Effect of Grape Pomace Polyphenols With or Without Pectin on TMAO Serum Levels Assessed by LC/MS-Based Assay: A Preliminary Clinical Study on Overweight/Obese Subjects.
Growing evidence suggests that trimethylamine N-oxide (TMAO) is recognized as a biomarker of increased cardiovascular risk. So far, the evaluation of TMAO serum levels in the clinical practice is limited due to the lack of developing new facile methods with reduced limitations. However, few approaches were achieved to determine TMAO in serum by using mass spectrometry-based technique, some limitations were reported including the use of internal standards. Therefore, in this work, a liquid chromatography-mass spectrometry (LC/MS) based-assay was developed to evaluate the effect of grape pomace extract (Taurisolo®, group A) or Taurisolo®+pectin (group B) on TMAO serum levels in a cohort of overweight/obese subjects. The serum levels of TMAO have been assessed before and after treatment, through LC/MS analysis. After 8-week treatment, in both intervention groups TMAO serum levels significantly decreased (-78.58% p = 0.006 and -76.76% p = 0.001, group A and group B, respectively). Moreover, we performed several analyses aimed to validate the LC/MS method we used. The method has high precision (% C.V = from 12.12 to 3.92% and from 8.25 to 1.07% for intraday and interday, respectively) and accuracy (% bias = from -5.52 to 0.5% and from -1.42 to 3.08% for intraday and interday, respectively). TMAO recoveries from serum ranged from 99 to 97%; LOD: 2 ng/ml and LOQ: 6 ng/ml. In conclusion, we demonstrated the efficacy of a novel nutraceutical formulation in reducing TMAO serum levels in high cardiovascular risk-subjects, and proposed a useful, versatile and rapid LC/MS method for identification and quantization of TMAO, without the use of marked/isotopic internal standards. It, thus, may represent a novel and practical method with applications in clinical practice and nutraceutical research. Clinical Trial Registration: This study is listed on the ISRCTN registry with ID ISRCTN10794277 (doi: 10.1186/ISRCTN10794277).


Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.
Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with unprecedented resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.


Allicin protects against H2O2-induced apoptosis of PC12 cells via the mitochondrial pathway.
Allicin is a major bioactive ingredient of garlic and has a broad range of biological activities. Allicin has been reported to protect against cell apoptosis induced by H2O2 in human umbilical vein endothelial cells. The present study evaluated the neuroprotective effect of allicin on the H2O2-induced apoptosis of rat pheochromocytoma PC12 cells in vitro and explored the underlying mechanism involved. PC12 cells were incubated with increasing concentrations of allicin and the toxic effect of allicin was measured by MTT assay. The cells were pretreated for 24 h with low dose (L-), medium dose (M-) and high dose (H-) of allicin, followed by exposure to 200 µM H2O2 for 2 h, and the cell viability was examined by MTT assay. In addition, cell apoptosis rate was analyzed by Annexin V-FITC/PI assay, while intracellular reactive oxygen species (ROS) and mitochondrial transmembrane potential (∆ψm) were measured by flow cytometry. Bcl-2, Bax, cleaved-caspase-3 and cytochrome c (Cyt C) in the mitochondria were also examined by western blotting. The results demonstrated that 0.01 µg/ml (L-allicin), 0.1 µg/ml (M-allicin) and 1 µg/ml (H-allicin) were non-toxic doses of allicin. Furthermore, H2O2 reduced cell viability, promoted cell apoptosis, induced ROS production and decreased ∆ψm. However, allicin treatment reversed the effect of H2O2 in a dose-dependent manner. It was also observed that H2O2 exposure significantly decreased Bcl-2 and mitochondrial Cyt C, while it increased Bax and cleaved-caspase-3, which were attenuated by allicin pretreatment. The results revealed that allicin protected PC12 cells from H2O2-induced cell apoptosis via the mitochondrial pathway, suggesting the potential neuroprotective effect of allicin against neurological diseases.


Patients with moderate to severe strokes (NIHSS score >10) undergoing urgent carotid interventions within 48 hours have worse functional outcomes.
Increasing evidence suggests that urgent carotid intervention after a nondisabling stroke is safe. However, the functional outcome of such patients has not been quantified for various degrees of stroke. We aimed to determine whether increased presenting stroke severity and timing to intervention are associated with poor functional outcomes in patients undergoing urgent carotid endarterectomy (CEA) or carotid artery stenting (CAS) after an acute transient ischemic attack or stroke. We reviewed all urgent carotid interventions from January 2013 through April 2017 at a single tertiary referral center. Preoperative variables analyzed included admission stroke severity, calculated by National Institutes of Health Stroke Scale (NIHSS). The primary end point was the patient's neurologic functional independence at discharge, quantified by the modified Rankin scale (mRS) score (≤2, functionally independent; ≥3, dependent). Primary complications were defined as new or worsened stroke, intracranial hemorrhage, and death. A total of 120 urgent carotid interventions (CEA, n = 96; CAS, n = 22; 1 CEA with middle cerebral artery aspiration thrombectomy and 1 carotid embolectomy) were performed. Bivariate analysis demonstrated a correlation between admission NIHSS score and mRS score when patients were divided into groups with an admission NIHSS score ≤10 and >10 (P = .0029). Patients presenting with larger strokes (NIHSS score >10) were 3.4 times more likely (95% confidence interval [CI], 1.2-9.6; P = .024) to have functional dependence (mRS score ≥3) at discharge than patients presenting with minor to moderate strokes (NIHSS score ≤10). Patients undergoing CEA or CAS before 48 hours were also associated with a worse discharge mRS score compared with those undergoing carotid interventions after 48 hours (odds ratio, 3.5; 95% CI, 1.4-8.7; P = .007). Even when emergent carotid interventions were excluded from the subgroup of patients undergoing CEA or CAS within 48 hours, discharge mRS correlated with time to procedure (days 1- 2 compared with >2 days). The odds of having discharge functional dependence (mRS score ≥3) were 3.4 times more likely for patients with the procedure performed at 1 to 2 days compared with >2 days (95% CI, 1.3-9.1; P = .014). Urgent carotid intervention performed in patients with moderate or severe strokes (NIHSS score >10) and before 48 hours is associated with functional dependence (mRS score ≥3) on hospital discharge. By demonstrating a clear correlation between admission NIHSS score and interval time to procedure with independent neurologic functional outcomes, these data aid in clinical decision-making for this high-risk subpopulation of patients who present with acute symptomatic carotid lesions.


Patient Safety During Chest Drain Insertion-A Survey of Current Practice.
The aim of this study was to identify the degree of awareness of the current guidelines and common practices for pleural drain insertion. A 10-item questionnaire was sent electronically to junior physicians from 4 different hospitals in the South Eastern Sydney and Illawarra Shoalhaven Local Health District. Participants were asked to give their level of experience and management practices for chest drain insertion. A total of 94 junior medical officers from 4 hospitals in the district completed the survey. More than 20% had never inserted a chest drain at the time; 72% had primarily learned from bedside teaching and peer learning, but 11% had no training at all. More than 50% of physicians felt that the biggest threat to the procedure was their own lack of confidence for drain insertion. Despite current guidelines, 25% insert chest drains routinely without the aid of ultrasound. A third of interviewees were aware of local guidelines but had not read them. Most physicians (86%) believe that formal standardized training should be available for junior physicians. Our findings demonstrate the ongoing need for improved procedural training in chest drain insertion, with emphasis on mandatory thoracic ultrasound. We consider it important to continue to raise concern and awareness that chest drain insertion is not a harmless procedure, and further physician procedural competence is required.


RapidArc treatment verification in 3D using polymer gel dosimetry and Monte Carlo simulation.
The aim of this study was to verify the advanced inhomogeneous dose distribution produced by a volumetric arc therapy technique (RapidArc) using 3D gel measurements and Monte Carlo (MC) simulations. The TPS (treatment planning system)-calculated dose distribution was compared with gel measurements and MC simulations, thus investigating any discrepancy between the planned dose delivery and the actual delivery. Additionally, the reproducibility of the delivery was investigated using repeated gel measurements. A prostate treatment plan was delivered to a 1.3 liter nPAG gel phantom using one single arc rotation and a target dose of 3.3 Gy. Magnetic resonance imaging of the gel was carried out using a 1.5 T scanner. The MC dose distributions were calculated using the VIMC-Arc code. The relative absorbed dose differences were calculated voxel-by-voxel, within the volume enclosed by the 90% isodose surface (VOI(90)), for the TPS versus gel and TPS versus MC. The differences between the verification methods, MC versus gel, and between two repeated gel measurements were investigated in the same way. For all volume comparisons, the mean value was within 1% and the standard deviation of the differences was within 2.5% (1SD). A 3D gamma analysis between the dose matrices were carried out using gamma criteria 3%/3 mm and 5%/5 mm (% dose difference and mm distance to agreement) within the volume enclosed by the 50% isodose surface (VOI(50)) and the 90% isodose surface (VOI(90)), respectively. All comparisons resulted in very high pass rates. More than 95% of the TPS points were within 3%/3 mm of both the gel measurement and MC simulation, both inside VOI(50) and VOI(90). Additionally, the repeated gel measurements showed excellent consistency, indicating reproducible delivery. Using MC simulations and gel measurements, this verification study successfully demonstrated that the RapidArc plan was both accurately calculated and delivered as planned.


Safety and Side Effects of Using Placenta-Derived Decidual Stromal Cells for Graft-versus-Host Disease and Hemorrhagic Cystitis.
Mesenchymal stromal cells (MSCs) are increasingly used in regenerate medicine. Placenta-derived decidual stromal cells (DSCs) are a novel therapy for acute graft-versus-host-disease (GVHD) and hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT). DSCs are more immunosuppressive than MSCs. We assessed adverse events and safety using DSCs among 44 treated patients and 40 controls. The median dose of infused cells was 1.5 (range 0.9-2.9) × 106 DSCs/kg. The patients were given 2 (1-5) doses, with a total of 82 infusions. Monitoring ended 3 months after the last DSC infusion. Three patients had transient reactions during DSC infusion. Laboratory values, hemorrhages, and transfusions were similar in the two groups. The frequency of leukemic relapse (2/2, DSC/controls) and invasive fungal infections (6/6) were the same in the two groups. Causes of death were those seen in HSCT patients: infections (5/3), respiratory failure (1/1), circulatory failure (3/1), thromboembolism (1/0), multiorgan failure (0/1), and GVHD and others (2/7). One-year survival for the DSC patients with GVHD was 67%, which was significantly better than achieved previously at our center. One-year survival was 90% in the DSC-treated HC group. DSC infusions appear safe. Randomized studies are required to prove efficacy.


Simultaneous and consistent labeling of longitudinal dynamic developing cortical surfaces in infants.
The human cerebral cortex develops extremely dynamically in the first 2years of life. Accurate and consistent parcellation of longitudinal dynamic cortical surfaces during this critical stage is essential to understand the early development of cortical structure and function in both normal and high-risk infant brains. However, directly applying the existing methods developed for the cross-sectional studies often generates longitudinally-inconsistent results, thus leading to inaccurate measurements of the cortex development. In this paper, we propose a new method for accurate, consistent, and simultaneous labeling of longitudinal cortical surfaces in the serial infant brain MR images. The proposed method is explicitly formulated as a minimization problem with an energy function that includes a data fitting term, a spatial smoothness term, and a temporal consistency term. Specifically, inspired by multi-atlas based label fusion, the data fitting term is designed to integrate the contributions from multi-atlas surfaces adaptively, according to the similarities of their local cortical folding with that of the subject cortical surface. The spatial smoothness term is then designed to adaptively encourage label smoothness based on the local cortical folding geometries, i.e., allowing label discontinuity at sulcal bottoms (which often are the boundaries of cytoarchitecturally and functionally distinct regions). The temporal consistency term is to adaptively encourage the label consistency among the temporally-corresponding vertices, based on their similarity of local cortical folding. Finally, the entire energy function is efficiently minimized by a graph cuts method. The proposed method has been applied to the parcellation of longitudinal cortical surfaces of 13 healthy infants, each with 6 serial MRI scans acquired at 0, 3, 6, 9, 12 and 18months of age. Qualitative and quantitative evaluations demonstrated both accuracy and longitudinal consistency of the proposed method. By using our method, for the first time, we reveal several hitherto unseen properties of the dynamic and regionally heterogeneous development of the cortical surface area in the first 18months of life.


Serum IgG antibodies to P0 dimer and 35 kDa P0 related protein in neuropathy associated with monoclonal gammopathy.
Peripheral neuropathies (PN) associated with monoclonal gammopathy (MG) are widely considered as autoimmune disorders, but the putative role of incriminated antigens is still not understood. Fifty five patients with PN associated with MG were studied to investigate whether new antigens could be found, and to evaluate their relation to clinical manifestations. An immunological study was conducted on patient sera to identify autoreactivities against nerve proteins by western blotting. Antigen proteins were purified and analysed by proteomic tools. Correlation with ultrastrucural and clinical features was then studied. Of the 55 patients suffering from PN associated with MG, 17 exhibited IgG autoantibodies directed against peripheral nerve proteins of 35, 58, and 60 kDa. N-terminal microsequencing and mass spectrometry analyses of the 35 kDa protein revealed perfect peptidic matching with 47% of the amino acid sequence of P0, whereas the 58 and 60 kDa proteins were identified as the reduced and non-reduced forms of a P0 dimer. Deglycosylation did not affect IgG binding to the 35 kDa P0 related protein, suggesting a peptidic epitope. In contrast, deglycosylation abolished IgG recognition of the P0 dimer protein, so that a carbohydrate moiety may be implicated in the epitope formation. This confirmed the existence of two different types of IgG, one recognising the 58 and 60 kDa proteins and one directed against the 35 kDa protein. This is the first report of antibody activity directed against the dimeric association of P0. Although P0 oligomerisation and adhesion properties play a crucial part in the myelin sheath compaction, the pathogenic significance of these autoantibodies needs further investigations to be elucidated.


Serum resolvin D1 levels as a marker of inflammation in constipation dominant irritable bowel syndrome.
The objective of this study is to determine the role of circulating resolvin D1 (RvD1) in patients with constipation subtype of irritable bowel syndrome (IBS-C) and evaluate the relationship between abdominal pain severity and RvD1 levels. This research included 55 patients with IBS-C and 36 healthy controls. Controls were selected from patients who applied to our department with similar complaints as IBS but were not diagnosed with any type of pathology after further investigations. All participants underwent complete blood count, C-reactive protein (CRP), and RvD1 levels measurements. We also recorded abdominal pain severity and the number of bowel movements. Patients with IBS-C were compared with respect to the demographic features and laboratory measurements. The median CRP concentration in patients with IBS-C was significantly higher than that of controls (p=0.003). However, the median RvD1 concentration was significantly lower in the IBS group than that of the control group (p<0.001). The receiver operating characteristic curve analyses revealed that RvD1 concentration lower than 0.47 ng/mL and CRP concentration higher than 3.40 mg/L may identify patients with IBS-C with a high specificity. In the IBS group, there was a strong negative correlation between abdominal pain severity and RvD1 concentration (r=-0.766, p=0.001). This research demonstrates that patients with IBS-C have higher CRP and lower RvD1 concentrations than healthy controls. Both RvD1 and CRP concentrations predict the presence of IBS-C. Additionally, RvD1 concentrations decreased with the increase in abdominal pain severity. Further research works are needed for investigating the role of the RvD1 analogs in the treatment of IBS.


[Reconstruction of tumor induced defects in head and neck surgery with individualized prefabricated three dimensional flaps with the use of continuous vacuum therapy].
Despite recent developments in oncologic head and neck surgery extensive tissue and functional defects following radical tumor resections remains a surgical challenge. Individually prefabricated free flaps to meet the needs of the functional defect can be generated with the help of continuous computer-assisted vacuum therapy. This accelerates the pre-fabrication of three-dimensional composite flaps and enhances therapeutic safety. Changes of the genuine structure of such flaps are induced by implantation of autologous or heterologous transplants alone or in combination with alloplastic materials as a supportive element. Application of vacuum therapy is useful to accelerate the process of pre-fabrication by the induction of angiogenesis. Besides this the continuous removal of wound exudate, possible seroma or haematoma and secondary compression of the different tissue layers improve the modelling of the three-dimensional construct. This article describes the technique of vacuum therapy for the pre-fabrication of three-dimensional pedicled or free flaps for reconstruction of defects after tumor resection in the head and neck area.


The mechanisms of prediction updating that impact the processing of upcoming word: An event-related potential study on sentence comprehension.
One of the most compelling pieces of evidence for the presence of predictions in language comprehension comes from event-related potential (ERP) studies which show that encountering an adjective whose gender marking is inconsistent with that of a highly expectable noun leads to an effect at the adjective. Until now the mechanism underlying this effect has been unknown. The present study tests a novel hypothesis whereby the effect at adjectives reflects prediction updating, which in turn impacts the N400 generated by the upcoming noun. In 2 experiments, native speakers of Polish read short stories that made several nouns likely at the position of a direct object in the story's final sentence. The noun was preceded by a gender-marked adjective which was shown in either of the 2 grammatical forms: (a) informative about the following noun (adjectival gender marking constrained which nouns can follow), or (b) less informative (the grammatical marking did not disambiguate the gender of the following noun). Importantly, the same stories and critical words were used in both conditions, which was possible thanks to exploiting syncretisms in Polish adjectival inflection. The results provide support for 1 or more mechanisms of prediction updating at the adjective that impact the amplitude of the N400 elicited by the following noun. Together, these results show that when only morphosyntactic cues are available, they are instantly used to update predictions about upcoming words. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Phase transition and crystal structure of the 37 degrees C form of cholesterol.
Crystalline cholesterol undergoes a phase transition a few degrees below human body temperature. The high-temperature form has an unusually complex structure with 16 independent molecules. In the transition two molecules change side chain conformation, four reorient about their long axes, and ten remain unchanged. The transition mechanism implies relatively nonspecific intermolecular interactions, qualitatively consistent with the behavior of cholesterol in biomembranes. The transition preserves a remarkably closely obeyed pseudosymmetry present in the structure.


Barriers and facilitators to implementing telehealth services during the COVID-19 pandemic: A qualitative analysis of interviews with cystic fibrosis care team members.
The COVID-19 pandemic forced cystic fibrosis (CF) care programs to rapidly shift from in-person care delivery to telehealth. Our objective was to provide a qualitative exploration of facilitators and barriers to: 1) implementing high-quality telehealth and 2) navigating reimbursement for telehealth services. We used data from the 2020 State of Care CF Program Survey (n=286 U.S. care programs) administered in August-September to identify two cohorts of programs, with variation in telehealth quality (n=12 programs) and reimbursement (n=8 programs). We conducted focus groups and semi-structured interviews with CF program directors and coordinators in December 2020, approximately 9 months from onset of the pandemic. We used the Consolidated Framework for Implementation Research to identify facilitators and barriers of implementation, and inductive thematic analysis to identify facilitators and barriers of reimbursement. Factors differentiating programs with greater and lower perceived telehealth quality included telehealth characteristics (perceived advantage over in-person care, cost, platform quality); external influences (needs and resources of those served by the CF program), characteristics of the CF program (compatibility with workflows, relative priority, available resources); characteristics of team members (individual stage of change), and processes for implementation (engaging patients and teams). Reimbursement barriers included documentation to optimize billing; reimbursement of multi-disciplinary team members, remote monitoring, and telephone-only telehealth; and lower volume of patients. A number of factors are associated with successful implementation and reimbursement of telehealth. Future efforts should provide guidance and incentives that support telehealth delivery and infrastructure, share best practices across CF programs, and remove barriers.


Allopregnanolone promotes success in food competition in subordinate male rats.
Allopregnanolone or 3α-hydroxy-5α-pregnan-20-one (AlloP) is normally sedative and anxiolytic, but can under provoking circumstances paradoxically induce aggressive behavior. Therefore, it is of particular interest to determine if there is a relationship between an anxiolytic effect and aggressive behavior following AlloP administration. Male Wistar rats were housed in triads comprising of 1 young rat (35 days) and 2 older rats (55 days), with the intent of producing a social hierarchy. The triads were sampled for total serum testosterone and submitted to a social challenge in the form of a food competition test (FCT), where the rats competed for access to drinking sweetened milk. At baseline, the younger rats were identified as subordinates. To test for the behavioral effect of AlloP, the subordinate rats were given intravenous AlloP injections of 0.5 and 1 mg/kg. To assess the optimal AlloP effect, 6 intervals (5, 10, 15, 20, 30 and 40 min) between injection and the FCT were used. In separate studies, AlloP was also given by subcutaneous and intraperitoneal administration at 10 and 17 mg/kg. AlloP (1 mg/kg, i.v.) increased drinking time and aggressive behavior in subordinate rats, with a positive correlation between these behaviors. The subcutaneous injection (17 mg/kg) also increased drinking time in subordinate animals. Serum testosterone concentration was higher in dominant compared to subordinate rats, and correlated with drinking time and weight. AlloP increased drinking time and aggressive behavior, and the correlation indicates a relationship between an anxiolytic effect and aggressive behavior.


Fano interference between localized plasmons and interface reflections.
Layers of subwavelength metal nanostructures that support localized surface plasmon resonances are of broad interest in applied nanotechnology, for example, in optical sensor development and solar energy harvesting devices. We measured specular reflection spectra as a function of incidence angle for two-dimensional layers of gold nanodisks on glass and found highly asymmetric line-shapes and a spectral red-shift of up to 0.2 eV, or 10% of the plasmon resonance energy, as the angle changed from normal toward grazing incidence. This dramatic angular dispersion is the result of a tunable Fano interference between the spectrally narrow plasmon emission and a "white" continuum caused by the interface reflection. The data are found to be in excellent agreement with predictions based on a theory for Fresnel reflection coefficients of an interface with subwavelength inclusions. The theory can also be used to derive analytical expressions for the Fano parameters.


CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report.
The use of high-throughput sequencing techniques has allowed the identification of numerous mutations in genes responsible for severe astheno-teratozoospermia due to multiple morphological abnormalities of the sperm flagella (MMAF). However, more than half of the analysed cases remain unresolved suggesting that many yet uncharacterised gene defects account for this phenotype. Based on whole-exome sequencing data from a large cohort of 167 MMAF-affected subjects, we identified two unrelated affected individuals carrying a homozygous deleterious mutation in CFAP70, a gene not previously linked to the MMAF phenotype. One patient had a homozygous splice variant c.1723-1G>T, altering a consensus splice acceptor site of CFAP70 exon 16, and one had a likely deleterious missense variant in exon 3 (p.Phe60Ile). The CFAP70 gene encodes a regulator protein of the outer dynein arms (ODA) strongly expressed in the human testis. In the sperm cells from the patient carrying the splice variant, immunofluorescence (IF) experiments confirmed the absence of the protein in the sperm flagellum. Moreover, IF analysis showed the absence of markers for the ODAs and the central pair complex of the axoneme. Interestingly, whereas CFAP70 staining was present in sperm cells from patients with mutations in the three other MMAF-related genes ARMC2, FSIP2 and CFAP43, we observed an absence of staining in sperm cells from patients mutated in the WDR66 gene, suggesting a possible interaction between two different axonemal components. In conclusion, this work provides the first evidence that loss of CFAP70 function causes MMAF and that ODA-related proteins may be crucial for the assembly and/or stability of the flagellum axoneme in addition to its motility.


Tenofovir Versus Entecavir for Hepatocellular Carcinoma Prevention in an International Consortium of Chronic Hepatitis B.
It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differ in their effectiveness for preventing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This retrospective cohort study analyzed an international consortium that encompassed 19 centers from 6 countries or regions composed of previously untreated CHB patients then treated with either ETV or TDF monotherapy. Those who developed HCC before antiviral treatment or within 1 year of therapy were excluded. The association between antiviral regimen and HCC risk was evaluated using competing-risk survival regression. We also applied propensity score matching (PSM) to 1:1 balance the 2 treatment cohorts. A total of 5,537 patients were eligible (n = 4,837 received ETV and n = 700 received TDF) and observed for HCC occurrence until December 23, 2018. Before PSM, the TDF cohort was significantly younger and had generally less advanced diseases. In the unadjusted analysis, TDF was associated with a lower risk of HCC (subdistribution hazard ratio [SHR], 0.45; 95% confidence interval [CI], 0.26-0.79; P = 0.005). The multivariable analysis, however, found that the association between TDF and HCC no longer existed (SHR, 0.81; 95% CI, 0.42-1.56; P = 0.52) after adjustment for age, sex, country, albumin, platelet, α-fetoprotein, cirrhosis, and diabetes mellitus. Furthermore, the PSM analysis (n = 1,040) found no between-cohort differences in HCC incidences (P = 0.51) and no association between regimens (TDF or ETV) and HCC risk in the multivariable-adjusted analysis (adjusted SHR, 0.89; 95% CI, 0.41-1.92; P = 0.77). TDF and ETV did not significantly differ in the prevention of HCC in patients with CHB.


Combining sea urchin embryo cell lineages by error-tolerant graph matching.
Obtaining the complete cell lineage tree of an embryo's development is a very appealing and ambitious goal, but fortunately recent developments both in optical imaging and digital image processing are bringing it closer. However, when imaging the embryos (sea urchin embryos for this work) with high enough spatial resolution and short enough time-step to make cell segmentation and tracking possible, it is currently not possible to image the specimen throughout its all embryogenesis. For this reason it is interesting to explore how cell lineage trees extracted from two different embryos of the same species and imaged for overlapping periods of time can be concatenated, resulting in a single lineage tree covering both embryos' development time frames. To achieve this we used an error-tolerant graph matching strategy by selecting a time point at which both lineage trees overlap, and representing the information about each embryo at that time point as a graph in which nodes stand for cells and edges for neighborhood relationships among cells. The expected output of the graph matching algorithm is the minimal-cost correspondence between cells of both specimens, allowing us to perform the lineage combination.


Divergence of a stereotyped call in northern resident killer whales.
Northern resident killer whale pods (Orcinus orca) have distinctive stereotyped pulsed call repertoires that can be used to distinguish groups acoustically. Repertoires are generally stable, with the same call types comprising the repertoire of a given pod over a period of years to decades. Previous studies have shown that some discrete pulsed calls can be subdivided into variants or subtypes. This study suggests that new stereotyped calls may result from the gradual modification of existing call types through subtypes. Vocalizations of individuals and small groups of killer whales were collected using a bottom-mounted hydrophone array in Johnstone Strait, British Columbia in 2006 and 2007. Discriminant analysis of slope variations of a predominant call type, N4, revealed the presence of four distinct call subtypes. Similar to previous studies, there was a divergence of the N4 call between members of different matrilines of the same pod. However, this study reveals that individual killer whales produced multiple subtypes of the N4 call, indicating that divergence in the N4 call is not the result of individual differences, but rather may indicate the gradual evolution of a new stereotyped call.


Selection of reference genes for diurnal and developmental time-course real-time PCR expression analyses in lettuce.
Real-time quantitative polymerase chain reaction (RT-qPCR) analysis is a low cost and sensitive technique that is widely used to measure levels of gene expression. Selecting and validating appropriate reference genes for normalising target gene expression should be the first step in any expression study to avoid inaccurate results. In this study, ten candidate genes were tested for their suitability for use as reference genes in diurnal and developmental timecourse experiments in lettuce. The candidate reference genes were then used to normalise the expression pattern of the FLOWERING LOCUS T (FT) gene, one of key genes involved in the flowering time pathway whose expression is known to vary throughout the day and at different stages of development. Three reference genes, LsPP2A-1 (PROTEIN PHOSPHATASE 2A-1), LsPP2AA3 (PROTEIN PHOSPHATASE 2A REGULATORY SUBUNIT A3) and LsTIP41 (TAP42-INTERACTING PROTEIN OF 41 kDa), were the most stably expressed candidate reference genes throughout both the diurnal and developmental timecourse experiments. In the developmental experiment using just LsPP2A-1 and LsTIP41 as reference genes would be sufficient for accurate normalisation, whilst in the diurnal experiment all three reference genes, LsPP2A-1, LsPP2AA3 and LsTIP41, would be necessary. The FT expression pattern obtained demonstrates that the use of multiple and robust reference genes for RT-qPCR expression analyses results in a more accurate and reliable expression profile. Reference genes suitable for use in diurnal and developmental timecourse experiments in lettuce were identified and used to produce a more accurate and reliable analysis of lsFT expression levels than previously obtained in such timecourse experiments.


Trait anger, anger expression, and suicide attempts among adolescents and young adults: a prospective study.
Previous studies of the relationship between anger, anger expression, and suicidal behavior have been largely cross-sectional and have yielded mixed findings. In a prospective, naturalistic study, we examined how trait anger and anger expression influenced the likelihood of suicide attempts among 180 adolescents followed for up to 13.3 years after discharge from an inpatient psychiatry unit. Results showed that higher trait anger and anger expressed outwardly over the follow-up was related to increased likelihood of suicide attempts among boys. For girls, trait anger and both the inward and outward expression of anger moderated the risk for suicide attempts associated with major depression. These results are interpreted in light of theory regarding behavioral activation and behavioral inhibition systems.


[Embryonic development of guppies in weightlessness].
The program of the Cosmos-1514 flight included an experiment the purpose of which was to study the effect of weightlessness on the embryonic development of the live-bearing guppy fish: three pregnant females were flown for 5 days. Prelaunch their embryos were at the stage of cerebral vesicle differentiation and somite formation; this implies that the basic stages of organogenesis developed in weightlessness. One female was fixed in Bouin's fluid two days postflight and the second fish was fixed nine days postflight. Fourteen days after flight the third female gave birth to 25 normal fry. Thereafter that fish was mated 6 times more, each time delivering normal offspring. In addition, the offspring of the second generation was normal. Histological analysis of the embryos that were developing in weightlessness revealed no abnormalities. It can be concluded that weightlessness produced no effect on the fish development, beginning with the stage of the axial complex formation.


Finite element model of polar growth in pollen tubes.
Cellular protuberance formation in walled cells requires the local deformation of the wall and its polar expansion. In many cells, protuberance elongation proceeds by tip growth, a growth mechanism shared by pollen tubes, root hairs, and fungal hyphae. We established a biomechanical model of tip growth in walled cells using the finite element technique. We aimed to identify the requirements for spatial distribution of mechanical properties in the cell wall that would allow the generation of cellular shapes that agree with experimental observations. We based our structural model on the parameterized description of a tip-growing cell that allows the manipulation of cell size, shape, cell wall thickness, and local mechanical properties. The mechanical load was applied in the form of hydrostatic pressure. We used two validation methods to compare different simulations based on cellular shape and the displacement of surface markers. We compared the resulting optimal distribution of cell mechanical properties with the spatial distribution of biochemical cell wall components in pollen tubes and found remarkable agreement between the gradient in mechanical properties and the distribution of deesterified pectin. Use of the finite element method for the modeling of nonuniform growth events in walled cells opens future perspectives for its application to complex cellular morphogenesis in plants.


The metabolic effects of oxytocin are mediated by a uterine type of receptor and are inhibited by oxytocin antagonist and by arginine vasopressin in the dog.
Infusion of oxytocin (OT) into normal dogs, in doses which produced plasma levels of OT in the physiological range, has been shown to increase plasma levels of glucose, insulin and glucagon and increase rates of glucose production and uptake. This study sought to determine whether there was a correlation between these metabolic effects and the oxytocic potency of four less potent oxytocic analogues when infused into normal dogs. The rank order of oxytocic potency of all 4 correlated well with the rise in plasma glucose levels, and in 3 of the 4 with the rise in plasma insulin levels. An antagonist of the oxytocic effect of OT suppressed the usual OT-induced rise in plasma glucose, insulin and glucagon as well as the increased glucose production and uptake. Arginine vasopressin (AVP) infusion, which by itself did not produce any metabolic effects, blocked completely the effects of OT infusion to raise plasma glucose and insulin levels and increase glucose production and uptake. The data suggest that the metabolic effects of OT in the dog are mediated by OT receptors that are similar to those producing the oxytocic effects. Whether the inhibition by AVP of the metabolic and hormonal effects of OT occurs at the receptor or post receptor level or via other mechanisms remains to be determined.


Magnetic field assisted stem cell differentiation - role of substrate magnetization in osteogenesis.
Among the multiple modulatory physical cues explored to regulate cellular processes, the potential of magneto-responsive substrates in magnetic field stimulated stem cell differentiation is still unperceived. In this regard, the present work demonstrates how an external magnetic field can be applied to direct stem cell differentiation towards osteogenic commitment. A new culture methodology involving periodic delivery of 100 mT static magnetic field (SMF) in combination with HA-Fe3O4 magnetic substrates possessing a varying degree of substrate magnetization was designed for the study. The results demonstrate that an appropriate combination of weakly ferromagnetic substrates and SMF exposure enhanced cell viability, DNA synthesis and caused an early switchover to osteogenic lineage as supported by Runx2 immunocytochemistry and ALP expression. However, the mRNA expression profile of early osteogenic markers (Runx2, ALP, Col IA) was comparable despite varying substrate magnetic properties (diamagnetic to ferromagnetic). On the contrary, a remarkable upregulation of late bone development markers (OCN and OPN) was explicitly detected on weak and strongly ferromagnetic substrates. Furthermore, SMF induced matrix mineralization with elevated calcium deposition on similar substrates, even in the absence of osteogenic supplements. More specifically, the role of SMF in increasing intracellular calcium levels and in inducing cell cycle arrest at G0/G1 phase was elucidated as the major molecular event triggering osteogenic differentiation. Taken together, the above results demonstrate the competence of magnetic stimuli in combination with magneto-responsive biomaterials as a potential strategy for stem cell based bone tissue engineering.


Comparison of mesiodistal crown dimension and arch width in subjects with and without hypodontia.
Tooth agenesis is one of the most common anomalies in the development of the human dentition and may have wider associations in the development of the dentition including tooth size. This study aimed to compare mesiodistal crown dimension and arch widths between subjects with hypodontia and subjects without hypodontia (control group). Dental casts were measured of 55 hypodontia patients and 55 patients with total permanent dentition (control group). Tooth agenesis was evaluated for hypodontia, excluding the third molars, from the panoramic radiograph. Mesiodistal crown dimensions were recorded by measuring all erupted teeth on study models with a digital Mitutoyo caliper (Mitutoyo U.K. Ltd, United Kingdom). Patients with hypodontia had smaller mesiodistal tooth dimensions than the control group, and this difference was statistically significant (p < 0.05) for all teeth in both genders. Upper lateral incisors, lower central incisors, and lower second molars showed the highest difference in tooth dimension. Also, the intercanine and intermolar arch widths in the hypodontia group were statistically significantly reduced (p < 0.05) compared with the control group. The findings indicate that the mesiodistal crown dimensions and arch widths are reduced in hypodontia patients. This should be taken into account when planning orthodontic treatment. Congenital absence of permanent teeth has direct clinical implications. Early detection of the number of missing teeth and evaluation of the tooth size and arch width is of immense value in the planning and managing treatment with a multidisciplinary team approach to achieve an aesthetic and functional dentition and reduce the complications of hypodontia.


Visualization and characterization of spore morphogenesis in Paenibacillus polymyxa ATCC39564.
Paenibacillus polymyxa is a spore-forming Gram-positive bacterial species. Both its sporulation process and the spore properties are poorly understood. Here, we investigated sporulation in P. polymyxa ATCC39564. When cultured at 37℃ for 24 h in sporulation medium, more than 80% of the total cells in the culture were spores. Time-lapse imaging revealed that cellular morphological changes during sporulation of P. polymyxa were highly similar to those of B. subtilis. We demonstrated that genetic deletion of spo0A, sigE, sigF, sigG, or sigK, which are highly conserved transcriptional regulators in spore forming bacteria, abolished spore formation. In P. polymyxa, spo0A was required for cell growth in sporulation medium, as well as for the initiation of sporulation. The sigE and sigF mutants formed abnormal multiple asymmetric septa during the early stage of sporulation. The sigG and sigK mutants formed forespores in the sporangium, but they did not become mature. Moreover, fluorescence reporter analysis confirmed compartment-specific gene expression of spoIID and spoVFA in the mother cell and spoIIQ and sspF in the forespore. Transmission electron microscopy imaging revealed that P. polymyxa produces multilayered endospores but lacking a balloon-shaped exosporium. Our results indicate that spore morphogenesis is conserved between P. polymyxa and B. subtilis. However, P. polymyxa genomes lack many homologues encoding spore-coat proteins that are found in B. subtills, suggesting that there are differences in the spore coat composition and surface structure between P. polymyxa and B. subtilis.


Psychopharmacology of combined activation of the serotonin1A and σ1 receptors.
The selective serotonin (5-HT) reuptake inhibitors (SSRIs) are generally used for the treatment of major depressive disorders, and the 5-HT1A and σ1 receptors are considered to be targets for treatment of psychiatric disorders. Some SSRIs such as fluvoxamine have agonistic activity towards for the σ1 receptor, but it is not known whether the effect on the receptor plays a key role in the pharmacological effects. We have recently demonstrated that fluvoxamine shows an anti-anhedonic effect in picrotoxin-induced model of anxiety/depression, while the SSRI paroxetine, which have little affinity for the σ1 receptor, does not. We also suggest that the anti-anhedonic effect of fluvoxamine is mediated by combined activation of the 5-HT1A and σ1 receptors and it is associated with activation of prefrontal dopaminergic system. In these studies, picrotoxin-treated mice and adrenalectomized/castrated mice were used as decreased GABAA receptor function and neurosteroid-deficient models, respectively. These findings suggest that the functional interaction between the 5-HT1A and σ1 receptors activates prefrontal dopaminergic system under the conditions of decreased brain GABAA receptor function and the neurochemical effect is linked to the behavioral effect. This review summarizes the pharmacological role of the 5-HT1A and σ1 receptors, focusing on the functional interaction between these receptors, and the role of prefrontal dopaminergic system in depressive-like behaviors.


Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) is characterized by frequent cardiac arrhythmias. To elucidate the underlying mechanisms and discover potential chemical modifiers, we created a zebrafish model of ACM with cardiac myocyte-specific expression of the human 2057del2 mutation in the gene encoding plakoglobin. A high-throughput screen identified SB216763 as a suppressor of the disease phenotype. Early SB216763 therapy prevented heart failure and reduced mortality in the fish model. Zebrafish ventricular myocytes that expressed 2057del2 plakoglobin exhibited 70 to 80% reductions in I(Na) and I(K1) current densities, which were normalized by SB216763. Neonatal rat ventricular myocytes that expressed 2057del2 plakoglobin recapitulated pathobiological features seen in patients with ACM, all of which were reversed or prevented by SB216763. The reverse remodeling observed with SB216763 involved marked subcellular redistribution of plakoglobin, connexin 43, and Nav1.5, but without changes in their total cellular content, implicating a defect in protein trafficking to intercalated discs. In further support of this mechanism, we observed SB216763-reversible, abnormal subcellular distribution of SAP97 (a protein known to mediate forward trafficking of Nav1.5 and Kir2.1) in rat cardiac myocytes expressing 2057del2 plakoglobin and in cardiac myocytes derived from induced pluripotent stem cells from two ACM probands with plakophilin-2 mutations. These observations pinpoint aberrant trafficking of intercalated disc proteins as a central mechanism in ACM myocyte injury and electrical abnormalities.


Chemdex: quantification and distributions of valence numbers, oxidation numbers, coordination numbers, electron numbers, and covalent bond classes for the elements.
The paper introduces Chemdex, a freely accessible web-based database of over 70 000 compounds characterised by crystallography from across the periodic table. Its software calculates for an atom of interest within each compound classifications including valence number, oxidation number, coordination number, electron number, several covalent bond classifications, and the attached atom set. Users may explore distributions of these classifications by percentages and heat map displays for individual elements or sets of elements, or in several cases for one classification plotted against a second. These properties often display clear periodicity. Based upon distributions across the periodic table of valence numbers, electron numbers, coordination numbers, and attached atom data suggestions are made regarding the placement of hydrogen in the periodic table, membership of group 3 in the periodic table, locations of the early actinoids in the periodic table, and assignments of certain elements as metalloids.


Phase resetting and annihilation in a mathematical model of sinus node.
A mathematical model of primary sinoatrial pacemaker activity was developed using modifications of Hodgkin-Huxley type equations of voltage- and time-dependent membrane currents. The computer simulation of action potential activity incorporates the results of several existing cardiac models and recent biological data in an attempt to generate a model that more closely approximates the phase-resetting behavior of sinoatrial pacemakers observed biologically in response to subthreshold or electrotonic stimuli. The model was also used to study annihilation, i.e., the cessation of rhythmic activity induced by a critically timed subthreshold stimulus. Perturbation analysis performed by scanning the pacemaker cycle with 50-ms subthreshold current pulses yielded biphasic phase-response relationships that closely resembled the biological data. The pacemaker current, although relatively unimportant in determining the degree of phase 4 depolarization in the simulated sinus nodal pacemaker, was nevertheless prominent in determining phase-resetting behavior. The characteristics of annihilation were studied in normal, "depressed," and hyperpolarized states. In all cases, successful annihilation depended in large part on the dynamic interaction between the slow inward and delayed rectifier outward currents. The annihilation point was found to be an unstable singularity point in which a critical combination of stimulus intensity and timing could cause the pacemaker to approach but never achieve a state of complete quiescence. The model provides the basis for further investigation of complex arrhythmias that may arise as a consequence of multiple-pacemaker interaction within the heart.


The pathophysiological effects of Moraxella bovis toxins on cattle, mice and guinea pigs.
In three experiments, cattle, mice and guinea pigs were inoculated with viable cultures of Moraxella bovis or fractions of this organism. Fractions were obtained by disruption of cells with a fractionator at 20,000 pounds per square inch, and separating the cell wall and cell sap fractions by differential centrifugation. Cell sap fractions were further separated by ultra-centrifugation, heating and precipitation with (NH(4))(2) SO(4). Different fractions induced different pathophysiological manifestations. The cell wall fractions caused localized lesions (necrosis) at the site of injection, and emphysema and congestion of the lungs. Cell sap fractions induced a "shock syndrome," as well as hemorrhage and inflammation of the intestines, hemorrhage and congestion of lymph nodes, liver, adrenal and spleen. Cell sap also induced conjunctivitis in mice and guinea pigs, and periocular edema, myosis, ocular pruritus and lacrimation in cattle. The authors suggest that M. bovis probably produces endotoxins and exotoxins as well as possibly a specific oculopathic substance, but more definitive work is needed to confirm this. They caution that consideration of these toxins should be made in any application of M. bovis for vaccines or other immunological studies.


Impact of Yoga on Inflammatory Biomarkers: A Systematic Review.
Many chronic conditions, including heart disease, cancer, and rheumatoid arthritis, are associated with underlying chronic inflammatory processes. Literature reviews have analyzed a variety of integrative therapies and their relationships with chronic inflammation. This systematic review is unique in reporting solely on yoga's relationship with inflammation. Its purpose was to synthesize current literature examining the impact of yoga interventions on inflammatory biomarkers in adults with chronic inflammatory-related disorders. Searches of several electronic databases were conducted. Inclusion criteria were (a) English language, (b) sample age >18 years old, (c) yoga interventions involving postures with or without yoga breathing and/or meditation, and (d) measured inflammatory biomarkers. The final review included 15 primary studies. Of these, seven were rated as excellent and eight as average or fair. There was considerable variability in yoga types, components, frequency, session length, intervention duration, and intensity. The most common biomarkers measured were interleukin-6 ( n = 11), C-reactive protein ( n = 10), and tumor necrosis factor ( n = 8). Most studies reported positive effects on inflammatory biomarkers ( n = 11) from baseline to post yoga intervention. Analysis of the dose showed higher total dose (>1,000 min) resulted in greater improvements in inflammation. This review suggests that yoga can be a viable intervention to reduce inflammation across a multitude of chronic conditions. Future studies with detailed descriptions of yoga interventions, measurement of new and well-established inflammatory biomarkers, and larger sample sizes are warranted to advance the science and corroborate results.


[On the effect of mutations of the fibroblast growth factor receptors as exemplified by three cases of craniosynostoses].
Craniosynostoses are premature ossifications of cranial sutures. They occur isolated and syndromic. Syndromic craniosynostoses are mainly associated with mutations of the Fibroblast Growth Factor Receptors (FGFR) 1 - 3. This paper gives an overview of the etiology and pathophysiology of isolated and syndromic craniosynostoses and discusses the molecular genetic results in 21 index cases (19 seemingly isolated craniosynostoses, 2 cases with a clinical diagnosis of Crouzon's syndrome). Mutation analysis in exons of the FGFR 1 - 3 known to be preferentially affected in craniosynostoses was performed on DNA samples from peripheral blood and bone specimen excised at the time of surgery to correct the craniosynostosis. In a girl with seemingly isolated plagiocephaly we identified a P250L (749C-->T) mutation in FGFR3. Her mother showed minor signs of craniosynostosis when the family was re-evaluated. She was shown to carry the same mutation. In two patients with suspected Crouzon's syndrome 2 different mutations were detected at the same nucleotide (1025G-->A or C) and confirmed the clinical diagnosis. No mutation was found in 18/19 seemingly isolated craniosynostosis cases. In contrast to syndromic forms isolated craniosynostoses are rarely associated with mutations in FGFR. The affection of further family members is a strong indication of involvement of FGFR mutations. Because of variable expressivity, parents should be examined carefully in isolated craniosynostoses to identify minor signs.


Lenalidomide (Revlimid, CC-5013) in myelodysplastic syndromes: is it any good?
The myelodysplastic syndromes (MDS) can be divided into "early" and "advanced" disease by evaluation of prognostic variables such as the number of cytopenias, karyotype, and percentage of myeloblasts. Patients with an isolated interstitial deletion of chromosome 5q31 represent a distinct subset who may derive particular benefit from immunomodulatory drugs. Goals of therapy for early MDS focus on hematologic improvement and maximizing quality of life. Thalidomide, the prototype of the immunomodulatory drugs, yields major erythroid responses in some patients with early MDS, but dose-limiting neurologic toxicities limit its potential clinical benefit. Lenalidomide, a more potent and non-neurotoxic derivative, has shown promising results in early MDS, yielding hematologic improvement in almost half of patients, and transfusion independence with cytogenetic remissions in approximately two thirds of patients harboring the chromosome 5q31 deletion.


Interrelationships between ghrelin, insulin and glucose homeostasis: Physiological relevance.
Ghrelin is a 28 amino acid peptide mainly derived from the oxyntic gland of the stomach. Both acylated (AG) and unacylated (UAG) forms of ghrelin are found in the circulation. Initially, AG was considered as the only bioactive form of ghrelin. However, recent advances indicate that both AG and UAG exert distinct and common effects in organisms. Soon after its discovery, ghrelin was shown to promote appetite and adiposity in animal and human models. In response to these anabolic effects, an impressive number of elements have suggested the influence of ghrelin on the regulation of metabolic functions and the development of obesity-related disorders. However, due to the complexity of its biochemical nature and the physiological processes it governs, some of the effects of ghrelin are still debated in the literature. Evidence suggests that ghrelin influences glucose homeostasis through the modulation of insulin secretion and insulin receptor signaling. On the other hand, insulin was also shown to influence circulating levels of ghrelin. Here, we review the relationship between ghrelin and insulin and we describe the impact of this interaction on the modulation of glucose homeostasis.


Default Mode Network Connectivity and Related White Matter Disruption in Type 2 Diabetes Mellitus Patients Concurrent with Amnestic Mild Cognitive Impairment.
As a risk factor for Alzheimer's disease (AD), type 2 diabetes mellitus (T2DM) itself causes cognitive impairment and has higher prevalence of mild cognitive impairment (MCI). The aim of this study was to explore the cognition especially the episodic memory difference, the DMN functional connectivity and DMN-related white matter integrity in patients with both T2DM and amnestic MCI (T2DM-MCI) as compared to patients with T2DM only. Focusing especially on T2DM population, we investigated the default mode network (DMN) through resting-state functional magnetic resonance imaging among 22 elderly T2DM-MCI patients and 24 elderly T2DM patients. Including primarily the bilateral cingulum, hippocampus and uncinate fasciculus, these DMN white matter fibers were also closely associated with episodic memory and the integrity of them was also investigated using diffusion tensor imaging in 19 elderly T2DM-MCI patients and 23 elderly T2DM patients. Compared with the patients with T2DM, the T2DM-MCI patients performed worse in several areas of cognition besides episodic memory, and showed stronger DMN functional connectivity in the left precuneus and weaker functional connectivity in the left calcarine, as well as decreased integrity of the left cingulate bundle and bilateral uncinate fasciculus. Furthermore, a correlation analysis indicated that higher left calcarine connectivity was associated with better episodic memory performance among the overall group. Our results demonstrated that T2DM patients with comorbid amnestic MCI had abnormal functional connectivity patterns and decreased white matter integrity, which could potentially serve as AD or AD risk biomarkers for early detection of those elderly individuals with T2DM.


Identification of the ATP binding domain of recombinant human 40-kDa 2',5'-oligoadenylate synthetase by photoaffinity labeling with 8-azido-[alpha-32P]ATP.
Three isoforms of the interferon-inducible 2',5'-oligoadenylate (2-5A) synthetase that require double-stranded RNA have been isolated and cloned. However, identification of the amino acid(s) of 2-5A synthetase directly interacting with ATP is crucial to the elucidation of the mechanism of the enzymatic conversion of ATP to 2',5'-oligoadenylates by 2-5A synthetase. Recombinant human 40-kDa 2-5A synthetase has been expressed as a glutathione S-transferase fusion protein in E. coli and purified to near homogeneity in milligram quantities. The azido photoprobe, 8-azido-[alpha-32P]ATP, has been used to identify the ATP binding domain of the recombinant human 40-kDa 2-5A synthetase. Specific covalent photoincorporation of 8-azido-[alpha-32P]ATP into the 2-5A synthetase, tryptic digestion of the covalently 32P-labeled enzyme, isolation of the photolabeled phosphopeptide by metal (Al3+) chelate chromatography, and high pressure liquid chromatography identified a 32P-pentapeptide, which has been assigned to the ATP binding domain of 2-5A synthetase. The radioactive pentapeptide has the sequence D196FLKQ200 in which the photoprobe, 8-azido-[alpha-32P]ATP, chemically modified the amino acid lysine 199. The catalytic importance of Lys199 was further established by mutation of lysine 199 to arginine 199 and histidine 199 using site-directed mutagenesis. The K199R and K199H recombinant human 40-kDa 2-5A synthetase mutants bind 8-azido-ATP and the allosteric activator, poly(I) poly(C) but are enzymatically inactive. These photoaffinity labeling and mutation data strongly suggest that lysine 199 is essential for the formation of a productive 2-5A synthetase-ATP-double-stranded RNA complex for the enzymatic conversion of ATP to 2-5A.


Deletion of yeast p24 genes activates the unfolded protein response.
Yeast cells lacking a functional p24 complex accumulate a subset of secretory proteins in the endoplasmic reticulum (ER) and increase the extracellular secretion of HDEL-containing ER residents such as Kar2p/BiP. We report that a loss of p24 function causes activation of the unfolded protein response (UPR) and leads to increased KAR2 expression. The HDEL receptor (Erd2p) is functional and traffics in p24 deletion strains as in wild-type strains, however the capacity of the retrieval pathway is exceeded. Other conditions that activate the UPR and elevate KAR2 expression also lead to extracellular secretion of Kar2p. Using an in vitro assay that reconstitutes budding from the ER, we detect elevated levels of Kar2p in ER-derived vesicles from p24 deletion strains and from wild-type strains with an activated UPR. Silencing the UPR by IRE1 deletion diminished Kar2p secretion under these conditions. We suggest that activation of the UPR plays a major role in extracellular secretion of Kar2p.


Design of compact and ultra efficient aspherical lenses for extended Lambertian sources in two-dimensional geometry.
The energy efficiency and compactness of an illumination system are two main concerns in illumination design for extended sources. In this paper, we present two methods to design compact, ultra efficient aspherical lenses for extended Lambertian sources in two-dimensional geometry. The light rays are directed by using two aspherical surfaces in the first method and one aspherical surface along with an optimized parabola in the second method. The principles and procedures of each design method are introduced in detail. Three examples are presented to demonstrate the effectiveness of these two methods in terms of performance and capacity in designing compact, ultra efficient aspherical lenses. The comparisons made between the two proposed methods indicate that the second method is much simpler and easier to be implemented, and has an excellent extensibility to three-dimensional designs.


Mitogen-induced phosphorylation of human B-lymphocyte proteins. Relationship to protein kinase C activation.
We have investigated the rapid phosphorylation of proteins in B-lymphocytes incubated with the tumour-promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), anti-Ig and combinations of TPA and the Ca2+ ionophore ionomycin. Two-dimensional electrophoretic analysis was used to identify the proteins phosphorylated in cells preincubated with [32P]Pi. TPA induced a characteristic pattern of labelled proteins, four of which (pp85, pp76, pp66 and pp63) showed a dose-dependent incorporation of 32P on serine residues. The phosphorylation of pp63 and pp66, in particular, correlated with the mitogenic dose-response curve. Addition of the Ca2+ ionophore ionomycin to B-cells also stimulated a characteristic incorporation of 32P into proteins, which included pp63 and pp66. With combined doses of TPA and ionomycin, these two proteins show an enhanced phosphorylation, which correlated well with the synergistic enhancement of proliferation shown by this combination of agents. Protein kinase C (PKC) was partially purified from B-cells and separated into alpha and beta subtypes. The activation of both PKCs was assessed with increasing doses of TPA and concentrations of Ca2+ of 0.1 microM and 2 microM. For both forms of PKC, in particular the beta form, higher concentrations of Ca2+ shifted the dose-response curve for TPA to the left and increased the maximum activation. Anti-Ig, which stimulated B-cells by cross-linking surface immunoglobulin and causing hydrolysis of PtdIns(4,5)P2, also caused increased phosphorylation of several proteins, which again included pp63 and pp66. These data suggest that PKC, particularly the beta form, is involved in the early part of the proliferation cascade for human B-lymphocytes. It is most probably activated in a synergistic manner by the increased Ca2+ and diacylglycerol levels which result from the earlier hydrolysis of PtdIns(4,5)P2.


Dietary chalcones with chemopreventive and chemotherapeutic potential.
Chalcones are absorbed in the daily diet and appear to be promising cancer chemopreventive agents. Chalcones represent an important group of the polyphenolic family, which includes a large number of naturally occurring molecules. This family possesses an interesting spectrum of biological activities, including antioxidative, antibacterial, anti-inflammatory, anticancer, cytotoxic, and immunosuppressive potential. Compounds of this family have been shown to interfere with each step of carcinogenesis, including initiation, promotion and progression. Moreover, numerous compounds from the family of dietary chalcones appear to show activity against cancer cells, suggesting that these molecules or their derivatives may be considered as potential anticancer drugs. This review will focus primarily on prominent members of the chalcone family with an 1,3-diphenyl-2-propenon core structure. Specifically, the inhibitory effects of these compounds on the different steps of carcinogenesis that reveal interesting chemopreventive and chemotherapeutic potential will be discussed.


Site-specific integration by adeno-associated virus.
Adeno-associated virus (AAV) has attracted considerable interest as a potential vector for gene delivery. Wild-type virus is notable for the lack of association with any human disease and the ability to stably integrate its genome in a site-specific manner in a locus on human chromosome 19 (AAVS1). Use of a functional model system for AAV DNA integration into AAVS1 has allowed us to conclude that the recombination event is directed by cellular DNA sequences. Recombinant junctions isolated from our integration assay were analyzed and showed characteristics similar to those found in latently infected cell lines. The minimal DNA signals within AAVS1 required for targeted integration were identified and shown to contain functional motifs of the viral origin of replication. A replication mediated model of AAV DNA integration is proposed.


Pelvic floor tonicity affects urodynamic measurements in children with myelomeningocele.
In a cystometry procedure in a child with myelomeningocele (MMC), a pressure increase in the abdominal pressure (P (abd)) tracing was detected during filling. This pressure alteration was not related to other known events (straining, talking, rectal contractions). This study was conducted to investigate this phenomenon. Forty-three children with MMC were enrolled in the study. A slow and gradual pressure increase associated with the bladder filling was sought in the P (abd) tracings. End filling and initial P (abd) gradient more than 3 cm H(2)O were considered as increased P (abd). If the defined pressure event occurs, the bladder was evacuated for verifying the filling-pressure relation. Age, gender, study position, pelvic floor tonicity and cystometric capacity were correlated with the pressure alteration. P (abd) increase was noted in 18 (41.8%) children. The mean P (abd) gradient between end and initial filling was 4.78 ± 1.63 cm H(2)O in these children. No statistically significant difference was noted for age, gender and study position. Statistically significant differences were noted with decreased pelvic floor tonicity and high values of cystometric capacity (p = 0.003 and p < 0.001, respectively). The pressure increase is thought to be a consequence of a posterior positional change in the bladder during filling die to decreased pelvic floor support in MMC. This pressure alteration was more obvious with increased bladder capacity. Urodynamic studies of children with MMC should be carefully evaluated for the presence of this phenomenon to prevent low measurement of the detrusor pressure, compliance and detrusor leak point pressure values.


Review of the repair of defects in articular cartilage: part I *.
A review of the literature was undertaken to determine the extent and nature of the repair of articular cartilage. While repair is normally limited, under appropriate conditions the repair process appears to be of clinical significance. J Orthop Sports Phys Ther 1982;3(4):186-192.


Trends in Oxidative Balance Score and Prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease in the United States: National Health and Nutrition Examination Survey 2001 to 2018.
Most studies have primarily focused on assessing the association between diet or exercise patterns and metabolic dysfunction-associated steatotic liver disease (MASLD). This study adopted a more comprehensive approach by introducing the oxidative balance score (OBS) to evaluate the combined effects of diet and lifestyle on the body's antioxidant ability. Our main objective was to investigate the association between OBS and the burden of MASLD in the United States. Participants with complete information from 2001 to 2018 were included. In the absence of other definite liver injury factors, the United States fatty liver index (us-FLI) ≥ 30 was used as the diagnostic criterion for MASLD. We first calculated the weighted prevalence for each cycle and stratified it according to demographic and metabolic-related disease characteristics. Subsequently, weighted multiple logistic regression was used to evaluate the relationship between OBS and MASLD. In addition, we explored the body's inflammatory state and the level of insulin resistance (IR) in mediating OBS and MASLD. From 2001 to 2018, the prevalence of MASLD in the U.S. population as a whole increased from 29.76% to 36.04%, and the rate was higher in people with metabolic-related diseases. Notably, OBS exhibited a negative correlation with MASLD. Participants in the highest tertile of OBS had a significantly lower prevalence of MASLD compared to those in the lowest tertile [OR: 0.72, 95%CI: (0.57, 0.92), p < 0.001]. Moreover, a high OBS is associated with a lower inflammatory state and level of IR. The body's inflammatory state and IR level mediated the association between OBS and MASLD by 5.2% and 39.7%, respectively (both p < 0.001). In this study, we observed an increasing prevalence of MASLD over the years. A higher OBS was associated with a lower risk of MASLD, especially when OBS ≥ 25. The body's inflammatory state and IR level mediate the association between OBS and MASLD, but the mechanism needs to be further investigated.


Heritable Pulmonary Arterial Hypertension Diagnosed during the Postpartum Period: A Case Report and Literature Review.
Approximately one-third of bone morphogenic protein receptor-2 (BMPR2) mutation carriers develop pulmonary arterial hypertension (PAH), which indicates that additional risk factors are needed for the manifestation of the disease. It is questionable whether pregnancy is a risk factor for PAH development in these patients. We represent a 30-year-old woman with a heterozygous BMPR2 mutation who was diagnosed with PAH during the postpartum period and reviewed the literature in this report. We also discussed the possible underlying mechanisms that might have resulted in PAH development during pregnancy in BMPR2 mutation carriers.


Acid-soluble phosphorus compounds in mammalian semen.
1. A method is described for the extraction, purification and separation of acid-soluble phosphorus compounds from mammalian semen. [8-(14)C]ATP and [8-(14)C]AMP were used as internal recovery standards to measure the breakdown and loss of these nucleotides in the procedure. 2. Bull, ram, boar and stallion semen was separated into seminal plasma and spermatozoa and the two fractions were examined separately. The overall composition of the mixture of the phosphorus compounds extracted from the two fractions was similar for the four species. 3. Glycerylphosphorylcholine and glycerylphosphorylinositol were the two phosphorus compounds identified in extracts of seminal plasma. ATP, ADP, AMP, GTP, GDP, NAD, fructose 1,6-diphosphate and glucose 6-phosphate were identified in extracts prepared from spermatozoa.


Impact of oral health education by audio aids, braille and tactile models on the oral health status of visually impaired children of Bhopal City.
Children with special needs face unique challenges in day-to-day practice. They are dependent on their close ones for everything. To improve oral hygiene in such visually impaired children, undue training and education are required. Braille is an important language for reading and writing for the visually impaired. It helps them understand and visualize the world via touch. Audio aids are being used to impart health education to the visually impaired. Tactile models help them perceive things which they cannot visualize and hence are an important learning tool. This study aimed to assess the improvement in oral hygiene by audio aids and Braille and tactile models in visually impaired children aged 6-16 years of Bhopal city. This was a prospective study. Sixty visually impaired children aged 6-16 years were selected and randomly divided into three groups (20 children each). Group A: audio aids + Braille, Group B: audio aids + tactile models, and Group C: audio aids + Braille + tactile models. Instructions were given for maintaining good oral hygiene and brushing techniques were explained to all children. After 3 months' time, the oral hygiene status was recorded and compared using plaque and gingival index. ANNOVA test was used. The present study showed a decrease in the mean plaque and gingival scores at all time intervals in individual group as compared to that of the baseline that was statistically significant. The study depicts that the combination of audio aids, Braille and tactile models is an effective way to provide oral health education and improve oral health status of visually impaired children.


Plant-based and cell-based approaches to meat production.
Advances in farming technology and intensification of animal agriculture increase the cost-efficiency and production volume of meat. Thus, in developed nations, meat is relatively inexpensive and accessible. While beneficial for consumer satisfaction, intensive meat production inflicts negative externalities on public health, the environment and animal welfare. In response, groups within academia and industry are working to improve the sensory characteristics of plant-based meat and pursuing nascent approaches through cellular agriculture methodology (i.e., cell-based meat). Here we detail the benefits and challenges of plant-based and cell-based meat alternatives with regard to production efficiency, product characteristics and impact categories.


Measurement of Radiation Exposure When Using the Mini C-Arm to Reduce Pediatric Upper Extremity Fractures.
Previous literature has underreported radiation exposure with the use of mini C-arm during pediatric forearm fracture reductions. The purpose of this study is to report an accurate amount of radiation exposure during fracture reductions using a mini C-arm that records the amount of kilovolts, milliamps, and the number of seconds of foot pedal use. Eighty-six consecutive pediatric patients undergoing upper extremity fracture reduction in the emergency department were studied. The orthopaedic resident, either a PGY2 or PGY3, performed a manipulative reduction and casting of the fracture with use of the mini C-arm. Postreduction, in cast, anteroposterior and lateral images from the mini C-arm were saved to the computerized radiology system. The mini C-arm recorded the amount of kilovolts, milliamps, and the number of seconds that the foot pedal was used for each reduction. A radiology physicist (S.K.) calculated the amount of millirem (mR) exposure for each reduction from these data. The resident using the mini C-arm and the fracture pattern affected the amount of radiation exposure. The average mini C-arm mR exposure for distal radius fractures was 63 mR; forearm 109 mR; elbow 53 mR; and hand 69 mR. For comparison, conventional anteroposterior/lateral forearm radiographs emit an average of 20 mR. Less-experienced PGY2 residents had a higher mR exposure per reduction compared with PGY3 residents. Radiation exposure when using the mini C-arm for reduction of pediatric fractures has been underestimated in previous literature. Radiation from the mini C-arm exceeded that from conventional radiographs in most cases. We recommend that residents receive training about the use of the mini C-arm before its utilization as an aid to reduce pediatric fractures in the emergency department.


Grasping a Chestnut Burr.
This work aimed to assess the role of manual laterality in action coding strategies and, subsequently, in environmental features relevant for each hand's action. Relying on Eder and Hommel's (2013) proposal, we distinguished stimulus-related and end state-related consequences in a Simon paradigm where right-handed participants were divided into two groups, one responding with gloves and one without. Two objects were presented pictorially: one for which sensory consequences of grasping were negatively valenced (a chestnut burr), and one for which they were positively valenced (an apricot). By these means, stimulus and end-state effects could be assessed separately, along with the relevance of each feature of the experimental settings. Results showed that the use of one's dominant or non dominant hand gives rise to different repercussions of stimulus-related and end state-related effects on response: Responses made with the right (dominant) hand were based on an elaborated coding (representing features of stimulus-related and end state-related consequences of action). In contrast, responses made with the left (non dominant) hand seemed to be based on a less elaborated coding (not taking into account end-state consequences of an action).


Optimization of solid fermentation of cellulase from Trichoderma koningii.
To exploit peashrub resources in Ordos as fodders, it is very crucial to realize industrial production of cheap cellulase of high activity by optimizing culture technology, especially culture substrate. In this study, a new prescription experiment based on uniform design ideal was invented and successfully applied in the solid fermentation of Trichoderma koningii F244, which was performed with two different temperature degrees. The activities of FPA, cotton lyase, CMCase and beta-glucosidase were assayed and then mathematical models of enzymatic activities, which were figured out by Unconstraint Mathematical Programming, were developed by Multivariate Regression Program of SPSS10.0. Enzymatic activities of optimized substrate prescriptions corresponding to mathematical models were forecasted to determine an ideal substrate prescription. It is revealed that in solid fermentation, Tween80 has negative effect on cellulase production. Furthermore, the ideal prescription for cellulase complex production by Trichoderma koningii F244 was straw powder 16.9%, wheat bran 26.5%, (NH4)2SO4 9.5% and water 47.1%, whose corresponding cellulase activity was expected to be at the same high level with that of Trichoderma reesei Q9414 on its own recommended substrate. Especially, goats mainly fed on peashrub tissues mixed with cellulase complex of this prescription and culture technology, got an incremental ratio of 0.3 kg/d, which brought a very promising feeding prospect for local peashrub resource. By populization of this cellulase complex, it can integrate living standard, economic construction of local residents into vegetational restoration tightly and thus this paper will be very meaningful to be use for reference for western China like Ordos to realize its sustainable development of economy, society and environment.


Sex differences in the acute and subchronic lung inflammatory responses of mice to nickel nanoparticles.
Nickel nanoparticles (NiNPs) are increasingly used in nanotechnology applications, yet information on sex differences in NiNP-induced lung disease is lacking. The goal of this study was to explore mechanisms of susceptibility between male and female mice after acute or subchronic pulmonary exposure to NiNPs. For acute exposure, male and female mice received a single dose of NiNPs with or without LPS by oropharyngeal aspiration and were necropsied 24 h later. For subchronic exposure, mice received NiNPs with or without LPS six times over 3 weeks prior to necropsy. After acute exposure to NiNPs and LPS, male mice had elevated cytokines (CXCL1 and IL-6) and more neutrophils in bronchoalveolar lavage fluid (BALF), along with greater STAT3 phosphorylation in lung tissue. After subchronic exposure to NiNPs and LPS, male mice exhibited increased monocytes in BALF. Moreover, subchronic exposure of male mice to NiNP only induced higher CXCL1 and CCL2 in BALF along with increased alveolar infiltrates and CCL2 in lung tissue. STAT1 in lung tissue was induced by subchronic exposure to NiNPs in females but not males. Males had a greater induction of IL-6 mRNA in liver after acute exposure to NiNPs and LPS, and greater CCL2 mRNA in liver after subchronic NiNP exposure. These data indicate that susceptibility of males to acute lung inflammation involves enhanced neutrophilia with increased CXCL1 and IL-6/STAT3 signaling, whereas susceptibility to subchronic lung inflammation involves enhanced monocytic infiltration with increased CXCL1 and CCL2. STAT transcription factors appear to play a role in these sex differences. This study demonstrates sex differences in the lung inflammatory response of mice to NiNPs that has implications for human disease.


Staging chest computed tomography and positron emission tomography in patients with pancreatic adenocarcinoma: utility or futility?
This study was conducted to determine if routine staging chest computed tomography (CT) or positron emission tomography (PET) scanning alters the clinical management of patients with newly diagnosed pancreatic adenocarcinoma. All new pancreas cancers seen in medical oncology, radiation oncology and surgery from 1 June 2008 to 20 June 2010 were retrospectively reviewed. Patients with metastatic disease on chest CT or PET, that had been unsuspected on initial imaging, were identified. Pancreatic adenocarcinoma was present in 247 consecutive patients. Abdominal CT demonstrated metastases in 108 (44%) and localized disease in 139 (56%) patients. Chest CT and PET were not performed in 15 (11%) of these 139 patients. In the remaining 124 patients, CT imaging suggested resectable disease in 46, borderline resectable disease in 52 and locally advanced disease in 26 patients. Chest CT demonstrated an unsuspected lymphoma in one patient with borderline resectable disease and PET identified extrapancreatic disease in two patients with locally advanced disease. Chest CT and PET added no information in 121 (98%) of the 124 patients. The addition of chest CT and PET to high-quality abdominal CT is of little clinical utility; additional sites of metastasis are rarely found. As the quality of abdominal imaging declines, the yield from other imaging modalities will increase. Dedicated pancreas-specific abdominal CT remains the cornerstone of initial staging in suspected or biopsy-proven pancreatic cancer.


[The benefit of a coronary stent in the reduction of major cardiac complications in acute coronary syndromes].
To assess the incidence of in-hospital major adverse cardiac events (MACE), we analyzed 694 procedures in 613 consecutive patients during one year period. Patient population included 550 (79.2%) patients with unstable angina, 43 (6.2%) with stable angina and 101 (14.5%) with acute myocardial infarction. Elective percutaneous transluminal coronary angioplasty (PTCA) was performed in 593 (85.4%) patients, rescue PTCA in 7 (1%), and primary PTCA in 94 (13.5%). Angiographic lesion morphology was as follows: type A 30%; type B 58%; type C 12%. We compared patient population who received stent with PTCA-balloon only. Technical success was 95% and clinical success was achieved in 80% of the cases. Overall mortality was 1% in the stent group and 3% in the conventional PTCA. The incidence of MACE was 4% and 15.1% in the stent and angioplasty balloon groups respectively. We found a dramatic impact on reduction of the incidence of acute complications in the groups with stenting for unstable angina (p = 0.0001) and acute myocardial infarction (p = 0.0001). The major clinical advantage of stenting over balloon angioplasty was a lower need for repeated procedures.


Liposuction and surgical recontouring of the neck: a retrospective analysis.
With the advent of tumescent liposuction, many advances in cosmetic surgery have occurred. Liposuction of excess adipose tissue from the submental area, jowls, and neck, along with cold steel surgery, has become an attractive alternative to the facelift for cervicomental aesthetic surgery. To describe new techniques for tumescent neck liposuction, platysma repair, and subcutaneous musculoaponeurotic system plication, evaluate results, and assess complications with the procedures. We reviewed the results of the last 35 patients who underwent neck liposuction, simultaneous platysma plication, subdermal CO2 laser resurfacing, and/or subcutaneous musculoaponeurotic system plication at our institution. Three of 35 patients (9%) experienced mild complications from the procedure. Two of the three complications (66%) were in patients who underwent subdermal and/or platysma laser resurfacing at the time of liposuction. Good to excellent results were achieved in 91% of patients and fair to good results were achieved in 9%. No major complications such as nerve injury occurred. Neck liposuction can be a safe method for facial rejuvenation when performed properly. Platysma repair, and in some cases subcutaneous musculoaponeurotic system plication, can further improve results when combined with the liposuction procedure.


Interventional endoscopic ultrasound-guided cholangiography: long-term experience of an emerging alternative to percutaneous transhepatic cholangiography.
Endoscopic retrograde cholangiography (ERC) with stenting is the procedure of choice for biliary decompression in patients with obstructive jaundice. In cases where biliary access cannot be achieved, interventional endoscopic ultrasound-guided cholangiography (IEUC) has become an alternative to percutaneous transhepatic cholangiography (PTC). We report on 5 years of experience in patients who underwent IEUC after failed endoscopic retrograde cholangiopancreatography (ERCP). Endoscopic ultrasound-guided access to the targeted biliary duct was attempted with one of two approaches: transgastric-transhepatic (intrahepatic) or transenteric-transcholedochal (extrahepatic). A stent was then advanced over the wire and into the biliary tree. A total of 49 patients underwent IEUC: 35 had biliary obstruction due to malignancy and 14 had a benign etiology. The overall success rate of IEUC was 84% (41/49), with an overall complication rate of 16%. Of the 35 patients who underwent the intrahepatic approach, 23 had a stent placed across the major papilla, one had a stent placed intraductally in the common bile duct, and three patients underwent placement of a gastrohepatic stent. Resolution of obstruction was achieved in 29 patients, with a success rate of 83%. In all, 14 patients underwent an extrahepatic approach. In 8/14 (57%), stent placement across the major papilla was achieved. A transenteric stent was placed in four patients. Biliary decompression was achieved in 12/14 cases (86%). Based on intention-to-treat analysis, the intrahepatic approach achieved success in 29 of 40 cases (73%), and the extrahepatic approach was successful in seven of nine cases (78%). There were no procedure-related deaths. IEUC offers a feasible alternative to PTC in patients with obstructive jaundice in whom ERC has failed.


A Multianalyte Panel Consisting of Extracellular Vesicle miRNAs and mRNAs, cfDNA, and CA19-9 Shows Utility for Diagnosis and Staging of Pancreatic Ductal Adenocarcinoma.
To determine whether a multianalyte liquid biopsy can improve the detection and staging of pancreatic ductal adenocarcinoma (PDAC). We analyzed plasma from 204 subjects (71 healthy, 44 non-PDAC pancreatic disease, and 89 PDAC) for the following biomarkers: tumor-associated extracellular vesicle miRNA and mRNA isolated on a nanomagnetic platform that we developed and measured by next-generation sequencing or qPCR, circulating cell-free DNA (ccfDNA) concentration measured by qPCR, ccfDNA KRAS G12D/V/R mutations detected by droplet digital PCR, and CA19-9 measured by electrochemiluminescence immunoassay. We applied machine learning to training sets and subsequently evaluated model performance in independent, user-blinded test sets. To identify patients with PDAC versus those without, we generated a classification model using a training set of 47 subjects (20 PDAC and 27 noncancer). When applied to a blinded test set (N = 136), the model achieved an AUC of 0.95 and accuracy of 92%, superior to the best individual biomarker, CA19-9 (89%). We next used a cohort of 20 patients with PDAC to train our model for disease staging and applied it to a blinded test set of 25 patients clinically staged by imaging as metastasis-free, including 9 subsequently determined to have had occult metastasis. Our workflow achieved significantly higher accuracy for disease staging (84%) than imaging alone (accuracy = 64%; P < 0.05). Algorithmically combining blood-based biomarkers may improve PDAC diagnostic accuracy and preoperative identification of nonmetastatic patients best suited for surgery, although larger validation studies are necessary.


Contrast-enhanced MRI-guided photodynamic cancer therapy with a pegylated bifunctional polymer conjugate.
To study contrast-enhanced MRI guided photodynamic therapy with a pegylated bifunctional polymer conjugate containing an MRI contrast agent and a photosensitizer for minimally invasive image-guided cancer treatment. Pegylated and non-pegylated poly-(L-glutamic acid) conjugates containing mesochlorin e6, a photosensitizer, and Gd(III)-DO3A, an MRI contrast agent, were synthesized. The effect of pegylation on the biodistribution and tumor targeting was non-invasively visualized in mice bearing MDA-MB-231 tumor xenografts with MRI. MRI-guided photodynamic therapy was carried out in the tumor bearing mice. Tumor response to photodynamic therapy was evaluated by dynamic contrast enhanced MRI and histological analysis. The pegylated conjugate had longer blood circulation, lower liver uptake and higher tumor accumulation than the non-pegylated conjugate as shown by MRI. Site-directed laser irradiation of tumors resulted in higher therapeutic efficacy for the pegylated conjugate than the non-pegylated conjugate. Moreover, animals treated with photodynamic therapy showed reduced vascular permeability on DCE-MRI and decreased microvessel density in histological analysis. Pegylation of the polymer bifunctional conjugates reduced non-specific liver uptake and increased tumor uptake, resulting in significant tumor contrast enhancement and high therapeutic efficacy. The pegylated poly(L-glutamic acid) bifunctional conjugate is promising for contrast enhanced MRI guided photodynamic therapy in cancer treatment.


Efficacy of vaccination against HPV infections to prevent cervical cancer in France: present assessment and pathways to improve vaccination policies.
Seventy percent of sexually active individuals will be infected with Human Papillomavirus (HPV) during their lifetime. These infections are incriminated for almost all cervical cancers. In France, 3,068 new cases of cervical cancer and 1,067 deaths from cervical cancer occurred in 2005. Two vaccines against HPV infections are currently available and vaccination policies aim to decrease the incidence of HPV infections and of cervical cancers. In France, vaccine coverage has been reported to be low. We developed a dynamic model for the heterosexual transmission of Human Papillomavirus types 16 and 18, which are covered by available vaccines. A deterministic model was used with stratification on gender, age and sexual behavior. Immunity obtained from vaccination was taken into account. The model was calibrated using French data of cervical cancer incidence. In view of current vaccine coverage and screening, we expected a 32% and 83% reduction in the incidence of cervical cancers due to HPV 16/18, after 20 years and 50 years of vaccine introduction respectively. Vaccine coverage and screening rates were assumed to be constant. However, increasing vaccine coverage in women or vaccinating girls before 14 showed a better impact on cervical cancer incidence. On the other hand, performing vaccination in men improves the effect on cervical cancer incidence only moderately, compared to strategies in females only. While current vaccination policies may significantly decrease cervical cancer incidence, other supplementary strategies in females could be considered in order to improve vaccination efficacy.


Healthcare professionals' voice as a road to burnout and work engagement? The role of relational outcomes: An exploratory study of European countries.
Healthcare professionals are key in healthcare organisations but are subject to long working hours and may have to make complex life-and-death decisions. As frontline agents dealing with human lives, giving them a voice is paramount. This study explores the impact of employee voice (assessed based on employee perceptions on how much they are consulted and how much influence they have on task-related decisions) on health professionals' work engagement and burnout when mediated by relational outcomes (perceived organisational support, workplace trust, workplace recognition and meaningful work). A sample of 3,266 health professionals retrieved from the European Working Condition Survey was used. The quantitative analysis was performed using the partial least square structural equation modelling and multiple regression analyses. The results indicate that employee voice has a direct positive impact on work engagement, but employee voice's direct effects on burnout still need to be confirmed. Relational outcomes are found to mediate the relationship between employee voice and burnout (decreasing it) and between employee voice and work engagement (increasing it). Practices of employee voice in the workplace are fundamental to promoting health professionals' well-being. Trust, recognition, support and the feeling of doing meaningful work increase the influence of employee voice, especially in reducing the levels of burnout. This is the first study that assesses, at a European level, the importance that 'giving health professionals a voice' has on crucial employee outcomes: work engagement, burnout and relational outcomes.


Recent advances on the development of pharmacotherapeutic agents on the basis of human serum albumin.
Human serum albumin (HSA), a major transport protein component in blood plasma, has been reported recently to play many important roles in pharmacotherapeutics development. Owing to its promising intrinsic binding capability of drug molecules, HSA offers favorable characteristics and can be directly used as its monomeric formula or can be fabricated into protein based nanoparticle platforms to realize the effective delivery of therapeutic molecules into targeted diseases areas. In addition, HSA can also serve as a protein stabilizer or environment-responsive moieties to hybridize with the functional materials including polymers or inorganic nanoparticles through the covalent reactions or electrostatic interactions, and can thus greatly alter the relevant biological distribution and pharmacokinetic behavior to improve their therapeutic efficacy. By right, extensive studies have been conducted to develop HSA-conjugated pharmacotherapeutic agents toward effective in vitro and in vivo diseases diagnosis and treatment. The current review gives an in-detail account of the latest progresses of HSA-based carriers as functional protein materials, mainly with respect to its conjugation types, formulation aspects, and importantly their promising applications towards enhanced drug delivery and medical diagnosis.