Distinct and redundant functions of Esama and VE-cadherin during vascular morphogenesis.
The cardiovascular system forms during early embryogenesis and adapts to embryonic growth by sprouting angiogenesis and vascular remodeling. These processes require fine-tuning of cell-cell adhesion to maintain and re-establish endothelial contacts, while allowing cell motility. We have compared the contribution of two endothelial cell-specific adhesion proteins, VE-cadherin (VE-cad/Cdh5) and Esama (endothelial cell-selective adhesion molecule a), during angiogenic sprouting and blood vessel fusion (anastomosis) in the zebrafish embryo by genetic analyses. Different combinations of mutant alleles can be placed into a phenotypic series with increasing defects in filopodial contact formation. Contact formation in esama mutants appears similar to wild type, whereas esama-/-; ve-cad+/- and ve-cad single mutants exhibit intermediate phenotypes. The lack of both proteins interrupts filopodial interaction completely. Furthermore, double mutants do not form a stable endothelial monolayer, and display intrajunctional gaps, dislocalization of Zo-1 and defects in apical-basal polarization. In summary, VE-cadherin and Esama have distinct and redundant functions during blood vessel morphogenesis, and both adhesion proteins are central to endothelial cell recognition during anastomosis.


Aging With Disability for Midlife and Older Adults.
This analysis brings "aging with disability" into middle and older ages. We study U.S. adults ages 51+ and ages 65+ with persistent disability (physical, household management, personal care; physical limitations, instrumental activities of daily living [IADLs], activities of daily living [ADLs]), using Health and Retirement Study data. Two complementary approaches are used to identify persons with persistent disability, one based directly on observed data and the other on latent classes. Both approaches show that persistent disability is more common for persons ages 65+ than ages 51+ and more common for physical limitations than IADLs and ADLs. People with persistent disability have social and health disadvantages compared to people with other longitudinal experiences. The analysis integrates two research avenues, aging with disability and disability trajectories. It gives empirical heft to government efforts to make aging with disability an age-free (all ages) rather than age-targeted (children and youths) perspective.


Effects of streptozotocin-induced diabetes and insulin on calcium responsiveness of the rat vas deferens.
In the present study, effects of streptozotocin-induced diabetes and insulin treatment on the reactivity of rat vas deferens to KCl and calmidazolium, a calmodulin antagonist, were evaluated and calmodulin levels in vas deferens tissue from diabetic and insulin-treated rats were determined. Diabetes was induced in rats by a single injection of streptozotocin. Five weeks after the induction of diabetes, one group of diabetic rats was injected with insulin for 3 weeks. After 8 weeks, vas deferens tissues on one side of diabetic and insulin-treated diabetic rats and their controls were mounted in organ bath to measure isometric tension, while the tissues on the other side of rats were homogenized to determine calmodulin levels by radioimmunoassay. Concentration-response curves to KCl were obtained in vas deferens tissues in the absence and presence of calmidazolium. The effects of KCl and calmidazolium on vas deferens isolated from 8-weeks diabetic rats were decreased. Calmodulin levels were also found to be decreased in vas deferens from diabetic rats. Decreased calmodulin levels in diabetic rat vas deferens were not corrected by insulin treatment. Only a partial correction following insulin treatment was observed in contractile effect of KCl on diabetic rat vas deferens, whereas insulin treatment increases the affinity of calmodulin in this muscle. Experimental diabetes causes an impairment in calcium/calmodulin-dependent contractile process of vas deferens, which is correctable partially following insulin therapy. The changes in the function of rat vas deferens due to streptozotocin diabetes seem to be related to impaired sexual functions in human diabetes.


JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment.
Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging.


Clustering of risk behaviours for oral and general health.
While it is recognised that risk behaviours for general health tend to cluster among individuals, it is less clear whether risk behaviours for oral health co-occur among these same individuals. To describe the distribution of health-relevant behaviours in a population sample, to examine whether oral and general risk behaviours cluster among individuals and to identify population groups with a shared risk profile. Self-reported data were obtained from a stratified random sample of adults aged 18+ who participated in the 2002 National Dental Telephone Interview Survey and completed a subsequent mailed questionnaire (n = 3,132). Data were weighted to represent a simple random sample of Australian adults and analysis was limited to dentate adults. Four oral health behaviours (toothbrushing frequency, interdental cleaning, exposure to non-milk extrinsic sugars, usual reason for a dental visit) and four general health behaviours (smoking, alcohol consumption, physical activity, Body Mass Index) were dichotomised. K-means cluster analysis identified two readily interpretable groups that differed significantly on each behaviour apart from alcohol consumption (ANOVA; p = 0.77). A significant relationship emerged between cluster memberships and sociodemographic characteristics. Over-represented in the risk behaviour group (40.7% of the sample) were males, young adults, Australian born, those who did not live in a major city, adults who rented their housing and those adults with lower levels of education and household income (Chi square; p < 0.05). The interrelatedness of oral and general risk behaviours and their sociodemographic associations supports the tailoring of integrated oral and general health promotion messages and services to targeted population groups.


[Electrophysiologic effects of propafenone in patients with sinus node dysfunction].
The electrophysiologic effects of intravenously administered Propafenon (1,5 mg/kg) were evaluated in 16 patients (mean age: 62,1 +/- 11 years) with sinus node dysfunction, shown by sinus bradycardia or intermittent sino-atrial block. The variations of sinus cycle length were not statistically significant (NS), (1137,1 +/- 244,9 msec versus 1191,9 +/- 321,1 msec). In one patient sinus rate markedly decreased from 36 to 28 beats/min. In 2 patients the cycle length of a junctional rhythm was comparable before and after drug administration; in both patients the rate of the junctional rhythm decreased and in one markedly (from 39 to 32 beats/min). Sinoatrial conduction time increased in 4 patients and decreased in 6. The variations were not statistically significant (223,8 +/- 76 msec versus 230,6 +/- 75,9 msec). In one patient the sinoatrial conduction time which was normal during the control study, could not be evaluated after Propafenon due to the appearance of a retrograde block between the atrium and the sinus node. Maximum corrected sinus node recovery time was prolonged by the drug in 9 patients and shortened in 5. In 2 patients the sinus node recovery time was prolonged to about 10 sec. The mean value of corrected sinus node recovery time increased from 883,6 +/- 995,8 msec to 1820,5 +/- 2894 msec (NS). Propafenon significantly prolonged the effective refractory period and the functional refractory period of the atrium, as well as the A-H, H-V and QRS intervals, the A-V node functional refractory period, the relative refractory period of His-Purkinje system and the ventricular effective refractory period.(ABSTRACT TRUNCATED AT 250 WORDS)


Screening of potential hub genes and key pathways associated with breast cancer by bioinformatics tools.
Breast cancer (BC) remains the leading cause of cancer-related death in women worldwide. The development of new targeted therapies that may improve patient survival remains an area of growing interest. This study aimed to identify new biomarkers involved in BC progression that could be used as potential targeted therapies. DEGs were selected from three gene expression profiles, GSE55715, GSE124646, and GSE87049, using the GEO2R tool and Venn diagram software. Gene Ontology and KEGG pathways were then performed using DAVID software. Next, the PPI network was constructed using STRING and visualized using Cytoscape software, and hub genes were extracted using the cytoHubba plug-in. Survival analysis was performed using the Kaplan-Meier Plotter, while the expression of hub genes in BC was verified using the GEPIA2 tool. Finally, transcription the factors of hub genes were determined using the NetworkAnalyst database, and the TIMER tool was employed to explore the infiltration levels of tumor immune cells with related genes. A total of 146 DEGs were identified in the three datasets, including 60 upregulated genes that were enriched in the cell cycle, and 86 downregulated genes that were mainly enriched in the TNF signaling pathway and pathways in cancer. Ten genes were identified: BUB1, CDK1, HMMR, MAD2L1, CEP55, AURKA, CCNB2, TPX2, MELK, and KIF20A. The overexpression of hub genes, except CDK1, was associated with poor survival in BC and was regulated by several transcription factors involved in DNA binding activity and transcription regulation. The infiltration levels of immune cells were positively correlated with hub genes, particularly macrophages and CD4+ T cells. This study identified new reliable molecular biomarkers that can serve as potential therapeutic targets for BC treatment.


Some data on postnatal maturation of the cerebral cortex in cat.
This paper describes the neurons in different cortical areas and traces their postnatal changes. Rapid Golgi and Golgi--Kopsch impregnation were carried out in 1-day-old and 9-day-old kittens. The maturation of the pyramidal neurons can be observed mainly on their basal dendritic orientation and on development of the dendritic spines. The differentiation of the interneurons (non-pyramidal) also proceeds on the first postnatal days. These, though slightly less mature than the associated pyramidal neurons, are identifiable already on the first postnatal day. It is concluded that there are significant differences in the maturation of the neurons in the various cortical areas.


Synthesis and application of DNA-CdS nanowires within a minute using microwave irradiation.
A very fast, electroless, microwave method is described to synthesize electrically conductive CdS nanowires on DNA just within 60 s. The electrical characterization indicates that the CdS wires are continuous, have very low contact resistance, and exhibit Ohmic behavior. Highly selective deposition on DNA is obtained by specific complexation between the Cd(II) ion and DNA, followed by decomposition of thioacetamide to S(2-) to form CdS. The nanowires are found to have a diameter of 140-170 nm and a length of approximately 8-12 microm. The one-step process developed here does not perturb the overall conformation of the DNA chain. The nanowires we fabricated can be used as building blocks for functional nanodevices, tiny computers, sensors, and optoelectronics.


Behavioral and genotoxic evaluation of rosmarinic and caffeic acid in acute seizure models induced by pentylenetetrazole and pilocarpine in mice.
The goal of this study was to investigate the effects of rosmarinic acid (RA) and caffeic acid (CA) in the acute pentylenetetrazole (PTZ) and pilocarpine (PIL) seizure models. We also evaluated the effect of RA and CA on the diazepam (DZP)-induced sleeping time test and its possible neuroprotective effect against the genotoxic damage induced by PTZ and PIL. Mice were treated intraperitoneally (i.p.) with saline, RA (2 or 4 mg/kg), or CA (4 or 8 mg/kg) alone or associated to low-dose DZP. After, mice received a single dose of PTZ (88 mg/kg) or PIL (250 mg/kg) and were monitored for the percentage of seizures and the latency to first seizure (LFS) >3 s. Vigabatrin and DZP were used as positive controls. In the DZP-induced sleeping time test, mice were treated with RA and CA and 30 min after receiving DZP (25 mg/kg, i.p.). The alkaline comet assay was performed after acute seizure tests to evaluate the antigenotoxic profiles of RA and CA. The doses of RA and CA tested alone did not reduce the occurrence of seizures induced by PTZ or PIL. The association of 4 mg/kg RA + low-dose DZP was shown to increase LFS in the PTZ model, compared to the group that received only the DZP. In the DZP-induced sleeping time test, the latency to sleep was reduced by 4 mg/kg RA and 8 mg/kg CA. The PTZ-induced genotoxic damage was not prevented by RA or CA, but the PIL-induced genotoxic damage was decreased by pretreatment with 4 mg/kg RA (in cortex) and 4 mg/kg CA (in hippocampus). In conclusion, RA and CA presented neuroprotective effect against PIL-induced genotoxic damage and reduced the latency to DZP-induced sleep. Of the rosmarinic acid, 4 mg/kg enhanced the DZP effect in the increase of latency to clonic PTZ-induced seizures.


Safety and diagnostic accuracy of tumor biopsies in children with cancer.
Tumor biopsies are central to the diagnosis and management of cancer and are critical to efforts in personalized medicine and targeted therapeutics. In the current study, the authors sought to evaluate the safety and accuracy of biopsies in children with cancer. All biopsies performed in children at the study institution with a suspected or established diagnosis of cancer from 2003 through 2012 were reviewed retrospectively. Patient characteristics and disease-related and procedure-related factors were correlated with procedure-related complications and diagnostic accuracy using logistic regression analysis. A total of 1073 biopsies were performed in 808 patients. Of 1025 biopsies with adequate follow-up, 79 (7.7%) were associated with an adverse event, 35 (3.4%) of which were minor (grade 1-2) and 32 (3.1%) of which were major (grade 3-4) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The most common major adverse events were blood transfusion (>10 mL/kg; 24 cases) and infection requiring intravenous antibiotics (6 cases). Eleven deaths (1.4%) occurred within 30 days after the procedure, but the procedure may have contributed to the outcome in only 2 cases. A total of 926 biopsies (90.3%) provided definitive histologic diagnoses. Using multivariable analysis, biopsy site, preprocedure hematocrit level, and body mass index were found to be associated with the risk of postprocedural complications (P<.0001, P<.0001, and P =.0029, respectively). Excisional biopsy and biopsy site were found to be independently associated with obtaining a diagnostic result (P =.0002 and P =.0008, respectively). Tumor biopsies in children with cancer are associated with a low incidence of complications and a high rate of diagnostic accuracy. The predictive factors identified for adverse outcomes may aid in risk assessment and preprocedural counseling.


A Pilot Study for Antimicrobial Stewardship Post-Discharge: Avoiding Pitfalls at the Transitions of Care.
Lack of patient follow-up is a major concern during care transitions, and the role of an antimicrobial stewardship program (ASP) in assessing antimicrobial regimens after hospital discharge is not well described. We implemented an expanded ASP to include patients recently discharged from the hospital and measured its impact on inappropriate antimicrobial therapy 72 hours after inpatient culture data were finalized. A prospective cohort study was conducted at a 583-bed tertiary care center in the Upper Midwest of America. All patients discharged from our facility on antimicrobial therapy with pending culture results between February 3, 2016, and March 2, 2016, were included for review. If a pathogen nonsusceptible to all prescribed antimicrobials was identified post-discharge, a recommendation for therapy modification was communicated to the prescriber. Thirty-eight patients discharged from our hospital on antimicrobial therapy with pending culture results were evaluated for intervention. When final culture susceptibilities were considered, 5 of 38 patients had been prescribed an inappropriate antimicrobial agent. An ASP pharmacist intervened on 4 of 5 patients, resulting in 3 of 5 patients transitioning to appropriate antimicrobial therapy. When compared to a historical cohort, our transitions-of-care ASP yielded a 3.6-fold increase in antimicrobial-related interventions among discharged patients while reducing inappropriate outpatient antimicrobial therapy by 39%. We believe this is the first pharmacist-driven ASP represented in the medical literature which evaluated all available inpatient culture data to serve patients discharged from the hospital. Antimicrobial stewardship for patients in care transitions may provide an opportunity to increase ASP interventions and reduce inappropriate antimicrobial therapy.


[Complete revascularisation of multivessel coronary artery disease during acute myocardial infarction. Results following hospitalization and after 30 months. Series of 86 interventions carried out with 167 multivessel disease patients; causes of failure].
This series studied 167 patients with multivessel disease, admitted consecutively for acute myocardial infarction (excluding cardiogenic shock), who underwent systematic angioplasty and stenting before the 12th hour of the culprit artery and the other vessels with >70% (QCA) angiographic stenosis, and followed up for a period of 8 to 68 months with an average follow-up of 2.5 years. The criteria of evaluation were: numbers of asymptomatic patients, deaths, new infarctions, residual ischaemias, cardiac failure, angioplasties or bypass surgeries. On admission, 43.1% of infarcts were anterior, 48.5% inferior or postero-inferior and 8.3% lateral wall infarcts. One hundred and twenty-two consecutive patients had double vessel disease and 45 has triple vessel disease. The failures of revascularisation of the culprit artery were excluded from the study. The feasibility rate of complete multivessel revascularisation in a single procedure was over half the cases (86 out of 167, 51.5%): 60.6% of double vessel disease and 26.9% of triple vessel disease, a simple favorable anatomical presentation being necessary to accomplish this objective. During the hospital period (30 days), 95.3% of patients who were completely revascularised remained totally asymptomatic, 2 (2.3%) had recurrent infarction, 1 (1%) had cardiac failure and 1 (1%) died of a non-cardiac cause. No cardiac deaths were observed in this series. Of the multivessel disease patients who could not be completely revascularised (N=81) (poor clinical state or complicated anatomical presentation), 83.6% were asymptomatic: there were 7.7% cases of cardiac failure, 2.4% of recurrent infarction; 1.2% died of non-cardiac causes and 1.2% died of a cardiac cause. The statistical difference was significant in favour of the patients who had successful complete revascularisation with respect to the others in terms of numbers of asymptomatic patients (p=0.004) and of numbers of cardiac failure (p=0.002). The follow-up rate of patients who had complete revascularisation in a single procedure was 98.8%. After two and a half years of follow-up, 74.1% of patients were totally asymptomatic; the cumulative major cardiac adverse event rate (death, infarction, angioplasty or bypass surgery) was 29.4% and the reoperation rate by angioplasty or bypass surgery was 27%.


Local shear stress and brachial artery functions in end-stage renal disease.
Physiologic laminar shear stress (SS) is crucial for normal vascular structure and function. As a result of anemia-related lower whole-blood viscosity (WBV), SS could be reduced in patients with ESRD and might be associated with arterial functional alterations. In 44 patients with ESRD and 25 control subjects, brachial artery (BA) compliance and BA diameter changes (flow-mediated dilation [FMD[) were evaluated in response to local shear rate and SS changes during hand warming-induced hyperemia. Patients with ESRD and control subjects had similar BA blood flow, but SS was lower in patients with ESRD (P < 0.001), with lower shear rate (P < 0.01) and lower WBV (P < 0.0001). In control subjects, SS was positively (and physiologically) correlated with arterial diameter (P < 0.001). In contrast, in patients with ESRD, larger arterial diameter was associated with low SS (P < 0.05) and increased arterial wall elastic modulus (P < 0.001). Anemia-associated low WBV aggravates low shear rate, further contributing to SS reduction. These abnormalities were associated with decreased vasodilating response to endothelial mechanical stimulation. Compared with control subjects, BA compliance and FMD increases in response to hand warming-induced increased SS were lower in ESRD patients (P < 0.01), whereas their BA diameter response to glyceryl trinitrate did not differ. The long-term WBV and SS increases after anemia correction improved FMD (P < 0.01) and BA compliance (P < 0.05) and heightened arterial wall sensitivity to mechanical stimulation. Maintenance low SS as a result of anemia could play an indirect role in arterial dysfunction in patients with ESRD.


Membrane proteins involved in potassium shifts during muscle activity and fatigue.
Muscle activity is associated with potassium displacements, which may cause fatigue. It was reported previously that the density of the large-conductance Ca2+-dependent K+ (BK(Ca)) channel is higher in the T tubule membrane than in the sarcolemmal membrane and that the opposite is the case for the ATP-sensitive K+ (K(ATP)) channel. In the present experiments, we investigated the subcellular localizations of the strong inward rectifier 2.1 K+ (Kir2.1) channel and the Na+-K+-2Cl- (NKCC)1 cotransporter with Western blot analysis of different muscle fractions. Furthermore, muscle function was studied while trying to manipulate the opening probability or transport capacity of these proteins during electrical stimulation of isolated soleus muscles. All experiments were made with excised muscle from male Wistar rats. Kir2.1 channels were almost undetectable in the sarcolemmal membrane but present in the T tubule membrane, whereas NKCC1 cotransporters were present in the sarcolemmal membrane. For muscles incubated in a buffer containing pinacidil, NS1619, Ba2+, or bumetanide, there was a faster reduction in peak force (P < 0.05). Furthermore, bumetanide incubation reduced the peak force at the onset of electrical stimulation (P < 0.05). Thus the effects on muscle force indicate that these drugs can affect K+-transporting proteins and thereby influence K+ accumulation, especially in the T tubules, suggesting that K(ATP) and BK(Ca) channels are responsible for K+ release and decrease in force during repeated muscle contractions, whereas Kir2.1 and NKCC1 may have a role in K+ reuptake.


Stable salt-water cluster structures reflect the delicate competition between ion-water and water-water interactions.
How salts affect water structure is an important topic in many research fields. Salt-water clusters can be used as model systems to extract interaction information that is difficult to obtain directly from bulk solutions. In the present study, integrated tempering sampling molecular dynamics (MD) are combined with quantum mechanics (QM) calculations to overcome the sampling problem in cluster structure searches. We used LiI(H2O)n and CsI(H2O)n as representatives to investigate the microsolvation of ion pairs. It was found that Li(+)-I(-) and Cs(+)-I(-) ion pairs interact with water molecules in very different ways, and the corresponding salt-water clusters have distinctly different structures. LiI strongly affects water-water interactions, and the LiI(H2O)n (n ≥ 5) clusters build around a Li(+)(H2O)4 motif. CsI only slightly perturbs the water cluster structure, and CsI(H2O)n favors the clathrate-like structure when n = 18 or 20. Consistent with the law of "matching water affinities", Li(+) and I(-) are more easily separated by solvent molecules than the Cs(+)-I(-) ion pair.


Vitamin D deficiency is not associated with graft versus host disease after hematopoietic stem cell transplantation: A meta-analysis.
Vitamin D status plays an important role in immunoregulation, and a deficiency is believed to be related to Graft Versus Host Disease (GVHD) in patients after hematopoietic stem cell transplantation (HSCT). We aim to study the association between vitamin D deficiency and GVHD after HSCT. A literature search was conducted utilizing MEDLINE, EMBASE, and The Cochrane Library Database from inception to July 2019. Eligible studies were required to1 be clinical trials or observational studies (cohort, case-control, or cross-sectional studies);2 provide data to calculate the odds ratios (OR) of GVHD in HSCT patients with vitamin D deficiency. Two reviewers independently extracted the data and assessed the risk of bias. Pooled odds ratios (OR) with 95% confidence interval (CI) were estimated using random-effects meta-analysis through the Comprehensive Meta-Analysis 3.3 software. In total, 8 observational studies consisting of 1335 HSCT patients were enrolled in this systematic review. Overall, there was no significant association between vitamin D deficiency and acute GVHD (OR = 1.06, 95% CI 0.74-1.53, P > 0.05). There was no significant association between vitamin D deficiency and chronic GVHD (OR = 1.75, 95% CI 0.72-4.26, P > 0.05). Funnel plots and Egger regression asymmetry test were performed and showed no publication bias. There is not a statistically significant association between vitamin D deficiency and neither acute nor chronic GVHD.


Recombinant protective antigen 102 (rPA102): profile of a second-generation anthrax vaccine.
Recent terrorist attacks involving the use of Bacillus anthracis spores have stimulated interest in the development of new vaccines for anthrax prevention. Studies of the pathogenesis of anthrax and of the immune responses following infection and immunization underscore the pivotal role that antibodies to the protective antigen play in protection. The most promising vaccine candidates contain purified recombinant protective antigen. Clinical trials of one of these, recombinant protective antigen (rPA)102, are underway. Initial results suggest that rPA102 is well tolerated and immunogenic. Additional trials are necessary to identify optimal formulations and immunization regimens for pre- and postexposure prophylaxis. Future licensure of these and other candidate vaccines will depend on their safety and immunogenicity profiles in humans, and their ability to confer protection in animal models of inhalational anthrax.


[Advances of studies on ecological risk of herbicide atrazine and its determination and remediation].
With wide application of chemical such as pesticide in farming, the coming problems of ecological risks and environmental pollution were increasingly serious. Residual material of atrazine was founded in the surface water, underground water, and atmospheric sedimentation, and it resulted in the global ecological influences. For atrazine could exit in soil for a long time and enrich in organism, it would bring about potential threaten on the safety of food. The results from experiments on animal indicated that atrazine had biological activity. So, there is an increasing demand for further studying on its ecological risks. In this paper, some viewpoints of the researches on atrazine were introduced. With the development of analytical techniques, the opportunities were created to study on the ecological risks of atrazine, and people should attach serious importance to the bioremediation techniques.


The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers.
Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions. We experimentally demonstrated the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and provide the evidence that RNA editing could selectively affect drug sensitivity. These results highlight RNA editing as an exciting theme for investigating cancer mechanisms, biomarkers, and treatments.


EGFL7: a new player in homeostasis of the nervous system.
EGFL7 drives the formation of neurons from neural stem cells. In the embryonic and adult brain this process is essential for neurogenesis and homeostasis of the nervous system. The function of adult neurogenesis is not fully understood but maybe it supports life-long learning and brain repair after injuries such as stroke. The transition of neural stem cells into mature neurons is tightly regulated. One of the essential signaling pathways governing this process is the Notch pathway, which controls metazoan development. In a recent publication, we identified a novel non-canonical Notch ligand, EGFL7, and described its impact on neural stem cells. We explored the molecular mechanisms, which this molecule affects to regulate the self-renewal capacity of neural stem cells and to promote their differentiation into neurons. In this review, we discuss the implications of our findings for adult neurogenesis and illustrate the potential of EGFL7 to serve as an agent to increase neurogenesis and the self-renewal potential of the brain


Antihypertensive effects of the new calcium antagonist benidipine hydrochloride in rats.
Using spontaneously hypertensive rats (SHR), DOCA-NaCl hypertensive rats (DHR) and normotensive rats (NTR), the antihypertensive action of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dic arb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was comparatively evaluated with those of nicardipine and hydralazine. Administration of KW-3049 at 0.5, 1 and 3 mg/kg (p.o.) showed dose-dependent antihypertensive action. This action appeared gradually and it lasted longer than those of nicardipine and hydralazine. The administration of KW-3049 at 0.5 mg/kg (p.o.) did not show any effect on the blood pressure of NTR, but a long-lasting blood pressure lowering action was observed by the administration at 1 and 3 mg/kg (p.o.). This antihypertensive action specific to the hypertensive animals was similar to that of nicardipine, however, it was different from that of hydralazine, with which the blood pressure in SHR, DHR and NTR was lowered in similar degrees. Also, administration of KW-3049 caused tachycardia concomitant with the fall of blood pressure, however, it was mild as compared with those of nicardipine and hydralazine. When KW-3049 at doses of 3 and 10 mg/kg (p.o.) once a day was continuously administered to SHR for 31 days and changes of the antihypertensive action were observed, no tolerance developed and rebound hypertension following the discontinuation of medication did not occur. When the effect on the urinary volume and electrolyte excretion was evaluated in rats loaded with physiological saline solution, a natriuretic effect was observed by the administration of KW-3049 at 0.5, 1 and 3 mg/kg (p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)


A novel robot-guided minimally invasive technique for brain tumor biopsies.
OBJECTIVEAs decisions regarding tumor diagnosis and subsequent treatment are increasingly based on molecular pathology, the frequency of brain biopsies is increasing. Robotic devices overcome limitations of frame-based and frameless techniques in terms of accuracy and usability. The aim of the present study was to present a novel, minimally invasive, robot-guided biopsy technique and compare the results with those of standard burr hole biopsy.METHODSA tubular minimally invasive instrument set was custom-designed for the iSYS-1 robot-guided biopsies. Feasibility, accuracy, duration, and outcome were compared in a consecutive series of 66 cases of robot-guided stereotactic biopsies between the minimally invasive (32 patients) and standard (34 patients) procedures.RESULTSApplication of the minimally invasive instrument set was feasible in all patients. Compared with the standard burr hole technique, accuracy was significantly higher both at entry (median 1.5 mm [range 0.2-3.2 mm] vs 1.7 mm [range 0.8-5.1 mm], p = 0.008) and at target (median 1.5 mm [range 0.4-3.4 mm] vs 2.0 mm [range 0.8-3.9 mm], p = 0.019). The incision-to-suture time was significantly shorter (median 30 minutes [range 15-50 minutes] vs 37.5 minutes [range 25-105 minutes], p < 0.001). The skin incision was significantly shorter (median 16.3 mm [range 12.7-23.4 mm] vs 28.4 mm [range 20-42.2 mm], p = 0.002). A diagnostic tissue sample was obtained in all cases.CONCLUSIONSApplication of the novel instrument set was feasible in all patients. According to the authors' data, the minimally invasive robot-guidance procedure can significantly improve accuracy, reduce operating time, and improve the cosmetic result of stereotactic biopsies.


Clinical and Functional Features of Epilepsy-Associated In-Frame Deletion Variants in SCN1A.
Naturally occurring in-frame deletion is a unique type of genetic variations, causing the loss of one or more amino acids of proteins. A number of in-frame deletion variants in an epilepsy-associated gene SCN1A, encoding voltage gated sodium channel alpha unit 1.1 (Nav1.1), have been reported in public database. In contrast to the missense and truncation variants, the in-frame deletions in SCN1A remains largely uncharacterized. We summarized the basic information of forty-four SCN1A in-frame deletion variants and performed further analysis on six variants identified in our cases with epilepsy. Mutants of the six in-frame deletions and one truncating variant used as comparison were generated and co-transfected with beta-1 and -2 subunits in tsA201 cells, followed by patch clamp recordings. Reviewing all the in-frame deletions showed that they spread over the entire Nav1.1 protein, without obvious "hot spots." The dominant type (54%) was single residue loss. There was no obvious relationship between the length or locations of deletions and their clinical phenotypes. The six in-frame deletions were two single residue deletions (p.M400del and p.I1772del), one microdeletion (p.S128_F130del) and three macrodeletions (p.T303_R322del, p.T160_Y202del, and p.V1335_V1428del). They scatter and affect different functional domains, including transmembrane helices, pore region, and P-loop. Electrophysiological recordings revealed no measurable sodium current in all of the six mutants. In contrast, the truncating mutant p.M1619Ifs*7 that loses a long stretch of peptides retains partial function. The complete loss-of-function in these shortened, abnormal mutants indicates that Nav1.1 protein is a highly accurate structure, and many of the residues have no redundancy to ion conductance. In-frame deletions caused particularly deleterious effect on protein function possibly due to the disruption of ordered residues.


Spontaneous closure of multiple enterocutaneous fistula due to abdominal tuberculosis using negative pressure wound therapy: a case report.
Enterocutaneous fistula (ECF) is one of the most challenging abdominal complications, for surgeons and other healthcare members, which involves significant morbidity and potentially mortality. Despite advancements in both operative and non-operative therapy, fistula-related complications are still unavoidable. Negative pressure wound therapy (NPWT) had been used years to treat chronic wound, to decrease tissue edema, improve circulation, promote healthy granulation tissue and inhibit bacterial growth. We report a 29-year-old male with complicated ECF due to abdominal tuberculosis, that was healed after treated using NPWT. This was the first ECF patient in our hospital treated using NPWT.


Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective.
Herpes zoster (HZ) is primarily a disease of nerve tissue but the acute and longer-term manifestations require multidisciplinary knowledge and involvement in their management. Complications may be dermatological (e.g. secondary bacterial infection), neurological (e.g. long-term pain, segmental paresis, stroke), ophthalmological (e.g. keratitis, iridocyclitis, secondary glaucoma) or visceral (e.g. pneumonia, hepatitis). The age-related increased incidence of HZ and its complications is thought to be a result of the decline in cell-mediated immunity (immunosenescence), higher incidence of comorbidities with age and social-environmental changes. Individuals who are immunocompromised as a result of disease or therapy are also at increased risk, independent of age. HZ and its complications (particularly postherpetic neuralgia) create a significant burden for the patient, carers, healthcare systems and employers. Prevention and treatment of HZ complications remain a therapeutic challenge despite recent advances. This is an overview of the multidisciplinary implications and management of HZ in which the potential contribution of vaccination to reducing the incidence HZ and its complications are also discussed.


Physical Activity as a Preventive Lifestyle Intervention Acts Through Specific Exosomal miRNA Species-Evidence From Human Short- and Long-Term Pilot Studies.
Exercise initiates systemic adaptation to promote health and prevent various lifestyle-related chronic diseases. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. Yet to date, a comprehensive profile of the exosomal miRNA (exomiR) content released following short-term (0.5 year in this study) and long-term (25 + years in this study) regular bouts of exercise is still lacking. However, a better understanding of these miRNA species would assist in clarifying the role of regular exercise at the molecular level in the prevention of chronic diseases. In the present pilot studies we analyzed serum exomiR expression in healthy young, sedentary participants (n = 14; age: 23 ± 2 years) at baseline and following a half year-long moderate-intensity regular exercise training. We also analyzed serum exomiR expression in older, healthy trained participants (seniors, n = 11; age: 62 ± 6 years) who engaged in endurance activities for at least 25 years. Following the isolation and enrichment of serum exosomes using Total Exosome Isolation Reagent (TEI) their exomiR levels were determined using the amplification-free Nanostring platform. Hierarchical cluster analysis revealed that the majority of exomiRs overlap for short-term (0.5 year in this study) and long-term (25 + years in this study) regular bouts of exercise. The top 12 significantly altered exomiRs (let-7a-5p; let-7g-5p; miR-130a-3p; miR-142-3p; miR-150-5p; miR-15a-5p; miR-15b-5p; miR-199a-3p; miR-199b-3p; miR-223-3p; miR-23a-3p, and miR-451a-3p) were used for further evaluation. According to KEGG pathway analysis a large portion of the exomiRs target chronic diseases including cancer, neurodegenerative and metabolic diseases, and viral infections. Our results provide evidence that exosomal miRNA modulation is the molecular mechanism through which regular exercise prevents various chronic diseases. The possibility of using such exomiRs to target diseases is of great interest. While further validation is needed, our comprehensive exomiR study presents, for the first time, the disease-preventive molecular pattern of both short and long-term regular exercise.


Microaggressions experienced by persons with mental illnesses: An exploratory study.
Microaggressions are subtle verbal or behavioral communications of disparaging messages to people based upon membership in a socially marginalized group. Their negative impact has been demonstrated for racial/ethnic groups, gender, sexual orientation, and physical disability, but currently no research exists on microaggressions as experienced by persons with mental illnesses. Qualitative data were gathered from 4 focus groups with 2 samples: adult mental health consumers in an assertive community treatment program and college students with mental illness diagnoses. Focus group transcripts were then analyzed using an open coding approach (Strauss & Corbin, 1990) to identify hierarchical themes and categories. Five major themes were identified, including invalidation, assumption of inferiority, fear of mental illness, shaming of mental illness, and second class citizen. Perpetrators of microaggressions were most commonly identified as being close friends, family members, and authority figures. Importantly, participants reported experiencing more overt discrimination experiences than subtle microaggression experiences. Reported negative outcomes related to microaggression experiences included isolation, negative emotions, and treatment nonadherence. Reported consequences of microaggressions have important implications for mental health treatment, especially as perpetrators were reported to include treatment providers and were usually unaware of such negative social exchanges. Loss of social support reported by participants and the frequent occurrence of microaggressions within close relationships implies these experiences could contribute to internalization of stigmatizing attitudes toward mental illness. Directions for future research include an investigation of motivation and reasoning behind perpetration of microaggressions against persons with mental illnesses.


Overexpression of regucalcin suppresses gene expression of insulin signaling-related proteins in cloned rat hepatoma H4-II-E cells: involvement of insulin resistance.
Overexpression of regucalcin has been shown to enhance glucose utilization and lipid production in the cloned rat hepatoma H4-II-E cells in vitro, and it induces insulin resistance. The effect of regucalcin on the gene expression of insulin signaling-related proteins was investigated in the cloned rat hepatoma H4-II-E cells overexpressing regucalcin in vitro. The hepatoma cells (wild-type) and stable regucalcin/ pCXN2-transfected cells (transfectants) were cultured for 72 h in a medium containing 10% fetal bovine serum (FBS) to obtain subconfluent monolayers. Cells with subconfluency were cultured for 24, 48, or 72 h in a medium containing either vehicle or insulin (10(-9)-10(-7) M) with or without supplementation of glucose (10, 25, or 50 mg/ml of medium). The expression of rat insulin receptor (Insr), phosphatidylinositol 3-kinase (PI3K), glucose transporter 2 (GLUT 2), or glyceroaldehyde-3-phosphate dehydrogenase (G3PDH) mRNAs was examined using reverse transcription-polymerase chain reaction analysis with specific primers. GLUT 2 mRNA expression was significantly increased in the transfectants, while Insr, PI3K, and G3PDH mRNA levels were not significantly changed in the transfectants. Culture with insulin (10(-8) or 10(-7) M) caused a significant increase in PI3K mRNA levels in wild-type cells cultured for 24 or 48 h, while it had no effect on Insr mRNA levels. The supplementation of glucose (10, 25, or 50 mg/ml) caused a significant increase in Insr and PI3K mRNA levels in wild-type cells. The effect of insulin or glucose supplementation on these gene expression levels was not seen in the transfectants. The combination of insulin (10(-7) M) and glucose (50 mg/ml) caused a significant increase in Ins and PI3K mRNA levels in wild-type cells. Such an effect was not seen in the transfectants. Culture with insulin or glucose supplementation failed to have a significant effect on GLUT2 and G3PDH mRNA levels in the wild-type cells or transfectants. This study demonstrates that overexpression of regucalcin suppresses the enhancing effect of insulin or glucose on the gene expression of insulin signaling-related proteins in the cloned rat hepatoma H4-II-E cells.


Multiorgan resection with inferior vena cava reconstruction for hepatic alveolar echinococcosis: A case report and literature review.
Alveolar echinococcosis (AE) is a life-threatening parasitic disease characterized by its tumor-like growth. Radical operation is deemed the curable method for AE treatment if R0-resection is achievable. We present a 26-year-old AE patient with AE lesions invading the right lobe of the liver, the inferior vena cava, inferior lobe of right lung, the right hemidiaphragm, and the right kidney. On the basis of precise preoperative and intraoperative evaluations, a radical surgery that removed the huge lesion en bloc was performed successfully with skillful surgical techniques. This patient had an uneventful postoperative recovery and a good prognosis. Multiorgan resection is justified and unavoidable in selected patients when AE lesions invade different organs and the main vascular structures.


Islands as nanometric probes of strain distribution in heterogeneous surfaces.
Many of the surface phenomena are driven by elastic energy and elastic interactions. Despite the fact that there are many microscopic techniques with nm and atomic resolution, an established technique to study the distribution of strain on the surface is still lacking. We present a study on the Gd(0001)/W(110) system, in which undulations in the Gd layer are detected by STM. This creates a heterogeneous surface with reduced strains, due to relaxation, on the crests of the waved surface and elevated strains in the troughs. An additional part of the strain is released through Stransky-Krastanov growth of Gd islands. Utilizing a strain-relief model, we show that the island size and shape reflect the strain variations on the surface. Strain maps were calculated, using the island as nanoprobes, with good correlation to the surface topography.


Streptomyces seymenliensis sp. nov., isolated from soil.
A novel actinomycete, designated strain B1041(T), isolated from soil collected from the Tuz (Salt) Lake in the central Anatolia region, in Turkey, was characterised using a polyphasic taxonomic approach. The isolate was found to have chemical and morphological properties typical of the members of the genus Streptomyces and formed a distinct phyletic line in the 16S rRNA gene tree. Strain B1041(T) was found to be most closely related to Streptomyces plumbiresistens CCNWHX 13-160(T) (98.46 % sequence similarity), Streptomyces pseudovenezuelae NBRC 12904(T) (97.81 %), Streptomyces novaecaesareae NBRC 13368(T) (97.68 %), Streptomyces graminifolii JL-22(T) (97.60 %), Streptomyces phaeoluteigriseus NRRL ISP-5182(T) (97.58 %), Streptomyces ciscaucasicus NBRC 12872(T) (97.53 %) and Streptomyces pratensis ch24(T) (97.52 %). Sequence similarities with other strains of the genus Streptomyces were lower than 97.5 %. The cell wall of the novel strain was found to contain LL-diaminopimelic acid and the whole cell sugars were identified as galactose, glucose and ribose. The major cellular fatty acids were identified as anteiso C15:0 , iso C16:0 and anteiso C17:0. The predominant menaquinones found were found to be MK-9(H8) and MK-9(H6). The polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, a phosphoglycolipid and two unknown phospholipids. The genomic DNA G+C content was determined to be 70.4 mol%. On the basis of the data from this polyphasic taxonomic study, strain B1041(T) can be considered to represent a novel species within the genus Streptomyces for which the name Streptomyces seymenliensis sp. nov. is proposed (type strain B1041(T) =KCTC 29245(T) = DSM 42117(T)).


Histologic features of breast capsules reflect surface configuration and composition of silicone bag implants.
The fibrous capsules that develop around silicone gel breast implants may become excessively thickened and result in painful hardened breasts. This article examines the microscopic anatomy of 80 periprosthetic breast capsules removed during a 2-year period (1990-1992), and describes the histopathologic characteristics of capsules adjacent to the more recently modified implant types. Capsules were examined by routine light microscopy, with and without polarization. Several distinctive histologic patterns were recognized, and these unique patterns could be correlated with the implant type used. All capsules were lined by a cellular membrane resembling synovium. Capsules adjacent to smooth-surfaced implants were lined by an intact histiocytic membrane of uniform thickness. In contrast, the membrane adjacent to textured implants varied in thickness, and was disrupted along its length. In addition, the inner surface of capsules adjacent to textured implants was conspicuously festooned with small (.25 to .5 mm) knob-like projections that were not seen in capsules adjacent to smooth-surfaced implants. A variety of foreign materials also were observed either within or adjacent to the capsules, and included droplets of liquid silicone, irregular solid fragments of the bag envelope, geometric crystalline fragments of polyurethane, and talc. Thus, the microanatomic features of periprosthetic breast capsules reflect the composition and surface configuration of the corresponding silicone bag type.


Sub-minimum inhibitory concentrations of colistin and polymyxin B promote Acinetobacter baumannii biofilm formation.
We investigated the numbers of planktonic and biofilm cells and the expression levels of genes encoding efflux pumps and biofilm-related proteins in 10 clinical isolates of multi-drug resistant Acinetobacter baumannii (MDRA) as well as in its standard strain ATCC 19606 in the presence of colistin (CST), polymyxin B (PMB), minomycin (MIN), and tigecycline (TGC) at their respective sub-MICs. The number of planktonic and biofilm cells of ATCC 19606 decreased in the presence of all aforementioned antibiotics in a dose-dependent manner. Cell number also decreased in two representative MDRA strains, R2 and R3, in the presence of MIN and TGC in a dose-dependent manner. In contrast, the number of biofilm cells in these two strains increased in the presence of CST, while they increased significantly in the presence of PMB in R2 only. Pearson correlation analysis revealed that the number of biofilm cells was positively and significantly correlated with the mRNA levels of genes encoding efflux pumps (adeB and adeG) and autoinducer synthase (abaI) in strain R2 and adeB, adeG, adeJ, poly-acetyl-glucosamine-porin (pgaA), and abaI in strain R3 in the presence of CST. It was positively and significantly correlated with the mRNA levels of genes encoding adeB in strain R2 and an outer membrane protein A (ompA) and biofilm-associated protein (bap) in strain R3 in the presence of PMB. These results provide valuable insights into the biofilm formation potency of clinical isolates of MDRA that depends on efflux pumps and biofilm-related genes and its regulation by antibiotics.


Thermal, structural and acetylation behavior of snail and periwinkle shells chitin.
This article reports a successful removal of CaCO3 from snail and periwinkle shells for the purpose of producing high quality chitin for possible application as bio-fillers in bone fixation materials. Experiment was designed with varying concentrations of acid and alkali for demineralization, deproteinization and deacetylation of the samples. Thermal characteristics, morphology, degree of de-acetylation, crystalline structure and hydrogen bonding characteristics of the extracted chitin were examined. Infra-red spectra, thermogravimetric analysis and X-ray diffraction patterns show that demineralization with 1.7 M HCl led to a successful removal of CaCO3. Subsequent deproteinization and deacetylation with 1.2 M NaOH led to a development of chitosan having a degree of deacetylation of 77 and 60% for periwinkle and snail shells, respectively. Generally, all results show that different treatments led to different chitin structure and consequently different properties.


Elasticity of Nuclear Pasta.
The elastic properties of neutron star crusts are relevant for a variety of currently observable or near-future electromagnetic and gravitational wave phenomena. These phenomena may depend on the elastic properties of nuclear pasta found in the inner crust. We present large-scale classical molecular dynamics simulations where we deform nuclear pasta. We simulate idealized samples of nuclear pasta and describe their breaking mechanism. We also deform nuclear pasta that is arranged into many domains, similar to what is known for the ions in neutron star crusts. Our results show that nuclear pasta may be the strongest known material, perhaps with a shear modulus of 10^{30} ergs/cm^{3} and a breaking strain greater than 0.1.


Effectiveness of early therapeutic intervention in phases one and two after COVID-19 infection: systematic review.
Although research in relation to new vaccines for the coronavirus, SARS-CoV-2 (COVID-19), is ongoing, it has been reported that medical teams are also considering the use of antiviral drugs in patients in order to verify their effectiveness when infection signs and symptoms present, mainly in stages one and two of the disease. For the selection of studies, the combination based on the Medical Subject Heading Terms (MeSH) was used, and the databases Medline (Pubmed), LILACS, SciELO, SCOPUS, Web of Science, and BIREME were searched. The search period for articles consisted of manuscripts published between January 2010 and July 2020 without language and localization restrictions. Initially, 20 articles were selected and then reduced to 19 after exclusion based on repetititve articles. Titles and abstracts were analyzed, and 14 articles were excluded because they did not meet the inclusion criteria and did not answer the guiding question. Studies show that patients receiving certain medications in the initial stages (one and two) indicate a reversal of complications during hospitalization or often do not require hospitalization in addition to being discharged in a shorter period of time. Studies have reported that effective drugs for treating COVID-19 exist. In addition, this study emphasizes the importance of performing therapeutic interventions in the initial stages of infection aimed at reversing the disease and minimizing public health costs.


Electrophysiological Correlates of Character Transposition in the Left and Right Visual Fields.
This study examined the brain activity elicited by the hemispheric asymmetries and morpheme transposition of two-character Chinese words (canonical and transposed word) and pseudowords using event-related potentials (ERPs) with a dual-target rapid serial visual presentation (RSVP) task. Electrophysiological results showed facilitation effects for canonical words with centrally presented visual field (CVF) and right visual field (RVF) presentations but not with left visual field (LVF) presentations, as reflected by less negative N400 amplitudes. Moreover, more positive late positive component (LPC) amplitudes were observed for both canonical words and transposed words irrespective of the visual fields. More importantly, transposed words elicited a more negative N400 amplitude and a less positive LPC amplitude compared with the amplitudes elicited by canonical words for CVF and RVF presentations. For LVF presentations, transposed words elicited a less negative N250 amplitude compared with canonical words, and there was no significant difference between canonical words and transposed words in the N400 effect. Taken together, we concluded that character transposition facilitated the mapping of whole-word orthographic representation to semantic information in the LVF, as reflected by the N250 component, and such morpheme transposition influenced whole-word semantic processing in CVF and RVF presentations, as reflected by N400 and LPC components.


Pressure denaturation of proteins: evaluation of compressibility effects.
One of the key pieces of information from pressure denaturation experiments is the standard volume change for unfolding (Delta V(o)). The pressure dependence of the volume change, the standard compressibility change (Delta K(o)T), is typically assumed to be zero in the analysis of these experiments. We show here that this assumption can be incorrect and that the neglect of compressibility differences can skew the interpretation of experimental results. Analysis of experimental, variable-pressure NMR data for bovine pancreatic ribonuclease A in 2H2O at pH 2.0 and 295 K yielded the following statistically significant, non-zero values: Delta K(o) T = 0.015 +/- 0.002 mL mol-1 bar-1, Delta V(o) = -21 +/- 2 mL mol-1, and Delta G(o) = 2.8 +/- 0.3 kcal mol-1. The experimental protein stability is in good agreement with one (Delta G(o) = 2.5 kcal mol-1) determined independently for the same protein by calorimetry at atmospheric pressure under equivalent conditions [Makhatadze, G. I., Clore, G. M., and Gronenborn, A. M. (1995) Nat. Struct. Biol. 2, 852-855]. The positive value for Delta K(o)T indicates that the denatured form of ribonuclease A is more compressible than the native form; this is explained in terms of an interplay between the intrinsic compressibility of the protein and solvation effects. When the same data were fitted to a model that assumes a zero compressibility change, the Delta G(o) value of 4. 0 +/- 0.1 kcal mol-1 returned by the model no longer agreed with the independent measurement, and the Delta V(o) returned by the model was a very different -59 +/- 1 mL mol-1. By contrast, it was not possible to carry out a similar thermodynamic analysis of fluorescence spectroscopic data for the denaturation of staphylococcal nuclease to yield well-defined values of Delta G(o), Delta V(o), and Delta K(o)T. This limitation was shown by evaluation of synthetic data to be intrinsic to spectroscopic data whose analysis requires fitting of the plateaus at either side of the transition. Because NMR data do not have this requirement, they can be analyzed more rigorously.


Utilization of a 3D printer to fabricate boluses used for electron therapy of skin lesions of the eye canthi.
This work describes the use of 3D printing technology to create individualized boluses for patients treated with electron beam therapy for skin lesions of the eye canthi. It aimed to demonstrate the effectiveness of 3D-printed over manually fabricated paraffin boluses. The study involved 11 patients for whom the construction of individual boluses were required. CT scans of the fabricated 3D-printed boluses and paraffin boluses were acquired and superimposed onto patient CT scans to compare their fitting, bolus homogeneity, and underlying dose distribution. To quantify the level of matching, multiple metrics were utilized. Matching Level Index (ML) values ranged from 0 to 100%, where 100% indicated a perfect fit between the reference bolus (planned in treatment planning system) and 3D-printed and paraffin bolus. The average ML (± 1 SD) of the 3D-printed boluses was 95.1 ± 2.1%, compared to 46.0 ± 10.1% for the manually fabricated paraffin bolus. Correspondingly, mean doses were closer to the prescribed doses, and dose spreads were less for the dose distributions from the 3D-printed boluses, as compared to those for the manually fabricated paraffin boluses. It was concluded that 3D-printing technology is a viable method for fabricating boluses for small eye lesions and provides boluses superior to our boluses manually fabricated from paraffin sheets.


Effects of Brimonidine, Omidenepag Isopropyl, and Ripasudil Ophthalmic Solutions to Protect against H2O2-Induced Oxidative Stress in Human Trabecular Meshwork Cells.
We investigated whether hydrogen peroxide (H2O2)-induced oxidative stress causes human trabecular meshwork (HTM) cell dysfunction observed in open angle glaucoma (OAG) in vitro, and the effects of topical glaucoma medications on oxidative stress in HTM cells. We used commercially available ophthalmic solutions of brimonidine, omidenepag isopropyl, and ripasudil in the study. HTM cells were exposed to H2O2 for 1 h, with or without glaucoma medications. We assessed cell viability and senescence via WST-1 and senescence-associated-β-galactosidase (SA-β-Gal) activity assays. After exposure to H2O2 and glaucoma medications, we evaluated changes in markers of fibrosis and stress by using real-time quantitative polymerase chain reaction (qPCR) to measure the mRNA levels of collagen type I alpha 1 chain (COL1A1), fibronectin, alpha-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP-2), endoplasmic reticulum stress markers of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and splicing X-box binding protein-1 (sXBP-1). HTM cell viability decreased and SA-β-Gal activity increased significantly after exposure to H2O2. Treatment with three ophthalmic solutions attenuated these changes. Real-time qPCR revealed that H2O2 upregulated the mRNA levels of COL1A1, fibronectin, α-SMA, CHOP, GRP78, and sXBP-1, whereas it downregulated MMP-2 mRNA expression significantly. Brimonidine suppressed the upregulation of stress markers CHOP and GRP78. Additionally, omidenepag isopropyl and ripasudil decreased the upregulation of COL1A1 and sXBP-1. Furthermore, ripasudil significantly suppressed fibrotic markers fibronectin and α-SMA, compared with the other two medications. In vitro, H2O2 treatment of HTM cells induced characteristic changes of OAG, such as fibrosis changes and the upregulation of stress markers. These glaucomatous changes were attenuated by additional treatments with brimonidine, omidenepag isopropyl, and ripasudil ophthalmic solutions.


Interactions between tetrahydrothiophene (THT) and silver species in AgNa-Y.
We studied the interaction between tetrahydrothiophene (THT), which is one of sulfur odorants in a pipeline natural gas, and AgNa-Y zeolites, which can be obtained via Ag+ exchange with Na+ of Na-Y and used for the adsorptive removal of THT at ambient temperature and atmospheric pressure, with a temperature-programmed desorption (TPD), a temperature-programmed reduction with H2 (H2-TPR), a transmission electron microscopy (TEM) with an energy dispersive X-ray spectroscopy (EDX) and an X-ray absorption fine structure (XAFS). The presence of the metallic Ag and the Ag+ in the fresh AgNa-Y can be supported with a TEM and an XAFS analysis. The fraction of metallic Ag in silver species increased with increasing the pretreatment temperature. The formation of Ag-S bond with concomitant decreasing the interaction between Ag+ and oxygen in the lattice as well as the interaction of Ag-Ag in the metallic Ag can be observed during the adsorption of THT at ambient temperature. This can explain why there is no noticeable difference in the adsorption capacity in between Ag+ -dominant AgNa-Y and Ag0-rich AgNa-Y. This Ag-S bond was transformed into the Ag-Ag bond during the heat treatment in an inert gas above 673 K. However, the fresh chemical and electronic state of Ag can be recovered after the heat treatment in air above 673 K.


QscR-mediated transcriptional activation of serine cycle genes in Methylobacterium extorquens AM1.
QscR, a LysR-type regulator, is the major regulator of assimilatory C1 metabolism in Methylobacterium extorquens AM1. It has been shown to interact with the promoters of the two operons that encode the majority of the serine cycle enzymes (sga-hpr-mtdA-fch for the qsc1 operon and mtkA-mtkB-ppc-mclA for the qsc2 operon), as well as with the promoter of glyA and its own promoter. To obtain further insights into the mechanisms of this regulation, we mapped transcriptional start sites for the qsc1 and qsc2 operons and for glyA via primer extension analysis. We also identified the specific binding sites for QscR upstream of the qsc1 and qsc2 operons and glyA by DNase I footprinting. The QscR protected areas were located at nucleotides -216 to -165, nucleotides -59 to -26, and nucleotides -72 to -39 within the promoter-regulatory regions upstream of transcriptional starts of, respectively, qsc1, qsc2 and glyA. To examine the nature of the metabolic signal that may influence QscR-mediated regulation of the serine cycle genes, Pqsc1::xylE translational fusions were constructed and expression of XylE monitored in the wild-type strain, as well as in knockout mutants defective in a variety of methylotrophy functions. The data from these experiments pointed toward formyl-H4F being a coinducer of QscR and possibly the major signal in the regulation of the serine cycle in M. extorquens AM1. The ability of formyl-H4F to enhance the binding of QscR to a specific region upstream of one of the serine cycle operons was demonstrated in gel retardation experiments.


Imaging Findings and Misdiagnosis of Bronchogenic Cysts: A Study of 83 Cases.
We characterize computed tomography (CT) and magnetic resonance imaging (MRI) features of bronchogenic cysts (BCs) and analyze misdiagnosis. The retrospective study consisted of 83 patients with BCs. CT and MRI images were assessed for mass location, maximum diameter, density, calcification, signal intensity, and enhancement pattern. Eighty-three patients underwent plain CT in which 53 underwent enhanced CT. Thirteen patients received both plain and enhanced MR, and only one received just a plain MR. Eighty-three masses were all solitary, with 71 having a roundish morphology, and twelve having a lobulated or irregular morphology. Sixty-six masses are mediastinal type, four are intrapulmonary type, and 13 are ectopic type. Calcification occurred in 14 lesions. On plain CT, 13 lesions displayed water-like attenuation (-20-20 Hu), and 70 showed soft-tissue attenuation (≥21 Hu). On T1WI, eight masses were hyperintense, three were isointense, and three were hypointense. Fourteen masses were hyperintense on T2WI and (Apparent Diffusion Coefficient) ADC sequence. On (Diffusion Weighted Imaging) DWI, six masses were hypointense and eight were hyperintense. Enhanced T1WI showed seven cases were unenhanced, while six were marginally enhanced. Twenty cases were misdiagnosed as thymomas, eleven as neurogenic tumors, six as lymphangiomas, and two as lung cancer. Five cases were misdiagnosed as other diseases. Patients with BCs underwent MR (42.9%) had a lower rate of misdiagnosis than those who underwent CT alone (53.0%). The imaging findings of BCs in the chest are generally consistent. Misdiagnosis occurs frequently when CT attenuation values exceed 20 Hu. Diagnostic accuracy of BCs tends to improve with preoperative MR examination.


Validation of malondialdehyde and 4-hydroxy-2-trans-nonenal measurement in plasma by NICI-GC-MS.
Measurement of the concentrations of aldehydes in biological samples has become the object of much effort due to their relevance in relation to the toxic effects of lipid peroxidation, through which a number of aldehydes are derived. We have reconsidered a previously proposed method based on gas chromatographic mass spectrometric analysis of derivatives obtained by the treatment of aldehydes with O-pentafluorobenzyl hydroxylamine followed by a trimethylsilylating agent. In view of the possible use of the method for the simultaneous evaluation of the plasma levels of malondialdehyde and 4-hydroxy-2-trans-nonenal, we have studied the linearity of the analysis using various internal standards. Commercially available, inexpensive 2,4-dihydroxybenzaldehyde gave optimal results, the correlation coefficient of the calibration curve for plasma being r > 0.995 in the 0.1-5 microM range for both the tested aldehydes. The between-day imprecision (%CV) and accuracy (%bias) of the procedure determined using plasma samples spiked with the two aldehydes and with an internal standard reached maximum values of 3 and 8%, and 5 and 12% for HNE and MDA, respectively. The results obtained on analysis of plasma samples before and after oxidation with copper ions indicate the flexibility of the method for evaluation of the levels of MDA and HNE in plasma samples both under basal conditions and after an oxidative burst.


Cardiac Amyloidosis Presenting with Pre-Excitation Syndrome, Heart Failure, and Severe Factor X Deficiency as Part of Systemic Amyloid Light-Chain (AL) Amyloidosis - A Fatal Combination.
BACKGROUND Amyloid light-chain (AL) amyloidosis is a disease that results in systemic amyloid deposition, which may present with multi-organ dysfunction. It carries a poor prognosis at the time of diagnosis. CASE REPORT A 37-year-old patient with a history of Wolff-Parkinson-White syndrome and thyroiditis presented with syncope and hypovolemia. ECG showed non-specific T wave inversions in the lateral leads with no signs of ischemia. Laboratory investigations revealed deranged coagulation parameters with prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) and follow-up factor assays revealed severe factor X deficiency. A transthoracic echocardiogram and subsequent cardiac MRI showed signs of cardiac amyloidosis. Bone marrow biopsy was consistent with AL amyloidosis, demonstrating period acid-Schiff (PAS)-positive adipose deposits and interstitial infiltration by clusters of lambda restricted plasma cells with aberrant expression of CD 56 and CD 117.The patient was treated with bortezomib, cyclophosphamide, and dexamethasone, but died early during his treatment due to cardiac arrest, suspected to be secondary to conduction abnormalities caused by cardiac infiltration. CONCLUSIONS This case represents a novel pattern of disease in AL amyloidosis with cardiac, thyroid, and hematological involvement as a result of systemic amyloid deposition.Our report highlights the need for physicians to be aware of cardiac amyloidosis-related complications and the morbidity and mortality associated with concurrent hematological involvement in these cases.


Reliability of a Proposed Ultrasonographic Grading Scale for Severity of Primary Knee Osteoarthritis.
The objective of this study was to examine the concordance of a grading scale (0-4) of medial femoral osteophytes in knee joint detected by ultrasound (US) compared with the corresponding grades (0-4) of Kellgren-Lawrence (K&L) scale of conventional radiography and clinical joint examination. A cross-sectional observational study included 160 patients with knee pain who fulfilled the American College of Rheumatology (ACR) criteria for knee osteoarthritis (KOA) and 20 patients with knee pain who have not fulfilled the ACR criteria for KOA. All patients were subjected to clinical assessment (Western Ontario and McMaster Universities Index of Osteoarthritis and global visual analog scale) and radiological assessment in the form of X-ray grading according to K&L grading scale and ultrasonographic assessment of medial femoral osteophytes according to a scale that was proposed by the first author and consisted of five grades (0-4), where grade 0 denoted no osteoarthritis and grade 4 denoted the most advanced grade of KOA. Grade 2 was divided into two subgrades A and B with grade 2B considered as a more advanced stage than grade 2A. The proposed US grading scale had high sensitivity and specificity in detecting the different grades of KOA compared with K&L grading scale (a total sensitivity of 94.6% and a total specificity of 93.3%). Intra- and interreader reliability of US was excellent (kappa >0.93 and >0.85, respectively). US can reliably detect the severity of KOA. Good agreement was found between the proposed US grading scale and K&L grading scale. The proposed US grading scale is simple and reliable.


Attenuated asthma phenotype in mice with a fetal-like antigen receptor repertoire.
We hypothesized that the scarcity of N-nucleotides might contribute to the inability of the neonate to mount a robust allergic immune response. To test this, we used terminal deoxyribunucleotidyl Transferase deficient (TdT-/-) mice, which express "fetal-like" T cell receptor and immunoglobulin repertoires with largely germline-encoded CDR3 regions. Intraperitoneal sensitization was followed by aerosol provocation with either PBS or the allergen OVA in both TdT-/- mice and wild-type mice to develop allergic respiratory inflammation. The effects of this procedure were investigated by lung function test, immunological analysis of serum and brochoalveolar lavage. The local TH2 cytokine milieu was significantly attenuated in TdT-/- mice. Within this group, the induction of total IgE levels was also significantly reduced after sensitization. TdT-/- mice showed a tendency toward reduced eosinophilic inflow into the bronchial tubes, which was associated with the elimination of respiratory hyperreactivity. In conclusion, in a murine model of allergic airway inflammation, the expression of fetal-like antigen receptors was associated with potent indications of a reduced ability to mount an asthma phenotype. This underlines the importance of somatically-generated antigen-receptor repertoire diversity in type one allergic immune responses and suggests that the fetus may be protected from allergic responses, at least in part, by controlling N addition.


Mechanical Testing of Epiphysiodesis Screws.
Epiphysiodesis is performed to treat leg-length discrepancies and angular deformities in children. However, when placed across a physis to modulate growth, screws can bend or break postoperatively. This study evaluated the mechanical properties of 3 different screw designs commonly used when performing an epiphysiodesis. Six 4.0-mm cannulated, fully threaded; six 4.0-mm cannulated, partially threaded; and six 4.0-mm noncannulated, partially threaded cancellous screws underwent cantilever bending and tension testing in a simulated physis. All screws were tested in simulated cancellous bone foam blocks. All testing was performed using a servo-hydraulic testing machine to determine stiffness and ultimate load. For statistical analysis, one-way analysis of variance with Tukey's honestly significant difference test in post hoc analysis was used to assess significant differences among groups (P<.05). The noncannulated, partially threaded screws had a significantly lower stiffness than the 2 cannulated screw types in the tension test (P<.001) and bending test (P<.001). Additionally, the noncannulated, partially threaded screws had significantly higher ultimate load to failure than the 2 cannulated screw types in the tension test (P<.001) and the cannulated, partially threaded screws in the bending test (P=.045). The results indicate that noncannulated, partially threaded screws have a higher ultimate load capacity and are less stiff than both cannulated, partially threaded screws and cannulated, fully threaded screws. Surgeons should take into consideration that noncannulated, partially threaded screws are less likely to fail following epiphysiodesis. [Orthopedics. 2018; 41(2):e240-e244.].


Leustroducsin B activates nuclear factor-kappaB via the acidic sphingomyelinase pathway in human bone marrow-derived stromal cell line KM-102.
The novel colony-stimulating factor (CSF) inducer leustroducsin B (LSN-B), which was isolated from Streptomyces platensis, has been shown to have potent cytokine-inducing activities in clonal human bone marrow-derived stromal cell line KM-102 and in primary human bone marrow-derived stromal cells. In this study, we investigated the signal transduction pathway of LSN-B using luciferase expression plasmids linked to the 5'-flanking region of interleukin-8 (IL-8) and that of the IL-11 gene. In KM-102 cells, LSN-B induced luciferase activity both in the wild-type and in the activated protein 1 (AP-1) site point-mutated IL-8 promoter. The mutation in the nuclear factor-kappaB (NF-kappaB) site abrogated LSN-B-stimulated induction of the reporter gene. LSN-B-inducing activity was inhibited by (1) N-acetyl-L-cysteine, a well-characterized antioxidant, (2) cationic amphiphilic drugs, inhibitors of acidic sphingomyelinase (A-SMase), and (3) D609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC). These observations suggest that LSN-B potentiates the A-SMase-mediated signaling pathway to stimulate NF-kappaB. In contrast, LSN-B did not induce IL-11 promoter-driven luciferase activity. The observed increase in IL-11 mRNA stability by LSN-B indicates that the inducible production of IL-11 by LSN-B is regulated at the posttranscriptional level. In addition, inhibition of LSN-B-mediated induction of IL-11 production by cationic amphiphilic drugs and D609 in KM-102 cells demonstrates that increased IL-11 mRNA stability by LSN-B might be mediated via NF-kappaB activation. From these results, we suggest that LSN-B induces cytokine production through at least two separate mechanisms, at the transcriptional level and at the posttranscriptional level via NF-kappaB activation.


Observation of exopolysaccharides (EPS) from Lactobacillus helveticus SBT2171 using the Tokuyasu method.
Some species of lactic acid bacteria used for the production of natural cheese produce exopolysaccharides (EPS). Electron microscopy is useful for analyzing the microstructure of EPS produced by lactic acid bacteria. However, pretreatments used to observe the microstructure of EPS by electron microscopy, such as dehydration and resin embedding, can result in EPS flowing out easily from the cell. Therefore, in this study, the Tokuyasu method was conducted on cryosection to reduce EPS outflow. Two types of observation method, namely, using lectin and ruthenium red, were conducted in an attempt to observe EPS produced by Lactobacillus helveticus SBT2171. Observation using the lectin method confirmed that colloidal gold particles conjugated with a lectin recognizing β-galactoside were present in the capsule. Structures that appeared to be β-galactoside-containing slime polysaccharides that were released from the cell wall were also observed. Observation using ruthenium red showed that capsular polysaccharides (CPS) in the capsule were present as a net-like structure. Colloidal gold conjugation with an anti-β-lactoglobulin antibody, in addition to ruthenium red staining, allowed the identification of slime polysaccharides released from the cell wall in the milk protein network derived from the culture medium. Based on these results, the Tokuyasu method was considered to be a useful pretreatment method to clarify and observe the presence of EPS. In particular, both CPS in the capsule and slime exopolysaccharides released from the cell wall were visualized.


The Association Between Maternal Chronic Inflammatory Bowel Disease and Long-term Health Outcomes in Children-A Nationwide Cohort Study.
Very little is known about the long-term impact of maternal inflammatory bowel disease (IBD) on the offspring's future health. We aimed to examine whether children born to mothers with IBD had an increased risk of long-term morbidities. In this nationwide register-based cohort study, including all children born alive in Denmark between 1989 and 2013, we investigated the association between maternal IBD and 15 selected disease categories of physical and mental conditions in the offspring. We used multivariate regression models estimating the hazard ratio (HR) of long-term child morbidities. The cohort comprised 9238 children born to women with IBD (exposed), and 1,371,407 born to women without IBD (unexposed). Median follow-up time among the exposed was 9.7 years (interquartile range [IQR] 4.9-15.7) and 13.8 (interquartile range 7.4-19.9) among the unexposed. In children, who in utero had been exposed to maternal ulcerative colitis, the HR of IBD in the offspring was 4.63 (95% confidence interval, 3.49-6.16). For maternal Crohn's disease, the HR of IBD in the offspring was 7.70 (95% confidence interval, 5.66-10.47). For all other diseases in the offspring, we did not find a significantly increased risk associated with maternal IBD. Children born to mothers with IBD are more likely to be diagnosed with IBD themselves, compared with children born to women without IBD. Our data otherwise do not provide evidence for an increased risk of any of the other examined diseases in the offspring.


[Development of highly stereoselective reactions based on tricarbonyl(eta 6-o-trimethylsilylbenzaldehyde)-chromium(o) complex].
Treatment of the tricarbonyl(eta 6-o-trimethylsilylbenzaldehyde)chromium (O) complex with cyclic silyl enol ether species under the Mukaiyama condition resulted in highly stereoselective formation of syn-aldol products, whereas the aldol reaction with O-silyl ketene O,S-acetals afforded the corresponding anti-products in a highly stereoselective manner. The tricarbonyl(eta 6-o-trimethylsilyl-benzaldehyde)chromium(O) complex has also emerged as an excellent substrate for highly regio- and stereoselective construction of cis-3,5-isoxazolidine derivatives in the 1,3-dipolar cycloaddition reaction. By taking advantage of our newly developed aldol reaction, we have succeeded in highly stereocontroled syntheses of some biologically active compounds such as C-13 side chains of taxol and taxotère, the N-terminal amino acid of nikkomycin B and Bx, and antitumor styryllactones: goniofufurone, goniotriol, and goniothalenol.


Utility of fiber-optic bronchoscopy in pulmonary infections among abdominal solid-organ transplant patients: A comprehensive review.
Pulmonary infections are frequent complications in abdominal solid-organ transplantation (aSOT) which may threaten patient and allograft survival. Accurate diagnosis and treatment of pulmonary infections in this population can be challenging. Immunosuppressive therapy not only increases the risk of acquiring opportunistic and non-opportunistic infections, but it also impairs the inflammatory responses associated with microbial invasion which in an otherwise normal host produce clinical and radiologic responses that allow for early identification of the offending pathogen. Serologic testing is not a reliable diagnostic modality. Direct microbiological sampling is often necessary to make a definitive diagnosis early in the clinical course to optimize timely, targeted therapy while reducing the risk of developing antimicrobial resistance, and minimize adverse effects of therapy, if any. Fiber-optic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) or transbronchial lung biopsy (TBB) offers such diagnostic advantage and possesses a potential therapeutic value too. This comprehensive review discusses the potential benefits of FOB alongside its risks and complications, indications and contraindications, and techniques. Additionally, the essay highlights FOB's utility and yield specifically with regard to type and timing of infections in aSOT patients.


A direct multiple histogram reweighting method for optimal computation of the density of states.
A simple nonparametric procedure is devised for constructing Boltzmann entropy functions from statistically weighted entropy differences calculated from overlapping histograms. The method is noniterative, avoids numerical problems associated with large state densities, and accommodates variable bin widths for reducing systematic and statistical errors inherent to histogram techniques. Results show that the procedure can yield thermodynamic functions for an Ising spin lattice model that have average errors comparable to ones obtained from a conventional approach. Analysis of thermofunctions computed for a polyalanine peptide simulated by hybrid Monte Carlo replica exchange indicates that method performance can be enhanced through the use of nonuniform state space discretization schemes. An extension of the reweighting procedure for multidimensional applications is presented through calculations of vapor-liquid equilibrium densities of a model fluid simulated by grand canonical replica exchange.


Fluorescence Spectroscopy Study of Protoporphyrin IX in Optical Tissue Simulating Liquid Phantoms.
Fluorescence spectroscopy has been extensively investigated for disease diagnosis. In this framework, optical tissue phantoms are widely used for validating the biomedical device system in a laboratory environment outside of clinical procedures. Moreover, it is fundamental to consider that there are several scattering components and chromophores inside biological tissues and the interplay between scattering and absorption may result in a distortion of the emitted fluorescent signal. In this work, the photophysical behaviour of a set of liquid, tissue-like phantoms containing different compositions was analysed: phosphate buffer saline (PBS) was used as the background medium, low fat milk as a scatterer, Indian ink as an absorber and protoporphyrin IX (PpIX) dissolved in dimethyl formamide (DMF) as a fluorophore. We examined the collected data in terms of the impact of surfactant Tween-20 on the background medium, scattering effects and combination of scattering and absorption within a luminescent body on PpIX. The results indicated that the intrinsic emission peaks are red shifted by the scattering particles or surfactant, whilst the scattering agent and the absorbent can alter the emission intensity substantially. We corroborated that phantoms containing higher surfactant content (>0.5% Tween 20) are essential to prepare stable aqueous phantoms.


Development of membrane ion channels during neural differentiation from human embryonic stem cells.
For human embryonic stem cells (hESCs) to differentiate into neurons, enormous changes has to occur leading to trigger action potential and neurotransmitter release. We attempt to determine the changes in expression of voltage gated channels (VGCs) and their electrophysiological properties during neural differentiation. The relative expressions of α-subunit of voltage gated potassium, sodium and calcium channels were characterized by qRT-PCR technique. Patch clamp recording was performed to characterize the electrophysiological properties of hESCs during their differentiation into neuron-like cells. Relative expression of α-subunit of channels changed significantly. 4-AP and TEA sensitive outward currents were observed in all stages, although TEA sensitive currents were recorded once in rosette structure. Nifedipine and QX314 sensitive inward currents were recorded only in neuron-like cells. K+ currents were recorded in hESCs and rosette structure cells. Inward currents, sensitive to Nifedipine and QX314, were recorded in neuron-like cells.


Why two endothelins and two receptors for ovulation and luteal regulation?
The ovary is a dynamic organ that undergoes cyclic structural and functional changes. Structurally, the internal architecture of the ovary constantly changes as follicles grow, rupture and transform into corpora lutea in a cyclical manner. Functionally, a variety of regulatory ovarian hormones are sequentially produced, and eggs are periodically released. As a highly vascularized organ, the ovarian structures and functions change in response to external stimuli that include but are not limited to pituitary gonadotropins. Following stimulation, the ovary synthesizes and releases autocrine and paracrine signals that play unique roles in regulating its function. Recent studies have identified endothelins as local regulators in the ovary that modulate multiple cyclic events, such as follicle growth, steroidogenesis, oocyte maturation, ovulation, corpus luteum formation and luteolysis. Interestingly, in all mammalian species examined to date, a common observation has been made: the ovary produces two pharmacologically similar endothelins (ET-1 and ET-2) but expresses two functionally different endothelin receptors (ET(A) and ET(B)) that often give rise to opposite physiological outcomes following activation by an endothelin. In this review, the physiological significance of the presence of the two ligand-two receptor endothelin system in the ovary will be discussed.


The Protective Effects of Epigallocatechin Gallate Against Distant Organ Damage After Severe Skin Burns--Experimental Study Using a Rat Model of Thermal Trauma.
Epigallocatechin gallate (EGCG), a green tea polyphenol, has potent antioxidant properties. The purpose of the present study was to examine the possible preventative effects of EGCG against internal organ injury due to large-surface skin burns in a rat model. The study design involved three groups of rats: a sham group and two groups with 25-30% full-thickness burns: (a) the sham group without burns or treatment (n=18); (b) the control burn group (burns+sterile saline, n=18); and (c) the burn treatment group (burns+treatment with EGCG, n=18). EGCG was administered intraperitoneally immediately after the thermal injury, and daily in 100 μmol/kg doses. Kidney and lung tissue samples were taken to determine the levels of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), and glutathione peroxidase (GPX) after the first, third and seventh post-burn days. In the EGCG-treated burn group, SOD and GPX activity were significantly higher than in the burn control group. Additionally, MDA and TNF-α levels were significantly lower in the EGCG-treated burn group. Based on this study, it might be anticipated that EGCG treatment may be beneficial in burn injury cases.


Quantitative risk assessment of Cryptosporidium species infection in dairy calves.
Cryptosporidium parvum is a zoonotic protozoan that infects many different mammals including cattle and humans. Cryptosporidiosis has become a concern for dairy producers because of the direct losses due to calves not performing well and the potential for environmental contamination with C. parvum. Identifying modifiable control points in the dynamics of infection in dairy herds will help identify management strategies that mitigate its risk. The quantitative risk assessment approach provides estimates of the risk associated with these factors so that cost-effective strategies can be implemented. Using published data from epidemiologic studies and a stochastic approach, we modeled the risk that C. parvum presents to dairy calves in 2 geographic areas: 1) the New York City Watershed (NYCW) in southeastern New York, and 2) the entire United States. The approach focused on 2 possible areas of exposure--the rearing environment and the maternity environment. In addition, we evaluated the contribution of many risk factors (e.g., age, housing, flies) to the end-state (i.e., total) risk to identify areas of intervention to decrease the risk to dairy calves. Expected risks from C. parvum in US dairy herds in rearing and maternity environments were 41.7 and 33.9%, respectively. In the NYCW, the expected risks from C. parvum in the rearing and maternity environments were 0.36 and 0.33%, respectively. In the US scenarios, the immediate environment contributed most of the risk to calves, whereas in the NYCW scenario, it was new calf infection. Therefore, within the NYCW, risk management activities may be focused on preventing new calf infections, whereas in the general US population, cleaning of calf housing would be a good choice for resource allocation. Despite the many assumptions inherent with modeling techniques, its usefulness to quantify the likelihood of risk and identify risk management areas is illustrated.


A patient with large granular lymphocytosis of unusual phenotype and polymorphic T-cell receptor beta-chain gene rearrangement.
The authors describe a patient with large granular lymphocytosis who presented with fever of unknown origin and jaundice. Immunophenotyping showed that most of the large granular lymphocytes (LGLs) were CD3-, CD16-, and NKH-1 (Leu-19)+ lymphocytes. Lymphocytosis of this subset of LGLs has not been reported. Analysis of T-cell receptor gene showed polymorphic T-cell receptor beta-chain (TCR beta) gene configuration. Functional studies showed reduced natural killer cell function. The clinical course was very aggressive and resistant to chemotherapy. These features again raise the controversial issues of the ontogeny and heterogeneity of LGLs and their relationship to natural killer cells and T-cells.


Nintedanib for Advanced Epithelial Ovarian Cancer: A Change of Perspective? Summary of Evidence from a Systematic Review.
Epithelial ovarian cancer (EOC) is the sixth most commonly diagnosed cancer among women. Results with available therapies are far from being satisfactory and, therefore, current research is focusing on new anticancer drugs to improve the clinical response of these patients. Nintedanib is an oral multiple tyrosine kinases inhibitor, which targets angiogenesis. Considering the current scenario, the aim of this systematic review is to highlight the prevailing knowledge about pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of Nintedanib for the treatment of advanced EOC. We performed a systematic review of the literature, screening all available articles about the treatment of advanced EOC with Nintedanib, including phase I, II, and III trials. Although in early phase clinical trials, Nintedanib has demonstrated anticancer activity and tolerability as monotherapy or in combination with carboplatin and paclitaxel. In the phase III trial AGO-OVAR 12, it obtained a modest improvement in progression-free survival (PFS) as first-line combination therapy for patients with advanced EOC. Interestingly, a PFS increase was observed in patients with non-high progression risk or low tumor burden. Despite the promising results, further studies are needed to evaluate Nintedanib efficacy in women affected by EOC.


Association of coronary calcification with obstructive disease in coronary arteries in Indian patients.
A total of 1150 consecutive patients (1052 males and 98 females; age 51.2 +/- 10.1 years) with suspected coronary artery disease (Group I) were subjected to fluoroscopy for detection of coronary artery calcification (CAC) and coronary angiography. Another group (Group II) of 120 patients (95 males and 25 females; age 51.4 +/- 9.4 years) catheterized for cardiac diseases other than coronary artery disease (CAD) were subjected to the same protocol of fluoroscopy and coronary angiography to exclude incidental CAD in view of their age. CAC was present in 240 patients (20.0%) in Group I. Of these, 200 (83.4%) had triple-vessel disease (TVD); 20 (8.3%) had double-vessel disease (DVD); 19 (7.9%) had single-vessel disease (SVD); and 37 (15.4%) patients had left main coronary disease (LMCAD). Only one of these patients had insignificant CAD considered as "normal" coronary arteries (NC). Incidence of LMCAD, TVD, DVD, SVD, and NC in patients without CAC was 4.4%, 56.3%, 18.2%, 14.0%, and 11.5%, respectively. Incidence of CAC in patients with LMCAD, TVD, DVD, SVD, and NC was 48.1%, 28.1%, 10.8%, 13.0%, and 1.0% respectively. In Group II (n = 120), 24 patients (20%) had CAD, CAC was present in 5 patients with CAD (20.9%), and in two patients without CAD (2%). CAC is relatively uncommon in Indian CAD patients. Its presence, however, indicates severe multivessel disease.


Structural Optimization of BIPPO Analogs as Potent Antimalarials.
Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC50 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC50 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC50 > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies.


Evidences of Conformal Invariance in 2D Rigidity Percolation.
The rigidity transition occurs when, as the density of microscopic components is increased, a disordered medium becomes able to transmit and ensure macroscopic mechanical stability, owing to the appearance of a space-spanning rigid connected component, or cluster. As a second-order phase transition it exhibits a scale invariant critical point, at which the rigid clusters are random fractals. We show, using numerical analysis, that these clusters are also conformally invariant, and we use conformal field theory to predict the form of universal finite-size effects. Furthermore, although connectivity and rigidity percolation are usually thought to be of fundamentally different natures, we provide evidence of unexpected similarities between the statistical properties of their random clusters at criticality. Our work opens a new research avenue through the application of the powerful 2D conformal field theory tools to understand the critical behavior of a wide range of physical and biological materials exhibiting such a mechanical transition.