Colloid supported lipid bilayers for self-assembly.
The use of colloid supported lipid bilayers (CSLBs) has recently been extended to create colloidal joints, that enable the assembly of structures with internal degrees of flexibility, and to study lipid membranes on curved and closed geometries. These novel applications of CSLBs rely on previously unappreciated properties: the simultaneous fluidity of the bilayer, lateral mobility of inserted (linker) molecules and colloidal stability. Here we characterize every step in the manufacturing of CSLBs in view of these requirements using confocal microscopy and fluorescence recovery after photobleaching (FRAP). Specifically, we have studied the influence of different particle properties (roughness, surface charge, chemical composition, polymer coating) on the quality and mobility of the supported bilayer. We find that the insertion of lipopolymers in the bilayer can affect its homogeneity and fluidity. We improve the colloidal stability by inserting lipopolymers or double-stranded inert DNA into the bilayer. We include surface-mobile DNA linkers and use FRAP to characterize their lateral mobility both in their freely diffusive and bonded state. Finally, we demonstrate the self-assembly of flexibly linked structures from the CSLBs modified with surface-mobile DNA linkers. Our work offers a collection of experimental tools for working with CSLBs in applications ranging from controlled bottom-up self-assembly to model membrane studies.


In vitro fertilization and embryo culture strongly impact the placental transcriptome in the mouse model.
Assisted Reproductive Technologies (ART) are increasingly used in humans; however, their impact is now questioned. At blastocyst stage, the trophectoderm is directly in contact with an artificial medium environment, which can impact placental development. This study was designed to carry out an in-depth analysis of the placental transcriptome after ART in mice. Blastocysts were transferred either (1) after in vivo fertilization and development (control group) or (2) after in vitro fertilization and embryo culture. Placentas were then analyzed at E10.5. Six percent of transcripts were altered at the two-fold threshold in placentas of manipulated embryos, 2/3 of transcripts being down-regulated. Strikingly, the X-chromosome harbors 11% of altered genes, 2/3 being induced. Imprinted genes were modified similarly to the X. Promoter composition analysis indicates that FOXA transcription factors may be involved in the transcriptional deregulations. For the first time, our study shows that in vitro fertilization associated with embryo culture strongly modify the placental expression profile, long after embryo manipulations, meaning that the stress of artificial environment is memorized after implantation. Expression of X and imprinted genes is also greatly modulated probably to adapt to adverse conditions. Our results highlight the importance of studying human placentas from ART.


Cytocompatible cerium oxide-mediated antioxidative stress in inhibiting ocular inflammation-associated corneal neovascularization.
As oxidative stress is involved with inflammation and neovascularization, blocking oxidative stress may be beneficial for reducing inflammation. To investigate the potential use of cerium oxide nanoparticles (CeNPs) in treating neovascularization-related ophthalmic diseases, various CeNP samples were synthesized, and the sample with the best antioxidant efficacy was used in a rat model of inflammation-associated corneal neovascularization. This synthesized cerium oxide showed good biocompatibility and was capable of mediating a decrease in the expression levels of inflammatory factors via antioxidative stress. Additionally, in vitro tests showed that the Ce3+/Ce4+ ratio of the CeNPs directly affected the antioxidative activity, with higher ratios achieving better efficacy. The anti-inflammatory efficacy of the functional CeNPs was examined both in vitro and in vivo. Slit-lamp biomicroscopy and histological analysis revealed the gradual development of corneal neovascularization, suggesting that inflammation and neovascularization could be controlled by reducing the level of oxidative stress. CeNP-induced antioxidation could serve as a new strategy in the development of long-acting functional agents for treating ophthalmic diseases.


ERRATUM: Kidney decontamination during perfusion for transplantation procedure: In vitro and ex vivo viability analysis.
Organ transplantations have an increasing medical relevance. It is becoming a regular procedure with an increase in individuals waiting for organs. The increase in the number of discarded organs is mostly due to the donor's bacterial and/or viral infection. In this article, we are demonstrating the feasibility of reduction of the bacterial load in the kidney model by using Ultraviolet-C (UV-C) as a germicidal agent in circulating liquids. Using Staphylococcus aureus as a bacteria model, we were able to demonstrate that in less than 30 min of liquid circulation and associated to irradiation, the bacterial load of the perfusate Custodiol® HTK, histidine-tryptophan-ketoglutarate (solution with 5 log CFU ml-1 ), was fully eliminated. A modeling approach was created to verify the possibility of bacterial load decrease, when an organ (here, a renal experimental model) is present in the circuit, releasing a varied rate of microorganisms over time, while the solution is irradiated. Finally, we use an ex vivo model with a swine kidney, circulating in the preservation solution with a Lifeport® Kidney Transporter machine, to demonstrate that we can contaminate the organ and then promote the elimination of the microbiological load. The results show the feasibility of the technique.


Microwave cyclodestruction for glaucoma in a rabbit model.
Microwave thermotherapy was used to treat experimentally induced glaucoma. Microwave-induced cyclodestruction was successful in reducing intraocular pressure in all treated glaucomatous eyes for 4 weeks. Two additional glaucomatous eyes were left untreated to serve as controls, and were noted to have persistently elevated intraocular pressures. Six additional eyes were then subjected to an equivalent treatment (50 degrees C in five 1-minute applications), which resulted in approximately 180 degrees of heat treatment just posterior to the corneoscleral limbus. These specimens were evaluated with light microscopy at baseline, 24 hours, and 7 days after treatment. Our clinical and histopathologic evaluations suggested that microwave thermotherapy (delivered under thermometry control) allowed for chorioretinal/ciliary body destruction that resulted in reductions of intraocular pressure in glaucomatous eyes.


Evaluation of reproterol's effectiveness in preventing exercise-induced bronchospasm in children.
The authors have evaluated the effectiveness of the protection of a new beta 2-adrenergic compound, reproterol, against broncho-constriction induced by physical exercise in a group of individuals of paediatric age sensitive to broncho-stimulation. This study has been carried out comparing reproterol with salbutamol, using placebo as a control, following a randomized single-blind crossover trial. The provocation test has been performed following the instructions of the Italian Society of Paediatrics. The drugs have been administered in the oral liquid form at the dose of 0.28 mg/kg and 0.1 mg/kg of reproterol and salbutamol, respectively. The two substances have shown a similar preventive effectiveness in controlling exercise-induced asthma up to 2 hours from administration with reproterol having a stronger action at the beginning of the observation.


The influence of distant surcharge load with a finite length on the cantilever walls.
The behavior of a sheet pile wall constructed on saturated sand soil and exposed to a distant surcharge load with a finite length at the top of the backfill soil is examined in this study. For this aim, various internal friction angles (φ), and natural ground surface for the groundwater level are considered. Furthermore, it is considered that the sheet pile wall acts as cantilevered and supports a six-meter-high (H) excavation. The simple "45° distribution" (AP) and uniform distribution of "Beton Kalender distribution" (BK) methods are examined with Coulomb's and Rankine's earth pressure theories in analytical solutions, while the finite element method (FEM) is used as a numerical method. The present research has two primary goals: a) determining the best analytical approach that provides the maximum bending moment (Mmax) values that are more comparable to those of the FEM b) examining the behavior of the sheet pile wall considering several effects of load scenarios, depth (D) and section type (ST) of the wall, and the soil properties together. In this context, parametrical analyses are performed. Consequently, it is found that the distance of the surcharge load (x1) has a pronounced effect than the intensity (q) and length (Ls) of the surcharge load on the behavior of the sheet pile, and this effect vanishes for the large values of x1. Furthermore, Coulomb theory provides more convenient values with FEM for Mmax than those obtained from Rankine theory. The Mmax values obtained from FEM are generally less than those from BK, while they are greater than those from APC.


Myoepithelial carcinoma of the breast.
Breast carcinoma is the commonest cancer among females in a majority of the Indian cities. The advances in the research and management have improved the breast cancer survival significantly in the past three decades globally. Adenocarcinoma is the commonest histological variant which arises from the ductal epithelia. The myoepithelial cells (ME) are the normal components of the breast parenchyma, which separate the ductal epithelia from the basement membrane and the stroma. The pure ME cell carcinoma is extremely rare and only 38 cases have been reported so far in the indexed literature. This may owe to the difficulties in the identification, and the non availability of established diagnostic criteria. We herein describe the clinical, radiological and the pathological characteristics of a case of myoepithelial carcinoma, to supplement the available literature. The possible impact of these cells in clinical practice was also reviewed. Identification and the further research on the genesis of these tumours, and the pathways by which the ME cells regulate the milieu interior of the breast epithelia, may unravel new molecular targets to prevent or treat both epithelial and myoepithelial cancers at early stages.


Multi-criteria decision analysis for health technology assessment in Canada: insights from an expert panel discussion.
Multi-criteria decision analysis (MCDA), a decision-making tool, has received increasing attention in recent years, notably in the healthcare field. For Canada, it is unclear whether and how MCDA should be incorporated into the existing health technology assessment (HTA) decision-making process. To facilitate debate on improving HTA decision-making in Canada, a workshop was held in conjunction with the 8th World Congress on Health Economics of the International Health Economics Association in Toronto, Canada in July 2011. The objective of the workshop was to discuss the potential benefits and challenges related to the use of MCDA for HTA decision-making in Canada. This paper summarizes and discusses the recommendations of an expert panel convened at the workshop to discuss opportunities and concerns with reference to the implementation of MCDA in Canada.


Bone cell mitogenic action of fluoroaluminate and aluminum fluoride but not that of sodium fluoride involves upregulation of the insulin-like growth factor system.
The fluoroaluminate (AlF(4)(-)) ion and sodium fluoride (NaF) have previously been shown to be bone cell mitogens. This study sought to determine whether the bone cell mitogenic action of AlF(4)(-) and/or NaF would involve the insulin-like growth factor (IGF) regulatory system. We evaluated the effect of mitogenic doses of AlF(4)(-) and NaF on the mRNA levels and the protein level (in conditioned media [CM]) of several components of the IGF system (i.e., IGF-2, IGF binding protein [IGFBP]-4, and IGFBP-5) in human TE85 osteosarcoma cells. Aluminum fluoride (AlF(3)) was included for comparison. NaF, AlF(3), and AlF(4)(-), each at 50-100 micromol/L, increased [3H]thymidine incorporation in TE85 cells. Mitogenic concentrations of AlF(3) and AlF(4)(-): (1) increased the mRNA (up to twofold after 24 h treatment) and protein (in CM) levels (up to 2.5-fold after 48 h treatment) of IGF-2; (2) increased the mRNA level (twofold) and the protein level in CM (up to threefold) of stimulatory IGFBP-5; and (3) either reduced slightly or had no effect on the mRNA and protein (in CM) levels of the inhibitory IGFBP-4. Conversely, mitogenic concentrations of NaF had no significant effects on the protein (in CM) or mRNA level of IGF-2, IGFBP-4, or IGFBP-5. The addition of an inhibitory concentration of IGFBP-4 completely abolished the bone cell mitogenic activity of AlF(3) and AlF(4)(-) but not that of NaF. The findings of this study provide strong evidence that the bone cell mitogenic activity of AlF(4)(-) and AlF(3), but not that of NaF, is mediated by the upregulation of the IGF regulatory system.


A synthetic de-greening gene circuit provides a reporting system that is remotely detectable and has a re-set capacity.
Plants have evolved elegant mechanisms to continuously sense and respond to their environment, suggesting that these properties can be adapted to make inexpensive and widely used biological monitors, or sentinels, for human threats. For a plant to be a sentinel, a reporting system is needed for large areas and widespread monitoring. The reporter or readout mechanism must be easily detectable, allow remote monitoring and provide a re-set capacity; all current gene reporting technologies fall short of these requirements. Chlorophyll is one of the best-recognized plant pigments with an already well-developed remote imaging technology. However, chlorophyll is very abundant, with levels regulated by both genetic and environmental factors. We designed a synthetic de-greening circuit that produced rapid chlorophyll loss on perception of a specific input. With induction of the de-greening circuit, changes were remotely detected within 2 h. Analyses of multiple de-greening circuits suggested that the de-greening circuit functioned, in part, via light-dependent damage to photosystem cores and the production of reactive oxygen species. Within 24-48 h of induction, an easily recognized white phenotype resulted. Microarray analysis showed that the synthetic de-greening initiated a process largely distinct from normal chlorophyll loss in senescence. Remarkably, synthetically de-greened white plants re-greened after removal of the inducer, providing the first easily re-settable reporter system for plants and the capacity to make re-settable biosensors. Our results showed that the de-greening circuit allowed chlorophyll to be employed as a simple but powerful reporter system useful for widespread areas.


Mobilizing serum factors and immune cells through exercise to counteract age-related changes in cancer risk.
An increasing body of evidence suggests that age-related immune changes and chronic inflammation contribute to cancer development. Recognizing that exercise has protective effects against cancer, promotes immune function, and beneficially modulates inflammation with ageing, this review outlines the current evidence indicating an emerging role for exercise immunology in preventing and treating cancer in older adults. A specific focus is on data suggesting that muscle- derived cytokines (myokines) mediate anti-cancer effects through promoting immunosurveillance against tumourigenesis or inhibiting cancer cell viability. Previous studies suggested that the exercise-induced release of myokines and other endocrine factors into the blood increases the capacity of blood serum to inhibit cancer cell growth in vitro. However, little is known about whether this effect is influenced by ageing. Prostate cancer is the second most common cancer in men. We therefore examined the effects of serum collected before and after exercise from healthy young and older men on the metabolic activity of androgen-responsive LNCaP and androgen-unresponsive PC3 prostate cancer cells. Exercise-conditioned serum collected from the young group did not alter cell metabolic activity, whereas post-exercise serum (compared with pre-exercise serum) from the older men inhibited the metabolic activity of LNCaP cancer cells. Serum levels of candidate cancer-inhibitory myokines oncostatin M and osteonectin increased in both age groups following exercise. Serum testosterone increased only in the younger men postexercise, potentially attenuating inhibitory effects of myokines on the LNCaP cell viability. The data from our study and the evidence in this review suggest that mobilizing serum factors and immune cells may be a key mechanism of how exercise counteracts cancer in the older population.


Cytotoxic T lymphocyte nonresponsiveness to the male antigen H-Y in the H-2Db mutants bm13 and bm14. Complementation of the response in F1 crosses with the I-Ab mutant bm12 nonresponder and failure of B6 or Db mutant mice tolerant of each other to respond to allogeneic male cells.
The cytotoxic T-lymphocyte (CTL) response against the male-specific antigen H-Y in C57BL/6 (B6, H-2b) mice is regulated by the I-Ab and Db molecules. From previous studies, we concluded that the bm12 I-Ab mutant does not respond to H-Y, because of a deletion in its T-helper-cell repertoire. We now demonstrate that two Db mutants, bm13 and bm14, also fail to generate a CTL response to H-Y. The bm12 class-II mutant on one hand and the bm13 and bm14 class-I mutants on the other complemented each other for the H-Y-specific CTL response in (bm12 X bm13)F1 and (bm 12 X bm 14)F1 hybrids. This indicates that the need for tolerance of the mutant class II and class I molecules in these hybrids does not create deletions in the I-Ab-restricted T helper cell and Db-restricted CTL repertoire for H-Y. This study constitutes the first demonstration with H-2 mutants that a CTL response controlled by class I and class II MHC molecules is complemented in an F1 cross between a class I and a class II nonresponder. (B6 X bm 13)F1 and (B6 X bm 14)F1 hybrids only responded to H-Y when the antigen was presented on F1 or B6 antigen-presenting cells (apc) but not on Db mutant apc. B6 or Db mutant responders rendered neonatally tolerant of each other failed to respond to the H-Y antigen presented on the tolerogenic allogeneic cell. In the tolerized animals, a response was only seen with responder (B6) type T cells and responder type (B6) apc, indicating that both the T cell source and the MHC type of the apc have to be taken into account in this system. Thus, Ir genes may act at the level of both the T cell repertoire and antigen presentation.


A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.
Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.


The role of the federal government in eliminating health disparities.
Minorities live sicker and die sooner from too many acute and chronic illnesses. To eliminate racial and ethnic disparities in health, Congress and the Bush administration must address the serious challenge of increasing minorities' access to health care and improving the quality of care they receive. We clearly need to expand Medicaid and the State Children's Health Insurance Program (SCHIP), but we must also develop and train culturally competent providers, increase the diversity of the health care workforce, collect better race/ethnicity health data, and make a greater investment in public health.


Didymium azorellae, a new myxomycete from cushion plants of cold arid areas of South America.
A new species of Didymium (Myxomycetes), D. azorellae, isolated from plant debris in a moist chamber, collected during studies of cold arid areas of Argentina and Peru, is described. It can be distinguished by its small size, the tightly packed layer of lime crystals on the peridium, the very scant, or absent, capillitium, and the unique spore ornamentation, especially by scanning electron microscopy. The species developed on dead leaves of cushion plants growing in the extremely harsh environments of the central Andean puna at almost 5000 m elevation and the Andino-Patagonian steppe. Morphology was examined with scanning electron microscopy and light microscopy, and micrographs of relevant details are included here. In order to confirm the identity of the new species described in this paper, a molecular study was conducted based on partial sequences of both the 18S rRNA and the elongation factor 1-alpha gene. Phylogenetic analysis including two specimens from different countries of the newly described species, Didymium azorellae, strongly supports the grouping of these specimens as a separate clade from the rest of the analyzed species.


Immunoglobulin G4-Related Disease Arising from the Bladder Wall.
Immunoglobulin G4-related disease (IgG4-RD) is a recently described inflammatory disease with multiorgan involvement. Although there were reports of IgG4-related kidney disease or prostatitis, this disease rarely presents in the bladder. In this report, we describe a case of IgG4-RD arising from bladder wall. This patient had a past history of autoimmune pancreatitis and presented with incidental bladder tumor. Magnetic resonance imaging showed low signal intensity tumor on T2-weighted image, and no invasion to the muscular layer. We performed transurethral resection. Pathological findings showed that there were chronic inflammatory changes infiltrates under the epithelium, and IgG4-positive plasma cells were scattered throughout the lesion. They met the pathological diagnostic criteria for IgG4-RD. We think this is the first case of IgG4-RD arising from and confined to the inside of the bladder wall.


Circulation of potassium across the plasma membrane of Blastocladiella emersonii: K+ channel.
A previous paper reported that the water mold Blastocladiella emersonii generates a transcellular electrical current, such that positive charges enter the rhizoid and leave from the thallus (Stump et al., Proc. Natl. Acad. Sci. U.S.A. 77: 6673-6677, 1980). To begin to understand the genesis of this current we investigated ionic relationships in this organism by use of intracellular microelectrodes. In cells suspended in buffered CaCl2, the membrane potential could be accounted for as a K+ diffusion potential; no evidence for an electrogenic pump was obtained. Potassium ions diffuse outward by a pathway that also carries Rb+ and Ba2+, but excludes both smaller and larger ions (Li+, Na+, Cs+, Mg2+, Ca2+, and choline). Chloride and other anions make little contribution to the potential, but the presence of Ca2+ in the external medium is required for successful potential measurements. In growing cells, the internal K+ concentration is generally somewhat higher than would be expected if the K+ distribution were determined entirely by the membrane potential. Under certain conditions, net uptake of K+ against the electrochemical potential gradient was observed. We suggest that K+ is actively accumulated by a primary transport system that may exchange K+ for H+, and that K+ leaks passively outward through the K+ channel. The K+ circulation across the membrane amounts to about 2% of the K+ pool per min, or 4.5 microA/cm2 of surface area. We propose that this K+ circulation is one arm of the transcellular current, carrying positive charge out of the thallus.


The indications for interbody fusion cages in the treatment of spondylolisthesis: analysis of 120 cases.
This study retrospectively examines outcomes of unilateral transforaminal lumbar interbody fusion (TLIF) with posterior fixation using anterior carbon fiber cages and 360 degrees fusion in spondylolisthesis. The goals were to examine the outcomes and perioperative complications of using anterior column support in the treatment of various types of spondylolisthesis. In 2000, Brantigan et al reported the Brantigan interbody fusion cage used as a posterior lumbar interbody fusion in the US IDE clinical trial. This is the largest series to date of TLIF cages specifically used in the treatment of spondylolisthesis. A comprehensive long-term follow-up study was conducted to evaluate the fusion success and morbidity following implantation with an anterior column support and posterior pedicle screw fixation. The 120 patients with spondylolisthesis were comprised by 11 cases, dysplastic; 58 cases, degenerative; and 51 cases, isthmic-acquired spondylolisthesis. Anterior column support was either a rectangular carbon fiber/PEEK device or a cylindrical carbon fiber/PEEK device. Twenty-eight cases (23%) were revisions. There were no pseudarthrosis, instrumentation failures, or significant subsidence at the TLIF level. The disc space height and foraminal height were restored as part of the surgical procedure. Disc height, as measured from the posterior edge of the superior vertebral body, increased from a mean of 5.6 mm before surgery to a mean of 9.3 mm after surgery. Although reduction of the slip was not the primary goal during the surgical procedure for the 120 cases with spondylolisthesis (isthmic-acquired = 51, degenerative = 58, and dysplastic = 11), the 23% slip reduction achieved at surgery was maintained at follow-up. Mean operative time was 143 +/- 33 minutes (range, 70-255 minutes) for all cases. Mean blood loss was 724 +/- 431 mL (range, 300-2,500 mL). There were seven incidental durotomies and three infections. One patient with Grade I degenerative spondylolisthesis required revision of the carbon fiber cage for posterior migration secondary to a traumatic event 3 months after surgery. Fusion success was 98% using the criteriaof Lenke for the posterior fusion and Brantigan and Steffee for the TLIF graft incorporation. Interbody cages in spondylolisthesis are useful to increase neuroforaminal height, to facilitate reduction, and to improve the chances of achieving a successful 360 degrees fusion.


Intracellular Pathogen Infections and Immune Response in Autism.
Perinatal exposure to infections during critical developmental periods is a promising area of study in autism spectrum disorder (ASD). Epidemiological data has highlighted this relationship, pointing out significant correlations between perinatal exposure to pathogens and the occurrence of ASD. The aim of this review is to critically examine the present state of the art on intracellular pathogenic infection during pregnancy and postnatally, pointing out possible correlations with the development of ASD. We reviewed and collected studies concerning potential associations between intracellular pathogens like viral, bacterial, and parasite infection and the risk of ASD. We included 14 publications, considering bacterial and/or viral infection that demonstrated the potential to trigger ASD. Nine case-control studies were included and 5 of them reported an association between infections and ASD. One of the 2 cohorts investigated demonstrated that maternal infection increased the risk of ASD in the offspring. Three cross-sectional studies demonstrated that ASD patients presented with chronic infections and active neuroinflammatory processes. Most of the reports suggest inflammatory response as a common factor, and interleukin 6 appears to be a key-player in this process. The immune responses generated by organisms that cause perinatal maternal infection, i.e., bacteria, viruses, or parasites, have been associated with the development of autism in offspring. Physiological changes transmitted from the mother during chronic or acute inflammation should be further investigated so that modulatory preventive measures can be developed.


Exosomes: Nanocarriers of Biological Messages.
Cell-cell communication is crucial to maintain homeostasis in multicellular organism. Cells communicate each other by direct contact or by releasing factors that, soluble or packaged in membrane vesicles, can reach different regions of the organism. To date numerous studies highlighted the existence of several types of extracellular vesicles that, differing for dimension, origin and contents, play a role in physiological and/or pathological processes. Among extracellular vesicles, exosomes are emerging as efficient players to modulate target cells phenotype and as new non-invasive diagnostic and prognostic tools in multiple diseases. They, in fact, strictly reflect the type and functional status of the producing cells and are able to deliver their contents even over a long distance. The results accumulated in the last two decades and collected in this chapter, indicated that exosomes, can carry RNAs, microRNAs, long non-coding RNAs, DNA, lipids, metabolites and proteins; a deeper understanding of their contents is therefore needed to get the most from this incredible cell product.


Galvanic action: a case report.
The presence of two dissimilar metals in the mouth acting as electrodes, with saliva serving as an electrolyte, can generate an intraoral electric current known as galvanic action. The result of these circuits is usually a transient, unpleasant feeling in the mouth, but occasionally other tissues in the body can be affected. This article presents a report of a patient with a presumable galvanic action that began with the insertion of orthodontic appliances and developed into a serious, debilitating illness.


Management of Pancreatolithiasis: A Nationwide Survey in Japan.
The aim of this study was to assess prevailing treatment of pancreatolithiasis in Japan. We surveyed clinical data from 1834 patients (1479 men and 355 women) at 125 hospitals. Extracorporeal shock-wave lithotripsy (ESWL) was performed alone in 103 patients (5.6%), ESWL plus an endoscopic procedure in 446 (24.3%), endoscopic treatment alone in 261 (14.2%), and surgery in 167 (9.1%). Other treatments were given to 358 (19.5%), whereas 499 (27.2%) received no treatment. Symptoms were relieved in 85.7% after ESWL, 80.8% after endoscopic treatment alone, and 92.8% after surgery. Early complication rates within 3 months after ESWL, endoscopic treatment alone, and surgery were 8%, 4.5%, and 27.1%, respectively. Late complications after ESWL, endoscopic procedures alone, and surgery were 1.7%, 2.5%, and 8.2%, respectively. Symptom relief but also early and late complications were greater after surgery than after ESWL and endoscopic treatment. Among 417 patients undergoing ESWL, 61 (14.6%) required surgery, as did 32 (16%) of 200 patients treated endoscopically. Surgery was required less frequently following initial operative treatment (11/164 patients [6.7%]). Nonsurgical initial treatments were chosen more frequently. First-line treatment of pancreatolithiasis should be ESWL with or without endoscopy because of minimal invasiveness and fewer complications.


Facilitation of macrofaunal assemblages in marinas by the habitat-forming invader Amathia verticillata (Bryozoa: Gymnolaemata) across a spatiotemporal scale.
Widespread habitat-forming invaders inhabiting marinas, such as the spaghetti bryozoan Amathia verticillata, allow exploring facilitation processes across spatiotemporal contexts. Here we investigate the role of this bryozoan as habitat for native and exotic macrofaunal assemblages across different ecoregions of Western Mediterranean and East Atlantic coasts, and a monthly variation over a year. While only 7 (all peracarid crustaceans) of the 54 associated species were NIS, they dominated macrofaunal assemblages in terms of abundance, raising the potential for invasional meltdown. NIS richness and community structure differed among marinas but not among ecoregions, highlighting the importance of marina singularities in modulating facilitation at spatial scale. Despite facilitation did not depend on bryozoan abundance fluctuations, it was affected by its deciduous pattern, peaking in summer and disappearing in late winter. Monitoring A. verticillata in marinas, especially in summer periods, may improve the detection and management of multiple associated NIS.


Leg perforators and leg length: an anatomic study focusing on topography and angiogenesis.
The highly variable anatomic distribution of lower leg perforators is explored, with a standardization based on leg length. The possibility of a correlation between leg length and number of perforators is investigated. Twenty-two lower limbs of cadavers were utilized for an anatomic study on the leg perforators branching from the three major vascular axes, anterior tibial, posterior tibial, and fibular. The parameters considered were the number of vascular pedicles per each major axis, the caliber, the distance of the fascial hole from the bony landmark (knee joint line), and the route of the vessels (muscular, septal). Arteries taken into account had a caliber of 0.5 mm or greater, with a maximum of 1.7 and a mean of 0.78. The perforators of the anterior tibial artery distribute along the entire length of the leg, but the peak of concentration is between second and third tenth and around the middle tenth. The fibular system provides perforators between the fourth and seventh tenth. The posterior tibial perforators concentrate to the middle third and to the supramalleolar region. A correlation exists between leg length and number of perforating vessels for the tibial vascular systems, possibly due to neoangiogenesis during growth, at the level of the metaphyseal plates. On the contrary no relationship was noticed for the fibular artery, whose perforators concentrate far from the growth cartilages. Some tenths where perforators concentrate are identifiable. Tibial systems have a perforator incidence depending on leg length, which, on the contrary, does not influence the number of fibular perforators.


Comparative analysis of mRNA and protein degradation in prostate tissues indicates high stability of proteins.
Deterioration of biomolecules in clinical tissues is an inevitable pre-analytical process, which affects molecular measurements and thus potentially confounds conclusions from cohort analyses. Here, we investigate the degradation of mRNA and protein in 68 pairs of adjacent prostate tissue samples using RNA-Seq and SWATH mass spectrometry, respectively. To objectively quantify the extent of protein degradation, we develop a numerical score, the Proteome Integrity Number (PIN), that faithfully measures the degree of protein degradation. Our results indicate that protein degradation only affects 5.9% of the samples tested and shows negligible correlation with mRNA degradation in the adjacent samples. These findings are confirmed by independent analyses on additional clinical sample cohorts and across different mass spectrometric methods. Overall, the data show that the majority of samples tested are not compromised by protein degradation, and establish the PIN score as a generic and accurate indicator of sample quality for proteomic analyses.


Seasonal variations in bipolar disorder admissions and the association with climate: a population-based study.
Although seasonal influences on bipolar disorder admissions have long been observed, the issues of seasonality on different subtypes of mood episodes and the effects of associated climatic parameters remain controversial. This study sets out to examine seasonal variations in bipolar disorder admissions and the association with climate in Taiwan, a subtropical area with fairly constant weather conditions. This retrospective population-based study uses the Taiwan National Health Insurance Research Database for 1999-2003, identifying 15,060 admissions for bipolar disorder, comprising of 8631 manic, 2078 depressive and 4351 mixed/unspecified episodes. The auto-regressive integrated moving average model was applied to examine the presence of seasonality and the association with climate in each subtype of mood episodes. Admission peaks were noted during spring/summer, early winter and early spring, for manic, depressive and mixed/unspecified episodes, respectively, while the associations with climatic parameters varied between the subtypes of mood episodes. Seasonality in bipolar disorder does exist for all subtypes of mood episodes. The distinct seasonal patterns and various associations with the climatic parameters imply different underlying mechanisms for the onset of each subtype of mood episodes. The association between admission rates and certain climatic variables found in this study is informative and could pave the way for future studies aimed at exploring the influence of climate on the psychopathology of bipolar patients as well as the underlying mechanisms.


Concentration-dependent displacement of cholesterol in micelles by hydrophobic rice bran protein hydrolysates.
Rice bran, containing about 100-150 g kg(-1) protein, is a by-product of rice milling that has only become an available ingredient in recent years owing to the centralisation of rice milling. Rice bran, but not its protein fraction or hydrolysates, has been shown to have a hypocholesterolaemic effect. Peptides from soy, milk and other foods have been proposed to have hypocholesterolaemic effects based on their ability to lower cholesterol solubility in bile acid/phosphotidyl choline micelles. Rice bran protein hydrolysates (RBPHs) were prepared and investigated for their potential to lower cholesterol concentration in micelles. The RBPHs were produced by digestion using four different peptidases, alcalase 2.4L(®), neutrase 0.8L(®), papaya latex papain and porcine pancreas trypsin, and then fractionated by hydrophobicity using styrene/divinylbeneze resins. Alcalase 2.4L(®) produced the highest degree of hydrolysis, and the resulting hydrolysates had the highest micellar cholesterol inhibition ability in an in vitro hypocholesterolaemic test. The adsorption dynamics of four different macroporous resins, DA201-C, Sepabeads SP207 and SP825 and Diaion HP20, were determined using the Langmuir isotherm model. DA201-C had the highest adsorption capacity with an equilibrium concentration of 220 mg g(-1). The hydrolysates eluted with 25, 50, 75 and 95% (v/v) ethanol lowered the micellar cholesterol concentration by 11.88, 14.76, 19.37 and 7.56% respectively. A hydrophobic fraction of RBPH had the highest inhibitory activity on micellar cholesterol, which suggests that it may have hypocholesterolaemic properties.


Effects of swimming training on children with asthma.
In a programme to examine the effect of 5 months of swimming training on school-children with asthma, 46 children swam a total distance of 3608 km (2242 miles) during 2806 training sessions. On post-training re-examination, nonspecific effects of physical conditioning were detected including improved posture and fitness, reduced fat folds, and enhanced swimming ability. Continuous monitoring of asthma and medication showed significant decreases in both parameters during the final phases of the study between children who continued to swim regularly and those who did not. The frequency and severity of exercise-induced asthma (after running) was unchanged by swimming training. Post-training questionnaires indicated a high degree of enthusiasm and acceptance of the programme by children and parents. No significant adverse effects were observed or reported during the study.


Differential effects of adenosine analogs on amygdala, hippocampus, and caudate nucleus kindled seizures.
This study explored the anticonvulsant effects of adenosine analogs at the focus of seizures kindled from various brain structures. Chemitrodes were implanted in the amygdala (AM), hippocampus (HIPP), or caudate nucleus (CN) of Long-Evans rats and electrically stimulated once daily until fully generalized seizures appeared (i.e., kindled). Once kindled, various doses (0.001-0.5 microgram/0.5 microliter) of the adenosine analogs, L-phenylisopropyladenosine (L-PIA), N-ethylcarboximidoadenosine (NECA) or vehicle were injected into the seizure focus 5 min prior to electrical stimulation. The afterdischarge (AD) and behavioral seizure stages were measured. L-PIA had potent anticonvulsant effects when injected directly into the kindled seizure focus in the AM, HIPP, or CN. NECA effects were statistically significant only in CN-kindled seizures. The regional differences in efficacy of the two adenosine analogs suggest that L-PIA, an A1 adenosine subtype agonist, may exert its effects through A1 adenosine receptors in the AM, HIPP, and CN, where A1 binding has been demonstrated, whereas NECA, an A2 adenosine receptor agonist, may only be maximally effective in the CN where A2 adenosine binding sites are located.


[Strategies directed to professionals for reducing unnecessary cesarean sections in Brazil].
Brazil is among the countries with the highest cesarean section rates, especially in the supplementary health sector. However, some characteristics are similar in both the public and private sectors in terms of the wishes and expectations of pregnant women regarding their delivery. There is a preference for vaginal delivery among women of all social, economic, and cultural levels, a fact that shifts the focus of the negative influence of this variable from women to other subjects involved in delivery care. No isolated factor is able to justify the complexity of making a decision for cesarean section, but the physician and the type of hospital are the main associated factors. The several harmful effects of a non-judicious performance of cesarean section are scientifically recognized. It is important to raise the awareness of doctors and of other health professionals about the real consequences of this decision, the ethical deviations when conducts are chosen without exclusively focusing on the patient`s health, and the need for constant updating for the management of the various possible conditions of childbirth.


Selective denervation: reinnervation for the control of adductor spasmodic dysphonia.
The objective of this study was to evaluate the efficacy of a new surgical procedure for adductor spasmodic dysphonia (AddSD). This surgery involves the bilateral selective division of the adductor branches of the recurrent laryngeal nerves with immediate reinnervation of the distal nerve trunks with branches of the ansa cervicalis (selective denervation-reinnervation). Our first six patients to undergo this procedure were enrolled in the study. All patients suffered from AddSD and had previously received botulinum toxin A (Botox, Allergen, Markham, ON) therapy. Patients were recorded preoperatively and all underwent the same surgical procedure performed by the same lead surgeon. All patients were surveyed postoperatively and then re-recorded. Expert and untrained judges undertook perceptual evaluation of voice quality. Voice samples were also objectively evaluated for aphonic voice breaks. No major surgical complications were noted. Patient satisfaction was excellent, and five of the six patients no longer require botulinum toxin therapy. In five of the six patients, the majority of untrained and expert listeners perceived the postoperative voice to be superior. Objectively, the rate of aphonic voice breaks was also reduced in five of the six patients.


Educational deficiencies in musculoskeletal medicine.
We previously reported the results of a study in which a basic competency examination in musculoskeletal medicine was administered to a group of recent medical school graduates. This examination was validated by 124 orthopaedic program directors, and a passing grade of 73.1% was established. According to that criterion, 82% of the examinees failed to demonstrate basic competency in musculoskeletal medicine. It was suggested that perhaps a different passing grade would have been set by program directors of internal medicine departments. To test that hypothesis, and to determine whether the importance of the individual questions would be rated similarly, the validation process was repeated with program directors of internal medicine residency departments as subjects. Our basic competency examination was sent to all 417 program directors of internal medicine departments in the United States. Each recipient was mailed a letter of introduction explaining the purpose of the study, a copy of the examination, and our answer key and scoring guide. There was no mention of the results of the first study. The subjects were requested to rate the importance of each question on the same visual analog scale, ranging from "not important" to "very important," as had been used by the orthopaedic program directors. These ratings were converted into numerical scores. The program directors were also asked to suggest a passing score for the examination, and this score was used to assess the examinees' performance on the examination. The results on the basis of the internal medicine program directors' responses and those according to the orthopaedic program directors' responses were compared. Two hundred and forty (58%) of the 417 program directors of internal medicine residency departments responded. They suggested a mean passing score (and standard deviation) of 70.0% +/- 9.9%. As reported previously, the mean test score of the eighty-five examinees was 59.6%. Sixty-six (78%) of them failed to demonstrate basic competency on the examination according to the criterion set by the internal medicine program directors. The internal medicine program directors assigned a mean importance score of 7.4 (of 10) to the questions on the examination compared with a mean score of 7.0 assigned by the orthopaedic program directors. The internal medicine program directors gave twenty-four of the twenty-five questions an importance score of at least 5 and seventeen of the twenty-five questions an importance score of at least 6.6. According to the standard suggested by the program directors of internal medicine residency departments, a large majority of the examinees once again failed to demonstrate basic competency in musculoskeletal medicine on the examination. It is therefore reasonable to conclude that medical school preparation in musculoskeletal medicine is inadequate.


Not all collectivisms are equal: opposing preferences for ideal affect between East Asians and Mexicans.
Previous research has revealed differences in how people value and pursue positive affect in individualistic and collectivistic cultural contexts. Whereas Euro-Americans place greater value on high activation positive affect (HAP; e.g., excitement, enthusiasm, elation) than do Asian Americans and Hong Kong Chinese, the opposite is true for low activation positive affect (LAP; e.g., calmness, serenity, tranquility). Although the form of collectivism present in East Asia dictates that individuals control and subdue their emotional expressions so as to maintain harmonious relationships, the opposite norm emerges in Mexico and other Latin American countries, in that the cultural script of simpatía promotes harmony through the open and vibrant expression of positive emotion. Across two studies, we found that Mexicans display a pattern of HAP/LAP preference different from those from East Asian collectivistic cultures, endorsing HAP over LAP.


Improving Medication Adherence through Graphically Enhanced Interventions in Coronary Heart Disease (IMAGE-CHD): a randomized controlled trial.
Up to 50 % of patients do not take medications as prescribed. Interventions to improve adherence are needed, with an understanding of which patients benefit most. To test the effect of two low-literacy interventions on medication adherence. Randomized controlled trial, 2 × 2 factorial design. Adults with coronary heart disease in an inner-city primary care clinic. For 1 year, patients received usual care, refill reminder postcards, illustrated daily medication schedules, or both interventions. The primary outcome was cardiovascular medication refill adherence, assessed by the cumulative medication gap (CMG). Patients with CMG<0.20 were considered adherent. We assessed the effect of the interventions overall and, post-hoc, in subgroups of interest. Most of the 435 participants were elderly (mean age=63.7 years), African-American (91 %), and read below the 9th-grade level (78 %). Among the 420 subjects (97 %) for whom CMG could be calculated, 138 (32.9 %) had CMG<0.20 during follow-up and were considered adherent. Overall, adherence did not differ significantly across treatments: 31.2 % in usual care, 28.3 % with mailed refill reminders, 34.2 % with illustrated medication schedules, and 36.9 % with both interventions. In post-hoc analyses, illustrated medication schedules led to significantly greater odds of adherence among patients who at baseline had more than eight medications (OR=2.2; 95 % CI, 1.21 to 4.04) or low self-efficacy for managing medications (OR=2.15; 95 % CI, 1.11 to 4.16); a trend was present among patients who reported non-adherence at baseline (OR=1.89; 95 % CI, 0.99 to 3.60). The interventions did not improve adherence overall. Illustrated medication schedules may improve adherence among patients with low self-efficacy, polypharmacy, or baseline non-adherence, though this requires confirmation.


Sustainable glycerol terpolycarbonates as temporary bioadhesives.
We describe the synthesis of poly(glycidyl acetate-co-glycidyl butyrate carbonate)s via the terpolymerization of glycidyl acetate (GA), glycidyl butyrate (GB), and CO2 by a cobalt salen complex in high atom economy. These new non-cytotoxic polycarbonates are pressure-sensitive adhesives, and peel testing shows the adhesive strength ranges from Scotch-Tape® to hot-melt glues based on glycidyl butyrate content. The tunable adherence, benign degradation products, and facile application and removal suggest their utility as temporary adhesives, such as those used in biomedical applications or medical devices. One polymer, (GA-co-GB)-87, exhibits the proper adhesive strength to sufficiently adhere a collagen buttress to the jaws of a steel surgical stapler and easily release the buttress after firing to successfully cut, close, and implant the buttress into lung tissue in an ex vivo sheep model.


Effects of encapsulation on the viability of potential probiotic Lactobacillus plantarum exposed to high acidity condition and presence of bile salts.
This study investigated the survival of encapsulated potential probiotic Lactobacillus plantarum which isolated from fermented cocoa beans. κ-Carrageenan was used to encapsulate the probiotic. Encapsulation techniques such as emulsification, freeze-drying or extrusion were adopted to encapsulate the probiotic. Freeze-drying and extrusion methods showed higher (p < 0.05) efficiency (89.48 ± 3.21 and 92.26 ± 1.45%, respectively) in encapsulating the probiotic compared to the emulsification method (82.19 ± 0.71% efficiency). Freeze-dried encapsulated probiotic L. plantarum was selected for further survival analysis as greater amount of beads were produced compared to the extrusion method. Freeze-dried probiotic was found to have significantly (p < 0.05) higher tolerance to acid at pH 2 with higher survival percentage compared to non-encapsulated probiotic. However, freeze-drying encapsulation was proven not to enhance the resistance of the probiotic to bile salt as evidenced by the one log colony reduction as for the non-encapsulated probiotic. Further modification of freeze-drying encapsulation technique is needed to enhance the survival of the encapsulated potential probiotic L. plantarum toward bile salt in the future.


Characterization of the multigene family TaHKT 2;1 in bread wheat and the role of gene members in plant Na(+) and K(+) status.
A member of the TaHKT2;1 multigene family was previously identified as a Na(+) transporter with a possible role in root Na(+) uptake. In the present study, the existing full-length cDNA of this member was used as a basis to query the International Wheat Genome Survey Sequence to identify all members of the TaHKT2;1 family. Individual TaHKT2;1 genes were subsequently studied for gene and predicted protein structures, promoter variability, tissue expression and their role in Na(+) and K(+) status of wheat. Six TaHKT2;1 genes were characterized which included four functional genes (TaHKT2;1 7AL-1, TaHKT2;1 7BL-1, TaHKT2;1 7BL-2 and TaHKT2;1 7DL-1) and two pseudogenes (TaHKT2;1 7AL-2 and TaHKT2;1 7AL-3), on chromosomes 7A, 7B and 7D of hexaploid wheat. Variability in protein domains for cation specificity and in cis-regulatory elements for salt response in gene promoters, were identified amongst the functional TaHKT2;1 members. The functional genes were expressed under low and high NaCl conditions in roots and leaf sheaths, but were down regulated in leaf blades. Alternative splicing events were evident in TaHKT2;1 7AL-1. Aneuploid lines null for each functional gene were grown in high NaCl nutrient solution culture to identify potential role of each TaHKT2;1 member. Aneuploid lines null for TaHKT2;1 7AL-1, TaHKT2;1 7BL-1 and TaHKT2;1 7BL-2 showed no difference in Na(+) concentration between Chinese Spring except for higher Na(+) in sheaths. The same aneuploid lines had lower K(+) in roots, sheath and youngest fully expanded leaf but only under high (200 mM) NaCl in the external solution. There was no difference in Na(+) or K(+) concentration for any treatment between aneuploid line null for the TaHKT2;1 7DL-1 gene and Chinese Spring. TaHKT2;1 is a complex family consisting of pseudogenes and functional members. TaHKT2;1 genes do not have an apparent role in controlling root Na(+) uptake in bread wheat seedlings under experimental conditions in this study, contrary to existing hypotheses. However, TaHKT2;1 genes or, indeed other genes in the same chromosome region on 7AL, are candidates that may control Na(+) transport from root to sheath and regulate K(+) levels in different plant tissues.


Comparative effectiveness and safety of a catheterization laboratory-only eptifibatide dosing strategy in patients undergoing percutaneous coronary intervention.
Eptifibatide, a small-molecule glycoprotein IIb/IIIa inhibitor, is conventionally administered as a bolus plus infusion. A growing number of clinicians are using a strategy of catheterization laboratory-only eptifibatide (an off-label use) as procedural pharmacotherapy for patients undergoing percutaneous coronary intervention although the comparative effectiveness of this approach is unknown. We compared the in-hospital outcome of patients undergoing percutaneous coronary intervention across 47 hospitals and treated with eptifibatide bolus plus infusion with those treated with a catheterization laboratory-only regimen. We used optimal matching to link the use of catheterization laboratory-only eptifibatide with clinical outcomes, including mortality, myocardial infarction, bleeding, and need for transfusion. Of the 84 678 percutaneous coronary interventions performed during 2010 to 2011, and meeting our inclusion criteria, eptifibatide was administered to 21 296 patients. Of these, a catheterization laboratory-only regimen was used in 4511 patients, whereas 16 785 patients were treated with bolus plus infusion. In the optimally matched analysis, compared with bolus plus infusion, a catheterization laboratory-only regimen was associated with a reduction in bleeding (optimally matched adjusted odds ratio, 0.74; 95% confidence interval, 0.58-0.93; P=0.014) and need for transfusion (optimally matched adjusted odds ratio, 0.70; 95% confidence interval, 0.52-0.92; P=0.012), with no difference in mortality or myocardial infarction. A catheterization laboratory-only eptifibatide regimen is commonly used in clinical practice and is associated with a significant reduction in bleeding complications in patients undergoing contemporary percutaneous coronary intervention.


Increased activator protein 1 activity as well as resistance to heat-induced radiosensitization, hydrogen peroxide, and cisplatin are inhibited by indomethacin in oxidative stress-resistant cells.
It has been established that tumor cells develop resistance to a variety of therapeutic agents after multiple exposures to these agents/drugs. Many of these therapeutic agents also appear to increase the activity of transcription factors, such as activator protein 1 (AP-1), believed to be involved in cellular responses to oxidative stress. Therefore, we hypothesized that cellular resistance to cancer therapeutic agents may involve the increased activity of transcription factors that govern resistance to oxidative stress, such as AP-1. To investigate this hypothesis, a previously characterized cisplatin, hyperthermia, and oxidative stress-resistant Chinese hamster fibroblast cell line, OC-14, was compared to the parental HA-1 cell line. Electrophoretic mobility shift and Western blot assays performed on extracts isolated from OC-14 cells demonstrated a 10-fold increase in constitutive AP-1 DNA-binding activity as well as increased constitutive c-Fos and c-Jun immunoreactive protein relative to HA-1 cells. Treatment of OC-14 cells with indomethacin inhibited constitutive increases in AP-1 DNA-binding activity and c-Fos/c-Jun-immunoreactive protein levels. Clonogenic survival assays demonstrated that pretreatment with indomethacin, at concentrations that inhibited AP-1 activity, significantly reduced the resistance of OC-14 cells to heat-induced radiosensitization, hydrogen peroxide, and cisplatin. These results demonstrate a relationship between increases in AP-1 DNA-binding activity and increased cellular resistance to cancer therapeutic agents and oxidative stress that is inhibited by indomethacin. These results support the hypothesis that inhibition of AP-1 activity with nonsteroidal anti-inflammatory drugs, such as indomethacin, may represent a useful adjuvant to cancer therapy.


Wallenberg syndrome caused by CSF metastasis from malignant intraventricular meningioma.
A 34-year-old male developed a malignant transitional meningioma of the left lateral ventricle at the trigone. Over a 12-month period, he underwent three apparently complete excisions and one course of radiation therapy, but each time developed rapid local recurrence. The tumor recurred a fourth time seven months following the third operation, was excised, and the patient referred for intracarotid chemotherapy infusion. A left Wallenberg syndrome was noted on exam and CT scan demonstrated a posterior fossa mass. He died two weeks post-infusion from bronchopneumonia, 21 months after initial presentation. At autopsy, the tumor appeared more sarcomatous and had metastasized via the cerebrospinal fluid to the left dorsal medulla as well as to the surface of the pineal gland, the left cerebellar surface, and to several levels of the spinal cord. No extraneural metastases were found.


Dioxin- and POP-contaminated sites--contemporary and future relevance and challenges: overview on background, aims and scope of the series.
Once they have been generated, polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and other persistent organic pollutants (POPs) can persist in soils and sediments and in waste repositories for periods extending from decades to centuries. In 1994, the US EPA concluded that contaminated sites and other reservoirs are likely to become the major source of contemporary pollution problems with these substances. With this in mind, this article is the first in a new series in ESPR under the title 'Case Studies on Dioxin and POP Contaminated Sites--Contemporary and Future Relevance and Challenges', which will address this important issue. The series will document various experiences from sites contaminated with PCDD/F and other POPs. This article provides an overview of the content of the articles comprising the series. In addition, it provides a review of the subject in its own right and identifies the key issues arising from dioxin/POP-contaminated sites. Additionally, it highlights the important conclusions that can be drawn from these examples. The key aim of this article and of the series as a whole is to provide a comprehensive overview of the types of PCDD/F contaminated sites that exist as a result of historical activities. It details the various processes whereby these sites became contaminated and attempts to evaluate their contemporary relevance as sources of PCDD/Fs and other POPs. It also details the various strategies used to assess these historical legacies of contamination and the concepts developed, or which are under development, to effect their remediation. Special sessions on 'Contaminated sites--Cases, remediation, risk and policy' were held at the DIOXIN conferences in 2006 and 2007, and this theme will be continued at DIOXIN 2008 to be held in Birmingham. Selected cases from the approximately 70 contributions made to these sessions, together with some additional invited case studies are outlined together with the key issues they raise. By evaluating these cases and adding details of experiences published in the current literature, an overview will be given of the different features and challenges of dioxin and POP-contaminated sites. This article provides a systematic categorisation of types of PCDD/F and POP-contaminated sites. These are categorised according to the chemical or manufacturing process, which generated the PCDD/Fs or POPs and also includes the use and disposal aspects of the product life cycle in question. The highest historical PCDD/F and dioxin-like polychlorinated biphenyl (PCB) contamination burdens have arisen as a result of the production of chlorine and of chlorinated organic chemicals. In particular, the production of chlorinated pesticides, PCBs and the related contaminated waste streams are identified being responsible for historical releases of toxic equivalents (TEQs) at a scale of many tonnes. Along with such releases, major PCDD/F contaminated sites have been created through the application or improper disposal of contaminated pesticides, PCBs and other organochlorine chemicals, as well through the recycling of wastes and their attempted destruction. In some extreme examples, PCDD/F contaminated sites have also resulted from thermal processes such as waste incinerators, secondary metal industries or from the recycling or deposition of specific waste (e.g. electronic waste or car shredder wastes), which often contain chlorinated or brominated organic chemicals. The examples of PCDD/F and dioxin-like PCB contamination of fish in European rivers or the impact of contaminated sites upon fishing grounds and upon other food resources demonstrate the relevance of these historical problems to current and future human generations. Many of the recent food contamination problems that have emerged in Europe and elsewhere demonstrate how PCDD/F and dioxin like PCBs from historical sources can directly contaminate human and animal feedstuffs and indeed highlight their considerable contemporary relevance in this respect. Accordingly, some key experiences and lessons learnt regarding the production, use, disposal and remediation of POPs from the contaminated sites are summarised. An important criterion for evaluating the significance and risks of PCDD/Fs and other POPs at contaminated sites is their present or future potential for mobility. This, in turn, determines to a large degree their propensity for off-site transport and environmental accessibility. The detailed evaluation of contaminated site cases reveals different site-specific factors, which influence the varied pathways through which poor water-soluble POPs can be mobilised. Co-contaminants with greater water solubility are also typically present at such sites. Hence, pumping of groundwater (pump and treat) is often required in addition to attempting to physically secure a site. At an increasing number of contaminated sites, securing measures are failing after relatively short time spans compared to the time horizon, which applies to persistent organic pollutant contamination. Due to the immense costs and challenges associated with remediation of contaminated sites 'monitored natural attenuation' is increasingly gaining purchase as a conceptual remediation approach. However, these concepts may well prove limited in their practical application to contaminated sites containing persistent organic pollutants and other key pollutants like heavy metals. It is inevitable, therefore, that dioxin/POP-contaminated sites will remain of contemporary and future relevance. They will continue to represent an environmental issue for future generations to address. The securing and/or remediation of dioxin/POP-contaminated sites is very costly, generally in the order of tens or hundreds of millions of dollars. Secured landfills and secured production sites need to be considered as constructions not made for 'eternity' but built for a finite time scale. Accordingly, they will need to be controlled, supervised and potentially repaired/renewed. Furthermore, the leachates and groundwater impacted by these sites will require ongoing monitoring and potential further remediation. These activities result in high maintenance costs, which are accrued for decades or centuries and should, therefore, be compared to the fully sustainable option of complete remediation. The contaminated site case studies highlight that, while extensive policies and established funds for remediation exist in most of the industrialised western countries, even these relatively well-regulated and wealthy countries face significant challenges in the implementation of a remediation strategy. This highlights the fact that ultimately only the prevention of contaminated sites represents a sustainable solution for the future and that the Polluter Pays Principle needs to be applied in a comprehensive way to current problems and those which may emerge in the future. With the continuing shift of industrial activities in developing and transition economies, which often have poor regulation (and weak self-regulation of industries), additional global challenges regarding POPs and other contaminated sites may be expected. In this respect, a comprehensive application of the "polluter pays principle" in these countries will also be a key to facilitate the clean-up of contaminated areas and the prevention of future contaminated sites. The threats and challenges of contaminated sites and the high costs of securing/remediating the problems highlight the need for a comprehensive approach based upon integrated pollution prevention and control. If applied to all polluting (and potentially polluting) industrial sectors around the globe, such an approach will prove to be both the cheapest and most sustainable way to underpin the development of industries in developing and transition economies.


[Hospitalization by court order: ethical dilemmas experienced by nurses].
A qualitative study aimed at describing the situations experienced and the ethical dilemmas of nurses in the process of referring and receiving hospitalized patients by court order who require admission to the Intensive Care Unit (ICU). A partially structured interview was conducted with 10 nurses who worked in the ICU and 10 who worked in the Emergency Room (ER) in public and private hospitals in the metropolitan area of Porto Alegre, Brazil. The data was analyzed following the Semantic Analysis. The results indicated that nurses experienced ethical dilemmas associated with problems of overcrowding in emergency rooms and ICUs, poor specialized technology and orientation as to the benefits provided by law. We concluded that it is essential for nurses to participate in discussions that allow the planning of the different instances that have been promoting this often chaotic situation.


Inspiratory muscle fatigue affects latissimus dorsi but not pectoralis major activity during arms only front crawl sprinting.
The purpose of this study was to determine whether inspiratory muscle fatigue (IMF) affects the muscle activity of the latissimus dorsi and pectoralis major during maximal arms only front crawl swimming. Eight collegiate swimmers were recruited to perform 2 maximal 20-second arms only front crawl sprints in a swimming flume. Both sprints were performed on the same day, and IMF was induced 30 minutes after the first (control) sprint. Maximal inspiratory and expiratory mouth pressures (PImax and PEmax, respectively) were measured before and after each sprint. The median frequency (MDF) of the electromyographic signal burst was recorded from the latissimus dorsi and pectoralis major during each 20-second sprint along with stroke rate and breathing frequency. Median frequency was assessed in absolute units (Hz) and then referenced to the start of the control sprint for normalization. After IMF inducement, stroke rate increased from 56 ± 4 to 59 ± 5 cycles per minute, and latissimus dorsi MDF fell from 67 ± 11 Hz at the start of the sprint to 61 ± 9 Hz at the end. No change was observed in the MDF of the latissimus dorsi during the control sprint. Conversely, the MDF of the pectoralis major shifted to lower frequencies during both sprints but was unaffected by IMF. As the latter induced fatigue in the latissimus dorsi, which was not otherwise apparent during maximal arms only control sprinting, the presence of IMF affects the activity of the latissimus dorsi during front crawl sprinting.


TaqMan minor groove binder real-time PCR analysis of beta-tubulin codon 200 polymorphism in small strongyles (Cyathostomin) indicates that the TAC allele is only moderately selected in benzimidazole-resistant populations.
TaqMan minor groove binder probes were evaluated as to their suitability for the real-time allelic discrimination of the beta-tubulin codon 200 TTC/TAC single nucleotide polymorphism in cyathostomin species. Amplification of titrated cloned full-length beta-tubulin cDNA revealed that the TaqMan minor groove binder PCR is capable of specifically detecting as few as 10 copies. Testing of DNA from single adult and larval stages of several different species of cyathostomin allowed reproducible genotyping of individual worms. Using the real-time PCR approach, the throughput of samples was considerably increased compared with conventional post-PCR readout procedure. Only 7.8% homozygous TAC L3 were found among 102 L3 which were genotyped from phenotypically BZ-resistant small strongyle populations. The percentages of the homozygous TTC and heterozygous TTC/TAC were 41.3% and 50.9%, respectively. This resulted in a total TAC-allele percentage of only 33.3%. These findings correspond to data obtained by genotyping of an experimentally selected BZ-resistant cyathostomin population. It is concluded that the beta-tubulin codon 200 polymorphism is not the sole mechanism involved in the process of BZ resistance in cyathostomins.


Synthesis and characterization of (68)Ga-labeled curcumin and curcuminoid complexes as potential radiotracers for imaging of cancer and Alzheimer's disease.
Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, (68)Ga-labeled complexes with CUR and two curcuminoids, namely diacetyl-curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic β-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting (68)Ga(3+) obtained from a (68)Ge/(68)Ga generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet-visible, and fluorescence spectroscopy on the equivalent (nat)Ga-curcuminoids (nat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)2(+) species formation. Identity of the (68)Ga(L)2(+) complexes was confirmed by coelution with the equivalent (nat)Ga(L)2(+) complexes in ultrahigh-performance liquid chromatography analyses.(68)Ga(CUR)2(+), (68)Ga(DAC)2(+), and (68)Ga(bDHC)2(+) were highly (87 ± 4, 90 ± 1%) and moderately (48 ± 2%), respectively, retained by synthetic β-amyloid fibrils in vitro. All the Ga-curcuminoid complexes showed an uptake in A549 lung cancer cells, at least equivalent to the respective free curcuminoids, confirming potential applications as cancer-detecting radiotracers.


Maintained Properties of Aged Dental Pulp Stem Cells for Superior Periodontal Tissue Regeneration.
Owing to excellent therapeutic potential, mesenchymal stem cells (MSCs) are gaining increasing popularity with researchers worldwide for applications in tissue engineering, and in treatment of inflammation-related and age-related disorders. However, the senescence of MSCs over passaging has limited their clinical application owing to adverse effect on physiological function maintenance of tissues as well as disease treatment. An inflammatory microenvironment is one of the key contributors to MSC senescence, resulting in low regeneration efficiency. Therefore, MSCs with high resistance to cellular senescence would be a benefit for tissue regeneration. Toward this end, we analyzed the senescence properties of different types of stem cells during culture and under inflammation, including dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), bone marrow mesenchymal stem cells (BMMSCs), and adipose-derived stem cells (ADSCs). Overall, the DPSCs had higher proliferation rates, lower cellular senescence, and enhanced osteogenesis maintenance compared to those of non-dental MSCs cultured from passage three to six. The expression profiles of genes related to apoptosis, cell cycle, and cellular protein metabolic process (contributing to the cell self-renewal ability and metabolic processes) significantly differed between DPSCs and BMMSCs at passage three. Moreover, DPSCs were superior to BMMSCs with regards to resistance to lipopolysaccharide-induced apoptosis and senescence, with enhanced osteogenesis in vitro, and showed improved periodontal regeneration after injection in a miniature pig periodontitis model in vivo. Overall, the present study indicates that DPSCs show superior resistance to subculture and inflammation-induced senescence and would be suitable stem cells for tissue engineering with inflammation.


Upregulation of NF-κB by USP24 aggravates ferroptosis in diabetic cardiomyopathy.
Recent investigations have proposed a potential causal association between the occurrence of ferroptosis, nuclear factor kappa B (NF-κB) and ubiquitin-specific protease 24 (USP24). Nevertheless, the mechanism of USP24 and NF-κB regulation of ferroptosis in the context of diabetic cardiomyopathy (DCM) remain unclear. In this study, a high-fat diet and a streptozotocin-induced mouse DCM model were established, and high glucose and palmitic acid treatment of H9c2 cells and neonatal mouse primary cardiomyocytes (NMPCs) was used as an in vitro DCM models. Utilizing both the in vivo and in vitro DCM models, we assessed of USP24, NF-κB, and ferroptosis levels, and explored the relationship among them. In in vivo and in vitro DCM models, increased expression of USP24, NF-κB, phosphorylated NF-κB (p-NF-κB) and fatty acid-CoA ligase 4 (FACL4) were detected, along with accumulated iron, as well as reduced ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and antioxidant capacity. Knockdown of USP24 resulted in a reduction of NF-κB levels, while knockdown of NF-κB did not lead to a decrease in USP24 expression. Moreover, in H9c2 cells, knockdown of USP24 and NF-κB separately resulted in reduced levels of FACL4, increased levels of SLC7A11 and FTH1, as well as improved antioxidant capacity and cell viability. In shUSP24 knockdown H9c2 cells, administration of phorbol 12-myristate 13-acetate (PMA) activated NF-κB, subsequently reversing the previously observed effect caused by USP24 knockdown. These findings show that USP24 upregulates NF-κB to promote ferroptosis in DCM.


Inequalities in rural communities: adapting national deprivation indices for rural settings.
Deprivation indices have been widely used in healthcare research and planning in the United Kingdom. Existing indices, however, are dominated by characteristics of urban populations that may be less relevant in capturing the nature of rural deprivation. We explore if deprivation indices can be modified to make them more sensitive to displaying rural disadvantage in England. The analysis focussed on the 2011 Carstairs Index (Carstairs2011) and the 2010 English Index of Multiple Deprivation (IMD2010). We removed all urban areas as identified by the Office for National Statistics Rural-Urban Area Classifications and mapped the Carstairs2011 and IMD2010 across the remaining rural areas using rural-specific quintiles. Our method was effective in displaying much greater heterogeneity in rural areas than was apparent in the original indices. We received positive feedback from Directors of Public Health who confirmed that the observed patterns mirror their experiences and first-hand knowledge on the ground. Our maps of Carstairs2011 and IMD2010 for rural areas might strengthen the evidence base for rural planning and service provision. The modified deprivation indices, however, were not specifically formulated for rural populations and further work is needed to explore alternative input variables to produce a more rural-specific measure of deprivation.


Typical Vine or International Taste: Wine Consumers' Dilemma Between Beliefs and Preferences.
The wine-growing sector is probably one of the agricultural areas where the ties between product quality and territory are most evident. Geographical indication is a key element in this context, and previous literature has focused on demonstrating how certification of origin influences the wine purchaser's behavior. However, less attention has been devoted to understanding how the value of a given name of origin may or may not be determined by the various elements that characterize the typicality of the wine product on that territory: vines, production techniques, etc. It thus seems interesting, in this framework, to evaluate the impacts of several characteristic attributes on the preferences of consumers. This paper will analyze, in particular, the role of the presence of autochthonous vines in consumers' choices. The connection between name of origin and autochthonous vines appears to be particularly important in achieving product "recognisability", while introducing "international" vines in considerable measure into blends might result in the loss of the peculiarity of certain characteristic and typical local productions. A standardization of taste could thus risk compromising the reputation of traditional production areas. The objective of this study is to estimate, through an experimental auction on the case study of Chianti, the differences in willingness to pay for wines produced with different shares of typical vines. The results show that consumers have a willingness to pay for wine produced with typical blends 34% greater than for wines with international blends. However, this difference is not confirmed by blind tasting, raising the issue of the relationship between exante expectations about vine typicality and real wine sensorial characteristics. Finally, some recent patents related to wine testing and wine packaging are reviewed.


Familial Absent Uvula With Velopharyngeal Incompetence-A New Syndrome?
We present a family with a previously undescribed abnormality of the palate and oropharynx which involved the absence of the uvula and the anterior pillar of the fauces, rudimentary posterior pillar of the fauces, and hypernasality. Eight family members over 4 generations are affected in a pattern consistent with autosomal dominant inheritance. A causal role for the FOXF2 gene has been identified and previously reported. We describe the management of the proband, which involved attempting to lengthen the palate and to retroposition the abnormally anteriorly directed velar musculature, along with speech therapy.


Behavioral and complementary approaches for the treatment of irritable bowel syndrome.
Irritable bowel syndrome (IBS) is one of the most common conditions seen in primary care settings. Despite this, there is no consensus as to the pathogenesis of this disorder or a consistently effective therapeutic regimen for many patients. This has encouraged the use of various alternative therapies from behavioral or complementary medicine. This review will address the evidence for alternative therapies, including the following: cognitive behavior therapy, hypnosis, elimination diets based on food antibody testing, nutrition supplements (such as fiber, probiotics, and prebiotics), and, finally, peppermint, l-glutamine, zinc, and cromolyn sodium. The review also explores the evidence for and the therapeutic ramifications of the hypothesis that increased intestinal permeability underlies the symptoms of IBS in many patients, and how a therapeutic plan that addresses nutrition, elimination diets, and nutrition supplements may be useful in restoring the integrity of the gut immune barrier.


Doctors, nurses, pharmacists and patients--the Rational Evaluation and Choice in Hypertension (REACH) survey of hypertension care delivery.
Despite ongoing efforts by the medical profession, many hypertensive patients either refuse treatment or have blood pressures that are not adequately controlled. A key reason is likely to be the side effects of many antihypertensive drugs. We have investigated further reasons for stopping or altering antihypertensive treatment, and the patterns of prescribing in Britain by mounting a series of surveys amongst family doctors, practice nurses and their patients with hypertension. A total of 178 GPs and 158 practice nurses provided completed replies suitable for analysis. In addition, 948 patients were surveyed via their GP and 1167 were surveyed via their local pharmacist (600 unprompted, 567 prompted). Thirty-two percent of GPs stated that hypertensive patients generally consulted because they were experiencing drug side effects and 42% of all switches of drug therapy occurred because patients experienced side effects. The GPs perceived that 18% of their hypertensive patients did not comply with the antihypertensive therapy, and, of non-compliant patients, 22% were not complying due to drug side effects. The 158 practice nurses reported that 29% of patients they saw discussed drug side effects. Hypertensive patients were more likely to discuss the side effects of their antihypertensive treatments with the practice nurse than their doctor. Forty-six percent of 948 patients who were surveyed via their GP did not know what antihypertensive drug class they were taking. The most frequently mentioned reason for patients changing medication was drug side effects (42%) or lack of efficacy (39%). Fifty-nine percent of patients had never asked about possible side effects, but 34% reported that they had experienced unacceptable side effects. With some prompting by pharmacists, many hypertensive patients would discuss their antihypertensive drugs and any side effects. This survey highlights the lack of communication about potential side effects between the doctor and hypertensive patient, and the important role of the practice nurse. Our survey also shows that hypertension is not being managed as effectively as it could be and GPs appear to be spending the majority of their consulting time discussing and dealing with the side effects of treatment. This, therefore, suggests that drugs with a cleaner side effect profile could save valuable GP time and resources. Better communication with patients about side effects is, therefore, likely to improve compliance with hypertensive treatment.


Tyrosine 116 of the herpes simplex virus type 1 IEalpha22 protein is an ocular virulence determinant and potential phosphorylation site.
To determine whether tyrosine 116 of the HSV-1 alpha22 protein is involved in virulence and is a potential phosphorylation site. Site-directed mutagenesis was used to revert the Y116C mutation in the alpha22 gene of the strain OD4 to wild type (C116Y), and the effect of virulence was tested by using a marker transfer-infection protocol in mice. Immunoblot analysis, tryptic phosphopeptide mapping, and phosphotyrosine pulldown-immunoblot protocols were used to assess the OD4 alpha22 isoforms. Reversion of the Y116C mutation resulted in a significant increase in the severity of ocular disease compared with the OD4 virus alone. Reversion of the Y116C and a previously identified mutation (S34A) together did not alter the severity of virulence compared with either mutation alone. Immunoblot analysis revealed a loss or reduction in alpha22 isoforms in the OD4 virus compared with wild type (CJ394 virus). The OD4 virus had numerous alterations in the alpha22 tryptic phosphopeptide pattern, including loss of specific peptides and shifts in the position of several peptides. Phosphotyrosine pulldowns revealed a loss of one or more isoforms and shifts in the apparent size of others. The data indicate that Y116 is a determinant of peripheral virulence in mice and that mutations at S34 and Y116 affect virulence independently. The data also show that the S34 and Y116 mutations substantially alter phosphorylation of the alpha22 protein, that Y116 is a potential phosphorylation site, and that the alpha22 protein contains at least two phosphotyrosines. These results are the first to show that mutation of a specific tyrosine in the alpha22 protein is associated with virulence.


Lipidomics by Supercritical Fluid Chromatography.
This review enlightens the role of supercritical fluid chromatography (SFC) in the field of lipid analysis. SFC has been popular in the late 1980s and 1990s before almost disappearing due to the commercial success of liquid chromatography (LC). It is only 20 years later that a regain of interest appeared when new commercial instruments were introduced. As SFC is fully compatible with the injection of extracts in pure organic solvent, this technique is perfectly suitable for lipid analysis and can be coupled with either highly universal (UV or evaporative light scattering) or highly specific (mass spectrometry) detection methods. A short history of the use of supercritical fluids as mobile phase for the separation oflipids will be introduced first. Then, the advantages and drawbacks of SFC are discussed for each class of lipids (fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, prenols, polyketides) defined by the LIPID MAPS consortium.


Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats.
This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identification study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD(Sprague-Dawley) rats and CD-1 mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6-16 (mice) or 6-19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no-observable-adverse-effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near-term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, significantly reduced fetal body weights per litter and increased incidences of cleft palate (classified as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study.


A prediction model for colon cancer surveillance data.
Dynamic prediction models make use of patient-specific longitudinal data to update individualized survival probability predictions based on current and past information. Colonoscopy (COL) and fecal occult blood test (FOBT) results were collected from two Australian surveillance studies on individuals characterized as high-risk based on a personal or family history of colorectal cancer. Motivated by a Poisson process, this paper proposes a generalized nonlinear model with a complementary log-log link as a dynamic prediction tool that produces individualized probabilities for the risk of developing advanced adenoma or colorectal cancer (AAC). This model allows predicted risk to depend on a patient's baseline characteristics and time-dependent covariates. Information on the dates and results of COLs and FOBTs were incorporated using time-dependent covariates that contributed to patient risk of AAC for a specified period following the test result. These covariates serve to update a person's risk as additional COL, and FOBT test information becomes available. Model selection was conducted systematically through the comparison of Akaike information criterion. Goodness-of-fit was assessed with the use of calibration plots to compare the predicted probability of event occurrence with the proportion of events observed. Abnormal COL results were found to significantly increase risk of AAC for 1 year following the test. Positive FOBTs were found to significantly increase the risk of AAC for 3 months following the result. The covariates that incorporated the updated test results were of greater significance and had a larger effect on risk than the baseline variables.


A study of ocular complications in leprosy.
A total of 380 leprosy patients were studied in four different leprosy hospitals. The involvement of eye was found in 18.95% of cases in which 10.97% in lepromatous leprosy and 8.16% in non-lepromatous leprosy cases. In total cases studied 52.63% were of lepromatous leprosy and 47.37% of non lepromatous leprosy cases. Among them 11.05% were males and 18.95% were females. In 72 cases of ocular involvement, males constituted 80.56% and females 19.44% of cases. Maximum cases (52.78%) of ocular involvement were in leprosy patient with 5 to 10 years of duration. Blindness among the total leprosy patients studied was 1.84% which was mainly due to corneal opacity following exposure keratitis and ulceration, iridocyclitis and its complications.


The helix-loop-helix transcription factor TWIST is dysregulated in myelodysplastic syndromes.
Patients with low-grade myelodysplastic syndromes (MDS) show high levels of tumor necrosis factor α (TNFα) and up-regulation of apoptosis in the marrow. In contrast, marrow cells in advanced MDS are typically resistant to TNFα-induced apoptosis but are rendered apoptosis-sensitive on coculture with stroma. The present studies show that CD34(+) marrow cells in advanced MDS express high levels of TWIST, a basic helix-loop-helix transcription factor that opposes p53 function. TWIST levels correlated with disease stage (advanced > low grade; P = .01). Coculture with HS5 stroma resulted in down-regulation of TWIST and increased apoptosis in response to TNFα in CD34(+) cells from advanced MDS; the same effect was achieved by TWIST-specific RNA interference in CD34(+) cells. In primary MDS marrow stroma TWIST expression was lower than in healthy controls; suppression of TWIST in stroma interfered with induction of apoptosis sensitivity in cocultured CD34(+) cells. Stroma cells so modified expressed reduced levels of intercellular adhesion molecule-1 (ICAM1; CD54); blockade of ICAM1 in unmodified stroma was associated with reduced apoptosis in cocultured CD34(+) MDS marrow cells. These data suggest role for dysregulation of TWIST in the pathophysiology of MDS. Conceivably, TWIST or components in the signaling pathway could serve as therapeutic targets for patients with MDS.


The Brazilian vaccine divide: How some municipalities were left behind in the Covid-19 vaccine coverage.
This study aims to assess the progress of geographic, socioeconomic, and demographic disparities in Covid-19 vaccination coverage in Brazil over the first two years of the vaccination campaign. Data from the National Immunization Program Information System were used to estimate covid-19 vaccine coverage. Brazilian municipalities were divided into two groups based on their vaccine coverage for the booster dose. The first group comprised 20% of municipalities with the lowest coverage, while the second group (80% of municipalities) had higher coverage. The analysis was conducted separately for four age groups: 5-11, 12-17, 18-59, and 60+. Explanatory variables included socioeconomic and health services indicators. Crude and adjusted logistic regression models were used to estimate the probability of a municipality being among those with the worst vaccination coverage according to the categories of exploratory variables. Between January/2021 and December/2022, Brazil administered 448.2 million doses of the covid-19 vaccine. The booster vaccination coverage varied from 24.8% among adolescents to 79.7% among the elderly. The difference between the group with the highest and lowest coverage increased during the national vaccination campaign. Municipalities with lower education levels, higher proportion of Black population, higher Gini index, and worse health service indicators had a greater likelihood of having lower vaccination coverage. High and increasing levels of inequality in Covid-19 vaccination were observed in Brazil across all age groups during the vaccination campaign in 2021-2022.


Carney's triad: role of transthoracic needle biopsy.
A triad of gastric epithelioid leiomyosarcoma, functioning extra-adrenal paraganglioma, and pulmonary chondroma, has been described in 7 patients, and a partial expression of this tumor complex consisting of 2 of the 3 tumors in at least 11 others. Sixteen of these 18 patients were female. The variable presentation and course of these patients warrants special attention. We present the nineteenth reported case: a 26-yr-old woman with a pulmonary chondroma and a gastric epithelioid leiomyosarcoma. It is suggested that in cases of this type thoracotomy may not be necessary for the diagnosis of the pulmonary chondroma, and extensive gastric resection of the leiomyosarcoma may be lifesaving.