[Neurosensory deafness: immunological aspects].
Seven hundred and twelve patients with first diagnosed pulmonary tuberculosis were examined; neurosensory hypoacusis was detected in 12.2% of the cases. The above patients underwent neurological, otolaryngological, and immunological studies. Second- and third-degree hypoacusis was found in 13.7 and 86.3%, respectively. Neurological syndromes were identified. These included vegetovascular dystonia in 50.5% of the patients, multiple cerebral minor symptoms in 45.5%, focal cerebral lesion in 4%/Comparison of the severity of nerve system disease and the level of hypoacusis has indicated that the more severe neurological disorders, neurosensory hypoacusis becomes more aggravated (K = 0.57). Positive skin Mantoux tests in all patients with neurosensory hypoacusis showed their allergization to Mycobacterium tuberculosis. In the examined patients, specific basophilic deformability (SBD) rates in the tuberculin test were 17.5 +/- 1.3% g, which differed significantly (p < 0.001) from those in the controls (5.1 +/- 0.9%). In second-degree neurosensory hypoacusis, SBD rates were significantly higher than those in first-degree one, which suggests that the allergic factor contributes to the development of neurosensory hypoacusis in the presence of tuberculosis. The values of antibodies to myeloperoxidase (1.869 +/- 0.02 optical density units (ODU) and to IgE (416.386 +/- 0.391 I.U./ml) significantly differed from those in the control group (0.08 +/- 0.02 ODU and 96.667 +/- 0.441 I.U./ml, respectively), which is indicative of primary lesions of minute blood vessels as the type of vasculitis and secondary nervous tissue involvement. Thus, allergic, vascular, and immune mechanisms are the main pathophysiological ones of neurosensory hypoacusis in the presence of first diagnosed and untreated tuberculosis.


Different approaches to advanced soft tissue sarcomas depending on treatment line, goal of therapy and histological subtype.
Introduction: Although rapid evolution over the past few years in advanced soft tissue sarcoma (STS) management has not been without its challenges, it has brought clarity in several areas.Areas covered: This article summarizes the proceedings of the third edition of the Soft Tissue Sarcoma: Evidence and Experience symposium held March 2019 in Madrid, Spain. An update is provided of current approaches to advanced STS management. Case studies illustrate the role of trabectedin in advanced STS management.Expert opinion: First-line treatment of advanced STS requires distinct therapeutic strategies depending on goal: tumor shrinkage or tumor control. Since all sarcoma patients benefit from active treatment irrespective of age or line of therapy, oncologists have a duty to offer active systemic therapies unless the patient is unfit for treatment or chooses to end active treatment. Beyond the first line, histology becomes increasingly relevant for treatment selection. Agents with activity in specific sarcoma subtypes have been identified. Rare tumors represent a substantial medical need requiring strong international collaboration between research groups, pharmaceutical companies, regulatory agencies, and patients to identify active drugs per subtype. Multidisciplinary care in an expert sarcoma center is the primary means of reducing morbidity and mortality in patients with sarcoma.


Imparting bone mineral affinity to osteogenic proteins through heparin-bisphosphonate conjugates.
Although numerous growth factors can promote the regeneration of bone upon parenteral administration, all exhibit undesirable side-effects that prevent their clinical utility. These side-effects arise due to the growth factors' inherent lack of bone affinity. The goal of this study was to develop a means to enhance the bone mineral affinity of osteogenic growth factors so as to minimize their extra-skeletal distribution. Heparin, a glycosaminoglycan that exhibits a high affinity to numerous growth factors, was modified with bisphosphonates to enhance its affinity to bone mineral (i.e. hydroxyapatite, HA). To this end, conjugation of 1-amino-1,1-diphosphonate methane (aminoBP) onto periodate-oxidized heparin using 4-(maleimidomethyl)cyclohexane-1-carboxyl-hydrazide was attempted. Using this chemistry, the number of aminoBPs conjugated onto heparin was modulated by varying the reacting reagent concentrations (to a maximum of 7 aminoBPs per heparin). Increasing the number of aminoBPs resulted in a more than twofold increase in heparin's affinity for HA in vitro. Subsequently, the ability of aminoBP-heparin conjugates to enhance the mineral affinity of basic fibroblast growth factor (bFGF) and bone morphogenetic protein-2 (BMP-2) was explored. The results revealed that the complexation between the conjugates and growth factors had occurred and that the conjugates increased the bone mineral affinity of bFGF and BMP-2 in an aminoBP-dependent manner. In conclusion, the conjugation of aminoBP onto heparin is a feasible approach to enhance the affinity of heparin-binding, osteogenic growth factors to HA.


Case Report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient.
A patient with WHIM syndrome immunodeficiency presented with sudden painless right eye blindness associated with advanced retinal and optic nerve damage. Toxoplasma gondii was detected by PCR in vitreous fluid but not serum. The patient was treated with trimethoprim-sulfamethoxazole. Vision did not return; however, the infection did not spread to involve other sites. Toxoplasmosis is rare in primary immunodeficiency disorders and is the first protozoan infection reported in WHIM syndrome.


Anomalous Skew-Scattering Nonlinear Hall Effect and Chiral Photocurrents in PT-Symmetric Antiferromagnets.
Berry curvature and skew scattering play central roles in determining both the linear and nonlinear anomalous Hall effects. Yet in PT-symmetric antiferromagnetic metals, Hall effects from either intrinsic Berry curvature mediated anomalous velocity or the conventional skew-scattering process individually vanish. Here we reveal an unexpected nonlinear Hall effect that relies on both Berry curvature and skew-scattering working in cooperation. This anomalous skew-scattering nonlinear Hall effect (ASN) is PT even and dominates the low-frequency nonlinear Hall effect for PT-symmetric antiferromagnetic metals. Surprisingly, we find that in addition to its Hall response, ASN produces helicity dependent photocurrents, in contrast to other known PT-even nonlinearities in metals that are helicity blind. This characteristic enables us to isolate ASN and establishes new photocurrent tools to interrogate the antiferromagnetic order of PT-symmetric metals.


Internal validity, dimensionality and performance of the Body Shape Questionnaire in a group of Brazilian college students.
To adapt the Body Shape Questionnaire for use in the Brazilian population; to study the internal validity and the dimensionality of the scale when used in a non- clinical Brazilian population. A cross- sectional study was accomplished comprising 164 students in the first 3 years of the School of Medicine conveniently selected at the Universidade Federal de São Paulo. The 34- item Body Shape Questionnaire version and a questionnaire to assess demographic and anthropometric information were used. The internal consistency of the Body Shape Questionnaire measured by Cronbach's alpha was 0.97, indicating that the questions of the scale converge to the same construct. The factor analysis of the scale resulted in a four- dimension solution accounting for 66.4% of the total data variability. Regarding the final score of Body Shape Questionnaire, the mean score was 58.7 +/- 25.1 for men and 89.7 +/- 31.3 for women. We found statistically significant gender differences in the means of the Body Shape Questionnaire scores. Women showed higher dissatisfaction than did men as to their appearance as measured by the Body Shape Questionnaire. The adapted version of the scale seems to maintain the characteristics of the original scale.


Liquid-vapor rectilinear diameter revisited.
In the modern theory of critical phenomena, the liquid-vapor density diameter in simple fluids is generally expected to deviate from a rectilinear law approaching the critical point. However, by performing precise scannerlike optical measurements of the position of the SF_{6} liquid-vapor meniscus, in an approach much closer to criticality in temperature and density than earlier measurements, no deviation from a rectilinear diameter can be detected. The observed meniscus position from far (10K) to extremely close (1mK) to the critical temperature is analyzed using recent theoretical models to predict the complete scaling consequences of a fluid asymmetry. The temperature dependence of the meniscus position appears consistent with the law of rectilinear diameter. The apparent absence of the critical hook in SF_{6} therefore seemingly rules out the need for the pressure scaling field contribution in the complete scaling theoretical framework in this SF_{6} analysis. More generally, this work suggests a way to clarify the experimental ambiguities in the simple fluids for the near-critical singularities in the density diameter.


Drosophila asymmetric division, polarity and cancer.
A limited number of adult stem cells (SCs) maintain the homoestasis of different tissues through the lifetime of the individual by generating differentiating daughters and renewing themselves. Errors in the SC division rate or in the fine balance between self-renewal and differentiation might result in tissue overgrowth or depletion, two potentially lethal conditions. A few types of SCs have been identified in Drosophila. These include the SCs of the adult intestine and malpighian tubes, (Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006; Singh et al., 2007), the prohematocytes that maintain the population of cells involved in the immunoresponse (Lanot et al., 2001; Lemaitre and Hoffmann, 2007), the SC of the follicle epithelia in the ovary (Nystul and Spradling, 2007), germ line SCs (GSCs) of both sexes (Fuller and Spradling, 2007) and neuroblasts (NBs), the fly neural SCs (Yu et al., 2006; Chia et al., 2008; Knoblich, 2008). Drosophila SCs have proved a fruitful model system to unveil some aspects of the molecular logic that sustains SC function. This review focuses on results obtained in the last few years from the study of NBs, particularly from the standpoint of the possible functional connection between asymmetric SC division and cancer.


Mortality and complications after treatment of acute diabetic Charcot foot.
Charcot foot is a rare but disabling complication to diabetic neuropathy, and can cause permanent, limb-threatening deformities. The aim of this study was to investigate a population of patients a Charcot foot on a case-by-case basis, in order to assess the consequences of an acute Charcot foot and its complications. The study was conducted a retrospective study of patients admitted to the Copenhagen Wound Healing Center between 1996 and 2015 with the diagnosis of Charcot foot (DM14.6) and diabetes mellitus type 1 or 2 (DE10.X and DE11.X). Physical and electronic records were used, and compared to data from the Danish Diabetes Registry. In total 392 patients were identified of which 173 were included. There were 26% with type 1 diabetes (initial HbA1c 81.7 ± 21.4 mmol/mol) and 74% with type 2 diabetes (initial HbA1c 66.5 ± 20.3 mmol/mol). Primary off-loading was with a removable walker in 95% of the cases (average off-loading time 8.3 months). The 5-year mortality was 14% with a mean survival time of 12.7 years. There was an association between lack of compliance and occurrence of foot complications, as well as between having a Charcot foot and leaving the workforce. More patients had type 1 diabetes compared to the background population, and they had a higher HbA1c than the general population of diabetes patients. A total of 67% developed complications such as ulcers, while patients non-compliant to treatment did significantly worse than those being compliant. The 5-year mortality was low, 14%, and comparable to diabetes patients without Charcot foot.


Pharmacotherapy for Refractory and Super-Refractory Status Epilepticus in Adults.
Patients with prolonged seizures that do not respond to intravenous benzodiazepines and a second-line anticonvulsant suffer from refractory status epilepticus and those with seizures that do not respond to continuous intravenous anesthetic anticonvulsants suffer from super-refractory status epilepticus. Both conditions are associated with significant morbidity and mortality. A strict pharmacological treatment regimen is urgently required, but the level of evidence for the available drugs is very low. Refractory complex focal status epilepticus generally does not require anesthetics, but all intravenous non-anesthetizing anticonvulsants may be used. Most descriptive data are available for levetiracetam, phenytoin and valproate. Refractory generalized convulsive status epilepticus is a life-threatening emergency, and long-term clinical consequences are eminent. Administration of intravenous anesthetics is mandatory, and drugs acting at the inhibitory gamma-aminobutyric acid (GABA)A receptor such as midazolam, propofol and thiopental/pentobarbital are recommended without preference for one of those. One in five patients with anesthetic treatment does not respond and has super-refractory status epilepticus. With sustained seizure activity, excitatory N-methyl-d-aspartate (NMDA) receptors are increasingly expressed post-synaptically. Ketamine is an antagonist at this receptor and may prove efficient in some patients at later stages. Neurosteroids such as allopregnanolone increase sensitivity at GABAA receptors; a Phase 1/2 trial demonstrated safety and tolerability, but randomized controlled data failed to demonstrate efficacy. Adjunct ketogenic diet may contribute to termination of difficult-to-treat status epilepticus. Randomized controlled trials are needed to increase evidence for treatment of refractory and super-refractory status epilepticus, but there are multiple obstacles for realization. Hitherto, prospective multicenter registries for pharmacological treatment may help to improve our knowledge.


Zinc depletion in alcoholic liver diseases.
Liver and serum zinc concentrations were investigated in 24 patients with alcoholic liver diseases, 22 patients with non-alcoholic liver diseases, and in 36 control subjects. The liver samples were obtained by percutaneous liver biopsies, and the ratio of hepatocytes to fibrous connective tissue was estimated. The liver zinc concentration was expressed in relation to the amount of hepatocytes, and the serum zinc concentration was calculated in relation to total, albumin-, and alpha 2-macroglobulin-bound serum zinc. The results show that the liver zinc concentration was decreased in patients with alcoholic liver diseases (P < 0.01), in contrast to in patients with non-alcoholic liver diseases. Albumin-bound serum zinc was decreased in both groups (P < 0.001). The results indicate that alcoholic liver damage is associated with zinc deficiency.


The determinants of the dimeric structure of seminal ribonuclease are located in its N-terminal region.
A chimeric cDNA was constructed, coding for the N-terminal region of BS-RNase (residues 1-49) and the C-terminal region of RNase A (residues 50-124). The resulting chimeric DNA was expressed in Escherichia coli and found to code for RNase chains that spontaneously assembled into a covalently dimeric ribonuclease.


Epidemic Emergence in the United States of Escherichia coli Sequence Type 131-H30 (ST131-H30), 2000 to 2009.
The H30 subclone of Escherichia coli sequence type 131 (ST131-H30) has become the leading antimicrobial resistance E. coli lineage in the United States and often exhibits resistance to one or both of the two key antimicrobial classes for treating Gram-negative infections, extended-spectrum cephalosporins (ESCs) and fluoroquinolones (FQs). However, the timing of and reasons for its recent emergence are inadequately defined. Accordingly, from E. coli clinical isolates collected systematically across the United States by the SENTRY Antimicrobial Surveillance Program in 2000, 2003, 2006, and 2009, 234 isolates were selected randomly, stratified by year, within three resistance categories: (i) ESC-reduced susceptibility, regardless of FQ phenotype (ESC-RS); (ii) FQ resistance, ESC susceptible (FQ-R); and (iii) FQ susceptible, ESC susceptible (FQ-S). Susceptibility profiles, phylogroup, ST, ST131 subclone, and virulence genotypes were determined, and temporal trends and between-variable associations were assessed statistically. From 2000 to 2006, concurrently with the emergence of ESC-RS and FQ-R strains, the prevalence of (virulence-associated) phylogroup B2 among such strains also rose dramatically, due entirely to rapid emergence of ST131, especially H30. By 2009, H30 was the dominant E. coli lineage overall (22%), accounting for a median of 43% of all single-agent and multidrug resistance (68% for ciprofloxacin). H30's emergence increased the net virulence gene content of resistant (especially FQ-R) isolates, giving stable overall virulence gene scores despite an approximately 4-fold expansion of the historically less virulent resistant population. These findings define more precisely the timing and tempo of H30's emergence in the United States, identify possible reasons for it, and suggest potential consequences, including more frequent and/or aggressive antimicrobial-resistant infections.


Clinical education: a challenging component of undergraduate nursing education.
Clinical education is an essential part of every undergraduate nursing curriculum. The main benefits are that it allows students to put theory into practice and experience the realities of the practice-based nursing profession. Limitations include the unstable nature of the clinical area as a learning environment and the challenges this produces with students' assessments. This article reviews the literature and concludes there is room for significant improvement in the area of clinical education and numerous strategies can be implemented to do so.


Streptococcus pneumoniae and Haemophilus influenzae type B Carriage, Central Asia.
A study of children was conducted in 3 Central Asian Republics. Approximately half of the Streptococcus pneumoniae isolates were serotypes included in available vaccine formulations. Approximately 6% of children carried Haemophilus influenzae type b (Hib). Using pneumococcal and Hib conjugate vaccines may decrease illness in the Central Asian Republics.


Evaluation of public awareness and performance toward the safe use of household disinfectants-cleaners to prevent COVID-19 in the Emirate of Abu Dhabi.
Disinfection is one of the most effective hygienic practices that would limit the spread of the Coronavirus Disease (COVID-19) through deactivating the coronavirus on contaminated skin, supplies, and surfaces. However, the type and concentration of disinfectants should be carefully selected to avoid damaging surfaces and to limit the side effects of these chemicals on household members and users. The aim of this study is to assess the public levels of awareness and performance concerning the safe use of household cleaning products and disinfectants during the spread of COVID-19 in the Emirate of Abu Dhabi. The cross-sectional study was conducted between October and December 2021 among 750 residents of Abu Dhabi, Al Dhafrah, and Al-Ain regions. A google survey was distributed electronically for the online recruitment of the general population. Mann-Whitney and Kruskal-Wallis tests were used to determine whether significant differences exist in the levels of awareness and performance with regard to gender, region, education level, and diagnosis with COVID-19. Spearman correlation was used to test if any correlation existed between levels of awareness and performance. Kruskal-Wallis test was also used to check if significant differences exist in the mean score of performance with respect to irritation-to-poisoning symptoms. The study population recorded a lower mean score of awareness (5.37 out of 12) than performance (11.75 out of 16). The majority of the study population claimed a minimum of one irritation-to-poisoning symptom during the handling of household cleaners and disinfectants. Significant differences exist in the awareness and performance mean scores among various educational levels (P < 0.001). The level of awareness was statistically significant with regard to infection with SARS-CoV-2 (P < 0.05). Also, the level of performance was significantly different between males and females (P < 0.001). Kruskal-Wallis test showed that the mean score of performance is statistically significant with all the studied irritation-to poisoning symptoms (P < 0.05). Awareness campaigns and training programs are recommended to address the safe use of household cleaning products and disinfectants in the United Arab Emirates (UAE).


Receptor activation and homer differentially control the lateral mobility of metabotropic glutamate receptor 5 in the neuronal membrane.
Glutamate receptors are clustered at the membrane through interactions with intracellular scaffolding proteins and cytoskeletal elements but can also be found in intracellular compartments or dispersed in the membrane. This distribution results from an equilibrium between the different pools of receptors whose dynamic is poorly known. The group I metabotropic glutamate receptor 5 (mGluR5) is concentrated in an annulus around the postsynaptic density but also found in large amounts in the extrasynaptic membrane. To analyze the dynamic of stabilization of mGluR5, we used single-particle tracking, force measurements, and fluorescence recovery to measure the mobility of mGluR5. We found that receptor activation increases receptor diffusion, whereas the scaffolding protein Homer favors confinement of receptor movements within clusters of Homer-mGluR5. However, this stabilization is reversible, because even in the presence of Homer, receptors still enter and exit from clusters at fast rates. Furthermore, clusters themselves are highly dynamic both in their movements and in their composition, which can vary within tens of seconds. Thus, exchange of receptors between dispersed and clustered states is fast and regulated during physiological processes. These properties may explain certain fast changes in receptor composition observed at postsynaptic densities.


Regulation of p56(lck) messenger turnover upon T cell activation: involvement of the 3' untranslated region in stability as determined in cell-free extracts.
Full activation of T lymphocytes transiently downregulates the steady state level of the tyrosine kinase p56(lck) mRNA. Here, we show that a decrease in messenger stability is involved in this downmodulation followed thereafter by a rapid and marked increase in mRNA half-life. In order to facilitate the study of p56(lck) messenger stability, an in vitro mRNA decay assay was developed and used to determine whether the 451 nucleotide long 3' untranslated region (3'UTR) of the messenger is implicated in the regulation of mRNA stability. Indeed, deletion of most of the 3'UTR led to a substantial increase in transcript half-life whereas deletion of a limited 3' portion did not, thus showing that the 146 nucleotides located in 5' of the 3'UTR contain destabilizing elements. Furthermore, the stability of both truncated transcripts was still modulated upon activation, thereby suggesting that the activation-responsive elements are located in a region distinct from the 3'UTR.


LRP1B is a Potential Biomarker for Tumor Immunogenicity and Prognosis of HCC Patients Receiving ICI Treatment.
New predictors of the efficacy of hepatocellular carcinoma (HCC) immunotherapy are needed. The ability of a single gene mutation to predict the therapeutic effect of immune checkpoint inhibitors (ICI) in HCC remains unknown. The most frequently mutated genes in HCC were analyzed using the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Mutant genes that correlated with the tumor mutational burden (TMB) and prognosis were obtained. The mutation pattern and immunological function of one of the most frequently mutated genes, LRP1B, were determined. A pan-tumor analysis of LRP1B expression, association with cancer prognosis, and immunological role was also explored. A retrospective clinical study was conducted using 102 HCC patients who received ICI treatment to further verify whether gene mutations can predict the effectiveness of immunotherapy and prognosis of HCC. LRP1B is among the most frequently mutated genes in HCC cohorts in TCGA and ICGC datasets. TCGA data showed that the LRP1B mutation activated immune signaling pathways and promoted mast cell activation. Patients with LRP1B mutations had significantly higher TMB than those with wild-type LRP1B. LRP1B expression correlated with the cancer-immunity cycle and immune cell infiltration. High LRP1B expression was also associated with poor survival among HCC patients. Results from the clinical study showed that HCC patients in the LRP1B mutation group had a poor response to ICI and worse prognosis than the wild-type group. The LRP1B mutation group had significantly higher TMB and mast cell infiltration in tumor tissues. This study is the first to report that a single gene LRP1B mutation is associated with a poor clinical response to ICI treatment and negative outcomes in HCC patients. HighLRP1B expression correlated with tumor immunity and HCC prognosis.


An efficient adaptive variational quantum solver of the Schrödinger equation based on reduced density matrices.
Recently, adaptive variational quantum algorithms, e.g., Adaptive Derivative-Assembled Pseudo-Trotter-Variational Quantum Eigensolver (ADAPT-VQE) and Iterative Qubit-Excitation Based-Variational Quantum Eigensolver (IQEB-VQE), have been proposed to optimize the circuit depth, while a huge number of additional measurements make these algorithms highly inefficient. In this work, we reformulate the ADAPT-VQE with reduced density matrices (RDMs) to avoid additional measurement overhead. With Valdemoro's reconstruction of the three-electron RDM, we present a revised ADAPT-VQE algorithm, termed ADAPT-V, without any additional measurements but at the cost of increasing variational parameters compared to the ADAPT-VQE. Furthermore, we present an ADAPT-Vx algorithm by prescreening the anti-Hermitian operator pool with this RDM-based scheme. ADAPT-Vx requires almost the same variational parameters as ADAPT-VQE but a significantly reduced number of gradient evaluations. Numerical benchmark calculations for small molecules demonstrate that ADAPT-V and ADAPT-Vx provide an accurate description of the ground- and excited-state potential energy curves. In addition, to minimize the quantum resource demand, we generalize this RDM-based scheme to circuit-efficient IQEB-VQE algorithm and achieve significant measurement reduction.


Tricuspid Valve Hemangioma Associated with Hypoplastic Left Heart Syndrome Presenting as Sudden Infant Death Syndrome.
Primary cardiac tumors are rare in children with a low incidence varying from 0.0017 to 0.28% in autopsy studies. Approximately 90% of the reported primary cardiac tumors in the pediatric population are benign and the most common subtype is rhabdomyomas accounting for approximately 60%, while hemangiomas are rare primary tumors with a 5% incidence. Hypoplastic left heart syndrome is abnormal development of the left-sided cardiac structures, leading to obstruction of blood flow from the left ventricle out-flow tract. Here we report a case of tricuspid hemangioma in association with hypoplastic left heart syndrome, a rare association not previously reported in the literature.


Management of corn leafhopper (Homoptera: Cicadellidae) and corn stunt disease in sweet corn using reflective mulch.
Plastic reflective mulches significantly reduced populations of corn leafhopper, Dalbulus maidis (DeLong & Wolcott), adults and the incidence of corn stunt disease caused by Spiroplasma kunkelii (CSS) in late planted sweet corn (Zea mays L.). The reflective mulches were more effective than were either foliar or soil applied insecticides in managing both the leafhopper and the pathogen it transmits. Yields of marketable ears were 1.5 to 2 times greater in reflective mulch plots than from fallow plots. This was due to larger ears (individual ear weight and length) rather than an increase in the number of ears. The use of reflective mulches provides an alternative strategy to insecticides in the management of both D. maidis and corn stunt disease. Such a strategy may prove useful to growers in Latin America and to limited resource growers and organic growers in the United States who wish to grow corn without the use of insecticides.


Pancreatic Cancer-Derived Exosomal miR-Let-7b-5p Stimulates Insulin Resistance in Skeletal Muscle Cells Through RNF20/STAT3/FOXO1 Axis Regulation.
Cancers trigger systemic metabolic disorders usually associated with glucose intolerance, which is an initially apparent phenomenon. One of the features of pancreatic cancer (PC) metabolic reprogramming is the crosstalk between PC and peripheral tissues (skeletal muscle and adipose tissues), emphasized by insulin resistance (IR). Our previous study reported that mice pancreatic cancer-derived exosomes could induce skeletal muscle cells (C2C12) IR, and exosomal microRNAs (miRNAs) may exert an important effect. However, the underlying mechanism remains to be further elucidated. qPCR was used to determine the expression of let-7b-5p in normal pancreatic islet cells and PC cells. Exosomes were purified from PC cell culture medium by ultracentrifugation. The role let-7b-5p on IR-mediated by PC cells-derived exosomes was asses by Oil Red O staining using miRNA inhibitor. Western blot assay was performed to examine the expression of IR-related genes and the activation of signaling pathways. A Luciferase experiment was applied to confirm how let-7b-5p regulated the expression of RNF20. IP/WB analysis further determined whether RNF20 promoted STAT3 ubiquitination. Rescue experiment using RNF20 overexpression plasmid was performed to confirm the role of RNF20 on IR-mediated using PC cell-derived exosomes in C2C12 myotube cells. miRNA-let-7b-5p was identified as the key exosomal miRNA, which could promote the IR in C2C12 myotube cells supported the lipid accumulation, the activation of STAT3/FOXO1 axis, and the decreased expression of IRS-1 and GLUT4. RNF20, an E3 ubiquitin ligase, was confirmed as the target gene of let-7b-5p and was found to improve IR by downregulating STAT3 protein expression via ubiquitination-mediated protein degradation. The ectopic expression of RNF20 could effectively attenuate the IR mediated by the pancreatic cancer-derived exosomes in C2C12 myotube cells. Our data suggest that exosomal miRNA-let-7b-5p may promote IR in C2C12 myotube cells by targeting RNF20 to activate the STAT3/FOXO1 axis.


Analysis of longitudinal censored semicontinuous data with application to the study of executive dysfunction: The Towers Task.
Executive dysfunction is a deficiency in skills of planning and problem solving that characterizes many neuropsychiatric disorders. The Towers Task is a commonly used measure of planning and problem solving for assessing executive function. Towers Task data are usually zero-inflated and right-censored, and ignoring these features can result in biased inference for the disease characterization of executive dysfunction. In this manuscript, a mixed-effects model for longitudinal censored semicontinuous data is developed for analyzing longitudinal Towers Task data from the PREDICT-HD study. The model is contrasted with current practice, and implications for general use are discussed.


High speed synchrotron x-ray phase contrast imaging of dynamic material response to split Hopkinson bar loading.
The successful process of amalgamating both the time-resolved imaging capabilities present at the Advanced Photon Source beamline 32ID-B and the proficiency of high-rate loading offered by the split Hopkinson or Kolsky compression/tension bar apparatus is discussed and verification of system effectiveness is expressed via dynamic experiments on various material systems. Single particle sand interaction along with glass cracking during dynamic compression, and fiber-epoxy interfacial failure, ligament-bone debonding, and single-crystal silicon fragmentation due to dynamic tension, were imaged with 0.5 μs temporal resolution and μm-level spatial resolution. Synchrotron x-ray phase contrast imaging of said material systems being loaded with the Kolsky bar apparatus demonstratively depicts the effectiveness of the novel union between these two powerful techniques, thereby allowing for in situ analysis of the interior of the material system during high-rate loading for a variety of applications.


Hospital and institution generating plant.
A huge amount of interest is now centred on making further improvements to the energy efficiency of healthcare facilities - reduction of carbon footprints is to the fore. Howeverthere is nothing new in ensuring the best is obtained from healthcare powersystems - the Health Estate Journal 'Then and now' feature below shows the specific focus on generating plant six decades ago. The feature offers advice on maximising returns from power systems and was originally published inthe October 1948 edition of The Hospital Engineer - the journal of the Institution of Hospital Engineers (now IHEEM).


Synthesis, Electrochemical and Spectroscopic Characterization of Selected Quinolinecarbaldehydes and Their Schiff Base Derivatives.
A new approach to the synthesis of selected quinolinecarbaldehydes with carbonyl groups located at C5 and/or in C7 positions is presented in this paper in conjunction with spectroscopic characterization of the products. The classical Reimer-Tiemann, Vilsmeier-Haack and Duff aldehyde synthesis methods were compared due to their importance. Computational studies were carried out to explain the preferred selectivity of the presented formylation transformations. A carbene insertion reaction based on Reimer-Tiemann methodology is presented for making 7-bromo-8-hydroxyquinoline-5-carbaldehyde. Additionally, Duff and Vilsmeier-Haack reactions were used in the double formylation of quinoline derivatives and their analogues benzo[h]quinolin-10-ol, 8-hydroxy-2-methylquinoline-5,7-dicarbaldehyde, 8-(dimethylamino) quinoline-5,7-dicarbaldehyde and 10-hydroxybenzo[h]quinoline-7,9-dicarbaldehyde. Four Schiff base derivatives of 2,6-diisopropylbenzenamine were prepared from selected quinoline-5-carbaldehydes and quinoline-7-carbaldehyde by an efficient synthesis protocol. Their properties have been characterized by a combination of several techniques: MS, HRMS, GC-MS, FTIR, electronic absorption spectroscopy and multinuclear NMR. The electrochemical properties of 8-hydroxy-quinoline-5-carbaldehyde, 6-(dimethylamino)quinoline-5-carbaldehyde and its methylated derivative were investigated, and a strong correlation between the chemical structure and obtained reduction and oxidation potentials was found. The presence of a methyl group facilitates oxidation. In contrast, the reduction potential of methylated compounds was more negative comparing to non-methylated structure. Calculations of frontier molecular orbitals supported the finding. The structures of 8-hydroxy-2-methylquinoline-5,7-dicarbaldehyde and four Schiff bases were determined by single-crystal X-ray diffraction measurements.


[Proteases of the elastase type].
Elastin in the most resistant fibrous protein of the organisms. Its degradation is catalysed by proteases designated as elastases. Elastic fibers appeared during phylogenesis at the level of the first Vertebrates and rendered possible the emergence of efficient circulatory and respiratory systems which were necessary for the development of the higher Vertebrates. Several pathological conditions, mostly age-dependent, are accompanied by the degradation of elastic fibers or their alteration due to increasing association with lipids and calcium salts. Several proteases (endopeptidases) of cellular origin were described over the last years, especially those of PMN leukocytes, platelets, monocytes-macrophages, smooth muscle cells and fibroblasts. Although less active on fibrous elastin than pancreatic elastase, these enzymes may well play an important role in the development of age-dependent pathologies such as athero-arteriosclerosis and emphysema. The involvement of cellular elastases in these pathologies is discussed in some detail. The age-dependent increase, both in vivo and in vitro of the elastase activity of fibroblasts and smooth muscle cells appears to play an important role in the modifications of cell behaviour observed in the above pathologies.


Relationship Between Symptoms of Temporomandibular Disorders and Estrogen Levels in Women With Different Menstrual Status.
To evaluate whether serum estrogen level is associated with chronic pain, masticatory dysfunction, and depressive symptoms and/or somatization in women with temporomandibular disorders (TMD) and different menstrual cycle status. A total of 64 women were allocated into one of three groups: one composed of women with normal menstrual cycles (Group 1), one composed of pregnant women (Group 2), and one composed of women in surgical menopause (Group 3). All respondents underwent a standardized clinical examination with the Research Diagnostic Criteria for TMD (RDC/TMD). Diagnoses were generated according to Axis I, and grades of chronic pain, depressive symptoms, and somatization were evaluated according to Axis II. The level of serum estradiol was measured by using the immunofluorescent method. Analysis of variance, Kruskal-Wallis test with post hoc comparisons via series of Mann-Whitney U tests, and Spearman correlation coefficient were used for comparisons between study participants. Reported pain was decreased with the progress of pregnancy among the women from Group 2 and was the lowest at the 36th week of pregnancy. Women in surgical menopause reported higher pain intensity as well as more difficulties with chewing and eating hard and soft food compared to the other subjects. Depressive symptoms and somatization were lowest among the women with advanced pregnancy and the highest among menopausal women. TMD-related chronic pain grade, masticatory dysfunction, and depressive symptoms and somatization are the highest when the estrogen level is the lowest.


Synergistic effect of iontophoresis and a series of fatty acids on LHRH permeability through porcine skin.
The effect of chemical penetration enhancers (e.g., fatty acids) in combination with iontophoresis was examined on the in vitro permeability of luteinizing hormone releasing hormone (LHRH) through porcine skin. Porcine epidermis was pretreated with either ethanol (EtOH) or 10% fatty acid/EtOH. The permeability coefficient of LHRH was significantly (p < 0.05) greater through EtOH, lauric acid/EtOH, palmitic acid/EtOH, oleic acid/EtOH, linoleic acid/EtOH, and linolenic acid/EtOH treated epidermis than the control (untreated epidermis). Iontophoresis further enhanced the permeability of LHRH (p < 0.05) through enhancer-pretreated epidermis in comparison with corresponding passive permeability. Among saturated fatty acids tested, 10% palmitic acid/iontophoresis showed the highest permeability coefficient [(59.52 +/- 2.40) x 10(-4) cm/h], which was approximately 16-fold higher than that of the control [(3.57 +/- 0.41) x 10(-4) cm/h]. Unsaturated cis-octadecenoic acids were more effective penetration enhancers when compared with octadecanoic acid. Among cis-octadecenoic acids in combination with EtOH, the greater iontophoretic permeability coefficient [(59.18 +/- 12.43) x 10(-4) cm/h] was obtained through linolenic acid treated epidermis, which was significantly greater (p < 0.05) than through saturated octadecanoic acid treated epidermis [(29.08 +/- 3.18) x 10(-4) cm/h]. Also, pretreatment of epidermis with 5% linolenic acid/propylene glycol (PG) resulted in greater (p < 0.05) iontophoretic flux of LHRH in comparison to 5% linolenic acid/EtOH. Furthermore, increases in the degree of unsaturation in octadecenoic acids did not produce corresponding increases in the degree of enhancement. Reversibility studies revealed that the postrecovery passive flux of LHRH through 5% linolenic acid in combination with EtOH or PG/iontophoresis treated epidermis was significantly (p < 0.05) reduced than the prerecovery value but could not completely recover to the baseline flux (i.e., flux of LHRH through untreated epidermis).


Clogging of granular materials in silos: effect of gravity and outlet size.
By means of extensive numerical simulations we disclose the role of the driving force in the clogging of inert particles passing through a constriction. We uncover the effect of gravity and outlet size on the flow rate and kinetic energy within the system, and use these quantities to deepen our understanding of the blocking process. First, we confirm the existence of a finite avalanche size when the driving force tends to zero. The magnitude of this limit avalanche size grows with the outlet size, as expected due to geometrical reasons. In addition, there is an augment of the avalanche size when the driving force is increased, an effect that is enhanced by the outlet size. This phenomenology is explained by assuming that in order to get a stable clog developed, two conditions must be fulfilled: (1) an arch spanning the outlet size should be formed; (2) the arch should resist until the complete dissipation of the kinetic energy within the system. From these assumptions, we are able to obtain the probability that an arch gets destabilized, which is shown to primarily depend on the square root of the kinetic energy. A minor additional dependence of the outlet size is also observed which is explained in the light of recent results of the arch resistance in vibrated silos.


The Precision of Hepatic Arterial Infusion Scintigraphy as a Quantitative Biomarker of Tumor Microvasculature.
Optimal clinical development of new cancer therapies targeting tumor vasculature requires new target-specific response assays. This clinical study examined the test-retest repeatability of SPECT as an in vivo assay of angiogenic hepatic tumor microvasculature using an intraarterial infusion of 99mTc-macroaggregated albumin (MAA) delivered via a hepatic artery infusion (HAI) pump. Patients with primary or secondary cancerous liver tumors with HAI pump-catheter implants placed for HAI chemotherapy underwent hepatic SPECT after separate arterial infusions of 37 and 185 MBq of 99mTc-MAA via an HAI pump. Quantitative measures of hepatic tumor MAA uptake were obtained from paired test-retest SPECT datasets. Repeatability was defined by quotients of paired measurands with 95% CIs and coefficients of repeatability (CRs). Test-retest HAI pump SPECT yielded highly repeatable measurements in quantitative indexes of tumor microvasculature. Variability in repeat test-retest measurements was small relative to the range of observed measurements between different tumors. The total hepatic tumor microvascular MAA accumulation (percentage injected dose) proved most repeatable, with test-retest value quotients near unity (quotients: median, 1.10 ± 0.09 [SD]; range, 1.03-1.32; 95% CI, 1.07-1.19) and 1.6% CR. Tumor MAA uptake values ranged from 5% to 18% injected dose. This article describes the precision of HAI SPECT as a quantitative biomarker of tumor microvasculature under conditions of repeatability. The results support clinical testing of HAI SPECT as a radiologic response biomarker for angiotropic tumor therapy.


Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma.
Extracellular adenosine 5'-triphosphate (ATP) causes neurogenic bronchoconstriction, inflammation, and coughs, and may play a mechanistic role in obstructive airway diseases. The aims of this study were to determine the effects of inhaled ATP on airway function, and to compare these effects with those of adenosine 5'-monophosphate (AMP). Prospective, randomized, double-blind study. Clinical research laboratory of a postgraduate teaching hospital. The effects of inhaled equimolar doses of ATP and AMP on airway caliber, perception of dyspnea quantified by the Borg score, and other symptoms were determined in 10 nonsmokers (age 41 +/- 3 years) and 10 patients with asthma (age 39 +/- 3 years) [+/- SEM]. None of the healthy nonsmokers responded to ATP or AMP. All the patients with asthma responded to ATP, and 90% responded to AMP. The geometric mean of the provocative dose causing a 20% fall in FEV1 (PD20) of ATP was 48.7 micromol/mL and that of PD20 AMP was 113.5 micromol/mL in responsive asthmatics (p < 0.05). In asthmatic patients, the percentage change in FEV1 caused by ATP was greater than that caused by AMP (deltaFEV1 ATP = 29% vs deltaFEV1 AMP = 22%, p < 0.05). Borg score increased significantly in asthmatics after ATP (from 0.1 to 3.3, p < 0.01) and after AMP (from 0.2 to 2.5, p < 0.01). This increase was also greater after ATP than AMP in asthma (deltaBorg ATP = 3.2 vs deltaBorg AMP = 2.3, p < 0.05). ATP induced cough in 16 subjects (80%), while AMP induced cough in 8 subjects (40%) [p < 0.05]; in addition, more subjects had throat irritation after inhalation of ATP than AMP (p < 0.05). ATP is a more potent bronchoconstrictor and has greater effects on dyspnea and other symptoms than AMP in asthmatic patients. Therefore, ATP could potentially be used as a bronchoprovocator in the clinical setting.


Kinetic mechanism for modeling of electrochemical reactions.
We propose a kinetic mechanism of electrochemical interactions. We assume fast formation and recombination of electron donors D- and acceptors A+ on electrode surfaces. These mediators are continuously formed in the electrode matter by thermal fluctuations. The mediators D- and A+, chemically equivalent to the electrode metal, enter electrochemical interactions on the electrode surfaces. Electrochemical dynamics and current-voltage characteristics of a selected electrochemical system are studied. Our results are in good qualitative agreement with those given by the classical Butler-Volmer kinetics. The proposed model can be used to study fast electrochemical processes in microsystems and nanosystems that are often out of the thermal equilibrium. Moreover, the kinetic mechanism operates only with the surface concentrations of chemical reactants and local electric potentials, which facilitates the study of electrochemical systems with indefinable bulk.


[Use of flexible needles and ways to control their placement in robot-assisted prostate brachytherapy].
The article provides an overview of developments in the field of flexible needles and methods of control over their behavior in the human body as a part of modern robotic systems for prostate cancer brachytherapy. The authors describe the advantages of flexible needles over standard ones, features of their design, and results of their tests in phantom models.


Residual fistula of fourth branchial arch anomalies and recurrent left-side cervical abscess: clinical case and review of the literature.
Congenital fourth branchial arch anomalies are uncommon entities. Most of these anomalies are diagnosed in childhood. The majority of cases occur on the left side. The clinical presentation of these anomalies varies with age. A respiratory distress is the usual clinical presentation in neonates, cervical cutaneous fistulas in late childhood or acute suppurative thyroiditis. Multiples diagnostic options have been described with different modalities of treatment. The majority of cases of fourth branchial arch anomalies are described only in case reports. We report a clinical case of recurrent cervical abscess in a young woman due to a residual fistula of fourth branchial arch.


[Maturation of Cordyceps sinensis associates with alterations of fungal expressions of multiple Ophiocordyceps sinensis mutants in stroma of Cordyceps sinensis].
To examine maturational changes in expressions of Ophiocordyceps sinensis (O.sinensis) transition and transversion mutation genotypes in Cordyceps sinensis (C.sinensis) stroma. MassARRAY single nucleotide polymorphism (SNP) matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrum genotyping was used, and 8 SNP extension primers were designed based on the scattered, multiple point mutations of known sequences for the O.sinensis mutants within their internal transcribed spacer (ITS) segments. Of the extension primers, 5 (not capable of distinguishing between the 2 AT-biased genotypes) located in rDNA ITS1 and ITS2 regions: 067721-211, 067721-240, 067721-477, 067721-531 and 067721-581. The other 3 extension primers located in 5.8S rDNA region: 067740-324, 067740-328 and 067740-360, to distinguish between the 2 AT-biased genotypes. MS chromatograms at the 8 SNP sites showed dynamic alterations of mutant alleles in C.sinensis stroma. The allele for the AT-biased genotypes at 067721-211 site showed higher peak height than its GC-biased counterpart in the premature C.sinensis stroma, but disappeared with C.sinensis maturation. Chromatograms displayed not only the transition mutation alleles, but also transversion mutants. Some of the transversion mutation alleles displayed higher peak heights than those for GC- and AT-biased alleles, but their peak heights and detection rates tended to be decreased with C.sinensis maturation. When distinguishing between the 2 AT-biases, AB067744 and AB067740 genotype alleles co-existed in the premature C.sinensis stroma. The allele peak height for AB067744 genotype was greatly decreased with C.sinensis maturation, while that for AB067740 genotype increased. Co-existence of at least 5 transition and transversion mutant genotypes of O.sinensis and the dynamic changes in their expressions in C.sinensis stroma along with C.sinensis maturation may be of extreme importance in C.sinensis stroma germination and maturation, enabling C.sinensis to complete its life cycle.


Noninvasive mechanical ventilation and acute respiratory failure: indications and limitations.
Noninvasive mechanical ventilation (NMV) now represents the first step in the management of acute on chronic respiratory failure (A/CRF). During the last 5 yrs, many studies have confirmed the feasibility of NMV in an acute setting, either by facial or nasal interface, used in addition to volumetric or barometric respirators, to manage A/CRF. The best indications for NMV are slowly progressive A/CRF, frequently represented by chronic obstructive pulmonary disease (COPD), or restrictive pulmonary disease. The criteria to initiate NMV in such patients are worsening of respiratory status and arterial blood gas (ABG) values, with increased hypoxia, hypercapnia and respiratory acidosis, despite optimal management with medication, physiotherapy and oxygen therapy. Respiratory encephalopathy is not an absolute contraindication; however, bronchial hypersecretion indicates that care is needed under NMV. Invasive mechanical ventilation with endotracheal (ET) intubation is discussed in the case of failure of NMV, when clinical status and ABG values worsen in spite of it. The signal for ET intubation is then obvious, represented by severe dyspnoea leading to respiratory pauses or arrest, severe cyanosis, and signs of haemodynamic instability. Despite immediate evidence of ominous cardiorespiratory inefficiency, ET intubation may be delayed and often avoided with the help of NMV. Criteria should be studied to identify guidelines for cessation of NMV, in order not to continue with the technique too long considering the safety of the patient. Indications for NMV in other kinds of ARF have received less study and are more controversial.


Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer.
To define the involvement of p16/CDKN2 and p15/MTS2 tumor-suppressor genes for response to chemotherapy in primary epithelial ovarian cancer, we analyzed alterations of the gene in 45 patients who were treated with primary cytoreductive surgery followed by 6 courses of cis-diamminedichloroplatinum (II) (cisplatin)-based combination chemotherapy. Homozygous deletion of p16/CDKN2 and p15/MTS2 genes was found in 8 (18%) and 15 (33%) cases, respectively. Response to the chemotherapy was confirmed by finding at second surgery after the chemotherapy in 26 patients, resulting in 17 responders and 9 nonresponders. The abundance of gene deletion in nonresponders (56%) was significantly higher (p = 0.0463) when compared to that in responders (18%). Moreover, the deletion of genes was a significant poor prognostic factor (p = 0.0441) in advanced ovarian cancer. These results suggest that deletion of p16/CDKN2 and/or p15/MTS2 is a potential indicator for poor chemotherapy response and adverse prognosis in ovarian cancer patients.


An electrochemical sensing platform with a molecularly imprinted polymer based on chitosan-stabilized metal@metal-organic frameworks for topotecan detection.
The present study aims to develop an electroanalytical method to determine one of the most significant antineoplastic agents, topotecan (TPT), using a novel and selective molecular imprinted polymer (MIP) method for the first time. The MIP was synthesized using the electropolymerization method using TPT as a template molecule and pyrrole (Pyr) as the functional monomer on a metal-organic framework decorated with chitosan-stabilized gold nanoparticles (Au-CH@MOF-5). The materials' morphological and physical characteristics were characterized using various physical techniques. The analytical characteristics of the obtained sensors were examined by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV). After all characterizations and optimizing the experimental conditions, MIP-Au-CH@MOF-5 and NIP-Au-CH@MOF-5 were evaluated on the glassy carbon electrode (GCE). MIP-Au-CH@MOF-5/GCE indicated a wide linear response of 0.4-70.0 nM and a low detection limit (LOD) of 0.298 nM. The developed sensor also showed excellent recovery in human plasma and nasal samples with recoveries of 94.41-106.16 % and 95.1-107.0 %, respectively, confirming its potential for future on-site monitoring of TPT in real samples. This methodology offers a different approach to electroanalytical procedures using MIP methods. Moreover, the high sensitivity and selectivity of the developed sensor were illustrated by the ability to recognize TPT over potentially interfering agents. Hence, it can be speculated that the fabricated MIP-Au-CH@MOF-5/GCE may be utilized in a multitude of areas, including public health and food quality.


Cannabinoids and neuronal damage: differential effects of THC, AEA and 2-AG on activated microglial cells and degenerating neurons in excitotoxically lesioned rat organotypic hippocampal slice cultures.
Cannabinoids (CBs) are attributed neuroprotective effects in vivo. Here, we determined the neuroprotective potential of CBs during neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures (OHSCs). OHSCs are the best characterized in vitro model to investigate the function of microglial cells in neuronal damage since blood-borne monocytes and T-lymphocytes are absent and microglial cells represent the only immunocompetent cell type. Excitotoxic neuronal damage was induced by NMDA (50 microM) application for 4 h. Neuroprotective properties of 9-carboxy-11-nor-delta-9-tetrahydrocannabinol (THC), N-arachidonoylethanolamide (AEA) or 2-arachidonoylglycerol (2-AG) in different concentrations were determined after co-application with NMDA by counting degenerating neurons identified by propidium iodide labeling (PI(+)) and microglial cells labeled by isolectin B(4) (IB(4)(+)). All three CBs used significantly decreased the number of IB(4)(+) microglial cells in the dentate gyrus but the number of PI(+) neurons was reduced only after 2-AG treatment. Application of AM630, antagonizing CB2 receptors highly expressed by activated microglial cells, did not counteract neuroprotective effects of 2-AG, but affected THC-mediated reduction of IB(4)(+) microglial cells. Our results indicate that (1) only 2-AG exerts neuroprotective effects in OHSCs; (2) reduction of IB(4)(+) microglial cells is not a neuroprotective event per se and involves other CB receptors than the CB2 receptor; (3) the discrepancy in the neuroprotective effects of CBs observed in vivo and in our in vitro model system may underline the functional relevance of invading monocytes and T-lymphocytes that are absent in OHSCs.


Pulmonary metabolism of reactive oxygen species.
Preexposure of rats to sublethal levels of hyperoxia or ozone reduces morbidity and mortality when the animals are subsequently exposed to lethal levels of either oxidant stress. Lung homogenates and isolated type II pneumocytes from rats exposed to these oxidant stresses demonstrate enhanced antioxidant enzyme activities. Antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase are responsible for the detoxification of partially reduced oxygen species, superoxide and hydrogen peroxide, to less reactive states. Potential pulmonary cellular loci of partially reduced oxygen include mitochondrial NADH dehydrogenase, endoplasmic reticulum-derived NADPH cytochrome c reductase, and cytosolic xanthine oxido reductase. Thus partially reduced oxygen species are hypothesized to mediate hyperoxia and ozone-induced pulmonary damage. This damage may be attenuated by enhanced intracellular antioxidant enzyme activities. Pharmacologic augmentation of pulmonary antioxidant enzymes may be accomplished via intratracheal or intravascular delivery of liposomes containing antioxidant enzymes. Rats pretreated with liposomes containing both superoxide dismutase and catalase, when subsequently exposed to lethal levels of hyperoxia, demonstrate enhanced survival compared with control animals or with animals treated with control liposomes or native antioxidant enzymes. Finally, knowledge obtained from in vitro investigations optimizing liposomal delivery to specific pulmonary cell types may further aid in reducing in vivo pulmonary damage to hyperoxia and ozone.


Management of Challenging Esthetic Anterior Cases with Limited Restorative Space: A Clinical Report.
With careful restorative planning and surgical placement, dental implants can be used to support and retain a wide range of esthetic prostheses. When implant planning or surgical executions are less than ideal, however, the resulting restorative space can be a significant obstacle to successful treatment. The aim of this article is to describe the use of a customized anterior bar to support a partial overdenture prosthesis for a youthful patient with a high smile line and a limited restorative space of 6 mm. Details of the treatment and an illustration of the customized design are also presented.


The MUC1 oncomucin regulates pancreatic cancer cell biological properties and chemoresistance. Implication of p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways.
MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To this aim, we undertook to study MUC1 biological effects on pancreatic cancer cells and identify pathways mediating these effects. Our in vitro experiments indicate that inhibiting MUC1 expression decreases cell proliferation, cell migration and invasion, cell survival and increases cell apoptosis. Moreover, lack of MUC1 in these cells profoundly altered their sensitivity to gemcitabine and 5-Fluorouracil chemotherapeutic drugs. In vivo MUC1-KD cell xenografts in SCID mice grew slower. Altogether, we show that MUC1 oncogenic mucin alters proliferation, migration, and invasion properties of pancreatic cancer cells and that these effects are mediated by p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways.


Autoimmune neutropenia associated with influenza virus infection in childhood: a case report.
Although neutropenia is relatively frequent in infants and children and is mostly a benign condition with a self-limited course, it can lead to life-threatening severe infections. Autoimmune neutropenia is a relatively uncommon hematological disorder characterized by the autoantibody-induced destruction of neutrophils. It is usually triggered by viral infections with very few documented cases after influenza virus. An 8-month-old male infant presented at the emergency room with a 5-days history of fever up to 39.7 °C, cough and runny nose. In the blood test performed, severe neutropenia was diagnosed (neutrophils 109/μL). A nasopharyngeal aspirate revealed a positive rapid test for Influenza A. Serum antineutrophil antibodies were determined with positive results. Neutropenia targeted panel showed no mutations. Despite maintenance of severe neutropenia for 9 months the course was uneventful without treatment. When severe neutropenia is diagnosed and confirmed, it is essential to rule out some potential etiologies and underlying conditions, since the appropriate subsequent management will depend on it. Although autoimmune neutropenia triggered by viral infections has been widely reported, it has seldom been reported after influenza infection. The benign course of the disease allows a conservative management in most cases.


Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum.
Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum because granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. In this study, we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to 7 d postinfection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕs) constituted most IL-10-producing cells. Deletion of HIF-1α in neutrophils or dendritic cells did not alter fungal burden, thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕs following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕs by IFN-γ and effective handling of H. capsulatum.


A New Case of Congenital Malabsorptive Diarrhea and Diabetes Secondary to Mutant Neurogenin-3.
Congenital diarrheal disorders are a group of rare enteropathies that often present with life-threatening diarrhea in the first weeks of life. Enteric anendocrinosis, characterized by a lack of intestinal enteroendocrine cells due to recessively inherited mutations in the Neurogenin-3 (NEUROG3) gene, has been described as a cause of congenital malabsorptive diarrhea. Diabetes mellitus also is typically associated with NEUROG3 mutations, be it early onset or a later presentation. Here we report a case of a 16-year-old male patient with severe malabsorptive diarrhea from birth, who was parenteral nutrition dependent and who developed diabetes mellitus at 11 years old. To the best of our knowledge, only 9 cases of recessively inherited NEUROG3 mutations have been reported in the literature to date. Our patient presents with several remarkable differences compared with previously published cases. This report can contribute by deepening our knowledge on new aspects of such an extremely rare disease.


In vitro protein phosphorylation in head preparations from normal and mutant Drosophila melanogaster.
We have characterized protein phosphorylation in vitro in subcellular fractions from Drosophila melanogaster heads. Optimal conditions for the incorporation of 32P into proteins, and its dependence on ATP, divalent cations, and cyclic nucleotides have been determined, as well as the effect of inhibitors of ATPase, protein phosphatase, and protein kinase on protein phosphorylation. Among these inhibitors, Zn2+ was found to affect the incorporation of 32P into specific bands and p-hydroxymercuribenzoate was found to be most suited for freezing the activity of both kinases and phosphatases. Cyclic AMP-dependent protein kinase (cAMP-dPK) activity was present in both supernatant (S2) and particulate (P2) fractions, with the majority (60-85%, depending on the homogenization medium) being associated with S2, as determined by phosphorylation of exogenous synapsin I. cAMP-dPK catalyzed the phosphorylation of at least 18 endogenous polypeptides in S2 and at least 10 endogenous polypeptides in P2. These proteins could be classified on the basis of the extent of stimulation of phosphorylation by cyclic nucleotides, dependence on cyclic nucleotide concentration, and rate of phosphorylation. A phosphoprotein of 51 kilodaltons (pp51) was a major component of the S2 and P2 fractions and displayed properties expected from the regulatory subunit of the cAMP-dPK, R-II. A phosphoprotein doublet of approximately 37 kilodaltons (pp37) was stimulated to the largest extent by cAMP in the P2 and S2 fractions. The phosphorylation of several proteins in both fractions was significantly lowered by the mammalian Walsh inhibitor of cAMP-dPK, whereas in some cases the stimulation of phosphorylation of the same proteins by exogeneous cAMP was relatively small. Phosphoproteins from two learning mutants known to be deficient in cAMP metabolism, dnc and rut, were analyzed for their extent of phosphorylation in the presence of a stable cAMP analogue; no significant differences from normal were detected, suggesting that the genetic defect in cAMP metabolism is not accompanied by constituent abnormalities in phosphorylated substrates in the adult fly, and that the physiological defects in these mutants result from aberrations in the interaction of the cAMP cascade with normal substrates. The majority of Ca2+/calmodulin kinase activity (80-90%, depending on the homogenization procedure) was associated with S2, as revealed by phosphorylation of exogenous synapsin I. Two endogenous substrates for this kinase in P2 had molecular masses of approximately 45 and 87 kilodaltons. At least 11 substrates for the Ca2+/calmodulin-dependent kinase were detected in S2.(ABSTRACT TRUNCATED AT 400 WORDS)


THE EVOLUTION OF FEMALE-BIASED SEXUAL SIZE DIMORPHISM: A POPULATION-LEVEL COMPARATIVE STUDY IN HORNED LIZARDS (PHRYNOSOMA).
Female-biased sexual size dimorphism is uncommon among vertebrates and traditionally has been attributed to asymmetric selective pressures favoring large fecund females (the fecundity-advantage hypothesis) and/or small mobile males (the small-male advantage hypothesis). I use a phylogenetically based comparative method to address these hypotheses for the evolution and maintenance of sexual size dimorphism among populations of three closely related lizard species (Phrynosoma douglasi, P. ditmarsi, and P. hernandezi). With independent contrasts I estimate evolutionary correlations among female body size, male body size, and sexual size dimorphism (SSD) to determine whether males have become small, females have become large, or both sexes have diverged concurrently in body size during the evolutionary Xhistory of this group. Population differences in degree of SSD are inversely correlated with average male body size, but are not correlated with average female body size. Thus, variation in SSD among populations has occurred predominantly through changes in male size, suggesting that selective pressures on small males may affect degree of SSD in this group. I explore three possible evolutionary mechanisms by which the mean male body size in a population could evolve: changes in size at maturity, changes in the variance of male body sizes, and changes in skewness of male body size distributions. Comparative analyses indicate that population differentiation in male body size is achieved by changes in male size at maturity, without changes in the variance or skewness of male and female size distributions. This study demonstrates the potential of comparative methods at lower taxonomic levels (among populations and closely related species) for studying microevolutionary processes that underlie population differentiation.


Cefoxitin for one day vs. ampicillin and metronidazole for three days in elective colorectal surgery. A prospective, randomized, multicenter study.
In a multicenter study the prophylactic efficacy of two antibiotic regimens was tested against postoperative septic complications following elective colorectal surgery. The study was conducted in a prospective block-randomized design. Patients were preoperatively allocated to either ampicillin, 1 gm, four times daily, and metronidazole, 0.5 gm, three times daily, for 72 hours, or to cefoxitin, 2 gm, given three times in a period of 10 hours. Both regimens were initiated immediately before surgery. Forty-five patients were withdrawn from the study after randomization. Three hundred fifty two patients (175 receiving ampicillin and metronidazole and 177 receiving cefoxitin) completed the study and were followed for one month postoperatively. The frequency of septic and nonseptic complications was not statistically significant different between the two regimens. About one third of all septic complications appeared more than two weeks after surgery. It is concluded that short-term treatment with cefoxitin is at least as efficient as a three-day treatment with ampicillin and metronidazole.


Rituximab therapy for flare-up of rheumatoid arthritis after total knee replacement surgery.
A variety of drug types are used alone or in combination to manage Rheumatoid Arthritis along with physiotherapy. We report herein the case of a 51 year old female patient with a history of Rheumatoid Arthritis whose disease remained active despite being on routinely used multiple disease modifying antirheumatic drugs. The patient underwent bilateral total knee arthroplasty with subtotal synovectomy due to the severe pain caused by her concomitant age related osteoarthritis which was only aggravated by her active rheumatoid arthritis disease. Three months following surgery, the patient's knee pain with typical rheumatoid flare and swelling reappeared for which a B cell monoclonal antibody, rituximab, was given. Her number of tender and swollen joints reduced to less than three and her C-reactive protein levels and erythrocyte sedimentation rate reduced significantly along with considerable improvement in her Global Assessment score. Her severity of pain also decreased to 3 from an initial score of 8 on the Visual Analog Scale. Thus, Rituximab helped improve our patient's symptoms from recurrence of synovitis after total knee replacement.


A patient with localized megacolon and intractable constipation: evidence for impairment of colonic muscle tone.
There have been descriptions of a variety of abnormalities in motor function in patients with megacolon; however, colonic tone in megacolon has not been measured to date. Recent data suggest that colonic hypertonicity of carcinoid diarrhea is measurable with an electronic barostat. Using a barostat method, we have evaluated colonic transit, motility, and tone in a patient with severe constipation and localized chronic megacolon. Transit measurements showed a significant delay beyond the mid transverse colon; motility studies in the dilated region of colon showed abnormally low tone but normal phasic contractility, as measured by the barostat. In contrast, manometry showed low amplitude contractions relative to control data; this discrepancy probably results from the large capacity of the segment of colon examined. Chronic megacolon can be associated with abnormal colonic tone, which can be measured by means of an electronic barostat.


The issue of "long-term" fit notes for depression in the UK: patient, GP and general practice variation.
Background: Depression is an important cause of certified sickness absence in the UK. It is not known what factors are associated with variation in length of sickness certificates issued by the GP to the depressed patient.Aims: The purpose of the study was to identify patient, GP and practice factors associated with the issue of a long-term (> 4 week) fit note for depression.Methods: Sixty-eight UK general practices collected sickness certification data for 12 months.Results: Over 35% of 8127 fit notes issued to 3361 patients for depression were classed as long-term (over four weeks in duration). Having previous fit notes for depression, not having "may be fit" advice on the fit note, older patient age, the patient living in a deprived neighbourhood and a higher practice deprivation status were all significant predictors of a long-term fit note. Depression fit notes issued by female GPs to female patients were less likely to be long-term. Other GP factors were not significant predictors of a long-term depression note.Conclusions: Reducing the number of long-term sickness certificates issued to people with depression should be considered part of return-to work and job retention strategies.


Neonatal herpes simplex virus infection following Jewish ritual circumcisions that included direct orogenital suction - New York City, 2000-2011.
Herpes simplex virus (HSV) infection commonly causes "cold sores" (HSV type 1 [HSV-1]) and genital herpes (HSV-1 or HSV type 2 [HSV-2]); HSV infection in newborns can result in death or permanent disability. During November 2000-December 2011, a total of 11 newborn males had laboratory-confirmed HSV infection in the weeks following out-of-hospital Jewish ritual circumcision, investigators from the New York City Department of Health and Mental Hygiene (DOHMH) learned. Ten of the 11 newborns were hospitalized; two died. In six of the 11 cases, health-care providers confirmed parental reports that the ritual circumcision included an ultra-Orthodox Jewish practice known as metzitzah b'peh, in which the circumciser (mohel, plural: mohelim) places his mouth directly on the newly circumcised penis and sucks blood away from the circumcision wound (direct orogenital suction). In the remaining cases, other evidence suggested that genital infection was introduced by direct orogenital suction (probable direct orogenital suction). Based on cases reported to DOHMH during April 2006-December 2011, the risk for neonatal herpes caused by HSV-1 and untyped HSV following Jewish ritual circumcision with confirmed or probable direct orogenital suction in New York City was estimated at 1 in 4,098 or 3.4 times greater than the risk among male infants considered unlikely to have had direct orogenital suction. Oral contact with a newborn's open wound risks transmission of HSV and other pathogens. Circumcision is a surgical procedure that should be performed under sterile conditions. Health-care professionals advising parents and parents choosing Jewish ritual circumcision should inquire in advance whether direct orogenital suction will be performed, and orogenital suction should be avoided.


[Chronic endogenous depression of youth].
To identify psychopathological features of chronic endogenous depression that develops in youth and determine most significant diagnostic and prognostic criteria. Sixty-two male inpatients were examined who had suffered from a chronic depressive state over 2 - years in their youth (16-25 years old) and were treated at FSBSI MHRC clinic in 2008-2010. The exclusion criteria were the presence of psychotic episodes, severe deficiency symptoms, as well as clinically significant somatic, neurological and mental disorders that complicated the study. Clinical-psychopathological, psychometric (HDRS, SANS and SOPS) and statistical methods were used. Youth chronic endogenous depression is characterized by the dominance of symptoms of negative affectivity in their structure. In addition, there are disorders that differ from those of an affective spectrum. Based on the analysis of psychopathological characteristics of youth chronic endogenous depressions, two typological varieties are identified: unitary depressions (type I) and supplementary depressions (type II). Among type II depressions, 2 subtypes are distinguished: with neurosis-like and with psychopathic- like disorders. The presence of psychopathic disorders in the structure of depression is a prognostically unfavorable sign.


Enhancing Separation and Constriction of Ion Mobility Distributions in Drift Tubes at Atmospheric Pressure Using Varying Fields.
A linearly decreasing electric field has been previously proven to be effective for diffusional correction of ions in a varying field drift tube (VFDT) system, leading to higher resolving powers compared to a conventional drift tube due to its capacity to narrow distributions midflight. However, the theoretical predictions in resolving power of the VFDT were much higher than what was observed experimentally. The reason behind this discrepancy has been identified as the difference between the theoretically calculated resolving power (spatial) and the experimental one (time). To match the high spatial resolving power experimentally, a secondary high voltage pulse (HVP) at a properly adjusted time is used to provide the ions with enough momentum to increase their drift velocity and hence their time-resolving power. A series of systematic numerical simulations and experimental tests have been designed to corroborate our theoretical findings. The HVP-VFDT atmospheric pressure portable system improves the resolving power from the maximum expected of 60-80 for a regular drift tube to 250 in just 21 cm in length and 7kV, an unprecedent accomplishment.


Measurement properties of health-related quality of life measures for people living with metastatic disease of the spine: a systematic review.
Patients with spinal metastases (SM) suffer from a significant quality of life (QoL) deterioration. The measurement of QoL has garnered significant attention. In this study, we aimed to investigate the frequency of QoL measurement, systematically appraise the measurement properties of identified instruments, and facilitate the effective selection of an appropriate QoL instrument for patients with SM. This systematic review adhered to the newly revised Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement guidelines. The methodological quality of studies was assessed using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist. Measurement property results were assessed using the adapted criteria. Each measurement property was allocated a separate rating (excellent, good, fair, or poor). "Best evidence synthesis" was performed using COSMIN outcomes and the quality of findings. Two hundred and nine publications were included, and 18 instruments were identified. ECOG, EuroQol-5D, SF-36, SOSGOQ, and EORTC-QLQ-C30 were the top five instruments used for patients with SM in published literature. The measurement properties evaluated included internal consistency (four instruments), reliability (three instruments), validity (five instruments), validity (nine measures), floor and ceiling effects (four instruments), responsiveness (four instruments), and interpretability (three measures). Based on the limited evidence, Brief Pain Inventory (BPI) had the best methodological quality. Owing to the limitation of BPI in assessment domains, we cannot fully support the use of BPI. For the lack of high-quality research, it is challenging to nominate a single appropriate measure. Additional studies needed to explore the evidence before a confirmatory decision is made.


Chronic delta infection and liver biopsy changes in chronic active hepatitis B.
The delta agent consists of particles of RNA nucleoprotein and is probably a defective virus present only in the livers of patients with B-viral acute or chronic liver disease. Its frequency is significantly greater in patients with chronic active hepatitis B than in those with persistent viral hepatitis B, suggesting that chronic delta infection may increase the severity of liver disease. We studied biopsy or autopsy tissue samples from 57 patients with chronic active hepatitis B for morphologic differences between chronic delta-positive and delta-negative cases. The delta-positive cases had significantly greater portal and parenchymal inflammatory change, parenchymal necrosis, and nuclear dysplastic and polyploid change than did the delta-negative cases. These findings suggest that chronic delta infection, with ongoing delta replication, may increase the degree of hepatic damage, and possibly hasten the progression of liver disease, in patients with chronic active hepatitis B.


Effects of a tyramine-enriched meal on blood pressure response in healthy male volunteers treated with selegiline transdermal system 6 mg/24 hour.
Monoamine oxidase inhibitors are well recognized as effective antidepressant agents but are rarely used due, in part, to the risk of hypertensive crisis following the ingestion of foods high in tyramine ("cheese reaction"). A selegiline transdermal system (STS) was developed to provide antidepressant concentrations of selegiline in the brain, while preserving the gastrointestinal monoamine oxidase A (MAO-A) barrier. The present study was conducted to determine the effect of the STS 6 mg/24 hour on cardiovascular safety following the ingestion of approximately 400 mg of tyramine consumed as a component of aged cheeses. In this open-label, single-center phase I study, cardiovascular vital signs were recorded following tyramine challenges during placebo and STS 6 mg/24 hr treatment. Subjects were observed for clinical signs and symptoms of a pressor response and/or potential hypertensive crisis during and following the challenges. Ingestion of tyramine-enriched meals following 13 consecutive days of treatment with the STS 6 mg/24 hr (pharmacokinetic steady-state) produced no clinically significant changes in cardiovascular vital signs in 12 healthy adult male subjects. No evidence of a tyramine pressor effect on systolic blood pressure or evidence of hypertensive crisis occurred during the STS treatment. These results suggest that STS 6 mg/24 hr may be administered without concern for dietary tyramine consumption.


The role of vascular endothelial growth factor (VEGF) in oral dysplasia and oral squamous cell carcinoma.
A better understanding of oral cancer pathogenesis is essential to improving patient prognosis and treatment modalities. Research has shown a significant increase in vascularity during the transition from normal oral mucosa, through differing degrees of dysplasia, to invasive carcinoma. A close association between tumour angiogenesis and tumour progression to late oral squamous cell carcinoma has also been reported. Vascular endothelial growth factor (VEGF) acts to induce endothelial proliferation, migration and specialisation in new and developing vascular beds. VEGF is also a promoter of angiogenesis in many tumour types, and has therefore been subject to numerous studies in oral dysplasia and squamous cell carcinomas. The contribution of VEGF to the development of oral dysplasia and invasive carcinomas is currently disputed due to conflicting results within the literature. More research is required before VEGF technology can be used to improve the diagnosis, prognosis and treatment of sufferers.


New insights in the photochromic spiro-dihydroindolizine/betaine-system.
We have revisited the photochromic spiro-dihydroindolizine/betaine (DHI/B) system applying state-of-the-art density functional theory (DFT) calculations in combination with stationary and time-resolved absorption measurements. DHI/B-systems are becoming increasingly important as potential molecular machines, molecular switches, and photoswitchable electron-acceptors. The knowledge of the exact mechanisms of ring opening and closure, as well as of the geometries of DHI and betaine can provide critical information that will enable the design of better molecular machines and optical switches. The first surprising result concerns the electronic structure of the betaines, which is quite different than commonly assumed. The photochemical ring opening of DHI's to betaines is a conrotatory 1,5 electrocyclic reaction, whereas the thermal ring-closing occurs in the disrotatory mode. According to our results, the electrocyclic back reaction of the betaines to the DHI is NOT rate determining, as previously thought, but instead the kinetics are dictated by the cis-trans-isomerization of the betaine.


Physical restraint of patients in a psychiatric hospital.
Use of physical restraint occurs within British psychiatric hospitals yet there has been little evaluative research on current practice. The present study aims to describe a group of disturbed in-patients who had required physical restraint at some point during the course of their stay in hospital and to classify the reasons for its use. Cases were identified using Case Register data and information obtained from patients' records. In the 48 episodes of physical restraint identified, patients were predominantly schizophrenic (60%), male (67%) and had been restrained because of physical violence to others (44%) or because they were attempting to abscond (31%). Although the majority of patients were compulsorily detained prior to the use of physical restraint, three remained informal. The findings are discussed in the context of the legal justifications for use of restraint. Further research on current practice is required to enable formulation of clear guidelines.


Clinical significance of serum E-cadherin levels in patients with haematological malignancies.
E-cadherin is a transmembrane glycoprotein that mediates Ca2+-dependent intracellular adhesion in normal epithelial cells. E-cadherin levels in serum are known to be significantly elevated in patients with epithelial carcinomas. However, the role of E-cadherin in haematopoietic cells is less clear. In this study, serum E-cadherin levels were therefore determined in patients with acute or chronic leukaemia, malignant lymphoma or myelodysplastic syndromes. Significant elevation of serum E-cadherin levels was detected in patients with haematological malignancies, and between types of acute leukaemias or subtypes of myelodysplastic syndromes, stages of malignant lymphoma, and phases of chronic leukaemia, respectively, compared with those in healthy adult volunteers. These findings suggest that E-cadherin might be expressed in malignant haematopoietic cells and might be useful as a diagnostic indicator in haematological malignancies.


Hormonal regulation of adrenal microvillar channel formation.
This study examined the in vivo relationship between expression of the HDL receptor scavenger receptor class B (SR-BI) and corresponding structural changes in the rat adrenocortical cell microvillar compartment. Using hormonal stimulation and withdrawal protocols, we were able to manipulate adrenal SR-BI levels and carry out qualitative and quantitative measurements correlating SR-BI expression with microvillar mass and microvillar channel formation. Young male rats were used as controls or treated with adrenocorticotropin hormone (ACTH) (24 h), 17alpha-ethinyl estradiol (17alpha-E2) (5 days), or dexamethasone (DEX) (24 h). Quantitative Western blot analysis and immunocytochemistry indicated that ACTH and 17alpha-E2 treatment greatly increased SR-BI expression in the adrenal (especially in the microvillar compartment of adrenocortical cells), whereas DEX treatment led to a decrease of SR-BI by all measurements. At the same time, striking ultrastructural changes occurred in the adrenocortical cell microvillar compartment: e.g., microvillar area and microvillar channel formation and complexity dramatically increased (compared with control values) after ACTH or 17alpha-E2 treatment, whereas the same values declined after DEX treatment. These measurements illustrate the exceptional flexibility and responsiveness of the microvillar compartment to hormonal stimuli, and suggest that regulation of SR-BI expression and structural configuration of the surface of steroidogenic cells goes hand in hand.


A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3E gene.
A severe immunodeficiency involving a complete loss of T lymphocytes and natural killer cells was observed in independent lines of transgenic mice containing > 30 copies of the human CD3E gene (pL12). T-cell- natural killer (NK)- mice could also be generated by using a gene fragment pL12 delta 1 (without exons 4A and 5) coding for the CD3-epsilon transmembrane region and its 55-amino acid nonenzymatic cytoplasmic tail. The abnormally small thymus gland in the homozygous transgenic animals, which was approximately 1% the size of a wild-type thymus, contained only a few (2-4%) prethymocytes with a Thy-1+Pgp-1+IL-2R alpha- CD3-4-8- phenotype. In mice with lower copy numbers of the transgene thymocyte development was blocked at the Thy-1+Pgp-1-IL-2R alpha+CD3-4-8- stage, and normal NK activity was detected. Mice generated with high-copy numbers of a transgene pL12 delta 2 (pL12 delta 1 minus exons 6), coding for a truncated protein from which the CD3-epsilon extracellular domain, its transmembrane region, and most of its cytoplasmic region were absent, contained normal numbers of T lymphocytes and NK cells. These transgene effects suggested that recruitment of signal-transduction molecules by the cytoplasmic tail of this protein played an important role in the abrogation of both lineages. Taken together these observations support the notion that T lymphocytes and NK cells stemmed from a common precursor.


Antiretroviral-Experienced HIV-1-Infected Patients Treated with Maraviroc: Factors Associated with Virological Response.
There are few data on the clinical and virological factors associated with the virological response (VR) of maraviroc (MVC) in clinical practice. This study aimed to identify factors associated with the VR to MVC-containing regimens in 104 treatment-experienced but CCR5 inhibitor-naive HIV-1 patients. VR was defined at month 3 (M3) as HIV-1 RNA viral load (VL) <50 copies/ml. The impact on VR of age, sex, baseline tropism, HIV subtype (B vs. non-B), nadir CD4 cell count and CD4 cell count, baseline VL, genotypic susceptibility score of treatment, once or twice daily treatment, presence of raltegravir in optimized background therapy, and MVC concentrations was investigated. Median baseline VL was 3.3 log10 copies/ml (range 1.7-6.0 log10 copies/ml) and CD4 cell count was 299 cells/mm(3) (range 7-841 cells/mm(3)). At M3, 53.8% of patients were responders. In univariate analysis, a better efficacy of the MVC-containing regimen was associated with a high CD4 cell count (p=0.0069) and there was a trend for low baseline VL, high nadir CD4 cell count, and HIV subtype (B versus non-B). Only low baseline VL remained significantly associated with better VR in the multivariate analysis. This study demonstrated a VR of an optimized antiretroviral treatment including MVC in clinical practice similar to that observed in clinical trials. The factors associated with VR were higher baseline CD4 cell count in univariate analysis and lower baseline VL in multivariate analysis.


Base-compositional biases and the bat problem. II. DNA-hybridization trees based on AT- and GC-enriched tracers.
We conducted a series of parallel DNA-hybridization experiments on a small group of bats (species of Pteropus, Rhinolophus, Noctilio and Pteronotus) and outgroups (Lemur, Cynocephalus, Didelphis), using whole-genome labels and tracers made from extracts enriched with AT and two levels of GC content. FITCH (additive phylogenetic trees) topologies were constructed from the four sets of comparisons, indexed as both delta Tmode and delta NPHs (normalized percentage of hybridization). Based on our previous work showing that the shared AT bias of pteropodids and some microchiropterans may affect the rank-ordering of taxa based on either AT- or GC-rich labels, our expectation was that the resulting trees would show differing topologies when generated from tracers made with the variously enriched DNA extracts. Whereas there was some variation among the trees, most of them grouped the bats together, and almost all paired the representative megachiropteran and rhinolophoid microchiropteran as sister-taxa in contrast to the other microchiropterans. As the pteropodid-rhinolophoid relationship is an unexpected and unlikely one, we attribute this association to an AT bias that was not obviated even by our most GC-rich labels, and suggest that such a bias may compromise the truth of some molecular trees. Accordingly, we believe the broader issue of bat monophyly remains unresolved by DNA-hybridization and probably also by gene-sequencing studies.


Online gamma-camera imaging of 103Pd seeds (OGIPS) for permanent breast seed implantation.
Permanent brachytherapy seed implantation is being investigated as a mode of accelerated partial breast irradiation for early stage breast cancer patients. Currently, the seeds are poorly visualized during the procedure making it difficult to perform a real-time correction of the implantation if required. The objective was to determine if a customized gamma-camera can accurately localize the seeds during implantation. Monte Carlo simulations of a CZT based gamma-camera were used to assess whether images of suitable quality could be derived by detecting the 21 keV photons emitted from 74 MBq (103)Pd brachytherapy seeds. A hexagonal parallel hole collimator with a hole length of 38 mm, hole diameter of 1.2 mm and 0.2 mm septa, was modeled. The design of the gamma-camera was evaluated on a realistic model of the breast and three layers of the seed distribution (55 seeds) based on a pre-implantation CT treatment plan. The Monte Carlo simulations showed that the gamma-camera was able to localize the seeds with a maximum error of 2.0 mm, using only two views and 20 s of imaging. A gamma-camera can potentially be used as an intra-procedural image guidance system for quality assurance for permanent breast seed implantation.


Grandmother breastfeeding support: what do mothers need and want?
Grandmothers are an important source of support for new mothers. Their infant feeding experience and knowledge can influence mothers' decisions to initiate and continue breastfeeding. The objective of this study was to explore mothers' perceptions of grandmothers' breastfeeding knowledge and support, as part of a larger study to design an intervention that facilitates the development of grandmothers' support of breastfeeding. Thirty mothers participated in one of four focus groups held in a North Texas metropolitan area. We analyzed the text of each focus group interview using the content analysis method and identified five themes within and across groups that described mothers' perceptions of grandmother breastfeeding support. The essence of what mothers needed and wanted from grandmothers could be summarized as grandmother breastfeeding advocacy, which is defined by the two themes, "valuing breastfeeding" and "loving encouragement." Three other themes, "acknowledging barriers,""confronting myths," and "current breastfeeding knowledge," reflected mothers' perceptions of what grandmothers need to become their advocates, particularly if they did not breastfeed their own children. Breastfeeding occurs within the context of an extended family in which grandmothers bring their own infant feeding practices and beliefs to their support of new mothers. Mothers need and want grandmothers' support, but their advice and concerns may reflect cultural beliefs that do not protect breastfeeding. Including grandmothers in conversations about breastfeeding practices can be one way for health caregivers to enhance grandmothers' knowledge and support of breastfeeding.


Clinical Characteristics of Idiopathic Epidermoid and Dermoid Cysts of the Ear.
Epidermoid and dermoid cysts are benign cystic lesions, lined by ectodermal squamous epithelium. They are not common in the head and neck areas, which constitute ~7% of all cases of epidermoid and dermoid cysts. The aim of this study was to investigate the clinical characteristics of epidermoid and dermoid cysts that developed around the ear. The clinical records were retrospectively reviewed for patients confirmed histologically as idiopathic epidermoid and dermoid cysts of the ear from January 2011 to December 2015. Total 15 cases consisted of 14 epidermoid cysts and only 1 dermoid cyst. There were 11 males and 4 females (mean age of 37.8±16.8 years old). Right side was 7 cases and left was 8. The cyst was located at the lobule in 4 cases, at the ear canal in 4 cases, at the preauricular area in 4 cases, and at the postauricular area in 3 cases. In cases of epidermoid cysts, there was no significant difference in age, sex, and size according to the location. Patients with cysts on helix were younger than others. This study demonstrated that most cutaneous cysts developing around the ear were epidermoid cysts and there was no site preference for occurrence of epidermoid cysts.


Quo vadis nanomedicine?
The interdisciplinary workshop 'Quo Vadis Nanomedicine?' was held on 10-11 April 2014 at the University of Exeter (Exeter, UK), coorganized by the Schumpeter-Research Group 'Innovations in Nanomedicine', funded by the VolkswagenStiftung at Exeter University, and the Sonderforschungsbereich (STB; collaborative research centre) 1066 'Nanodimensional Polymer Therapeutics for Tumor Therapy', funded by the German Research Council (DFG) at the Johannes Gutenberg-University (Mainz, Germany). This international workshop brought together scientists, philosophers and social scientists in order to reflect, discuss and rethink the practices, concepts, methods, models and metaphors, as well as the medical and regulatory needs in current nanomedical research and its possible futures.