Emerging strategies to target the dysfunctional cohesin complex in cancer.
Mutations in cohesin genes have been described in numerous solid cancers and hematologic malignancies; subsequent experimental evidence has linked these mutations with carcinogenesis. Areas covered: In this review, we present current information about the physiological role of the cohesin complex in normal and malignant cells and describe current therapeutic strategies that are being explored in cohesin-mutated cancers. We discuss a range of targets and strategies that should be explored to develop targeted therapies for patients with aberrant cohesin. Expert opinion: Targeting of the cohesin complex is an underexplored area of drug development. There is a high frequency of cohesin mutations in multiple cancers, hence specific targeting strategies should be explored. Cohesins play a crucial role in cellular organization; therefore, we expect a narrow therapeutic window of direct inhibitors of cohesin components. Exploiting experimental approaches that correct dysfunctional cohesins and coupling them with current therapeutic strategies can provide novel, innovative and more effective treatment regimens.


[Elderly caregiver: the knowledge available in LILACS database].
This study aimed at analyzing the scientific production about the elderly assistance. Bibliographic review was utilized as a methodological approach based on 2000-2007 LILACS data base. Sixty-four abstracts of the articles were analyzed and categorized per year of publication of the scenery and the methodology and theme presented. As a result, it was noticed that in 2004 there was the largest number of publications, prevailingly in the Southeast of Brazil. As to the scenery, the prevalence of choice was the domicile and the methodological approach was that of qualitative type with the themes grouped into four areas, as follows: institutionalized elderly care, the family and the elderly care, care in its ethical implications, elderly people and nursing care.


Endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitors.
The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, time-dependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.


[Autoantibodies to nerve growth factor and astroglial protein S-100 in Rett's syndrome].
The levels of autoantibodies (AAB) to nerve growth factor (NGF) and to S-100 protein were examined in blood of both mentally normal girls and girls with Rett's syndrome (RS). The elevated titer of anti-NGF AAB, but not of anti-S-100 AAB was determined in the blood of patients with RS. There was relative individual stability of anti-NGF AAB level which didn't depend on the stage of the disease. At the same time, a reverse correlation was found between the level of these antibodies and severity of the disease: the mild form of the disease (with relative preservation of the speech elements and locomotor functions as well as with the later age of the onset of the disease and the later development of the regressive symptoms) is characterized by the higher AAB level. Autoimmune processes role (anti-NGF AAB) in formation of RS clinical features is discussed.


Lipoprotein Subclasses Associated With High-Risk Coronary Atherosclerotic Plaque: Insights From the PROMISE Clinical Trial.
BACKGROUND More than half of major adverse cardiovascular events (MACE) occur in the absence of obstructive coronary artery disease and are often attributed to the rupture of high-risk coronary atherosclerotic plaque (HRP). Blood-based biomarkers that associate with imaging-defined HRP and predict MACE are lacking. METHODS AND RESULTS Nuclear magnetic resonance-based lipoprotein particle profiling was performed in the biomarker substudy of the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial (N=4019) in participants who had stable symptoms suspicious for coronary artery disease. Principal components analysis was used to reduce the number of correlated lipoproteins into uncorrelated lipoprotein factors. The association of lipoprotein factors and individual lipoproteins of significantly associated factors with core laboratory determined coronary computed tomographic angiography features of HRP was determined using logistic regression models. The association of HRP-associated lipoproteins with MACE was assessed in the PROMISE trial and validated in an independent coronary angiography biorepository (CATHGEN [Catheterization Genetics]) using Cox proportional hazards models. Lipoprotein factors composed of high-density lipoprotein (HDL) subclasses were associated with HRP. In these factors, large HDL (odds ratio [OR], 0.70 [95% CI, 0.56-0.85]; P<0.001) and medium HDL (OR, 0.84 [95% CI, 0.72-0.98]; P=0.028) and HDL size (OR, 0.82 [95% CI, 0.69-0.96]; P=0.018) were associated with HRP in multivariable models. Medium HDL was associated with MACE in PROMISE (hazard ratio [HR], 0.76 [95% CI, 0.63-0.92]; P=0.004), which was validated in the CATHGEN biorepository (HR, 0.91 [95% CI, 0.88-0.94]; P<0.001). CONCLUSIONS Large and medium HDL subclasses and HDL size inversely associate with HRP features, and medium HDL subclasses inversely associate with MACE in PROMISE trial participants. These findings may aid in the risk stratification of individuals with chest pain and provide insight into the pathobiology of HRP. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT01174550.


The Art of Electrosurgery: Trainees and Experts.
The benefits of electrosurgery have been acknowledged since the early 1920s, and nowadays more than 80% of surgical procedures involve devices that apply energy to tissues. Despite its widespread use, it is currently unknown how the operator's choices with regard to instrument selection and application technique are related to complications. As such, the manner in which electrosurgery is applied can have a serious influence on the outcome of the procedure and the well-being of patients. The aim of this study is to investigate the variety of differences in usage of electrosurgical devices. Our approach is to measure these parameters to provide insight into application techniques. A sensor was developed that records the magnitude of electric current delivered to an electrosurgical device at a frequency of 10 Hz. The sensor is able to detect device activation times and a reliable estimate of the power-level settings. Data were recorded for 91 laparoscopic cholecystectomies performed by different surgeons and residents. Results of the current measurement data show differences in the way electrosurgery is applied by surgeons and residents during a laparoscopic cholecystectomy. Variations are seen in the number of activations, the activation time, and the approach for removal of the gallbladder. Analysis showed that experienced surgeons have a longer activation time than residents (3.01 vs 1.41 seconds, P < .001) and a lower number of activations (102 vs 123). This method offers the opportunity to relate application techniques to clinical outcome and to provide input for the development of a best practice model.


Aspirin in the prevention and treatment of venous thromboembolism.
This review summarizes available evidence on effects of aspirin on incidence and outcomes of venous thromboembolism (VTE). From a pathophysiological point of view, inhibition of platelet aggregation is associated with an impaired thrombus formation both in an experimental model of venous thrombosis and in vivo. Epidemiological evidence in support of a beneficial effect of acetylsalicylic acid on VTE incidence is provided by the Antiplatelet Trialists' Collaboration meta-analysis of studies on the use of antiplatelet agents in cardiovascular risk reduction, showing a significant 25% risk reduction of pulmonary embolism. Moreover, a meta-analysis on older trials of antiplatelet agents in postsurgical VTE prevention and the large Pulmonary Embolism Prevention trial demonstrate a protective effect of the same magnitude: 25-30%. However, as low-molecular-weight heparins (LMWH) and vitamin K antagonists (VKA) have shown a superior efficacy and safety profile, and no direct comparisons have been made between aspirin, LMWH and VKA in prolonged use, the most recent guidelines advise against aspirin monotherapy for thromboprophylaxis in the surgical patient. Currently, there is no evidence to support a role for aspirin in air travel-related VTE. Regarding prevention of recurrent VTE, studies are ongoing to determine the potential role of aspirin after a first unprovoked VTE.


Familial diarrhea syndrome caused by an activating GUCY2C mutation.
Familial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis. We used linkage analysis, based on arrays with single-nucleotide polymorphisms, to identify a candidate region on chromosome 12 and then sequenced GUCY2C, encoding guanylate cyclase C (GC-C), an intestinal receptor for bacterial heat-stable enterotoxins. We performed exome sequencing of the entire candidate region from three affected family members, to exclude the possibility that mutations in genes other than GUCY2C could cause or contribute to susceptibility to the disease. We carried out functional studies of mutant GC-C using HEK293T cells. We identified a heterozygous missense mutation (c.2519G→T) in GUCY2C in all affected family members and observed no other rare variants in the exons of genes in the candidate region. Exposure of the mutant receptor to its ligands resulted in markedly increased production of cyclic guanosine monophosphate (cGMP). This may cause hyperactivation of the cystic fibrosis transmembrane regulator (CFTR), leading to increased chloride and water secretion from the enterocytes, and may thus explain the chronic diarrhea in the affected family members. Increased GC-C signaling disturbs normal bowel function and appears to have a proinflammatory effect, either through increased chloride secretion or additional effects of elevated cellular cGMP. Further investigation of the relevance of genetic variants affecting the GC-C-CFTR pathway to conditions such as Crohn's disease is warranted. (Funded by Helse Vest [Western Norway Regional Health Authority] and the Department of Science and Technology, Government of India.).


Patients with End-Stage Renal Disease and Acute Surgical Abdomen: Opportunities for Palliative Care.
Background: End-stage renal disease (ESRD) is a life-limiting condition that is often complicated by acute abdominal emergency. Palliative care (PC) has been shown to improve the quality of life in patients with serious illness and yet is underutilized. We hypothesize that ESRD patients with abdominal emergency have high unmet PC needs. Objective: To characterize the outcomes of ESRD patients with acute surgical abdomen, define PC utilization patterns, and identify areas of unmet PC needs. Design: Retrospective study querying the National Inpatient Sample database (2009-2013). Setting and Subjects: Subjects were identified using ICD-9 codes for those aged ≥50 with preexisting diagnosis of ESRD with an acute abdominal emergency diagnosis of gastrointestinal perforation, obstruction, or ischemia. Measurements: Outcomes included PC rate, in-hospital mortality, discharge disposition, and intensity of care. Multivariable logistic regression analysis was used to identify predictors of PC. Results: A total of 9363 patients met the inclusion criteria; 24% underwent surgery, 16% died in hospital, and 43% were discharged to dependent living. Among in-hospital deaths, 23% received PC. Only 4% of survivors with dependent discharge received PC. Surgical mortality was 26%. PC was less utilized in surgical patients than nonsurgical patients. PC was associated with shorter hospital stay. Predictors of PC included increasing age, severity of underlying illness, white race, teaching hospitals, and the Western region. Conclusions: Patients with ESRD admitted for acute abdominal emergency have high risk for mortality and functional dependence. Despite this, few receive PC and have a high utilization of nonbeneficial life support at the end of life.


Characterisation of mineralogical forms of barium and trace heavy metal impurities in commercial barytes by EPMA, XRD and ICP-MS.
This study was carried out to characterise the mineralogical forms of barium and the trace heavy metal impurities in commercial barytes of different origins using electron probe microanalysis (EPMA), X-ray diffraction (XRD) and inductively coupled plasma mass spectrometry (ICP-MS). Qualitative EPMA results show the presence of typically eight different minerals in commercial barytes including barite (BaSO4), barium feldspar, galena (PbS), pyrite (FeS2), sphalerite (ZnS), quartz (SiO2), and silicates, etc. Quantitative EPMA confirms that the barite crystals in the barytes contain some strontium and a little calcium, whereas trace heavy metals occur in the associated minerals. Analysis of aqua regia extracts of barytes samples by ICP-MS has shown the presence of a large number of elements in the associated minerals. Arsenic, copper and zinc concentrations correlate closely in all 10 samples. The findings suggest that barytes is not, as traditionally thought, an inert mineral, but is a potentially toxic substance due to its associated heavy metal impurities, which can be determined by an aqua regia digest without the need for complete dissolution of the barite itself. X-ray powder diffraction was not informative as the complex barite pattern masks the very weak lines from the small amounts of associated minerals.


Ribosome-catalyzed formation of an abnormal peptide analogue.
The peptidyl-tRNA analogue N-(chloroacetyl)phenylalanyl-tRNAPhe was prepared by chemical aminoacylation and prebound to the P site of Escherichia coli ribosomes in response to poly(uridylic acid). Admixture of phenylalanyl-tRNAPhe to the A site resulted in the formation of two "dipeptides", one of which was formed by displacement of chloride ion from the peptidyl-tRNA. This constitutes the first example of ribosome-mediated formation of a peptide of altered connectivity and suggests a need for revision of the current model of peptide bond formation. Also suggested by the present finding is the feasibility of utilizing tRNAs to prepare polypeptides of altered connectivity in an in vitro protein biosynthesizing system.


The study of polythiophene/water interfaces by sum-frequency generation spectroscopy and molecular dynamics simulations.
Semiconducting polymer/water interfaces are gaining increasing attention due to a variety of promising applications in the fields of biology and electrochemistry, such as electrochemically-gated transistors and photodetectors, which have been used for biosensing and neuroscience applications. However, a detailed characterization of the polymer surface in the presence of an aqueous environment is still lacking. In this work, we employed sum-frequency generation vibrational spectroscopy, a surface-specific technique compatible with electrochemical/biological conditions, to demonstrate that the surface of thin films of regio-regular poly-3-hexylthiophene (rr-P3HT) undergoes a molecular reorientation when exposed to aqueous electrolytes, with respect to their surface structure in air. Experimental results are corroborated by molecular dynamics simulations. Since surface molecular orientation is believed to play a fundamental role in electrochemical and environmental stability of conjugated polymers, the reported findings not only contribute to the fundamental understanding of conjugated polymer/water interfaces, but they may also have implications in the design of conjugated polymers for enhancing their performance in electrolytic environments.


Molecular-dynamics simulations with explicit hydrodynamics I: on the friction coefficients of deformed polymers.
We implement large-scale Molecular-Dynamics (MD) simulations which incorporate hydrodynamic interactions via the inclusion of explicit Lennard-Jones solvent to examine the behaviour of polymer chains in sieving media. We begin by examining the friction coefficients of polymers in long-lived states responsible for inducing length-dependent mobility, i.e., allowing separation of polymers (or polyelectrolytes) by molecular weight. In particular, the conformations we examine occur in devices which utilize arrays of molecular obstacles or dilute solutions of polymers. We compare the results from our MD simulations with expressions from macroscopic hydrodynamics for four specific cases: i) a random coil excluded-volume Zimm polymer, ii) a rigid polymer moving perpendicular to its major axis iii) a rigid polymer moving parallel to its major axis and iv) a rigid polymer, folded at different points along its contour. We also examine the behaviour of the friction coefficient of a fully flexible molecule pulled by its middle monomer as a function of an applied force F and show that there are several distinct frictional regimes.


Is there a neighborhood frequency effect in English? Evidence from reading and lexical decision.
What is the effect of a word's higher frequency neighbors on its identification time? According to activation-based models of word identification (J. Grainger & A. M. Jacobs, 1996; J. L. McClelland & D. E. Rumelhart, 1981), words with higher frequency neighbors will be processed more slowly than words without higher frequency neighbors because of the lexical competition mechanism embodied in these models. Although a critical prediction of these models, this inhibitory neighborhood frequency effect has been elusive in studies that have used English stimuli. In the present experiments, the effect of higher frequency neighbors was examined in the lexical decision task and when participants were reading sentences while their eye movements were monitored. Results suggest that higher frequency neighbors have little, if any, effect on the identification of English words. The implications for activation-based models of word identification are discussed.


Understanding organisational development, sustainability, and diffusion of innovations within hospitals participating in a multilevel quality collaborative.
Between 2004 and 2008, 24 Dutch hospitals participated in a two-year multilevel quality collaborative (MQC) comprised of (a) a leadership programme for hospital executives, (b) six quality-improvement collaboratives (QICs) for healthcare professionals and other staff, and (c) an internal programme organisation to help senior management monitor and coordinate team progress. The MQC aimed to stimulate the development of quality-management systems and the spread of methods to improve patient safety and logistics. The objective of this study is to describe how the first group of eight MQC hospitals sustained and disseminated improvements made and the quality methods used. The approach followed by the hospitals was described using interview and questionnaire data gathered from eight programme coordinators. MQC hospitals followed a systematic strategy of diffusion and sustainability. Hospital quality-management systems are further developed according to a model linking plan-do-study-act cycles at the unit and hospital level. The model involves quality norms based on realised successes, performance agreements with unit heads, organisational support, monitoring, and quarterly accountability reports. It is concluded from this study that the MQC contributed to organisational development and dissemination within participating hospitals. Organisational learning effects were demonstrated. System changes affect the context factors in the theory of organisational readiness: organisational culture, policies and procedures, past experience, organisational resources, and organisational structure. Programme coordinator responses indicate that these factors are utilised to manage spread and sustainability. Further research is needed to assess long-term effects.


[Study on quantitative analysis with near-infrared spectra using latent root regression model].
The latent root regression model with near-infrared spectra of 40 soybean samples was founded for analyzing the content of soybean protein in this study. The contents of protein in another 32 soybean samples were predicted by this model. The predicting results were compared with PLS, which shows that the latent root regression model can practically be used for the quantitative analysis of the biological samples with near-infrared spectra. This method is a new kind of chemometrics calibration method, which is modified from PCR. Because the method takes the role of sample composition into account when extracting the principal component from the NIR spectra of samples, the model has a good result in analyzing samples. Further more, the results showed that it is necessary to take account of the role of sample composition when building quantitative analysis model using NIR spectra.


Alpha 2 macroglobulin of the rat, an acute phase protein, mitigates the early course of endotoxin shock.
Normal rats and rats with high levels of alpha 2 macrofetoprotein (alpha M FP), an acute phase globulin induced by pretreatment with BaSO4 i.p., were injected with sublethal doses of endotoxin. One hour survival was better in the group with high levels of alpha M FP (36%) than in controls (9%). All rats receiving purified alpha M FP i.p. survived. Recovery of mean arterial blood pressure, expressed as the surface area under the curve, was significantly better in the groups with high alpha M FP levels. Leakage of i.v. administered human albumin was the same in control and BaSO4 pretreated rats. BaSO4 induces peritonitis which could explain the albumin leakage. Experiments were repeated therefore in rats pretreated with adrenaline which also initiates the production of alpha M FP. In this group, I h survival after endotoxin administration was 100% and albumin leakage was significantly less than in rats receiving either endotoxin only or BaSO4-pretreatment. In early endotoxin shock prostaglandins, including PGE2 a potent vasodilatator, are released into the circulation. From previous data it is known that alpha M FP prevents the vasodilatation and increased vascular permeability caused by PGE2. Rats with high levels of alpha M FP had a smaller fall in diastolic blood pressure after PGE2 administration than did controls with normal alpha M FP levels. The effects of alpha M FP on the haemodynamic events in early endotoxin shock could well be due to inhibition of PGE2 activity.


Salmonella enterica serovar Typhi possesses a unique repertoire of fimbrial gene sequences.
Salmonella enterica serotype Typhi differs from nontyphoidal Salmonella serotypes by its strict host adaptation to humans and higher primates. Since fimbriae have been implicated in host adaptation, we investigated whether the serotype Typhi genome contains fimbrial operons which are unique to this pathogen or restricted to typhoidal Salmonella serotypes. This study established for the first time the total number of fimbrial operons present in an individual Salmonella serotype. The serotype Typhi CT18 genome, which has been sequenced by the Typhi Sequencing Group at the Sanger Centre, contained a type IV fimbrial operon, an orthologue of the agf operon, and 12 putative fimbrial operons of the chaperone-usher assembly class. In addition to sef, fim, saf, and tcf, which had been described previously in serotype Typhi, we identified eight new putative chaperone-usher-dependent fimbrial operons, which were termed bcf, sta, stb, ste, std, stc, stg, and sth. Hybridization analysis performed with 16 strains of Salmonella reference collection C and 22 strains of Salmonella reference collection B showed that all eight putative fimbrial operons of serotype Typhi were also present in a number of nontyphoidal Salmonella serotypes. Thus, a simple correlation between host range and the presence of a single fimbrial operon seems at present unlikely. However, the serotype Typhi genome differed from that of all other Salmonella serotypes investigated in that it contained a unique combination of putative fimbrial operons.


Diversity of intratumoral regulatory T cells in B-cell non-Hodgkin lymphoma.
Tumor-infiltrating regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. Despite extensive studies, the prognostic impact of tumor-infiltrating Tregs in B-cell non-Hodgkin lymphomas (B-NHLs) remains unclear. Emerging studies suggest substantial heterogeneity in the phenotypes and suppressive capacities of Tregs, emphasizing the importance of understanding Treg diversity and the need for additional markers to identify highly suppressive Tregs. Here, we applied single-cell RNA sequencing and T-cell receptor sequencing combined with high-dimensional cytometry to decipher the heterogeneity of intratumoral Tregs in diffuse large B-cell lymphoma and follicular lymphoma (FL), compared with that in nonmalignant tonsillar tissue. We identified 3 distinct transcriptional states of Tregs: resting, activated, and unconventional LAG3+FOXP3- Tregs. Activated Tregs were enriched in B-NHL tumors, coexpressed several checkpoint receptors, and had stronger immunosuppressive activity compared with resting Tregs. In FL, activated Tregs were found in closer proximity to CD4+ and CD8+ T cells than other cell types. Furthermore, we used a computational approach to develop unique gene signature matrices, which were used to enumerate each Treg subset in cohorts with bulk gene expression data. In 2 independent FL cohorts, activated Tregs was the major subset, and high abundance was associated with adverse outcome. This study demonstrates that Tregs infiltrating B-NHL tumors are transcriptionally and functionally diverse. Highly immunosuppressive activated Tregs were enriched in tumor tissue but absent in the peripheral blood. Our data suggest that a deeper understanding of Treg heterogeneity in B-NHL could open new paths for rational drug design, facilitating selective targeting to improve antitumor immunity.


Fabrication of hexagonal compound eye microlens array using DMD-based lithography with dose modulation.
In this study, a method is proposed for the rapid fabrication of a hexagonal compound eye microlens array (HCE-MLA) using maskless lithography technique based on digital micromirror device (DMD), in which a hexahedron array is lithographed, and subsequently, a microlens structure is lithographed layer by layer upon the hexahedron. Owing to the high filling rate of the hexagon and the aspheric surface of the paraboloid profile of the microlens, after the distribution of the required exposure dose of HCE-MLA was calculated based on dose modulation, a series of circular pattern with different radius could be obtained by equal-arc-mean slicing strategy that can adapt to the variable curvature of the target contour and improve its reconstruction precision. Then, after a hexagonal photoresist island was fabricated on the substrate, and the dose accumulated over multiple exposures, the required exposure dose profiles were reconstructed on the hexagonal photoresist island. Finally, a high-quality HCE-MLA with a smooth surface was fabricated via thermal reflow. The fabrication of the designed HCE-MLA using this method was demonstrated in experiments. The results indicate that the actual profile of HCE-MLA shows good agreement with the design profile and that simultaneously increasing the number of the slicing layers can improve the quality of the profile. The research indicated that this method is feasible and convenient for the fabrication of high-quality HCE-MLA.


Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial.
Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity. Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338). Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85). The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points. Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide. Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks. ClinicalTrials.gov Identifier: NCT04074161.


A new tumor model for angiographic investigations: feline sarcoma virus tumor induction in adult cats.
This article describes the first successful virus induction of sarcomas in adult immunosuppressed cats. The method of tumor induction, the immunosuppression regimen, and the gross, histologic, and angiographic findings in these induced sarcomas are described. The simplicity of the model, the rapid and reliable growth of the tumors, and the size of the animals permit repeated angiography. The model is well suited to studies of angiographically directed therapy with embolic agents, radioactive implants, or chemotherapeutic drugs. The use of a feline model permits repeated selective angiography, which is not the case with small laboratory animals, in which such studies are difficult. In this investigation, tumors were induced into the right hepatic lobe because of the relative homogeneity of peripheral hepatic vascularity and the ease with which early neoplastic changes can be detected. There is good evidence to indicate that virus induction sites in other organs would also be successful.


Falls and comorbid conditions among community dwelling Arkansas older adults from a population-based survey.
The prevalence of self-reported falls and associated comorbid conditions among community dwelling Arkansas older adults (ages 65 years and older) was estimated using data from the 2010 Behavioral Risk Factor Surveillance System survey. 1,653 Arkansas older adults were surveyed. Eighteen percent of them had sustained a fall at least once in the past three months prior to the survey period. After adjusting for age, general health, coronary heart disease, diabetes status and quality rest or sleep in a multinomial logistic regression, we found that older adults with visual impairment (OR = 1.47; 95% CI: 1.02, 2.12), and those who use special equipment (OR = 2.85; 95% CI: 1.94, 4.19) were more likely to have sustained a fall. An integrated multidisciplinary approach in caring for older adults is imperative for preventing falls and fall-related injuries. This can also reduce-fall-related hospitalizations and potentially result in substantial cost savings as well as improve the quality of life of older Arkansans.


Extracellular matrix of glioblastoma inhibits polarization and transmigration of T cells: the role of tenascin-C in immune suppression.
Dense accumulations of T cells are often found in peritumoral areas, which reduce the efficiency of contact-dependent lysis of tumor cells. We demonstrate in this study that the extracellular matrix (ECM) produced by tumors can directly regulate T cell migration. The transmigration rate of several T cells including peripheral blood primary T cell, Jurkat, and Molt-4 measured for glioma cells or glioma ECM was consistently low. Jurkat cells showed reduced amoeba-like shape formation and delayed ERK activation when they were in contact with monolayers or ECM of glioma cells as compared with those in contact with HepG2 and MCF-7 cells. Phospho-ERK was located at the leading edge of migrating Jurkat cells. Glioma cells, but not MCF-7 and HepG2 cells, expressed tenascin-C. Knocking down the tenascin-C gene using the short hairpin RNA strategy converted glioma cells to a transmigration-permissive phenotype for Jurkat cells regarding ERK activation, transmigration, and amoeba-like shape formation. In addition, exogenous tenascin-C protein reduced the amoeba-like shape formation and transmigration of Jurkat cells through MCF-7 and HepG2 cell monolayers. A high level of tenascin-C was visualized immunohistochemically in glioma tumor tissues. CD3(+) T cells were detected in the boundary tumor area and stained strongly positive for tenascin-C. In summary, glioma cells can actively paralyze T cell migration by the expression of tenascin-C, representing a novel immune suppressive mechanism achieved through tumor ECM.


Antitumor activity of gemcitabine can be potentiated in pancreatic cancer through modulation of TLR4/NF-κB signaling by 6-shogaol.
Advanced pancreatic cancer still has a poor prognosis, even with the approval of several drugs, such as gemcitabine. Therefore, developing effective and safe antitumor agents is urgently needed. 6-Shogaol, a phenol extracted from ginger, has been linked to suppression of proliferation and survival of cancer with different mechanisms. In the present study, we investigated whether 6-shogaol could suppress pancreatic cancer progress and potentiate pancreatic cancer to gemcitabine treatment in vitro and in vivo. We found that 6-shogaol prevented the activation of toll like receptor 4 (TLR4)/NF-κB signaling. The modulation of NF-κB signaling by 6-shogaol was ascertained by electrophoretic mobility shift assay and western blot analysis. The suppression of NF-κB signaling and key cell survival regulators including COX-2, cyclinD1, survivin, cIAP-1, XIAP, Bcl-2, and MMP-9 brought the anti-proliferation effects in pancreatic cancer cells and sensitized them to gemcitabine treatment. Furthermore, in a pancreatic cancer xenograft model, we found a decreased proliferation index (Ki-67) and increased apoptosis by TUNEL staining in 6-shogaol treated tumors. It was also shown that 6-shogaol combined with gemcitabine treatment was more effective than drug alone, consistent with the downregulation of NF-κB activity along with its target genes COX-2, cyclinD1, survivin, cIAP-1, and XIAP. Overall, our results suggest that 6-shogaol can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing of TLR4/NF-κB-mediated inflammatory pathways linked to tumorigenesis.


The effect of urinary diversion on long-term kidney function after cystectomy.
Cystectomy with urinary diversion is associated with decreased long-term kidney function due to several factors. One factor that has been debated is the type of urinary diversion used: ileal conduit (IC) vs. neobladder (NB). We tested the hypothesis that long-term kidney function will not vary by type of urinary diversion. We retrospectively identified all patients who underwent cystectomy with urinary diversion at our institution from January 1, 2007, to January 1, 2018. Data were collected on patient demographics, comorbid conditions, perioperative radiotherapy, and complications. Creatinine values were measured at several time points up to 120 months after surgery. Glomerular filtration rate (GFR) (ml/min per 1.73 m2) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. A linear mixed model with inverse probability of treatment weighting (IPTW) was used to compare GFR between the IC and NB cohorts over time. Multiple sensitivity analyses were performed based on 2 different calculations of GFR (Chronic Kidney Disease Epidemiology Collaboration equation vs. Modification of Diet in Renal Disease), with and without excluding patients with preoperative GFR less than 40 ml/min per 1.73 m2. Among 563 patients who underwent cystectomy with urinary diversion, a NB was used for 72 (12.8%) individuals. Patients who had a NB were significantly younger, had a lower American Society of Anesthesiologists score, greater baseline GFR, better Eastern Cooperative Oncology Group performance status, lower median Charlson comorbidity index, and were less likely to have received preoperative abdominal radiation (all P < 0.05). Both NB and IC patients had decreased kidney function over time, with mean GFR losses at 5 years of 17% and 14% of baseline values, respectively. The IPTW-adjusted linear mixed model revealed that IC patients had slightly more deterioration in kidney function over time, but this was not statistically significant (estimate, 0.12; P = 0.06). The sensitivity analyses yielded a similar trend, in that GFR decrease appeared to be greater in the IC cohort. This trend was statistically significant when using Modification of Diet in Renal Disease (P = 0.04). Among highly selected patients with an NB, deterioration of kidney function may potentially be lower over time than among IC patients. However, the statistical significance varied between analyses and we cautiously attribute these observed differences to patient selection.


Kinetics of electrophysiologic changes during oral loading of amiodarone and after withdrawal of amiodarone in the unsedated dog.
We examined the temporal kinetics of onset and offset of the cardiac electrophysiologic effects of orally administered amiodarone in chronically instrumented, unsedated adult dogs (n = 8). Right atrial (RA), atrioventricular nodal (AVN), and right ventricular (RV) effective refractory period (ERP), and AVN functional refractory period (FRP), were determined daily for 21 days during amiodarone loading (24 mg/kg/day) and for 21 days after cessation of amiodarone. Left ventricular (LV) ERP was assessed in four of eight animals. Group mean RA-ERP peaked and plateaued early during amiodarone loading (time to reach one-half observed peak change [t1/2 onset] = 1.2 +/- 0.5 days) and rapidly returned toward baseline after cessation of drug (decay time to one-half peak value [t1/2 offset] = 2.0 +/- 1.7 days). Group mean RV-ERP rose in a linear manner throughout the loading period (t1/2 onset = 9.3 +/- 2.1 days) and remained elevated after cessation of drug (t1/2 offset greater than 21.0 days). Group mean AVN-ERP and FRP exhibited temporal kinetics intermediate between those of the RA-ERP and RV-ERP, both during amiodarone loading and after cessation of the drug. Group mean LV-ERP onset kinetics (assessed in a limited number of animals, n = 4) appeared to differ from RV-ERP onset kinetics (t1/2 onset = 2.5 +/- 2.5 days), whereas LV-ERP and RV-ERP offset kinetics appeared similar (t1/2 offset greater than 21 days). In summary, our findings demonstrate that during oral loading, the temporal sequence of onset of amiodarone-induced electrophysiologic effects is site dependent. Similarly, after cessation of amiodarone, the persistence of drug-induced electrophysiologic effects is both variable and site dependent.


Use of nitrogen from ammoniated alfalfa hay, urea, soybean meal, and animal protein meal by lactating cows.
Midbloom alfalfa hay was baled (16% moisture) and treated with approximately 2% anhydrous NH3 (percentage of DM). Concentrations (percentage of DM) of total N (4.7% vs. 3.4%), NPN (1.3% vs. 0.4%), soluble N (14.8% vs. 8.2%), RUP (6.3% vs. 4.8%), and NDF (52.5% vs. 45.7%) were higher 3 wk after ammoniation than before treatment. Diets (15% CP) that provided 26% of total CP from N added to hay by ammoniation, urea, soybean meal, or a commercial blend of animal protein meals were fed to lactating cows. All diets provided concentrations of CP and RUP as recommended by the NRC, but diets with ammoniated hay, urea, and soybean meal provided only 70% of NRC recommendations for RUP (100% for the animal protein diet). Apparent digestibilities of DM, N, and fiber fractions were not affected by diet. Diet did not affect N balance, but cows fed the urea diet excreted more N in urine and had higher concentrations of ruminal NH3 and plasma urea than did cows fed ammoniated hay. Production (30 kg/d) and composition of milk and DMI were largely unaffected by diet. Diverse sources of dietary N did not greatly influence N utilization by dairy cows.


Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.
There is increasing evidence that impairment of mitochondrial energy metabolism plays an important role in the pathophysiology of autism spectrum disorders (ASD; OMIM number: 209850). A significant proportion of ASD cases display biochemical alterations suggestive of mitochondrial dysfunction and several studies have reported that mutations in the mitochondrial DNA (mtDNA) molecule could be involved in the disease phenotype. We analysed a cohort of 148 patients with idiopathic ASD for a number of mutations proposed in the literature as pathogenic in ASD. We also carried out a case control association study for the most common European haplogroups (hgs) and their diagnostic single nucleotide polymorphisms (SNPs) by comparing cases with 753 healthy and ethnically matched controls. We did not find statistical support for an association between mtDNA mutations or polymorphisms and ASD. Our results are compatible with the idea that mtDNA mutations are not a relevant cause of ASD and the frequent observation of concomitant mitochondrial dysfunction and ASD could be due to nuclear factors influencing mitochondrion functions or to a more complex interplay between the nucleus and the mitochondrion/mtDNA.


A food-derived synergist of NGF signaling: identification of protein tyrosine phosphatase 1B as a key regulator of NGF receptor-initiated signal transduction.
Neurotrophins, such as the nerve growth factor (NGF), play an essential role in the growth, development, survival and functional maintenance of neurons in the central and peripheral systems. They also prevent neuronal cell death under various stressful conditions, such as ischemia and neurodegenerative disorders. NGF induces cell differentiation and neurite outgrowth by binding with and activating the NGF receptor tyrosine kinase followed by activation of a variety of signaling cascades. We have investigated the NGF-dependent neuritogenesis enhancer potential of a food-derived small molecule contained in Brassica vegetables and identified the protein tyrosine phosphatase (PTP) 1B as a key regulator of the NGF receptor-initiated signal transduction. Based on an extensive screening of Brassica vegetable extracts for the neuritogenic-promoting activity in the rat pheochromocytoma cell line PC12, we found the Japanese horseradish, wasabi (Wasabia japonica, syn. Eutrema wasabi), as the richest source and identified 6-methylsulfinylhexyl isothiocyanate (6-HITC), an analogue of sulforaphane isolated from broccoli, as one of the major neuritogenic enhancers in the wasabi. 6-HITC strongly enhanced the neurite outgrowth and neurofilament expression elicited by a low-concentration of NGF that alone was insufficient to induce neuronal differentiation. 6-HITC also facilitated the sustained-phosphorylation of the extracellular signal-regulated kinase and the autophosphorylation of the NGF receptor TrkA. It was found that PTP1B act as a phosphatase capable of dephosphorylating Tyr-490 of TrkA and was inactivated by 6-HITC in a redox-dependent manner. The identification of PTP1B as a regulator of NGF signaling may provide new clues about the chemoprotective potential of food components, such as isothiocyanates.


False-positive meconium test results for fatty acid ethyl esters secondary to delayed sample collection.
Meconium analysis for fatty acid ethyl esters (FAEEs) is a validated method for identifying heavy prenatal ethanol (EtOH) exposure. This study investigated whether delayed sample collection can result in false-positive test results for FAEEs because of collection of samples potentially contaminated with postnatally produced stool. Serial excretions were prospectively collected from neonates born to nondrinking mothers to capture the transition from meconium to postnatal stool. These were analyzed for FAEEs using headspace-solid phase microextraction and gas chromatography-mass spectrometry. Experiments involving incubation of samples with glucose or EtOH were performed to explore a potential mechanism of FAEE elevation. A total of 136 samples were collected from 30 neonates during their first few days of life (median of 4 samples/baby over a mean period of 68.5 hours postpartum). Although the first-collected meconium sample tested negative for FAEEs in all babies, later samples tested above the 2 nmol/g positive cutoff in 19 of 30 babies. Median time to appearance of FAEE-positive samples was 59.2 hours postpartum. In vitro experiments demonstrated that FAEE levels can be further increased in late samples (likely containing postnatal stool) after incubation with glucose, and that FAEEs are readily formed in meconium in the presence of EtOH. Collection of samples excreted later in the postpartum period can lead to false-positive test results for FAEEs, which could be because of contamination with dietary components of postnatally produced stool and EtOH-producing microorganisms. Clinically, it is critical to collect the earliest possible excretion for determination of FAEEs to ensure that the FAEE content is representative of in utero EtOH exposure.


Excimer laser refractive surgery versus phakic intraocular lenses for the correction of moderate to high myopia.
Myopia is a condition in which the focusing power (refraction) of the eye is greater than that required for clear distance vision. There are two main types of surgical correction for moderate to high myopia; excimer laser and phakic intraocular lenses (IOLs). Excimer laser refractive surgery for myopia works by removing corneal stroma to lessen the refractive power of the cornea and to bring the image of a viewed object into focus onto the retina rather than in front of it. Phakic IOLs for the treatment of myopia work by diverging light rays so that the image of a viewed object is brought into focus onto the retina rather than in front of the retina. They can be placed either in the anterior chamber of the eye in front of the iris or in the posterior chamber of the eye between the iris and the natural lens. To compare excimer laser refractive surgery and phakic IOLs for the correction of moderate to high myopia by evaluating postoperative uncorrected visual acuity, refractive outcome, potential loss of best spectacle corrected visual acuity (BSCVA) and the incidence of adverse outcomes. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to February 2014), EMBASE (January 1980 to February 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 February 2014. We included randomised controlled trials (RCTs) comparing excimer laser refractive surgery and phakic IOLs for the correction of myopia greater than 6.0 diopters (D) spherical equivalent. Two authors independently assessed trial quality and extracted data. We performed data analysis. We summarised data for outcomes using odds ratios. We used a fixed-effect model as only three trials were included in the review. This review included three RCTs with a total of 228 eyes. The range of myopia of included patients was -6.0 D to -20.0 D of myopia with up to 4.0 D of myopic astigmatism. The percentage of eyes with uncorrected visual acuity (UCVA) of 20/20 or better at 12 months postoperative was not significantly different between the two groups. Phakic IOL surgery was safer than excimer laser surgical correction for moderate to high myopia as it results in significantly less loss of best spectacle corrected visual acuity (BSCVA) at 12 months postoperatively. However there is a low risk of developing early cataract with phakic IOLs. Phakic IOL surgery appears to result in better contrast sensitivity than excimer laser correction for moderate to high myopia. Phakic IOL surgery also scored more highly on patient satisfaction/preference questionnaires. The results of this review suggest that, at one year post surgery, phakic IOLs are safer than excimer laser surgical correction for moderate to high myopia in the range of -6.0 to -20.0 D and phakic IOLs are preferred by patients. While phakic IOLs might be accepted clinical practice for higher levels of myopia (greater than or equal to 7.0 D of myopic spherical equivalent with or without astigmatism), it may be worth considering phakic IOL treatment over excimer laser correction for more moderate levels of myopia (less than or equal to 7.0 D of myopic spherical equivalent with or without astigmatism). Further RCTs adequately powered for subgroup analysis are necessary to further elucidate the ideal range of myopia for phakic IOLs. This data should be considered alongside comparative data addressing long-term safety as it emerges.


European perspective on multiple myeloma treatment strategies in 2014.
The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our recommendations for the management of patients with myeloma. Treatment approaches depend on "fitness," with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two- and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results.


Dietary influences on ethanol metabolism.
Ethanol was orally administered to seven normal volunteers after three dietary control periods. Diet cycle I was high in protein and calories, cycle II was high in protein but hypocaloric, and cycle III was a combined low-protein, hypocaloric diet. Ethanol elimination was significantly altered by the changes in macronutrients. All volunteers demonstrated diminished ethanol clearance while consuming the hypocaloric diets, and further reduction was seen with an inadequate protein intake. A marked dietary influence on ethanol clearance has been demonstrated in normal male volunteers who have not been exposed to previous ethanol consumption.


Clinical consideration for choosing combination therapies in advanced non-small-cell lung cancer: age, Eastern Cooperative Organization performance status 2, steroids and antibiotics.
Immune checkpoint inhibition completely changed our approach of cancer therapeutics and led to interesting response rate in a wide spectrum of tumors. However, only a portion of patients benefits from immune checkpoint blockers. To improve response rates, monoclonal antibodies targeting costimulatory receptors called PD-1 or CTLA-4 are combined together or with different therapies such as chemotherapy or antiangiogenic drugs. Some of these combinations are already approved and used in daily practice, but the safety and efficacy in particular populations such as older patients, Eastern Cooperative Organization performance status 2 or patients taking corticosteroids or antibiotics remain unclear. This special report focuses on the data available for these populations with a focus on non-small-cell lung cancer.


COVID-19 Community Stabilization and Sustainability Framework: An Integration of the Maslow Hierarchy of Needs and Social Determinants of Health.
All levels of government are authorized to apply coronavirus disease 2019 (COVID-19) protection measures; however, they must consider how and when to ease lockdown restrictions to limit long-term societal harm and societal instability. Leaders that use a well-considered framework with an incremental approach will be able to gradually restart society while simultaneously maintaining the public health benefits achieved through lockdown measures. Economically vulnerable populations cannot endure long-term lockdown, and most countries lack the ability to maintain a full nationwide relief operation. Decision-makers need to understand this risk and how the Maslow hierarchy of needs and the social determinants of health can guide whole of society policies. Aligning decisions with societal needs will help ensure all segments of society are catered to and met while managing the crisis. This must inform the process of incremental easing of lockdowns to facilitate the resumption of community foundations, such as commerce, education, and employment in a manner that protects those most vulnerable to COVID-19. This study proposes a framework for identifying a path forward. It reflects on baseline requirements, regulations and recommendations, triggers, and implementation. Those desiring a successful recovery from the COVID-19 pandemic need to adopt an evidence-based framework now to ensure community stabilization and sustainability.


Photoimmunoconjugates: novel synthetic strategies to target and treat cancer by photodynamic therapy.
Photodynamic therapy (PDT) combines a photosensitizer (PS) with the physical energy of non-ionizing light to trigger cell death pathways. PDT has potential as a therapeutic modality to be used in alternative or in combination with other conventional cancer treatment protocols (e.g. surgery, chemotherapy and radiotherapy). Still, due to the lack of specificity of the current PSs to target the tumor cells, several studies have exploited their conjugation with targeting moieties. PSs conjugated with antibodies (Abs) or their fragments, able to bind antigens overexpressed in the tumors, have demonstrated potential in PDT of tumors. This review provides an overview of the most recent advances on photoimmunoconjugates (PICs) for cancer PDT, which involve the first and second-generation PSs conjugated to Abs. This is an update of our previous review "Antibodies armed with photosensitizers: from chemical synthesis to photobiological applications", published in 2015 in Org. Biomol. Chem.


B-Site Co-Alloying with Germanium Improves the Efficiency and Stability of All-Inorganic Tin-Based Perovskite Nanocrystal Solar Cells.
Colloidal lead-free perovskite nanocrystals have recently received extensive attention because of their facile synthesis, the outstanding size-tunable optoelectronic properties, and less or no toxicity in their commercial applications. Tin (Sn) has so far led to the most efficient lead-free solar cells, yet showing highly unstable characteristics in ambient conditions. Here, we propose the synthesis of all-inorganic mixture Sn-Ge perovskite nanocrystals, demonstrating the role of Ge2+ in stabilizing Sn2+ cation while enhancing the optical and photophysical properties. The partial replacement of Sn atoms by Ge atoms in the nanostructures effectively fills the high density of Sn vacancies, reducing the surface traps and leading to a longer excitonic lifetime and increased photoluminescence quantum yield. The resultant Sn-Ge nanocrystals-based devices show the highest efficiency of 4.9 %, enhanced by nearly 60 % compared to that of pure Sn nanocrystals-based devices.


Integrative review of singing and music interventions for family carers of people living with dementia.
The majority of people living with dementia are cared for by their families. Family carers play a vital role in upholding the formal care system. Caring for a family member with dementia can be fulfilling. However, this role can have a considerable negative impact on family carers' mental and physical health and quality of life. Several empirical research studies have recently been conducted that explore the potential benefits of music interventions for family carers of people living with dementia. Singing has been the primary musical medium employed. This article presents the first review of this literature to date. It investigates the impact of music interventions on the health and well-being of family carers of people living with dementia, and how they experience and perceive these interventions. Whittemore and Knafl's five-stage integrative review framework was utilized: (i) problem identification; (ii) literature search; (iii) data evaluation; (iv) data analysis and synthesis; and (v) presentation of the findings. A total of 33 studies met the inclusion criteria. Analysis and synthesis resulted in three overarching themes: impact on family carers, carer perceptions of music interventions and null quantitative findings in small studies. The review found that singing and music interventions may improve family carers' social and emotional well-being, enhance their ability to cope and care and ameliorate the caring relationship, contributing to experiences of flourishing. However, it highlighted that this area is under-researched and pointed to the need for larger, more rigorous studies.


[Independent denaturation of albumin and globulins in human serum].
The independent melting of albumin, gamma-globulin, transferrin, and protease inhibitors in the composition of donor blood serum was studied by differential scanning microcalorimetry. It was found that the number of domains in gamma-globulin in donor blood serum and in diluted solutions is the same, whereas the number of domains of albumin in solution and in the composition of blood serum is three and two, respectively. In blood serum, the N-terminal domain melts by the "all-or-none" mechanism. Therefore, the decomposition of peaks of the denaturation curve was made under the assumption that the denaturation of blood serum proteins occurs by the "all-or-none" principle. It is assumed that comparing the calculated melting parameters (Td, delta Td, delta Hd, delta Cd) of domains of blood serum proteins of donor with the corresponding parameters of patients with oncological and nononcological diseases can be used as a basis for a more precise diagnostics of these diseases.


PI3K-δ inhibition using CAL-101 exerts apoptotic effects and increases doxorubicin-induced cell death in pre-B-acute lymphoblastic leukemia cells.
The frequency of dysregulated PI3K in acute lymphoblastic leukemia (ALL) coupled with the critical role of this signaling pathway in the acquisition of chemoresistant phenotype lend compelling weight to the application of PI3K inhibitors for the treatment of ALL. In this study, we found that abrogation of the PI3K pathway using CAL-101, a selective inhibitor of PI3K p110-δ, exerts a cytotoxic effect against Nalm-6 pre-B-ALL cells. Our results showed that the growth-suppressive effect is mediated, at least partially, by G1 arrest as a result of upregulated p21. CAL-101 also leads to induction of caspase-dependent apoptosis probably through reactive oxygen species-dependent upregulation of FOXO3a and subsequent induction of the proapoptotic target genes of p53. In conclusion, this study highlighted the potent efficacy of CAL-101 as either a single agent or in combination with doxorubicin in Nalm-6 cells; however, further investigation is needed to provide valuable clues to add this inhibitor for the treatment of ALL.


Effect of eosinophil peroxidase on airway epithelial permeability in the guinea pig.
Increased numbers of eosinophils and increased concentrations of plasma proteins have been found in the airways of patients with mild asthma. We used an intact guinea pig trachea model to investigate the role of eosinophil peroxidase (EPO) in altering the function of the airway epithelial barrier. EPO in the presence of hydrogen peroxide (H(2)O(2)) and bromide (Br(-)) catalyzes the production of hypobromous acid (HOBr), which is felt to have a toxic effect on airway epithelial cells. An intact guinea pig trachea was mounted on an apparatus in a way that would allow the tracheal epithelium to be exposed to different solutions. Following these exposures, a test solution containing (14)C-sucrose (S), (3)H-inulin (I), and FITC-dextran-20 (D) was placed in the tracheal lumen and positioned in the center of the segment for 90 minutes. Flux of these molecules across the epithelial barrier into a bath was measured, and the permeability (P) was calculated for each molecule to quantify epithelial barrier function. Light and electron micrographic studies were performed to assess cellular damage. We found that there was a dose response to EPO (in the presence of fixed amounts of H(2)(O)(2) and Br(-)). EPO at 7.3 x 10(-7) M caused no increase in P over controls (Ringer's solution alone) for S, I, or D (P> 0.05), whereas EPO at 2.7 x 10(-6) M caused a significant increase in P over controls (P = 0.008) for all test molecules. Light and electron micrographs of the latter tracheas showed no evidence of microscopic changes despite the increased P. Further testing verified that the increase in permeability was caused by the EPO catalyzed reaction and not the individual substrates themselves, and that the reaction was inhibited by a peroxidase inhibitor. We conclude that EPO can alter the barrier function of the airway epithelium before gross cellular damage becomes visible. We hypothesize that changes in the tight junctions are responsible for the alteration in the barrier function of the airway epithelium and that this may play an important role in the pathophysiology of mild asthma.


Hydrolysis in Acidic Environment and Degradation of Satraplatin: A Joint Experimental and Theoretical Investigation.
For the synthesis and selection of active platinum-based anticancer drugs that perform better than cisplatin and its analogues, six-coordinate octahedral Pt(IV) complexes appear to be promising candidates as, being kinetically more inert and more resistant to ligand substitution than four-coordinate Pt(II) centers, they are able to minimize unwanted side reactions with biomolecules prior to DNA binding. Due to their kinetic inertness, Pt(IV) complexes have also been exploited to bypass inconvenient intravenous administration. The most prominent example is satraplatin (Sat.) which is the first platinum antineoplastic agent reported to have oral activity. The present paper deals with a theoretical DFT investigation of the influence that the acidity of the biological environment can have on the activity of satraplatin and analogous octahedral Pt(IV) complexes having two carboxylates as axial ligands. Moreover, here the outcomes of a joint electrospray ionization mass spectrometry and DFT investigation of the fragmentation pathways of the protonated satraplatin are reported. Calculations show that the simulated acidic environment has an important impact on the satraplatin reactivity causing a significant lowering of the barrier that is necessary to overcome for the hydrolysis of the first acetate ligand to occur. Data from electrospray ionization mass spectrometry, 1H NMR, and potentiometric experiments strongly suggest that the loss of CH3COOH from the protonated satraplatin ion [Sat. + H]+ takes place almost immediately upon dissolution of satraplatin in methanol-water, D2O, and water solutions, respectively, at room temperature.


Tetramethypyrazine inhibits renal cell carcinoma cells through inhibition of NKG2D signaling pathways.
Tetramethypyrazine (TMP), one of the active compounds extracted from the traditional Chinese medicinal herb (Chuanxiong), has been verified as an anticancer compound against several types of cancer. However, understanding of the molecular mechanisms have not been fully elucidated. In the present study, the anticancer efficacy of TMP was investigated in human clear cell renal cell carcinoma (ccRCC) cells. We showed that TMP significantly inhibited ccRCC cell viability, proliferation, apoptosis, invasion and migration through the methods of MTT, flow cytometry, wound healing and transwell assays. Furthermore, reverse transcription polymerase chain reaction (RT-PCR), western blotting and immunofluorescence results demonstrated TMP upregulation of the expression of NKG2D ligands (NKG2DLs) MHC class I chain-related molecules A and B (MICA/B) and epithelial cell expression marker of E-cadherin, and downregulation of mesenchymal cell expression markers of vimentin and fibronectin. Taken together, the inhibition of TMP on ccRCC cells might be mediated via inhibition of NKG2D related signaling pathway to further suppress epithelial-mesenchymal transition (EMT) progression. The binding of NKG2D to its ligands activates NK cells, giving the rationale for studies on the utilization of TMP as a potential cancer therapeutic compound to increase NK cells-mediated cytotoxicity against high MICA/B expression in cancer cells.


Debating the psychology of tyranny: fundamental issues of theory, perspective and science.
In our rejoinder, we concentrate on responding to Zimbardo's criticisms. These criticisms involve three broad strategies. The first is to turn broad discussion about the psychology of tyranny into narrow questions about the replication of prison conditions. The second is to confuse our scientific analysis with the television programmes of 'The Experiment'. The third is to make unsupported and unwarranted attacks on our integrity. All three lines of attack are flawed and distract from the important theoretical challenge of understanding when people act to reproduce social inequalities and when they act to challenge them. This is the challenge that Turner identifies and engages with in his commentary.


A review and perspective on the assessment, management and prevention of fragility fractures in patients with osteoporosis and chronic kidney disease.
This article aims to review the methods used for the assessment of fracture risk and the use of osteoporosis medications for fracture prevention in the population with CKD, and highlights the difficulties faced by clinicians in the management of these patients and the latest recommendations and guidelines. Chronic kidney disease (CKD) and osteoporosis often co-exist in older adults, and they present a major healthcare challenge. CKD mineral and bone disorder (CKD-MBD) occurs as renal function declines and this syndrome affects most patients in CKD stages 4 and 5. The biochemical abnormalities of CKD-MBD, renal bone disease and risk factors associated with age-related bone loss and osteoporosis lead to a cumulative effect on fracture risk and mortality. There is a need for routine evaluation of fracture risk and fracture prevention in this population. Measurement of bone mineral density (BMD) and the use of the FRAX tool have predictive value for incident fractures in the general population and in CKD. This enables physicians to identify CKD patients most at risk of sustaining a fragility fracture and allows a more targeted approach to fracture prevention. Data analysis from the pivotal trials of therapeutic agents used in osteoporosis show that these drugs can be considered in mild and moderate CKD (stages 1-3 CKD). Off-label drug use in patients with CKD-MBD and more severe renal impairment (CKD stages 4 and 5) could offer significant benefits to sub-groups of patients when carefully tailored to each individual's bone turnover and calcium and phosphate balance. However, this requires a selective approach and treatment decisions based on inference from pathophysiology while we await further trials. Guidelines advocate the correction and/or reduction of the biochemical abnormalities of CKD-MBD before initiation of treatment with osteoporosis drugs and close monitoring during treatment.


Increased carbonylation, protein aggregation and apoptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis.
Previous work from our laboratory implicated protein carbonylation in the pathophysiology of both MS (multiple sclerosis) and its animal model EAE (experimental autoimmune encephalomyelitis). Subsequent in vitro studies revealed that the accumulation of protein carbonyls, triggered by glutathione deficiency or proteasome inhibition, leads to protein aggregation and neuronal cell death. These findings prompted us to investigate whether their association can be also established in vivo. In the present study, we characterized protein carbonylation, protein aggregation and apoptosis along the spinal cord during the course of MOG (myelin-oligodendrocyte glycoprotein)(35-55) peptide-induced EAE in C57BL/6 mice. The results show that protein carbonyls accumulate throughout the course of the disease, albeit by different mechanisms: increased oxidative stress in acute EAE and decreased proteasomal activity in chronic EAE. We also show a temporal correlation between protein carbonylation (but not oxidative stress) and apoptosis. Furthermore, carbonyl levels are significantly higher in apoptotic cells than in live cells. A high number of juxta-nuclear and cytoplasmic protein aggregates containing the majority of the oxidized proteins are present during the course of EAE. The LC3 (microtubule-associated protein light chain 3)-II/LC3-I ratio is significantly reduced in both acute and chronic EAE indicating reduced autophagy and explaining why aggresomes accumulate in this disorder. Taken together, the results of the present study suggest a link between protein oxidation and neuronal/glial cell death in vivo, and also demonstrate impaired proteostasis in this widely used murine model of MS.


Towards Translation of Discrete Frequency Infrared Spectroscopic Imaging for Digital Histopathology of Clinical Biopsy Samples.
Fourier transform infrared (FT-IR) spectroscopic imaging has been widely tested as a tool for stainless digital histology of biomedical specimens, including for the identification of infiltration and fibrosis in endomyocardial biopsy samples to assess transplant rejection. A major barrier in clinical translation has been the slow speed of imaging. To address this need, we tested and report here the viability of using high speed discrete frequency infrared (DFIR) imaging to obtain stain-free biochemical imaging in cardiovascular samples collected from patients. Images obtained by this method were classified with high accuracy by a Bayesian classification algorithm trained on FT-IR imaging data as well as on DFIR data. A single spectral feature correlated with instances of fibrosis, as identified by the pathologist, highlights the advantage of the DFIR imaging approach for rapid detection. The speed of digital pathologic recognition was at least 16 times faster than the fastest FT-IR imaging instrument. These results indicate that a fast, on-site identification of fibrosis using IR imaging has potential for real time assistance during surgeries. Further, the work describes development and applications of supervised classifiers on DFIR imaging data, comparing classifiers developed on FT-IR and DFIR imaging modalities and identifying specific spectral features for accurate identification of fibrosis. This addresses a topic of much debate on the use of training data and cross-modality validity of IR measurements. Together, the work is a step toward addressing a clinical diagnostic need at acquisition time scales that make IR imaging technology practical for medical use.


Rare gene capture in predominantly androgenetic species.
The long-term persistence of completely asexual species is unexpected. Although asexuality has short-term evolutionary advantages, a lack of genetic recombination leads to the accumulation over time of deleterious mutations. The loss of individual fitness as a result of accumulated deleterious mutations is expected to lead to reduced population fitness and possible lineage extinction. Persistent lineages of asexual, all-female clones (parthenogenetic and gynogenetic species) avoid the negative effects of asexual reproduction through the production of rare males, or otherwise exhibit some degree of genetic recombination. Another form of asexuality, known as androgenesis, results in offspring that are clones of the male parent. Several species of the Asian clam genus Corbicula reproduce via androgenesis. We compared gene trees of mitochondrial and nuclear loci from multiple sexual and androgenetic species across the global distribution of Corbicula to test the hypothesis of long-term clonality of the androgenetic species. Our results indicate that low levels of genetic capture of maternal nuclear DNA from other species occur within otherwise androgenetic lineages of Corbicula. The rare capture of genetic material from other species may allow androgenetic lineages of Corbicula to mitigate the effects of deleterious mutation accumulation and increase potentially adaptive variation. Models comparing the relative advantages and disadvantages of sexual and asexual reproduction should consider the possibility of rare genetic recombination, because such events seem to be nearly ubiquitous among otherwise asexual species.


The Validity of the SQoL-18 in Patients with Bipolar and Depressive Disorders: A Psychometric Study from the PREMIUM Project.
The S-QoL 18 is a self-administered questionnaire that assesses quality of life (QoL) among individuals with schizophrenia. This study aims to validate the S-QoL 18 in bipolar and depressive disorders for a more widespread use in psychiatric settings. This study was conducted in a non-selected sample of individuals with bipolar and depressive disorders in the day hospital of a regional psychiatric academic hospital. Two-hundred and seventy-two stable outpatients with bipolar (n = 73) and recurrent and persistent depressive (n = 199) disorders were recruited over a 12 month-period. The S-QoL 18 was tested for construct validity, reliability, and external validity. The eight-factor structure of the S-QoL 18 was confirmed by confirmatory factor analysis (RMSEA = 0.075 (0.064-0.086), CFI = 0.972, TLI = 0.961). Internal consistency and reliability were satisfactory. External validity was confirmed via correlations between S-QoL 18 dimension scores, symptomatology, and functioning. The percentage of missing data for the eight dimensions did not exceed 5%. INFIT statistics were ranged from 0.7 to 1.2, ensuring that all items of the scale measured the same QoL concept. In conclusion, the S-QoL 18 appears to be a valid and reliable instrument for measuring QoL in patients with bipolar and depressive disorders. The S-QoL 18 may be used by healthcare professionals in clinical settings to accurately assess QoL in individuals with bipolar and depressive disorders, as well as in schizophrenia.


[Long non-coding RNAs--"tuning fork" in regulation of cell processes].
Most of RNA transcripts, instead of serving templates for protein synthesis, perform different functions such as control of embryogenesis, differentiation, imprinting, X-chromosome inactivation, immune response, and stress reactions. A large portion of these RNAs are denoted as long non-coding RNAs (lncRNAs) which function as signaling molecules, navigating systems and platforms for ribonucleic complexes assembly. They also participate in the organization of specific cellular domains. Moreover, they are able to bind regulatory proteins and micro-RNAs, and serve as precursors for small RNAs. It was shown that lncRNAs participate in transcription regulation; they are also involved in alternative splicing, RNA editing, traffic, translation and degradation of RNA. The three-dimensional structure of lncRNAs plays a crucial role in processes of chromatin remodeling and transcription regulation. In this review we discuss various aspects of lncRNAs functioning.


[The epidemiology of acute pulmonary thromboembolism].
In contrast to the decreasing incidence of pulmonary thromboembolism in Western countries, the incidence examined as determined by autopsy, vital statistics, and clinical surveys is increasing in Japan. The combination of these data indicates the possibility of low diagnostic ability in Japan. The causes of the disease and the predictors of in-hospital death are summarized. The most popular congenital coagulopathies in Western countries, factor V Leiden and prothrombin G20210A mutation, have not been found in Japan. But recent reports showed that coagulopathy might have a greater contribution to the occurrence of the disease than was previously thought. We introduce reports that show a relation between the disease and life style.


[Ultrastructure of rat oocytes during the induction of superovulation].
The ultrastructure of ovocytes, fixed no later than 4-5 hours after the beginning of ovulation, the number of cells with the signs of organelle alterations is increased. This is presumably connected with a change in conditions of hormonal regulation of late stages of gametogenesis.


Chinese hamster ovary cell mutants with temperature-sensitive defects in endocytosis. I. Loss of function on shifting to the nonpermissive temperature.
We have isolated three independent Chinese hamster ovary cell mutants (B3853, I223, and M311) with temperature-sensitive, pleiotropic defects in receptor-mediated endocytosis. Activities affected at 41 degrees C include uptake via the D-mannose 6-phosphate receptor, accumulation of Fe from diferric transferrin, uptake of alpha 2-macroglobulin, compartmentalization of newly synthesized acid hydrolases, resistance to ricin, and sensitivity to diphtheria and Pseudomonas toxins and modeccin. The three mutants also displayed decreased sialylation of some secreted glycoproteins at 41 degrees C, reminiscent of the nonconditional mutant DTG1-5-4 that showed both endocytic and Golgi-associated defects (Robbins, A.R., C. Oliver, J.L. Bateman, S.S. Krag, C.J. Galloway, and I. Mellman, 1984, J. Cell Biol., 99:1296-1308). Phenotypic changes were detectable within 30 min after transfer of the mutants to 41 degrees C; maximal alteration of most susceptible functions was obtained 4 h after temperature shift. At 39 degrees C, the mutants exhibited many but not all of the changes manifested at 41 degrees C; resistance to diphtheria and Pseudomonas toxins required the higher temperature. Analysis of cell hybrids showed that B3853 and DTG1-5-4 are in one complementation group ("End1"); M311 and I223 are in another ("End2"). In the End1 mutants, loss of endocytosis correlated with complete loss of ATP-dependent endosomal acidification in vitro; in the End 2 mutants partial loss of acidification was observed. At the nonpermissive temperature, residual levels of endocytic activity in B3853 and M311 were nearly identical; thus, we conclude that the differences measured in endosomal acidification in vitro reflect the different genetic loci affected, rather than the relative severity of the genetic lesions. The mutations in M311 and I223 appear to have different effects on the same protein; in I223 (but not in M311) the full spectrum of phenotypic changes could be produced at the permissive temperature by inhibition of protein synthesis.


Genes and Diet in the Prevention of Chronic Diseases in Future Generations.
Nutrition is a modifiable key factor that is able to interact with both the genome and epigenome to influence human health and fertility. In particular, specific genetic variants can influence the response to dietary components and nutrient requirements, and conversely, the diet itself is able to modulate gene expression. In this context and the era of precision medicine, nutrigenetic and nutrigenomic studies offer significant opportunities to improve the prevention of metabolic disturbances, such as Type 2 diabetes, gestational diabetes, hypertension, and cardiovascular diseases, even with transgenerational effects. The present review takes into account the interactions between diet, genes and human health, and provides an overview of the role of nutrigenetics, nutrigenomics and epigenetics in the prevention of non-communicable diseases. Moreover, we focus our attention on the mechanism of intergenerational or transgenerational transmission of the susceptibility to metabolic disturbances, and underline that the reversibility of epigenetic modifications through dietary intervention could counteract perturbations induced by lifestyle and environmental factors.


[Theoretical aspects of and technological equipment for hydromonitored microsurgery of the eye].
A new method of removing the cataracta and vitreous body, called less than hydromonitor greater than is grounded theoretically. It is based on the use of destructive properties of superthin, high-speed liquid spray, affected pathological intraocular structures. Surgical tools and a hydro-drive system have already been developed for the accomplishment of hydromonitoring method. It was successfully tried in experiment and clinic and positive evaluations were given to both the method itself and the facilities for its realization.


A clinical case report of Hashimoto's thyroiditis and its impact on the treatment of chronic periodontitis.
Periodontitis is a multifactorial disease with microbial dental plaque as the initiator of periodontal disease. However, the manifestation and progression of the disease is influenced by a wide variety of determinants and factors. The strongest type of causal relationship is the association of systemic and periodontal disease. Hashimoto's thyroiditis has also been considered as one of the causes of periodontal disease. This clinical case report highlights the impact of Hashimoto's thyroiditis on the outcome of periodontal therapy.


Thermodynamics of dimer and tetramer formations in rabbit muscle phosphofructokinase.
The self-association of rabbit muscle phosphofructokinase (PFK) was monitored as a function of temperature, pH, and ionic strength in order to understand the thermodynamics of this aggregation process. Thermodynamic parameters obtained from the temperature study show that the dimerization of PFK is characterized by negative entropy and enthalpy changes of -270 +/- 5 eu and -87 +/- 1 kcal/mol, respectively, with no observable change in heat capacity. This is in contrast to the formation of the tetramer, which is governed by positive entropy and enthalpy changes and a positive heat capacity change of 5000 +/- 2000 cal/mol. Low ionic strength also favors the formation of the dimer without a significant influence on the tetramerization, which is enhanced by increasing the pH from 6.00 to 8.55. Furthermore, Wyman linkage analysis [Wyman, J. (1964) Adv. Protein Chem. 19, 224-285] reveals that the formation of the tetramer from the monomer between pH 6.00 and pH 8.55 involves the loss of 3.3 protons. Further analysis shows that ionization of residues with an apparent pKa of 6.9 is linked to the formation of PFK tetramers. The conclusion of this study indicates that the major noncovalent forces governing the formation of the dimer are different from those for the association of the tetramer.


The etiology and porotic hyperostosis among the prehistoric and historic Anasazi Indians of Southwestern United States.
Porotic hyperostosis was studied in 539 crania from maize-growing prehistoric and historic groups who occupied two dissimilar ecological zones of the Plateau country of Arizona and New Mexico--canyon bottoms and sage plain. Defined as abnormal localized sieve-like structural changes involving the hematopoietic areas of the cranium, it was found in 185 (34.3%) of these skulls. More frequent in children than in adults, it shows significant frequency differences between both children and adults of the two ecological zones. The two ecological zones differ in the availability of iron in the diet; the canyon inhabitants depended heavily on maize (which interferes with iron absorption) while the sage plain people consumed more iron-rich animal products. We hypothesize that an increased dependence on maize produced more iron deficiency anemia and resulted in more porotic hyperostosis. Maize is known to have permitted a food surplus which in turn allowed for increased Southwestern population growth in marginal areas like the canyon bottoms. Heavy dependency on a single food type with consequent hematologic problems may have been an important reason for the subsequent abandonment of the Anasazi region.


Localization of fractionally charged quasi-particles.
An outstanding question pertaining to the microscopic properties of the fractional quantum Hall effect is understanding the nature of the particles that participate in the localization but that do not contribute to electronic transport. By using a scanning single electron transistor, we imaged the individual localized states in the fractional quantum Hall regime and determined the charge of the localizing particles. Highlighting the symmetry between filling factors 1/3 and 2/3, our measurements show that quasi-particles with fractional charge e* = e/3 localize in space to submicrometer dimensions, where e is the electron charge.


Yersiniosis as a possible cause of acute pancreatitis.
In some cases of acute pancreatitis no cause can be identified. An etiologic role of Yersinia enterocolitica type 3 was suggested in two previous reports. A case is now presented which supports this hypothesis by simultaneity of reactive phase of yersiniosis and an acute attack of pancreatitis of otherwise unknown cause. Although the coincidence may have been fortuitous, the pattern common to this and the earlier published cases suggests that it may yield a further clue to an etiologic understanding of acute pancreatitis.


Survival of Escherichia coli strains in Mediterranean brackish water in the Bizerte lagoon in northern Tunisia.
This study investigated survival and virulence of Escherichia coli strains exposed to natural conditions in brackish water. Two E. coli strains (O126:B16 and O55:B5) were incubated in water microcosms in the Bizerte lagoon in northern Tunisia and exposed for 12 days to natural sunlight in June (231 to 386 W/m2, 26 +/- 1 degrees C, 30 g/L) and in April (227 to 330 W/m2, 17 +/- 1 degrees C, 27 g/L) or maintained in darkness for 21 days (17 +/- 1 degrees C, 27 g/L). The results revealed that sunlight was the most significant inactivating factor (decrease of 3 Ulog within 48 hours for the two strains) compared to salinity and temperature (in darkness). Survival time of the strains was prolonged as they were maintained in darkness. Local strain (E. coli O55:B5) showed better survival capacity (T90 = 52 hours) than E. coli O126:B16 (T90 = 11 h). For both, modifications were noted only for some metabolic activities of carbohydrates hydrolysis. Cytotoxicity of the two strains, tested on Vero cell, was maintained during the period of survival.


Association between Cervical Cancer and Dietary Patterns in Colombia.
Cervical cancer is a global public health problem. It is the second leading cause of death among women of childbearing age worldwide. Several factors, including diet, have been shown to influence the risk of persistent HPV infection and tumor progression. This paper determines the relationship between dietary patterns and cervical cancer. It is an ecological study of multiple groups, based on two national sources: the High-Cost Account and the National Survey of Nutritional Situation of Colombia of 2015. The population consisted of 3472 women aged 35 to 64. The incidence of cervical cancer was used as the dependent variable while the independent variables included food consumption according to established patterns, area of residence, age, physical activity, and BMI, among other variables. The statistical analysis performed through associations between variables was evaluated by multiple linear regression using R2. 38.9% of the evaluated population belonged to the first quartile of wealth, and 76.5% resided in the municipal capital. The incidence of cervical cancer in Colombia was associated with being affiliated to a state-subsidized health regime and having diabetes mellitus. A conservative eating pattern, as well as belonging to a rural area, are evidenced as protective factors. These results invite the need to encourage public policies and promote healthy lifestyles.


Cutaneous herpes simplex infections and their treatment.
Herpes simplex virus causes many important systemic as well as cutaneous diseases. The most common cutaneous diseases are herpes gingivostomatitis, labialis, and genitalis. Many new treatments for these diseases are proclaimed each year. There are so many treatments that one would believe that either everything works or nothing works. As there is no Federal Drug Administration approved treatment for cutaneous herpes simplex, the latter statement is probably more correct. Regardless of this dilemma, the physician must continue to diagnose and treat many cutaneous herpetic infections. In this paper the basic concepts of the herpes simplex virus will be briefly presented. Additionally, the most common cutaneous herpes infections will be reviewed with emphasis on critical analysis of their proposed methods of treatment.


Effect of viscosity on tear drainage and ocular residence time.
An increase in residence time of dry eye medications including artificial tears will likely enhance therapeutic benefits. The drainage rates and the residence time of eye drops depend on the viscosity of the instilled fluids. However, a quantitative understanding of the dependence of drainage rates and the residence time on viscosity is lacking. The current study aims to develop a mathematical model for the drainage of Newtonian fluids and also for power-law non-Newtonian fluids of different viscosities. This study is an extension of our previous study on the mathematical model of tear drainage. The tear drainage model is modified to describe the drainage of Newtonian fluids with viscosities higher than the tear viscosity and power-law non-Newtonian fluids with rheological parameters obtained from fitting experimental data in literature. The drainage rate through canaliculi was derived from the modified drainage model and was incorporated into a tear mass balance to calculate the transients of total solute quantity in ocular fluids and the bioavailability of instilled drugs. For Newtonian fluids, increasing the viscosity does not affect the drainage rate unless the viscosity exceeds a critical value of about 4.4 cp. The viscosity has a maximum impact on drainage rate around a value of about 100 cp. The trends are similar for shear thinning power law fluids. The transients of total solute quantity, and the residence time agrees at least qualitatively with experimental studies. A mathematical model has been developed for the drainage of Newtonian fluids and power-law fluids through canaliculi. The model can quantitatively explain different experimental observations on the effect of viscosity on the residence of instilled fluids on the ocular surface. The current study is helpful for understanding the mechanism of fluid drainage from the ocular surface and for improving the design of dry eye treatments.


Influence of abdominal aortic aneurysm size on the feasibility of endovascular repair.
To assess the effect of abdominal aortic aneurysm (AAA) size on overall aneurysm morphology with special attention to possible relationships among various anatomic variables that determine the feasibility of endovascular repair. One hundred sixty-eight patients were assessed with spiral computed tomographic angiography to measure the length and diameter of the AAA, the proximal neck, and the common iliac arteries. Anatomic variables were correlated with aneurysm size using Spearman's rank order correlation coefficients (rS); comparisons among small, intermediate, and large aneurysms were made using the Chi-square test. Correlations between aneurysm size and the anatomic variables above were weak. The strongest association was between aneurysm size and aortic length (rS = 0.41, p < 0.001). Subgroup analysis showed no difference in proximal neck length, neck diameter, or overall suitability for endovascular repair between aneurysms greater or smaller than 5.5-cm diameter. However, significantly more short (< 1.5 cm), wide (> 3 cm), and hence, unsuitable proximal necks were found in patients with aneurysms > 7 cm in diameter (chi 2 = 7.8, p < 0.01). Shortening and widening of the proximal neck seems to increase with aneurysm size but only after the aneurysm expands beyond 7 cm in diameter. Aneurysms with diameters in the 4.5- to 5.5-cm range are no more suitable for endovascular repair than those between 5.5 and 7 cm. The lack of any significant correlation between anatomic variables emphasizes the need for accurate preoperative assessment of the anatomy of each individual patient before endovascular repair.