol is accompanied by degradation of POE chain rather than the hydrocarbon chain, the number of EO units lost up to the time at which the solution becomes turbid being about 14. The significance of such measurements is discussed in relation to the detection of decomposition and pending rapid decomposition in synthesized and commercial surfactants.


Effects of cigarette smoking status on delay discounting in schizophrenia and healthy controls.
Delay discounting is a measure of future-oriented decision-making and impulsivity. Cigarette smoking is associated with rapid discounting of the value of delayed outcomes. In schizophrenia, however, cigarette smoking improves certain neurocognitive impairments associated with the disorder which may explain the high smoking rates in this population. This study examined the relationship between cigarette smoking and delay discounting in schizophrenia and control participants. A total of N=130 participants, including those with schizophrenia (n=68) and healthy controls (n=62) were assessed on the Kirby Delay Discounting Task and compared across smoking status (smokers; non-smokers) and smoking history (current, former; never smokers). Smokers exhibited higher discounting rates (i.e., were more impulsive) than non-smokers of the same diagnostic group. Current and former smokers with schizophrenia exhibited similar and significantly higher discounting rates than never smokers, suggesting that in schizophrenia delay discounting is a trait-dependent phenomenon independent of current cigarette smoking. Consistent with previous studies, there was a trend for higher discounting rates in control current smokers compared to control former and never smokers. Smokers with and without schizophrenia have higher rates of delay discounting than non-smokers. However, in schizophrenia, rapid delay discounting appears to be a trait associated with having ever been a smoker (i.e., current and former smoking).


Pneumococcal colonization and invasive disease studied in a porcine model.
Streptococcus pneumoniae, a Gram-positive bacterium carried in the human nasopharynx, is an important human pathogen causing mild diseases such as otitis media and sinusitis as well as severe diseases including pneumonia, meningitis and sepsis. There is a strong resemblance between the anatomy, immunology and physiology of the pig and human species. Furthermore, there are striking similarities between S. suis pathogenesis in piglets and S. pneumoniae pathogenesis in humans. Therefore, we investigated the use of piglets as a model for pneumococcal colonization and invasive disease. Intravenous inoculation of piglets with an invasive pneumococcal isolate led to bacteraemia during 5 days, showing clear bacterial replication in the first two days. Bacteraemia was frequently associated with fever and septic arthritis. Moreover, intranasal inoculation of piglets with a nasopharyngeal isolate led to colonization for at least six consecutive days. This demonstrates that central aspects of human pneumococcal infections can be modelled in piglets enabling the use of this model for studies on colonization and transmission but also on development of vaccines and host-directed therapies. Moreover this is the first example of an animal model inducing high levels of pneumococcal septic arthritis.


Three-dimensional structural analysis of papillary thyroid carcinoma nuclei with serial block-face scanning electron microscopy (SBF-SEM).
Nuclear morphology of carcinoma cells is critical for the pathological diagnosis of papillary thyroid carcinoma (PTC). However, three-dimensional architecture of PTC nuclei is still elusive. In this study, we analyzed the three-dimensional ultrastructure of PTC nuclei using serial block-face scanning electron microscopy which takes advantage of the high-throughput acquisition of serial electron microscopic images and three-dimensional reconstruction of subcellular structures. En bloc-stained and resin-embedded specimens were prepared from surgically removed PTCs and normal thyroid tissues. We acquired two-dimensional images from serial block-face scanning electron microscopy and reconstructed three-dimensional nuclear structures. Quantitative comparisons showed that the nuclei of carcinoma cells were larger and more complex than those of normal follicular cells. The three-dimensional reconstruction of carcinoma nuclei divided intranuclear cytoplasmic inclusions into "open intranuclear cytoplasmic inclusions" connecting to cytoplasm outside the nucleus and "closed intranuclear cytoplasmic inclusions" without that connection. Cytoplasm with abundant organelles was observed in open inclusions, but closed inclusions contained fewer organelles with or without degeneration. Granules with a dense core were only observed in closed inclusions. Our observations suggested that open inclusions originate from nuclear invaginations, and disconnection from cytoplasm leads to closed inclusions.


Comparison of 3H-spiperone binding in caudate nuclei of rabbits and rats.
3H-Spiperone binding and inhibition by competing ligands were studied in caudate nucleus homogenates from Sprague-Dawley rats and New Zealand albino rabbits. 3H-Spiperone binding sites were very similar in the two species and had pharmacological profiles characteristic of D2-dopamine receptors, in accordance with previous reports. However, differences occurred between the species in the potencies with which dopaminergic ergots and other drugs interacted with these binding sites and with regard to the compounds used to define specific binding. These findings suggest that slight differences in relative proportions of subtypes of 3H-spiperone binding sites, or of neuroleptic potencies at these subtypes, may exist between rabbits and rats.


Telemedicine and the environment: life cycle environmental emissions from in-person and virtual clinic visits.
Concern over climate change is growing in the healthcare space, and telemedicine has been rapidly expanding since the start of the COVID19 pandemic. Understanding the various sources of environmental emissions from clinic visits-both virtual and in-person-will help create a more sustainable healthcare system. This study uses a Life Cycle Assessment with retrospective clinical data from Stanford Health Care (SHC) in 2019-2021 to determine the environmental emissions associated with in-person and virtual clinic visits. SHC saw 13% increase in clinic visits, but due to the rise in telemedicine services, the Greenhouse Gas emissions (GHGs) from these visits decreased 36% between 2019 and 2021. Telemedicine (phone and video appointments) helped SHC avoid approximately 17,000 metric tons of GHGs in 2021. Some departments, such as psychiatry and cancer achieved greater GHG reductions, as they were able to perform more virtual visits. Telemedicine is an important component for the reduction of GHGs in healthcare systems; however, telemedicine cannot replace every clinic visit and proper triaging and tracking systems should be in place to avoid duplicative care.


Spontaneous mutation in Big Blue mice from fetus to old age: tissue-specific time courses of mutation frequency but similar mutation types.
Transgenic mouse mutation detection systems permit rapid determination of the frequency and type of mutations allowing direct examination of mutational markers for aging, neurodegeneration, and cancer. The Big Blue transgenic mouse mutation detection system was used to determine the frequency and nature of spontaneous mutations versus age in multiple tissue types. Nuclear DNA was extracted from whole fetus at 13.5 days postcoitus (dpc) and from six tissues postbirth (cerebellum, forebrain, thymus, liver, adipose tissue, and male germline) of Big Blue transgenic mice at four ages: 10 days and at 3, 10, and 25 months postbirth. Forty million total plaque-forming units (pfu) were screened. The time course of mutation frequency with age had a significantly different shape in different tissues (P < 10(-6)). By 13.5 dpc, the whole fetus mutation frequency had already started increasing from the theoretical zero at conception to a value that was about one-half the mid-adulthood (3-10 months) average. From 10 days to 3 months, mutation frequency increased significantly in liver (P = 0.007) and showed an increasing trend in cerebellum, forebrain, and thymus. From 3 to 10 months, there was no significant change in mutation frequency in any tissue examined. From 10 to 25 months, the mutation frequency increased significantly in liver (P < 10(-6)) and adipose tissue (P = 0.002), but not in the other tissues examined (cerebellum, forebrain, and male germline). It is of interest that the mutation frequency in the male germline is consistently the lowest, remaining essentially unchanged in old age. The spectrum of mutation types was unaltered with age, tissue type and gender, although, as previously reported, tandem GG-->TT mutations are tissue specific and show significant increases with age and certain hotspots (Buettner VL et al. [1999]: Environ Mol Mutagen 33:320-324; Hill KA et al. [2003]: Mutat Res 534:173-186). The spectrum of mutation types was generally the same for all tissue types, despite the tissue-specific increases in mutation frequency with age. These data provide a useful reference for future studies of endogenous and exogenous mutagenesis.


[Interdisciplinary consensus to management of lupus nephritis in Germany].
In October 2006 a German ad hoc committee consisting of rheumatologists and nephrologists developed a consensus statement on the current practice in the management of lupus nephritis. The published results are summarized.


Ultrasound-aided pH-shift processing for resource-smart valorization of salmon and herring side streams.
The possibility of reducing the amount of fresh water used during alkaline the pH-shift processing of salmon head (SH) and herring frame (HF) was evaluated with ultrasound (US) as a tool to mitigate its negative effects on protein yield. The role of water ratio and US for homogenate viscosity, mass yield, crude composition, functional properties and lipid oxidation of the SH and HF protein isolates were also investigated. Applying US during the solubilization step of the pH-shift process completely compensated for the reduced protein yield coming from using 3 rather than 6 volumes of water for HF, but not for SH. Using US had no negative effect on the composition and protein functionality of the HF protein isolate. However, it slightly increased its level of secondary lipid oxidation products. Altogether, applying US during the pH-shift processing at low water ratios can be a promising solution for more resource-smart valorization of herring side streams.


Identification, nuclear localization, and DNA-binding activity of the zinc finger protein encoded by the Evi-1 myeloid transforming gene.
Activation of the Evi-1 zinc finger gene is a common event associated with transformation of murine myeloid leukemias. To characterize the gene product, we developed antisera against various protein domains. These antisera primarily detected a 145-kilodalton nuclear protein that bound double-stranded DNA. Binding was inhibited by chelating agents and partially restored by zinc ions.


Radiofrequency ablation therapy combined with cementoplasty for painful bone metastases: initial experience.
The purpose of this study was to assess the efficacy and safety of percutaneous radiofrequency (RF) ablation therapy combined with cementoplasty under computed tomography and fluoroscopic guidance for painful bone metastases. Seventeen adult patients with 23 painful bone metastases underwent RF ablation therapy combined with cementoplasty during a 2-year period. The mean tumor size was 52 x 40 x 59 mm. Initial pain relief, reduction of analgesics, duration of pain relief, recurrence rate of pain, survival rate, and complications were analyzed. The technical success rate was 100%. Initial pain relief was achieved in 100% of patients (n=17). The mean VAS scores dropped from 63 to 24 (p<0.001) (n=8). Analgesic reduction was achieved in 41% (7 out of 17 patients). The mean duration of pain relief was 7.3 months (median: 6 months). Pain recurred in three patients (17.6%) from 2 weeks to 3 months. Eight patients died and 8 patients are still alive (a patient was lost to follow-up). The one-year survival rate was 40% (observation period: 1--30 months). No major complications occurred, but one patient treated with this combined therapy broke his right femur 2 days later. There was transient local pain in most cases, and a hematoma in the psoas muscle (n=1) and a hematoma at the puncture site (n=1) occurred as minor complications. Percutaneous RF ablation therapy combined with cementoplasty for painful bone metastases is effective and safe, in particular, for bulky tumors extending to extraosseous regions. A comparison with cementoplasty or RF ablation alone and their long-term efficacies is needed.


Comparable Patency of Open and Hybrid Treatment of Venous Anastomotic Lesions in Thrombosed Haemodialysis Grafts.
Arteriovenous graft (AVG) failures are typically associated with venous anastomotic (VA) stenosis. Current evidence regarding AVG thrombosis management compares surgical with purely endovascular techniques; few studies have investigated the "hybrid" intervention that combines surgical balloon thrombectomy and endovascular angioplasty and/or stenting to address VA obstruction. This study aimed to describe outcomes after hybrid intervention compared with open revision (patch venoplasty or jump bypass) of the VA in thrombosed AVGs. Retrospective cohort study. Consecutive patients with a thrombosed AVG who underwent thrombectomy between January 2014 and July 2018 were divided into open and hybrid groups based on VA intervention; patients who underwent purely endovascular thrombectomy were excluded. Patient demographics, previous access history, central vein patency, AVG anatomy, type of intervention, and follow up data were recorded. Kaplan-Meier curves were used to analyse time from thrombectomy to first re-intervention (primary patency) and time to abandonment (secondary patency). Cox regression analysis was performed to evaluate predictors of failure. This study included 97 patients (54 females) with 39 forearm, 47 upper arm, and 11 lower extremity AVGs. There were 34 open revisions (25 patches, nine jump bypasses) and 63 hybrid interventions, which included balloon angioplasty ± adjunctive procedures (15 stents, five cutting balloons). Technique selection was based on physician preference. Primary patency for the open and hybrid groups was 27.8% and 34.2%, respectively, at six months and 17.5% and 12.9%, respectively, at 12 months (p = .71). Secondary patency was 45.1% and 38.5% for open and hybrid treatment, respectively, at 12 months (p = .87). An existing VA stent was predictive of graft abandonment (hazard ratio 4.4, 95% confidence interval 1.2-16.0; p = .024). Open vs. hybrid intervention was not predictive of failure or abandonment. Hybrid interventions for thrombosed AVGs are not associated with worse patency at six and 12 months compared with open revision.


Saturated fatty acid palmitate aggravates neointima formation by promoting smooth muscle phenotypic modulation.
Obesity is a major risk factor of atherosclerotic cardiovascular disease. Circulating free fatty acid levels are known to be elevated in obese individuals and, along with dietary saturated fatty acids, are known to associate with cardiovascular events. However, little is known about the molecular mechanisms by which free fatty acids are linked to cardiovascular disease. We found that administration of palmitate, a major saturated free fatty acid, to mice markedly aggravated neointima formation induced by carotid artery ligation and that the neointima primarily consisted of phenotypically modulated smooth muscle cells (SMCs). In cultured SMCs, palmitate-induced phenotypic modulation was characterized by downregulation of SMC differentiation markers, such as SM α-actin and SM-myosin heavy chain, and upregulation of mediators involved in inflammation and remodeling of the vessel wall, such as platelet-derived growth factor B and matrix metalloproteinases. We also found that palmitate induced the expression of proinflammatory genes via a novel toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor-κB/NADPH oxidase 1/reactive oxygen species signaling pathway: nuclear factor-κB was activated by palmitate via toll-like receptor 4 and its adapter, MyD88, and once active, it transactivated Nox1, encoding NADPH oxidase 1, a major reactive oxygen species generator in SMCs. Pharmacological inhibition and small interfering RNA-mediated knockdown of the components of this signaling pathway mitigated the palmitate-induced upregulation of proinflammatory genes. More importantly, Myd88 knockout mice were resistant to palmitate-induced exacerbation of neointima formation. Palmitate seems to promote neointima formation by inducing inflammatory phenotypes in SMCs.


Developmental risk I: depression and the developing brain.
This article discusses recent findings on the neurobiology of pediatric depression as well as the interplay between genetic and environmental factors in determining the risk for the disorder. Utilizing data from both animal and human studies, the authors focus on the evolving understanding of the developmental neurobiology of emotional regulation, cognitive function and social behavior as it applies to the risk and clinical course of depression. Treatment implications and directions for future research are also discussed.


Associations Between Resting-State Functional Connectivity and a Hierarchical Dimensional Structure of Psychopathology in Middle Childhood.
Previous research from the Adolescent Brain Cognitive Development (ABCD) Study delineated and validated a hierarchical 5-factor structure with a general psychopathology (p) factor at the apex and 5 specific factors (internalizing, somatoform, detachment, neurodevelopmental, externalizing) using parent-reported child symptoms. The present study is the first to examine associations between dimensions from a hierarchical structure and resting-state functional connectivity (RSFC) networks. Using 9- to 11-year-old children from the ABCD Study baseline sample, we examined the variance explained by each hierarchical structure level (p-factor, 2-factor, 3-factor, 4-factor, and 5-factor models) in associations with RSFC. Analyses were first conducted in a discovery dataset (n = 3790), and significant associations were examined in a replication dataset (n = 3791). There were robust associations between the p-factor and lower connectivity within the default mode network, although stronger effects emerged for the neurodevelopmental factor. Neurodevelopmental impairments were also related to variation in RSFC networks associated with attention to internal states and external stimuli. Analyses revealed robust associations between the neurodevelopmental dimension and several RSFC metrics, including within the default mode network, between the default mode network with cingulo-opercular and "Other" (unassigned) networks, and between the dorsal attention network with the Other network. The hierarchical structure of psychopathology showed replicable links to RSFC associations in middle childhood. The specific neurodevelopmental dimension showed robust associations with multiple RSFC metrics. These results show the utility of examining associations between intrinsic brain architecture and specific dimensions of psychopathology, revealing associations especially with neurodevelopmental impairments.


A branch and efficiency algorithm to design a sustainable two-echelon supply chain network considering traffic congestion and uncertainty.
This work aims to design a sustainable two-echelon supply chain not only based on the widely used cost perspective, but also based on the efficient use and preservation of limited resources. For this purpose, a branch and efficiency (B&E) algorithm is developed, which includes an optimization model and an evaluation model. The proposed tri-objective optimization model simultaneously minimizes the total cost of the supply chain, maximizes the sustainability score, and minimizes inequity among customers. The solutions obtained from the optimization model are then evaluated by extended data envelopment analysis (EDEA) models based on common criteria (i.e., cost and service) and traffic congestion criterion. To take into account real-world conditions, parameters related to labor and demand are assumed under uncertainty. Since the presented models consist of more than one objective function, fuzzy goal programming (FGP) method is utilized to tread the multi-objectiveness. The obtained results from tackling a case study problem demonstrate that considering sustainability issues can positively affect both the economic and social aspects of the problem. Furthermore, the developed B&E algorithm is able to reduce costs in each iteration; this is what supply chain managers are interested in. On the other hand, this algorithm can provide more services to applicants compared to one of the competing algorithms.


Energy efficient IRS assisted 6G network for Industry 5.0.
The real world applications are more prone to difficulties of challenges due to fast growth of technologies and inclusion of artificial intelligence (AI) based logical solutions. The massive internet-of-things (IoT) devices are involved in number of Industry 5.0 applications like smart healthcare, smart manufacturing, smart agriculture, smart transportation. Advanced wireless techniques, customization of services and different technologies are experiencing a major transformation. The desire to increase the communication reliability without adding energy overhead is the major challenge for massive IoT enabled networks. To cope up with the above challenges, Industry 5.0 requirements needs to be monitored at the remote level which again adds on the communication challenge. Use of relays in 6G based wireless networks is denied due to high requirement of energy. Therefore in this paper, Intelligent reflecting surfaces (IRSs) assisted energy constrained 6G wireless networks are studied. To provide seamless connection between the communicating mobile nodes, IRS with an array of reflecting elements are configured in the system set up. A use-case scenario of IRS enabled network in Internet-of-Underwater things (IoUT) for smart ocean transportation is also provided. The IRS assisted wireless network is evaluated for target rates achieved. A power consumption model of the IRS supported system is also proposed to optimise the energy efficiency of the system. Further, the paper evaluates the impact of number of reflecting elements N on the IRS and the phase resolution b of each element on the system performance. The energy efficiency improves by 20% for IRS with [Formula: see text] with [Formula: see text] over IRS with [Formula: see text].


Growth and differentiation factor-15 as a potential prognostic biomarker for status-epilepticus-associated-with-fever: A pilot study.
Biomarkers predicting poor outcomes of status-epilepticus-associated-with-fever (SEF) at an early stage may contribute to treatment guidance. However, none have been reported thus far. We investigated the dynamics of serum growth and differentiation factor (GDF)-15 after seizure onset in patients with SEF and determined whether GDF-15 can predict poor outcomes, particularly in the first 6 h after seizure onset. We enrolled 37 pediatric patients with SEF and eight patients with simple febrile seizures (SFS) and collected their blood samples within 24 h of seizure onset and eight febrile control patients between March 1, 2017 and September 30, 2020. All patients were aged ≤15 years. In the SEF group, the median post-seizure serum GDF-15 values were 1,065 (<6h), 2,720 (6-12 h), and 2,411 (12-24 h) pg/mL. The median serum GDF-15 in the first 6 h was measured in patients with SEF without a significant past medical history (n = 21) and was found to be statistically significantly higher (1,587 pg/mL) than in the febrile control (551 pg/mL) and SFS (411 pg/mL) groups. The median serum GDF-15 was statistically significantly higher in patients with SEF with sequelae (n = 5) and patients with acute encephalopathy with biphasic seizures/reduced diffusion/hemorrhagic shock and encephalopathy syndrome (n = 6) than in patients with SEF without sequelae (n = 16) (15,898 vs 756 pg/mL) and patients with prolonged FS (n = 15) (9,448 vs 796 pg/mL). This study demonstrates the dynamics of serum GDF-15 in patients with SEF and indicates the potential of GDF-15 as an early predictor of poor outcomes.


Variations in Pu isotopic composition in soils from the Spitsbergen (Norway): Three potential pollution sources of the Arctic region.
Although the polar regions have not been industrialised, numerous contaminants originating from human activity are detectable in the Arctic environment. This study reports evidence of 240Pu/239Pu atomic ratios in the tundra and initial soils from different parts of west and central Spitsbergen and recognizes possible environmental inputs of non-global fallout Pu. The average atomic ratio of 240Pu/239Pu equal to 0.179 (ranging between 0.129 and 0.201) in tundra soils are comparable to the characteristic ratio for global fallout (0.180). However, the 240Pu/239Pu atomic ratios in the initial soils from proglacial zone of glaciers change within wide range between 0.1281 and 0.234 with the mean value of 0.169. By combining alpha and mass spectrometry, the three-sources model was used to identify the Pu sources in initial soils. Our study indicated that the main source of Pu is nuclear tests and that a second source with lower Pu ratio may come from weapons grade Pu (unexploded weapons grade Pu ie. material from bomb which didn't undergo nuclear explosions for example for security tests). Additionally, we found samples with high 238Pu/239+240Pu activity ratios and with typical global fallout 240Pu/239Pu atomic ratios, which are associated with separate sources of pure 238Pu from the SNAP-9A satellite burn up in the atmosphere.


Determinants of Dutch parents' decisions to vaccinate their child.
This study examines the factors that influence parents' decisions to have their children vaccinated under the Dutch National Immunisation Programme. A computer questionnaire was sent to 500 parents in 1999 (the response rate was 98.2%). The intention to vaccinate was most strongly determined by attitudes. The belief that vaccination is safe and the best way to protect children against infectious diseases positively influenced parents' attitudes. The idea that children receive too many vaccines simultaneously and that vaccination interferes with natural development had a negative effect on attitudes. Dutch parents believe that doctors only inform them about the benefits of vaccination and disregard possible drawbacks. Since attitudes did not appear to be the result of thorough deliberation, parents could easily be influenced by negative publicity about vaccination. Educational campaigns and practitioners' advice should provide complete information about all aspects of the question, enabling parents to make well-considered and therefore enduring decisions.


Environmental challenges related to cyanidation in Central American gold mining; the Remance mine (Panama).
Mine tailings are a potential source of environmental pollution because they typically contain potentially toxic elements (PTEs) and the residue of chemical compounds used during extraction processes. The Remance gold mine (NW Panama) is a decommissioned mine with mining activity records dating from the 1800s and several periods of abandonment. Very little remediation work has been performed, and waste is exposed to climatic conditions. This study aimed to evaluate the PTEs and cyanide contents in mine waste after mining operations ceased some 20 years ago, and to evaluate the degree of pollution and the environmental risks they pose with the use of the Pollution Load Index (PLI) and the Ecological Risk Index (RI). Although the total cyanide (T-CN) concentration (1.4-1.9 mg kg-1) found in most of the study area falls within the limits of gold mining tailing values for American sites (1.5-23 mg kg-1), it is worth noting that the values of the tailings of the last used mining operation exceed it (25.2-518 mg kg-1) and persist at the site. The PLI and RI suggest that the tailings from the mine and mine gallery sediments represent a source of pollution for soils and surrounding areas given their high content of PTEs (As, Cu, Sb, Hg) and T-CN, which pose serious ecological risks for biota. Therefore, it is necessary to draw up a remediation plan for this area.


Characterization of monoclonal antibodies that recognize the amino- and carboxy-terminal epitopes of the pseudorabies virus UL42 protein.
The pseudorabies virus (PRV) UL42 protein, known as the DNA polymerase processivity factor, is an essential protein required for viral replication. The in vitro function of UL42 has been characterized; however, there is little information concerning the linear B cell epitopes of UL42 that are recognized during humoral immune responses. We generated and characterized six UL42-reactive monoclonal antibodies (mAbs) from mice that had been immunized with a recombinant form of UL42. Through western blotting analysis, we identified two regions of UL42 (amino acids 39-148 and 302-384) that reacted with these mAbs. We then synthesized a panel of UL42-derived peptides spanning the two regions and screened the six mAbs. We were able to identify three linear epitopes ((116)SGGVLDALK(124), (354)KRPAAPR(360), and (360)RMYTPIAK(367)) by enzyme-linked immunosorbent assays. The (116)SGGVLDALK(124) epitope was located at the amino-terminus, while the other two epitopes were at the carboxy-terminus. Using these mAbs, we found that UL42 localized to the nucleus during viral replication and could be immunoprecipitated from PRV-infected PK-15 cells. We also established a UL42 mAb-based immunoperoxidase monolayer assay for the determination of PRV titers. Sequence analysis showed that the linear epitopes of UL42 were highly conserved among PRV strains. Taken together, our results indicate that the six generated mAbs could be useful tools for investigating the structure and function of UL42 during viral replication. In addition, these mAbs could be applied to diagnostic and therapeutic approaches for the effective control of PRV infections.


Identity and neuroanatomical localization of messenger RNAs that change expression in the neural tube of mouse embryos within 1 h after ethanol exposure.
Changes in the expression of various species of messenger RNA (mRNA) are likely to be one of the initial responses of an embryo to in utero ethanol exposure. However, the identity and range of the initial species of mRNAs that change expression in an embryo after acute prenatal ethanol exposure are unknown. mRNA was isolated from embryos treated on embryonic day 9.5 and examined 1 h after treatment. Ethanol-exposed embryos were compared to similarly treated maltose/dextrin and no injection control embryos. Subtractive hybridization was used to find the species of mRNAs. The identity of the differentially expressed mRNAs was ascertained using standard sequencing techniques while in situ hybridization defined the anatomical localization of each message. Four messages from ethanol-treated embryos were differentially expressed. One message has no homology to any known gene in GenBank while three messages are homologous to known genes: the transmembrane molecule mh19, the heterologous ribonuclear protein hnRNP A3, and the mitochondrial enzyme AK2. One message (the novel gene) was turned on, while mh19, AK2 and hnRNP A3 were up-regulated in ethanol-exposed embryos. All messages were expressed in the developing neural tube of the ethanol-exposed embryos, although there were differences in regional localization and extent of expression. Thus, the initial response of the embryo is rapid with changes in expression of multiple genes observed within 1 h after ethanol exposure. Further, these differentially expressed mRNAs are candidates for modulating the type and extent of ethanol-induced damage in the developing CNS.


Synthesis of Lewis X and three Lewis X trisaccharide analogues in which glucose and rhamnose replace N-acetylglucosamine and fucose, respectively.
Three analogues of the Le(x) trisaccharide: alpha-L-Fucp-(1-->3)-[beta-D-Galp-(1-->4)]-D-GlcNAcp as well as the Le(x) trisaccharide itself were synthesized as methyl glycosides. In the analogues, either only the fucose residue is replaced by rhamnose or both the N-acetylglucosamine and the fucosyl residues are replaced by glucose and rhamnose, respectively. Our synthetic strategy relied on the use of lactoside and 2-azido lactoside derivatives as disaccharide acceptors, which were submitted to either fucosylation or rhamnosylation. Our results confirm that the reactivity of lactose in protection and glycosylation reactions is greatly affected by (1) the structure of the aglycone and (2) the presence of an azido substituent at C-2 of the glucose moiety. Thus, a methyl lactoside acceptor was easily glycosylated at O-3 with perbenzylated beta-thiophenyl fucoside and rhamnoside to give anomerically pure alpha-fucosylated and alpha-rhamnosylated trisaccharides, respectively. In contrast, the same reactions on a 2-azido methyl lactoside acceptor led to the formation of anomeric mixtures. While the alpha- and beta-fucosylated 2-azido trisaccharides could be separated by RP-HPLC, such separation was not possible for the rhamnosylated anomers. The desired rhamnosylated trisaccharide was finally obtained anomerically pure using an isopropylidene-protected rhamnosyl donor. The deprotection sequences also showed that the presence of a 2-azido substituent at C-2 of the glucose residue conferred stability to the vicinal fucosidic linkage at C-3. To test their relative affinity for anti-Le(x) Abs the Le(x) analogues will be used as competitive inhibitors against methyl Le(x). In addition, their conformational behavior will be studied by NMR spectroscopy and molecular modeling experiments.


Identification of Salmonella enteritidis outer membrane proteins expressed during attachment to human intestinal epithelial cells.
To express and identify the Salmonella enterica ser. Enteritidis outer membrane proteins that are involved in the attachment to human intestinal epithelial cells. Salmonella Enteritidis attachment proteins were expressed by infection of human intestinal epithelial cells (int-407) with Salm. Enteritidis strain SE28, followed by pulse labelling with [35S]-methionine. Outer membrane proteins were separated by TritonX-114 phase partitioning, and were detected by Salm. Enteritidis-specific polyclonal antibody. Outer membrane proteins of molecular weights 82.3, 75.6, 49.3, 35.5 and 19.3 kDa were newly synthesized. Expression of 31.2 and 16 kDa proteins was up-regulated, whereas the expression of 40.7 kDa protein was down-regulated. Polyclonal antibodies against the 82.3 and 75.6 kDa proteins significantly (P < 0.05) reduced the binding of Salm. Enteritidis to int-407 cells in vitro. Outer membrane proteins 82.3 and 75.6 kDa are potentially involved in the attachment of Salm. Enteritidis to the intestinal mucosa. Outer membrane proteins 82.3 and 75.6 kDa identified in this study could be used as potential vaccines to block or reduce Salm. Enteritidis colonization in chickens.


The Effects of Light-Accelerated Degradation on the Aggregation of Marketed Therapeutic Monoclonal Antibodies Evaluated by Size-Exclusion Chromatography With Diode Array Detection.
Research into the effects that exposure to light can have on therapeutic proteins is essential for ensuring the quality and safety of the medicines in which they are used. It is important to understand the effects of light on aggregation to help avoid undesirable colloidal instabilities, both in the original medicines and in the formats in which they are finally administered. In this study, 5 marketed therapeutic mAbs, namely bevacizumab, cetuximab, infliximab, rituximab, and trastuzumab, were investigated for this purpose. The medicines and 2 diluted preparations in 0.9 NaCl (2 mg/mL and 5 mg/mL)-commonly used in clinical practice-were subjected to controlled light-accelerated degradation. The formation of aggregates was monitored by size-exclusion chromatography. The results indicated that light induced protein aggregation. This process of protein damage was influenced above all by mAb concentration, although the particular characteristics of each mAb were also important. Photodegradation also produced the fragmentation of the mAbs. The damage caused to the mAbs as a result of light-induced aggregation and/or fragmentation was demonstrated both in the medicines and in the diluted preparation forms. These findings should be carefully considered when handling the medicines for administration and when recommending beyond-use dates in normal hospital conditions.


Sinus node reentrant tachycardia.
This review article discusses the electrophysiological basis of sinus node reentry, clinical features of sinus node reentry, and the management of this uncommon tachycardia with drugs and ablative therapy. It also proposes the use of the term "sinoatrial reentrant tachycardia" for this form of tachycardia.


The RETRIEVE trial: safety and effectiveness of the retrievable crux vena cava filter.
To evaluate the safety and effectiveness of the Crux vena cava filter in patients at risk for pulmonary embolism (PE). The Crux Biomedical Evaluation of the Crux Inferior Vena Cava Filter System trial was an international prospective, multicenter, single-arm clinical trial in 125 patients implanted with the Crux filter between June 2010 and June 2011. Follow-up was 180 days after filter placement and 30 days after filter retrieval. The primary objective was to determine whether the clinical success rate was at least 80%. Clinical success was defined as technical success of deployment and freedom from definite PE, filter migration, and device-related adverse events requiring intervention. The clinical success rate was 96.0% (120 of 125), with a one-sided lower limit of the 95% confidence interval of 91.8%. The rate of technical success was 98.4% (123 of 125). There were three cases of definite PE (2.4%), two cases of deployment failure, and no cases of device migration, embolization, fracture, or tilting. Investigators observed nine cases of thrombus (all nonocclusive) in or near the filter (six during retrieval evaluation vena cavography, two during computed tomography [CT] scans for PE symptoms, and one during CT for cancer management) and 13 cases of deep vein thrombosis. Device retrieval was attempted at a mean of 84.6 days±57.6 (range, 6-190 d) after implantation and was successful for 98.1% of patients (53 of 54). All deaths (n = 14) were determined to be unrelated to the filter or PE. The Crux vena cava filter performed safely, with high rates of clinical, technical, and retrieval success.


Airflow dynamics of coughing in healthy human volunteers by shadowgraph imaging: an aid to aerosol infection control.
Cough airflow dynamics have been previously studied using a variety of experimental methods. In this study, real-time, non-invasive shadowgraph imaging was applied to obtain additional analyses of cough airflows produced by healthy volunteers. Twenty healthy volunteers (10 women, mean age 32.2±12.9 years; 10 men, mean age 25.3±2.5 years) were asked to cough freely, then into their sleeves (as per current US CDC recommendations) in this study to analyze cough airflow dynamics. For the 10 females (cases 1-10), their maximum detectable cough propagation distances ranged from 0.16-0.55 m, with maximum derived velocities of 2.2-5.0 m/s, and their maximum detectable 2-D projected areas ranged from 0.010-0.11 m(2), with maximum derived expansion rates of 0.15-0.55 m(2)/s. For the 10 males (cases 11-20), their maximum detectable cough propagation distances ranged from 0.31-0.64 m, with maximum derived velocities of 3.2-14 m/s, and their maximum detectable 2-D projected areas ranged from 0.04-0.14 m(2), with maximum derived expansion rates of 0.25-1.4 m(2)/s. These peak velocities were measured when the visibility of the exhaled airflows was optimal and compare favorably with those reported previously using other methods, and may be seen as a validation of these previous approaches in a more natural setting. However, the propagation distances can only represent a lower limit due to the inability of the shadowgraph method to visualize these cough airflows once their temperature cools to that of the ambient air, which is an important limitation of this methodology. The qualitative high-speed video footage of these volunteers coughing into their sleeves demonstrates that although this method rarely completely blocks the cough airflow, it decelerates, splits and redirects the airflow, eventually reducing its propagation. The effectiveness of this intervention depends on optimum positioning of the arm over the nose and mouth during coughing, though unsightly stains on sleeves may make it unacceptable to some.


Head and neck manifestations of Beckwith-Wiedemann syndrome.
Beckwith-Wiedemann syndrome is a congenital disorder manifested by organomegaly, omphalocele, hypoglycemia, and macroglossia. We have found a significant number of these children to be at risk for upper airway obstruction during infancy or childhood. In this review of 13 children, 2 required tracheotomy during infancy for cor pulmonale caused by macroglossia. Seven of nine children older than 1 year required tonsillectomy and adenoidectomy to relieve upper airway obstruction. Although macroglossia can be a cause of airway obstruction in infants with Beckwith-Wiedemann syndrome, we have found that airway obstruction during childhood is related to tonsillar and adenoidal hypertrophy and not to macroglossia. Anterior tongue reduction is reserved for the correction of malocclusion, articulation errors, or cosmesis, whereas tonsillectomy and adenoidectomy may be curative of obstructive symptoms.


Bis(benzo[h]quinolin-10-olato-κ2 N,O)bromidomanganese(III).
The title compound, [MnBr(C13H8NO)2], consists of a manganese(III) atom, which is coordinated by one bromido and two benzo[h]quinolin-10-olato ligands. The MnIII complex exhibits a distorted square-pyramidal coordination geometry with the Br ligand in the apical position. Neighbouring complexes are held together by π-π inter-actions and weak C-H⋯Br hydrogen bonds.


The mechanics of the primary cilium: an intricate structure with complex function.
The primary cilium is a non-motile singular cellular structure that extends from the surface of nearly every cell in the body. The cilium has been shown to play numerous roles in maintaining tissue homeostasis, through regulating signaling pathways and sensing both biophysical and biochemical changes in the extracellular environment. The structural performance of the cilium is paramount to its function as defective cilia have been linked to numerous pathologies. In particular, the cilium has demonstrated a mechanosensory role in tissues such as the kidney, liver, endothelium and bone, where cilium deflection under mechanical loading triggers a cellular response. Understanding of how cilium structure and subsequent mechanical behavior contributes to the roles that cilium plays in regulating cellular behavior is a compelling question, yet is a relatively untouched research area. Recent advances in biophysical measurements have demonstrated the cilium to be a structurally intricate organelle containing an array of load bearing proteins. Furthermore advances in modeling of this organelle have revealed the importance of these proteins at regulating the cilium's mechanosensitivity. Remarkably, the cilium is capable of adapting its mechanical state, altering its length and possibly it's bending resistance, to regulate its mechanosensitivity demonstrating the importance of cilium mechanics in cellular responses. In this review, we introduce the cilium as a mechanosensor; discuss the advances in the mechanical modeling of cilia; explore the structural features of the cilium, which contribute to its mechanics and finish with possible mechanisms in which alteration in structure may affect ciliary mechanics, consequently affecting ciliary based mechanosensing.


Optical spin-to-orbital plasmonic angular momentum conversion in subwavelength apertures.
Within the framework of the Huygens-Fresnel approach, we evaluate the coherent superposition of surface plasmon (SP) modes excited by an incident circularly polarized light propagating through an array of subwavelength holes. Numerical results of the plasmonic distribution exhibit a rich structure that reveals the creation and annihilation of vortex arrays in the field phase. These phase singularities stem from total transfer of the spin angular momentum (AM) of the incident radiation to the orbital AM of the SP.


How early career pharmacists understand resilience - A qualitative study of experiences, challenges and strategies.
Resilience assists healthcare professionals in negotiating challenges, remaining positive when experiencing adversity, and in constructively dealing with difficult work situations and environments. There is increasing research about how early career healthcare professionals, understand and maintain resilience but little is known about support early career pharmacists may need and value. To explore early career pharmacists' understanding of resilience, their strategies to enhance and maintain resilience as healthcare professionals and to identify resilience-fostering programmes they perceive could be implemented to support them. Three focus groups and 12 semi-structured interviews with a total of 15 hospital pharmacists and 10 community pharmacists (both less than 3 years post-registration) were conducted. An inductive thematic analysis of transcripts was performed to identify main themes and subthemes. Pharmacists understood resilience as the capability to adapt to and learn from challenges and setbacks, which they can build through experience and exposure. Resilience in the workplace was challenged by their working environment and workload, which could lead to ego depletion, the transition from intern to registered pharmacist and working during the COVID-19 pandemic, which both added pressure and uncertainty to their role. Professional resilience was supported on individual, social and organisational levels and through self-care strategies. Pharmacists perceived mentorship and sharing experiences, experiential placements and constructive but challenging role play as potentially beneficial in building resilience during undergraduate studies and internship. Pharmacists defined resilience constructively and identified challenges testing but also strategies supporting their resilience in the workplace. Workplaces can support pharmacists by monitoring workload and workplace relationships, creating opportunities for peer and mentor support and by allowing pharmacists to implement their personal, individualised resilience maintaining strategies. Early career pharmacists' experiences and insights would be valuable when considering the design and implementation of resilience-fostering programmes.


Ramsay Hunt syndrome.
Ramsay Hunt syndrome is a viral infection that combines facial palsy and pinnal vesicular rash. To detail diagnostic criteria, treatment and prognosis in Ramsay Hunt syndrome. A retrospective study of 15 patients with Ramsay Hunt syndrome admitted to the ENT department of La Rabta Hospital (Tunis) from 2003 to 2009. The main presenting symptom was facial palsy associated with conchal vesicular rash. House-Brackmann classification of facial nerve function ranged from III to V. All patients were treated with acyclovir and corticosteroids. Mean follow-up was 8 months. Ten patients showed improvement in facial palsy, four had permanent palsy and one moved from grade IV to grade III. Ramsay Hunt syndrome involves severe dysfunction, with poorer facial nerve prognosis than in Bell's palsy.


Effect of ouabain on myocardial ultrastructure and cytoskeleton during the development of ventricular hypertrophy.
The aim of this work is to study cytoskeletal impairment during the development of ouabain-induced ventricular hypertrophy. Male Sprague-Dawley rats were treated with either ouabain or saline. Systolic blood pressure (SBP) was recorded weekly. At the end of the 3rd and 6th week, the rats were killed and cardiac mass index were measured. Hematoxylin-eosin and Sirius red staining were carried out and cardiac ultrastructure were studied using transmission electron microscopy. The mRNA level of Profilin-1, Desmin, PCNA, TGF-β(1) and ET-1 in the left ventricle were measured using real-time quantitative PCR while their protein levels were examined by Western blot or immunohistochemistry. After 3 weeks, there was no significant difference in the mean SBP, cardiac mass index, mRNA and protein expression of PCNA, TGF-β(1) and ET-1 between the two groups. However, ouabain-treated rats showed disorganized cardiac cytoskeleton with abnormal expression of Profilin-1 and Desmin. After 6 weeks, the cardiac mass index remained the same in the two groups while PCNA, TGF-β(1), and ET-1 have been upregulated in ouabain-treated rats. The cardiac cytoskeletal impairment was more severe in ouabain-treated rats with further changes of Profilin-1 and Desmin. Cytoskeletal abnormality is an ultra-early change during ouabain-induced ventricular hypertrophy, before the release of hypertrophic factors. Therapy for prevention of ouabain-induced hypertrophy should start at the early stage by preventing the cytoskeleton from disorganization.


Analysis of a new therapeutic target and construction of a prognostic model for breast cancer based on ferroptosis genes.
Breast cancer, which is the most common malignant tumor among women worldwide and an important cause of death in women. The existing prognostic model for patients with breast cancer is not accurate as breast cancer is resistant to commonly used antitumor drugs. Ferroptosis is a novel mechanism of programmed cell death that depends on iron accumulation and lipid peroxidation. Various studies have confirmed the role of ferroptosis in tumor regulation and ferroptosis is now considered to play an important role in breast cancer development. At present, the association between breast cancer prognosis and ferroptosis-related gene expression remains unclear. Further exploration of this research area may optimize the evaluation and prediction of prognosis of patients with breast cancer and finding of new therapeutic targets. In this study, clinical factors and the expression of multiple genes were evaluated in breast cancer samples from the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database database. Eleven prognostication-related genes (TP63, IFNG, MT3, ANO6, FLT3, PTGS2, SLC1A4, JUN, SLC7A5, CHAC1, and TF) were identified from differentially expressed genes to construct a survival prediction model, which showed a good prediction ability. KEGG pathway analysis revealed that immune-related pathways were the primary pathways. ssGSEA analysis showed significant differences in the distribution of certain immune-related cell subsets, such as CD8+T cells and B cells, and in the expression of multiple immune genes, including type II IFN response and APC coinhibition. In addition, 10 immune targets related to ferroptosis in breast cancer were found: CD276, CD80, HHLA2, LILRA2, NCR3LG1, NECTIN3, PVR, SLAMF9,TNFSF4, and BTN1A1. Using TCGA, new ferroptosis genes related to breast cancer prognosis were identified, a new reliable and accurate prognosis model was developed, and 10 new potential therapeutic targets different from the traditional targeted drugs were identified to provide a reference for improving the poor prognosis of patients with breast cancer.


Multicomponent synthesis of spiroisoxazolines.
A three-component one-pot procedure (3-MCR) was developed to assemble the spiroisoxazoline nucleus from commercially available materials. This new methodology affords the title compounds in high yields and without the use of chromatography.


Coronary collateral development during chronic ischemia: serial assessment using harmonic myocardial contrast echocardiography.
We sought to characterize collateral development in an experimental model of chronic myocardial ischemia by using myocardial contrast echocardiography (MCE). Coronary collaterals maintain myocyte viability during myocardial ischemia. The natural history and determinants of collateral development are difficult to study serially in vivo. The left anterior descending coronary artery (LAD) in nine dogs was encircled (day 0) with a hydraulic occluder and ameroid constrictor to enable reversible and gradual total LAD occlusion, respectively. Myocardial contrast echocardiography was performed using intravenous injection of perfluorocarbon gas-containing microbubbles during two-dimensional harmonic echocardiographic imaging. Myocardial contrast echocardiography images and radiolabeled microsphere flow measurements were obtained during transient LAD occlusion on day 0. Over the ensuing six weeks, MCE imaging was performed during LAD occlusion at 10-day intervals. Myocardial contrast echocardiography risk area size (expressed as a percent of the left ventricular short axis slice) decreased over the course of six weeks (32%+/-3% on day 0, 21% +/-3% at day 10, 5+/-3% at day 20, 1%+/-1% at day 30 and 1%+/-1% at day 42, p< or =0.001 vs. day 0). Radiolabeled microsphere-derived LAD flow, normalized to left circumflex flow, correspondingly increased between day 0 and day 42 (0.14+/-0.02 to 0.90+/-0.07, p<0.02). Collateral development occurs relatively early and rapidly in this chronic canine model. Myocardial contrast echocardiography using harmonic imaging and intravenous injection of microbubbles can uniquely track the spatial and temporal course of collateral growth, and may be a powerful tool for noninvasively mapping the efficacy of therapeutic angiogenic strategies in vivo.


Magnetohydrodynamic blood flow study in stenotic coronary artery using lattice Boltzmann method.
Cardiovascular diseases such as atherosclerosis are the first engender of death in the world. The malfunctioning of cardiovascular system is attributed mainly to hemodynamics. However, blood magnetic properties are of major haemodynamic interest, with significant clinical applications. The aim of this work is to study numerically the effect of high magnetic field on blood flow in stenotic artery. In this paper, a double population D2Q9 lattice Boltzmann model is proposed. Velocity and magnetic field are both solved using Lattice Boltzmann method with single relaxation time. Blood is considered homogeneous and Newtonian bio-magnetic fluid. The results of the proposed model are compared and validated by recent numerical and experimental studies in the literature and show good agreement. In this study, simulations are carried out for both hydrodynamics and magneto-hydrodynamics. For the magneto-hydrodynamic case, five values of Hartmann number of 10, 30, 50, 75 and 100 at Reynolds number of 400, 600 and 800 are investigated Results: The results show that velocity and recirculation zone increase with the increase of the degree of stenosis and Reynolds number. In addition, a considerable decrease in velocity, recirculation zones and pressure drop across the stenotic artery is noticed with the increase of Hartmann number. The suggested model is found to be effective and accurate in the treatment of magneto-hydrodynamic blood flow in stenotic artery. The found results can be used by clinicians in the treatment of certain cardiovascular disorders and in regulating blood flow movement, especially during surgical procedures.


Morphological characterization of vegetation by real-time three-dimensional transesophageal echocardiography in infective endocarditis: Prognostic impact.
Vegetation size is a prognostic predictor in infective endocarditis (IE) and guides surgical management. The aim of this study was to evaluate the accuracy of real-time 3-dimensional transesophageal echocardiography (RT3DTEE) compared to 2DTEE in the diagnosis and characterization of vegetation, as well as its potential clinical impact. Two hundred and three consecutive patients with IE were recruited (2009-2016) and retrospectively analyzed. Vegetation diameters and area from 68 patients were measured by 2DTEE and RT3DTEE at admission. The association between size and systemic embolisms was evaluated with logistic regression models. Differences in the discriminative power for the best dimensions' cutoff points were assessed by comparing the area under the ROC curves (AUC). Vegetation size and area were larger by RT3DTEE (P < 0.001) than by 2DTEE, and RT3DTEE was especially relevant in the characterization of nonfiliform vegetation, Morphology was strongly associated with friability, being sessile vegetation less likely to embolize, compared to filiform and raceme-shaped ones (15.4% vs 46% vs 50%). Major diameter by RT3DTEE had better embolic predictive performance than 2DTEE (AUC 0.76 [0.57-0.89] vs 0.71 [0.53-0.86]; P = 0.611). The best cutoff points associated with embolic events during the infection were 17 mm for RT3DTEE and 15 mm for 2DTEE. Based exclusively on vegetation size, the proportion of patients meeting a surgical indication according to current guidelines is higher using RT3DTEE. RT3DTEE allows a better characterization of IE vegetation than 2DTEE, what may have a clinical impact on surgical management and also prognostic due to a more accurate prediction of embolic risk.


c-Rel is essential for B lymphocyte survival and cell cycle progression.
c-Rel is a lymphoid-specific member of the NF-kappaB/Rel family of transcriptional factors. To investigate the role of c-Rel in B lymphocyte function, we generated a c-Rel(-/-) mouse via a gene targeting approach. Although early lymphocyte development is normal in c-Rel(-/-) mice, there are significantly fewer B cells displaying a memory (IgM/IgD-) phenotype. Upon immunization, c-Rel(-/-) mice generate fewer B cells with a germinal center (PNAhi) phenotype. In vitro, c-Rel(-/-) B cells proliferate poorly upon ligation of their surface IgM or CD40 receptors or when stimulated with either lipopolysaccharide (LPS) or T cell help. Early molecular events that precede proliferation, such as increases in RNA synthesis as well as IL-2 receptor alpha chain expression, are greatly diminished in c-Rel(-/-) B cells. Furthermore, c-Rel(-/-) B cells are impaired in the ability to receive survival signals generated by anti-IgM or LPS. In contrast, CD40-mediated cell survival is normal in c-Rel(-/-) B cells, suggesting the involvement of a survival-signaling pathway that is independent of c-Rel. When c-Rel (-/-) B cells are co-stimulated with either anti-IgM and CD40 or LPS and CD40, they are rendered capable of progressing through the cell cycle. Finally, co-culture experiments suggest that the defects observed in c-Rel(-/-) B cells are intrinsic to the cell and can not be rescued through either cell-cell contact or addition of soluble factors. Thus, c-Rel is requisite for differentiation to the germinal center and memory B cells in vivo and is required for the transduction of survival and cell cycle progression signals mediated by anti-IgM and LPS in vitro. Furthermore, while c-Rel is involved in CD40-induced proliferation, it is apparently dispensable for the survival signals transduced by CD40.


Characterization of the atypical karyotype of the black-winged kite Elanus caeruleus (Falconiformes: Accipitridae) by means of classical and molecular cytogenetic techniques.
The karyotype of the black-winged kite (Elanus caeruleus), a small diurnal raptor living in Africa, Asia and southern Europe, was studied with classical (G-, C-, R-banding, and Ag-NOR staining) and molecular cytogenetic methods, including primed in-situ labelling (PRINS) and fluorescence in-situ hybridization (FISH) with telomeric (TTAGGG) and centromeric DNA repeats. The study revealed that the genome size, measured by flow cytometry (3.1 pg), is in the normal avian range. However, the black-winged kite karyotype is particularly unusual among birds in having a moderate diploid number of 68 chromosomes, and containing only one pair of dot-shaped microchromosomes. Moreover, the macrochromosomes are medium-sized, with the Z and W gonosomes being clearly the largest in the set. C-banding shows that constitutive heterochromatin is located at the centromeric regions of all chromosomes, and that two pairs of small acrocentrics and the pair of microchromosomes are almost entirely heterochromatic and G-band negative. The distribution pattern of a centromeric repeated DNA sequence, as demonstrated by PRINS, follows that of C-heterochromatin. The localization of telomeric sequences by FISH and PRINS reveals many strong telomeric signals but no extratelomeric signal was observed. The atypical organization of the karyotype of the black-winged kite is considered in the context of the modes of karyotypic evolution in birds.


Randomized Comparison of Two Vaginal Self-Sampling Methods for Human Papillomavirus Detection: Dry Swab versus FTA Cartridge.
Human papillomavirus (HPV) self-sampling (self-HPV) is valuable in cervical cancer screening. HPV testing is usually performed on physician-collected cervical smears stored in liquid-based medium. Dry filters and swabs are an alternative. We evaluated the adequacy of self-HPV using two dry storage and transport devices, the FTA cartridge and swab. A total of 130 women performed two consecutive self-HPV samples. Randomization determined which of the two tests was performed first: self-HPV using dry swabs (s-DRY) or vaginal specimen collection using a cytobrush applied to an FTA cartridge (s-FTA). After self-HPV, a physician collected a cervical sample using liquid-based medium (Dr-WET). HPV types were identified by real-time PCR. Agreement between collection methods was measured using the kappa statistic. HPV prevalence for high-risk types was 62.3% (95%CI: 53.7-70.2) detected by s-DRY, 56.2% (95%CI: 47.6-64.4) by Dr-WET, and 54.6% (95%CI: 46.1-62.9) by s-FTA. There was overall agreement of 70.8% between s-FTA and s-DRY samples (kappa = 0.34), and of 82.3% between self-HPV and Dr-WET samples (kappa = 0.56). Detection sensitivities for low-grade squamous intraepithelial lesion or worse (LSIL+) were: 64.0% (95%CI: 44.5-79.8) for s-FTA, 84.6% (95%CI: 66.5-93.9) for s-DRY, and 76.9% (95%CI: 58.0-89.0) for Dr-WET. The preferred self-collection method among patients was s-DRY (40.8% vs. 15.4%). Regarding costs, FTA card was five times more expensive than the swab (~5 US dollars (USD)/per card vs. ~1 USD/per swab). Self-HPV using dry swabs is sensitive for detecting LSIL+ and less expensive than s-FTA. International Standard Randomized Controlled Trial Number (ISRCTN): 43310942.


Magnetic resonance imaging of primary malignant bone tumors.
The authors report a retrospective study that suggests that MRI may be superior to CT for the preoperative evaluation of bone tumors.


Neonatal vs delayed-onset fourth branchial pouch anomalies: therapeutic implications.
To determine the presentation of third or fourth branchial pouch anomalies in various age groups of children and evaluate endoscopic cauterization as a treatment technique. Retrospective study of patients treated from 2000 to 2009. Tertiary care children's hospital. Pediatric patients aged 0 to 18 years (mean age, 5.5 years), including 5 neonates. Endoscopic and/or open surgical management of third and fourth branchial pouch anomalies; clinical and endoscopic follow-up. Absence of clinical recurrence; closure of the sinus tract. Two forms of presentation were identified: a neonatal form, characterized by a voluminous and compressive cervical mass (5 of 20 [25%]) and a childhood form, presenting as a cervical abscess (15 of 20 [75%]). The vast majority of our patients regardless of presentation were treated endoscopically (n = 19), with a success rate of 68% (13 of 19) after 1 procedure, 79% (15 of 19) after 2 procedures, and 89% (17 of 19) after 3 procedures. Neonatal and adult presentations require slightly different therapeutic approaches. Third and fourth branchial pouch anomalies can present in 2 distinct forms: a neonatal form and a childhood form. The endoscopic technique should be the favored approach for both forms: whenever possible, in view of its simplicity, rapidity, and the lack of serious postoperative complications. Recurrences can be treated by repeated cauterization using the same technique, with good long-term outcomes. An age-based management algorithm has been developed.


Fracture Toughness of Nanohybrid and Hybrid Composites Stored Wet and Dry up to 60 Days.
Patients' demand for tooth-colored restoratives in the posterior region is increasing. Clinicians use universal nanohybrid resin composites for both anterior and posterior regions. There are few published reports comparing fracture toughness of nonohybrids and that of hybrid composite stored wet and dry. To investigate the fracture toughness of three nanohybrids compared to that of a hybrid resin composite stored dry or wet up to 60 days, using four-point bending test. Four resin composites were used: three nanohybrids; Filtek Supreme (3M), Ice (SDI), TPH3 (Dentsply) and one hybrid Filtek P60 (3M). For each material, 40 rectangular notched beam specimens were prepared with dimensions of 30 mm × 5mm × 2mm. The specimens were randomly divided into 4 groups (n = 10) and stored at 37ºC either in distilled water or dry for 1 and 60 days. The specimens were placed on the four-point test jig and subjected to force (N) using universal testing machine loaded at a crosshead speed of 0.5mm/min and maximum load at specimen failure was recorded and KIC was calculated. Three-way ANOVA showed a significant interaction between all the factors (all p < .0001). Except for TPH3, all tested materials showed significantly higher KIC when stored dry than stored wet (p < 0.05). After 1 day of dry storage, Ice showed the highest KIC (2.04± 0.32) followed by Filtek P60 and the lowest was for Filtek Supreme (1.39± 0.13) The effect of time on fracture toughness was material dependent. Wet storage adversely affected the fracture toughness of almost all materials. Keeping the restoration dry in the mouth may increase their fracture toughness. Therefore, using a coating agent on the surface of restoration may protect them from early water uptake and increase their strength during a time period.


The Rossetti-Nissen fundoplication--effective in managing gastro-oesophageal reflux disease.
The report herein details a prospective audit of a unit's eight-year experience of the Rossetti-Nissen fundoplication using a predominantly laparoscopic technique, selective hiatal repair, no bougie and a standardised protocol of pre- and post-operative functional endoscopic and symptom assessment. Three hundred and seventy-eight patients underwent the Rossetti-Nissen fundoplication. All patients had documented data on endoscopy, health related quality of life (HR-QoL), surgical details and complications pre-operatively and at six months post-operatively. Repeat physiological testing was performed at six months. At a median follow-up of six (range 3-13) months there was improved symptom scoring and HR-QoL after fundoplication with an 89% patient satisfaction rate. Ninety-five patients (25%) reported some early dysphagia, and 91 of these reported the outcome of surgery to be excellent or good. Thirty-eight patients (10%) had recurrent heartburn and 28 (7%) were back on medication at six months post-operatively. At follow-up pH study at a median of six months, 89% of patients had normalised acid reflux scores. Rossetti-Nissen fundoplication, with no use of an oesophageal bougie and no division of short gastric vessels, is an effective procedure giving 89% patient satisfaction and significant improvement in QoL parameters and physiological measurements.


Executive Function Predicting Longitudinal Change in Type 1 Diabetes Management During the Transition to Emerging Adulthood.
The objective of this study was to examine 1) whether teens' glycemic control and adherence to type 1 diabetes treatment regimen worsen during the transition from late adolescence to emerging adulthood, and 2) whether teens' executive function (EF), as measured by performance and self-reported problems with EF, is predictive of these changes (after controlling for general intelligence). High school seniors with type 1 diabetes (N = 236; mean age 17.74 years) were assessed at three yearly time points. At baseline, during the senior year of high school, participants completed a self-report measure of problems with EF and performance-based measures of EF and general intelligence (IQ). Glycemic control was determined on the basis of results collected from HbA1c assay kits, and teens reported their adherence at all three time points. HbA1c increased significantly across the three time points and adherence declined. EF performance was not associated with adherence or HbA1c at baseline, nor with changes in adherence over time. However, better EF performance predicted slower increases in HbA1c over time (i.e., slope) while controlling for IQ. Teens' self-reported problems with EF were associated with worse glycemic control and poorer adherence at baseline (i.e., intercept), but they did not predict changes in either HbA1c or adherence over time (i.e., slope). Abilities involved in performance on EF tests may be one resource for maintaining better glycemic control during the transition to emerging adulthood. Assessment of such EF abilities may allow for the identification of individuals who are most at risk for deterioration of glycemic control during this transition.


New strategies in immunosuppression.
New immunosuppressive strategies that can prevent both acute and chronic rejection are being investigated to achieve graft tolerance and to minimize side effects and toxicity that may lead to graft loss. Drug pharmacokinetics and pharmacodynamics, as well as pharmacogenetics, all play a role in customizing treatment to the individual patient. To improve patient compliance, new drug formulations are on trial, such as the modified- release oral form of tacrolimus MR4 for once daily administration, which seems to be equivalent to bid administration in terms of steady-state exposure. Monoclonal/polyclonal antibodies are increasingly used in the induction phase in protocols where steroids are discontinued early. However, discontinuing steroids carries a high risk of acute rejection or organ failure in some subgroups of patients. The supposed benefit of steroid discontinuation may not be enjoyed by all patients. Minimizing anticalcineurin agents may prove to be similarly or even more advantageous. The use of new drugs and new combinations has greatly improved short-term transplant outcomes. The new goal is, therefore, to improve long-term results and particularly to prevent chronic rejection, thus increasing patient and organ survival.


Intraocular pressure changes in secondary positions of gaze in normal subjects and in restrictive ocular motility disorders.
One hundred normal Caucasian eyes and 29 eyes with restrictive disorders of ocular motility were studied in order to delineate intraocular pressure changes in secondary positions of gaze. Applanation tonometry was performed in the primary position and at an angle of 22 degrees. In patients with restrictive syndromes the changes of intraocular pressure in the secondary positions of gaze were significantly higher (p less than 0.0001) than in normal subjects. The range of variation in normal subjects was 0, +3 mmHg for supraduction and -3, +1 mmHg for abduction. Patients with restrictive syndromes showed changes between +1 and +15 mmHg for supraduction and between +3 and +10 mmHg for abduction. Results obtained in the two groups showed the existence of false negatives. This test is thus a practical and useful diagnostic tool, but its results must be evaluated cautiously.


A mutation in P23, the first gene in the RNA polymerase sigma A (sigma 43) operon, affects sporulation in Bacillus subtilis.
Mutations within P23, the first gene of the Bacillus subtilis sigma A operon, were not detrimental to vegetative growth or sporulation. One deletion of P23 resulted in a strain that sporulated earlier than the wild type. This aberrant phenotype may be due to the simultaneous deletion of a sigma H promoter from the sigma A operon.


Both high glucose and phosphate overload promote senescence-associated calcification of vascular muscle cells.
The NAD+-dependent deacetylase, sirtuin 1 (SIRT1), plays an important role in vascular calcification induced by high glucose and/or high phosphate levels. However, the mechanism by which SIRT1 regulates this process is still not fully understood. Thus, this study aimed to determine the role of high glucose and phosphate in vascular calcification and the molecular mechanisms underlying SIRT1 regulation. Vascular smooth muscle cells (VSMCs) were cultured under normal, high phosphate, and/or high-glucose conditions for 9 days. Alizarin red staining and calcification content analyses were used to determine calcium deposition. VSMC senescence was detected by β-galactosidase (SA-β-Gal) staining and p21 expression. Mouse VSMCs exposed to high phosphate and high glucose in vitro showed increased calcification, which was correlated with the induction of cell senescence, as confirmed by the increased SA-β-galactosidase activity and p21 expression. SRT1720, an activator of SIRT1, inhibits p65 acetylation, the nuclear factor-κ-gene binding (NF-κB) pathway, and VSMC transdifferentiation, prevents senescence and reactive oxygen species (ROS) production, and reduces vascular calcification. In contrast, sirtinol, an inhibitor of SIRT1, increases p65 acetylation, activates the NF-κB pathway, induces vascular smooth muscle cell transdifferentiation and senescence, and promotes vascular calcification. High glucose and high phosphate levels induce senescence and vascular calcification in VSMCs, and the combined effect of high glucose and phosphate can inhibit SIRT1 expression. SIRT1 inhibits vascular smooth muscle cell senescence and osteogenic differentiation by inhibiting NF-κB activity, thereby inhibiting vascular calcification.


Characterization of SARS-CoV-2 Omicron BA.4 and BA.5 isolates in rodents.
The BA.2 sublineage of the SARS-CoV-2 Omicron variant has become dominant in most countries around the world; however, the prevalence of BA.4 and BA.5 is increasing rapidly in several regions. BA.2 is less pathogenic in animal models than previously circulating variants of concern1-4. Compared with BA.2, however, BA.4 and BA.5 possess additional substitutions in the spike protein, which play a key role in viral entry, raising concerns that the replication capacity and pathogenicity of BA.4 and BA.5 are higher than those of BA.2. Here we have evaluated the replicative ability and pathogenicity of BA.4 and BA.5 isolates in wild-type Syrian hamsters, human ACE2 (hACE2) transgenic hamsters and hACE2 transgenic mice. We have observed no obvious differences among BA.2, BA.4 and BA.5 isolates in growth ability or pathogenicity in rodent models, and less pathogenicity compared to a previously circulating Delta (B.1.617.2 lineage) isolate. In addition, in vivo competition experiments revealed that BA.5 outcompeted BA.2 in hamsters, whereas BA.4 and BA.2 exhibited similar fitness. These findings suggest that BA.4 and BA.5 clinical isolates have similar pathogenicity to BA.2 in rodents and that BA.5 possesses viral fitness superior to that of BA.2.


Dichotomy of Atom-Economical Hydrogen-Free Reductive Amidation vs Exhaustive Reductive Amination.
Rh-catalyzed one-step reductive amidation of aldehydes has been developed. The protocol does not require an external hydrogen source and employs carbon monoxide as a deoxygenative agent. The direction of the reaction can be altered simply by changing the solvent: reaction in THF leads to amides, whereas methanol favors formation of tertiary amines.


Development of automated segmentation of visceral adipose tissue in computed tomography.
Imaging modalities such as computed tomography (CT) or magnetic resonance imaging have been used to measure adiposity. However, manual segmentation of visceral adipose tissue (VAT) in the entire abdomen is laborious and time-consuming. We aimed to develop a new method for accurate visceral fat segmentation by automatically dividing the three anatomical compartments of the lung, soft tissue, and post-vertebral spaces. To automatically separate visceral fat, a three-step process was performed that sequentially divided tissues and regions in a three-dimensional CT image. Manual segmentation was performed in 99 individuals who underwent 18-fluoro-2-deoxyglucosepositron emission tomography/CT for cancer screening between January 2010 and December 2018 to validate the automated segmentation. The similarity index and Pearson's correlation analysis were performed to compare automated segmentation with manual segmentation. Clinical data, such as weight, height, and glucose and insulin levels, were measured. Pearson's correlation analysis was performed to investigate the association between the two methods. VAT volume of automated segmentation (3,594.6 ± 1,776.5 cm3) strongly correlated with that of manual segmentation (3,375.7 ± 1567.5 cm3) (r = 0.9676, p < 0.0001). The similarity index positively correlated with the VAT volume (r = 0.6396, p < 0.0001) and negatively correlated with the mean Hounsfield units (HU) (r = -0.4328, p < 0.0001). Bland-Altman plots are presented with 5.1 % for VAT volume and 7.1 % for mean HU were outside 1.96 standard deviation from the mean value. We developed an automated segmentation method for VAT in the entire abdomen. This automated segmentation method is feasible for measuring the VAT volume and VAT HU. This method could be employed in daily clinical practice to provide more detailed information about VAT.


Implementation and adoption of advanced care planning in the elderly trauma patient.
Geriatric trauma has high morbidity and mortality, often requiring extensive hospital stays and interventions. The number of geriatric trauma patients is also increasing significantly and accounts for a large proportion of trauma care. Specific geriatric trauma protocols exist to improve care for this complex patient population, who often have various comorbidities, pre-existing medications, and extensive injury within a trauma perspective. These guidelines for geriatric trauma care often suggest early advanced care planning (ACP) discussions and documentation to guide patient and family-centered care. A provincial ACP program was implemented in April of 2012, which has since been used by our level 1 trauma center. We applied a before and after study design to assess the documentation of goals of care in elderly trauma patients following implementation of the standardized provincial ACP tool on April 1, 2012. Documentation of ACP in elderly major trauma patients following the implementation of this tool increased significantly from 16 to 35%. Additionally, secondary outcomes demonstrated that many more patients received goals of care documentation within 24 h of admission, and 93% of patients had goals of care documented prior to intensive care unit (ICU) admission. The number of trauma patients that were admitted to the ICU also decreased from 17 to 5%. Early advanced care planning is crucial for geriatric trauma patients to improve patient and family-centered care. Here, we have outlined our approach with modest improvements in goals of care documentation for our geriatric population at a level 1 trauma center. We also outline the benefits and drawbacks of this approach and identify the areas for improvement to support improved patient-centered care for the injured geriatric patient. Here, we have provided a framework for others to implement and further develop.


Treatment of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome in Denmark: a nationwide comparative study of anatomical outcome and complications.
To compare the long-term anatomical outcome and complications in treatments of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. A historical comparative follow-up study using medical chart reviews. Public hospitals. A nationwide cohort of patients diagnosed with MRKH syndrome (n = 168). McIndoe vaginoplasty (n = 54), self-dilation (n = 60), coital dilation (n = 20), Baldwin vaginoplasty (n = 4), Williams vaginoplasty (n = 3), Davydov vaginoplasty (n = 2), or no treatment (n = 29). Mean vaginal depth at follow-up, anatomical treatment success rates at levels of ≥6 cm, ≥7 cm, and ≥8 cm, complications, and resurgery. Mean vaginal depths were 7.4 cm (95% confidence interval [CI] 6.8-8.1 cm), 7.3 cm (95% CI 6.7-7.9 cm), and 8.7 cm (95% CI 7.9-9.5 cm) at follow-up in patients treated by McIndoe vaginoplasty, self-dilation, and coital dilation, respectively. Overall complication rates in the three groups were 35/54 (65%), 21/52 (35%), and 1/20 (5%), respectively. Eighteen (33%) of the patients who underwent McIndoe vaginoplasty needed resurgery. Our findings support the current recommendations of dilation therapy as the first-line treatment of vaginal agenesis and emphasize the relevance of coital dilation in patients able to regularly engage in coital activity. However, further studies of functional outcome and patient satisfaction are needed.


Occult renal artery pseudoaneurysm causing persistent hematuria after flexible Thulium fibered laser lithotripsy: A case report and literature review of rare but potentially fatal complication.
Renal artery pseudoaneurysm may develop after laser flexible ureteroscopy stone lithotripsy (FURSL). Typical symptoms include flank pain, persistent hematuria, delayed refractory anemia, or hemorrhagic shock in case of pseudoaneurysm rupture. This complication of laser FURSL is very rare with only five cases reported in the literature as of April 2023, of which one involved Thulium laser. We report the case of a 65-year-old man with recurrent renal lithiasis who underwent FURSL using Thulium fibered laser (TFL) for 8 mm stone of left kidney upper pole. Persistent hematuria developed postoperatively, secondary to a pseudoaneurysm from a segmental branch of the left renal artery. It was diagnosed on arteriography performed for sudden hemorrhagic shock 27 days after surgery. Selective embolization with metallic micro-coils resolved hematuria. Although laser FURSL is often uncomplicated and TFL is regarded as safe, this complication should be suspected when refractory hematuria or hemodynamic instability follows the procedure. We report this case to add support to the current literature and outline procedural risk factors and useful precautions during the procedure.


A network pharmacology approach and experimental validation to investigate the anticancer mechanism and potential active targets of ethanol extract of Wei-Tong-Xin against colorectal cancer through induction of apoptosis via PI3K/AKT signaling pathway.
Wei-Tong-Xin (WTX), derives from the Chinese herbal decoction (CHD) of Wan-Ying-Yuan in ancient China, has been shown to be effective therapeutic herbal decoction for treating gastrointestinal diseases. Present studies have demonstrated that WTX had potential to alleviate the symptoms of gastrointestinal inflammation, gastric ulcer and improve gastric motility. The study primarily focused on exploring the therapeutic effect and possible pharmacological mechanism of WTX on colorectal cancer (CRC) based on network pharmacology, in vitro and in vivo experiments. Firstly, colorectal cancer and WTX associated with targets were searched from GeneCards database and TCM Systems Pharmacology Database and Analysis Platform (TCMSP) respectively. The protein-protein interaction (PPI) network also was constructed to screening key targets. In addition, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were applied to predict the underlying biological function and mechanism involving in the anti-colorectal cancer effect of WTX. Next, CCK-8, colony formation and transwell assays were performed to verify the influence of proliferation and metastasizing ability of HCT116 cells after treated with WTX. Cell cycle, apoptosis and reactive oxygen species (ROS) were analysis by flow cytometry. Hoechst 33258 staining was conducted to observe nuclear morphology changes. Protein expression of apoptosis and PI3K/AKT signaling as well as mRNA expression of ferroptosis and apoptosis were determined by Western Blotting and RT-qPCR. The effects of WTX and LY294002 combination on the PI3K/Akt/mTOR signaling pathway were measured by Western Blotting. Finally, the xenograft tumor mouse model was established by subcutaneous injection of CT26 cells to measure tumors volume and weight. Hematoxylin and eosin (HE) staining and immunohistochemical analysis were used to observe the pathological changes and the protein expression in tumor tissues. There were 286 potential treatment targets from 130 bioactive compounds in WTX, 1349 CRC-related targets were identified. Eleven core targets (TP53, AKT1, STAT3, JUN, TNF, HSP90AA1, IL-6, MAPK3, CASP3, EGFR, MYC) were found by PPI network analysis constructed of 142 common targets. The results of KEGG enrichment displayed PI3K/AKT signaling pathway as core pathway. After the treatment of WTX, the inhibitory of viability, metastases and cell cycle arrest at G2/M phase were observed in HCT116 cells. Moreover, WTX induced an increase in the expression of apoptosis proteins (Bak, cytochrome c, cleaved caspase-9/caspase-9 and cleaved caspase-3/caspase-3) and the levels of ROS and MDA, a decrease in the expression of PI3K/AKT signaling related proteins (PI3K, p-PI3K, p-AKT/AKT and p-mTOR/mTOR) and the level of SOD. WTX treatment significantly reduced the tumor weight, increased cleaved caspase-3 positive area and decreased that of ki67 in xenograft mouse model. Through a network pharmacology approach and in vitro experiments, we predicted and verified the effect of WTX on colorectal cancer cells mainly depended on the regulation of intrinsic apoptosis via PI3K/AKT signaling pathway, and further animal experiments proved that WTX has a good anti-colon cancer effect in vivo.


Dose-Based Radiomic Analysis (Dosiomics) for Intensity Modulated Radiation Therapy in Patients With Prostate Cancer: Correlation Between Planned Dose Distribution and Biochemical Failure.
Although radiation therapy is one of the most significant treatment modalities for localized prostate cancer, the prognostic factors for biochemical recurrence (BCR) regarding the treatment plan are unclear. We aimed to develop a novel dosiomics-based prediction model for BCR in patients with prostate cancer and clarify the correlations between the dosimetric factors and BCR. This study included 489 patients with localized prostate cancer (BCR: 96; no-BCR: 393) who received intensity modulated radiation therapy. A total of 2475 dosiomic features were extracted from the dose distributions on the prostate, clinical target volume (CTV), and planning target volume. A prediction model for BCR was trained on a training cohort of 342 patients. The performance of this model was validated using the concordance index (C-index) in a validation cohort of 147 patients. Another model was constructed using clinical variables, dosimetric parameters, and radiomic features for comparisons. Kaplan-Meier curves with log-rank analysis were used to assess the univariate discrimination based on the predictive dosiomic features. The dosiomic feature derived from the CTV was significantly associated with BCR (hazard ratio, 0.73; 95% CI, 0.57-0.93; P = .01). Although the dosiomics model outperformed the dosimetric and radiomics models, it did not outperform the clinical model. The performance significantly improved by combining the clinical variables and dosiomic features (C-index: 0.67; 95% CI, 0.65-0.68; P < .0001). The predictive dosiomic features were used to distinguish high-risk and low-risk patients (P < .05). The dosiomic feature extracted from the CTV was significantly correlated with BCR in patients with prostate cancer, and the dosiomics model outperformed the model with conventional dose indices. Hence, new metrics for evaluating the quality of a treatment plan are warranted. Moreover, further research should be conducted to determine whether dosiomics can be incorporated in a clinical workflow or clinical trial.


Local skin necroses after intramuscular injection -Experimental animal studies-.
The pathogenesis of local skin necroses after intramuscular injection of various drugs such as phenylbutazone (Embolia cutis medicamentosa, Nicolau's syndrome) is not clear. In an attempt to simulate this clinical feature experiments were performed on the rabbit ear lobe. A 20% phenylbutazone solution was injected paraarterial, intraarterial and paraarterial after perforation of the vessel. The drug produced a violent inflammation with all kinds of application. The local inflammation induced by paraarterial injection resulted in a fine scarring. Both other kinds of application produced necroses or even perforations. The histological examinations in these cases revealed massive destructions of the inner arterial wall. In control-experiments necroses or perforations were nerve observed. From these data the following conclusions on the etiology of Nicolau's syndrome can be drawn: Phenylbutazone injected into the vascular or perivascular tissue causes an obligatory inflammation. After lesion of an artery complete destruction of the vessel followed by necrosis of the skin may occur. It seems obvious that this secondary effect can not completely be avoided.


Structural dynamics of retroviral genome and the packaging.
Retroviruses can cause diseases such as AIDS, leukemia, and tumors, but are also used as vectors for human gene therapy. All retroviruses, except foamy viruses, package two copies of unspliced genomic RNA into their progeny viruses. Understanding the molecular mechanisms of retroviral genome packaging will aid the design of new anti-retroviral drugs targeting the packaging process and improve the efficacy of retroviral vectors. Retroviral genomes have to be specifically recognized by the cognate nucleocapsid domain of the Gag polyprotein from among an excess of cellular and spliced viral mRNA. Extensive virological and structural studies have revealed how retroviral genomic RNA is selectively packaged into the viral particles. The genomic area responsible for the packaging is generally located in the 5' untranslated region (5' UTR), and contains dimerization site(s). Recent studies have shown that retroviral genome packaging is modulated by structural changes of RNA at the 5' UTR accompanied by the dimerization. In this review, we focus on three representative retroviruses, Moloney murine leukemia virus, human immunodeficiency virus type 1 and 2, and describe the molecular mechanism of retroviral genome packaging.


Civilian and military genetics: nondiscrimination policy in a post-GINA world.
Evidence is emerging of a growing societal consensus about appropriate and inappropriate uses of genetic information. The Genetic Information Nondiscrimination Act of 2008 provides new legal protections to Americans by prohibiting the discriminatory use of genetic information by health insurers and employers. Additionally, the United States military recently created new policies for fair use of genetic information in the determination of benefits for servicemen and servicewomen leaving military service. Although critical issues remain, such as the potential for genetic information to be used to deny people other forms of insurance, and how the military will use genetic medicine overall, significant progress has been made.


Subjective sleep quality in relation to objective sleep estimates: comparison, gender differences and changes between the acute phase and the six-month follow-up after stroke.
To describe sleep experiences after stroke using subjective and objective indicators and identify possible gender differences in sleep in the acute phase and at 6-month follow-up. Sleep disturbances after stoke are recognized, but poorly described. Gender differences in sleep exist in other populations, but have not been reported after stroke. A longitudinal cohort study. Subjective sleep quality was measured with the Pittsburgh Sleep Quality Index and objective sleep was estimated with actigraphy in 100 patients in the acute phase and six months after stroke, from April 2007-March 2009. Subjective sleep quality was better and objective wake percentage was lower at follow-up than in the acute phase after stroke. Actigraphy estimated low sleep efficiency and many awakenings at both time points. Subjective and objective measures were correlated at the 6-month follow-up, but not in the acute phase. Women's subjective sleep efficiency and total score on the Pittsburgh Sleep Quality Index were worse than men's in the acute phase, but actigraphy estimated that women slept more than men in the course of a day. Women's subjective sleep quality was better at follow-up than in the acute phase. Men reported worse subjective sleep quality, but better subjective sleep efficiency at follow-up than in the acute phase, and also had lower objective wake percentage at follow-up. Subjective sleep quality was poor and actigraphy indicated disturbed sleep-wake patterns in the acute phase and at 6-month follow-up. Gender differences existed in subjective and objective sleep in the acute phase, but not at follow-up.


Dynamic transurethral sonography and 3-dimensional reconstruction of the rhabdosphincter and urethra: initial experience in continent and incontinent women.
The purpose of this study was to evaluate the female urethra and the striated urinary sphincter, the rhabdosphincter (RS), by means of dynamic transurethral sonography and sonographic 3-dimensional (3D) reconstructions. In 15 female patients with urinary stress incontinence (mean age, 67.5 years) and 5 continent women (mean age, 48.3 years), morphologic characteristics and function of the RS and urethra were examined with a 10-MHz transurethral ultrasound transducer. With the help of a mechanical pullback system, the transducer was slowly retracted to scan the whole urethra and the RS from the bladder neck to the urethral orifice. Subsequently, 3D reconstructions of the urethra using an integrated computer system were performed. The RS as well as the length of the urethra were investigated under contracted and noncontracted conditions to measure contractility of the RS and dynamic changes of the lower urinary tract. Partial or complete loss of RS function was detected in patients with stress incontinence. The findings on sonography were found to correlate well with the grade of incontinence. Furthermore, under contraction of the RS, a median increase in urethral length was observed. In incontinent patients, the increase in the urethral length was statistically significantly less (P = .04), which was related to the reduced contractility of the RS. Dynamic transurethral sonography with subsequent 3D reconstructions allows for assessment of function and morphologic characteristics of the RS and urethra. Normal contraction of the RS results in an elongation of the urethra.


Comparison of DRASTIC and DRASTICL groundwater vulnerability assessments of the Burdekin Basin, Queensland, Australia.
In the Burdekin Basin, Queensland, Australia, groundwater contamination due to agricultural activities has led to concerns over its impacts on globally significant ecosystems such as the Great Barrier Reef. An appropriate method for groundwater vulnerability assessment is essential for the sustainable use of this groundwater resource and its longer-term environmental management. The aim of this study is to apply and assess the suitability of the standard DRASTIC index-based method for groundwater vulnerability assessment of the Burdekin Basin. The intrinsic groundwater vulnerability is calculated in ArcGIS, using data for the period 2010 to 2021. The results are compared to available water quality data. The calculated DRASTIC scores are found to be only weakly correlated with water quality parameters, including the nitrate concentration (R = 0.07), which should behave as a proxy measure of groundwater vulnerability. To address this, a modified DRASTICL method containing a land use parameter is also implemented, to assess the specific groundwater vulnerability. The correlation between DRASTICL scores and nitrate levels (R = 0.2) is more significant but is still relatively weak. From this study, it is recommended that alternative methods be developed to assess groundwater vulnerability in the Burdekin Basin, and other comparable aquifer systems.