Management of lung cancer in older adults.
Lung cancer is the leading cause of cancer death in the United States. At the time of diagnosis, most patients are older than 65 years and have Stage III or IV disease. More than 80% of patients have non-small cell lung cancer and the rest have small cell lung cancer. Age is not a significant prognostic factor for overall survival and response to treatment for patients with either type of lung cancer. Treatment options should be tailored to older patients based on the same selection process and benefits seen in the population as a whole. This article reviews the available data regarding surgery, radiation, and systemic treatment for older patients with lung cancer and considers the role of geriatric assessment in the evaluation of older patients.


Molecular reactivity of mesocorticolimbic brain areas of high and low grooming rats after elevated plus maze exposure.
High and low grooming rats (HG and LG), selected by extremities in stress-induced self-grooming on the elevated plus maze (EPM), display differences in stress coping style on the EPM, their motivation to self-administer cocaine, and differences in the reactivity of dopaminergic nerve terminals in mesocorticolimbic brain areas. This indicates a link between coping with a stressful/anxiogenic situation and drug intake. Here, we aimed to determine the molecular correlates of these differences by analyzing the reactivity of the mesocorticolimbic brain areas (the medial prefrontal cortex (mPFC) nucleus accumbens shell (NAS) and ventral tegmental area (VTA)) of HG and LG rats in response to EPM exposure. We report by measuring levels of immediate early gene (IEG) transcripts that EPM exposure-induced IEG expression was not significantly different between HG and LG rats. On the other hand, novel IEG expression patterns upon stress (EPM exposure) were apparent in all three areas including arc induction in the mPFC and NAS, CRH, BDNF, and Nr4a3 induction in the NAS, and serum glucocorticoid-regulated kinase (sgk) induction in the VTA. It is concluded that although the mPFC, NAS, and VTA play a role in modulating stress and grooming behavior, the neuronal reactivity in these regions measured by the IEG response is not related with behavioral extremities in stress coping style displayed on the EPM.


Microsurface potential measurements: repulsive forces between polyelectrolyte brushes in the presence of multivalent counterions.
We propose a new way to determine weak repulsive forces operative between colloidal particles by measuring the rate of slow coagulation. The rate of slow coagulation is directly related to the competition of the repulsion with thermal motion. Since the thermal forces are weak, measurements of the coagulation rate can lead to precise information on repulsive potentials having a magnitude of just a few kT. We demonstrate this novel way by studying colloidal spherical polyelectrolyte brush (SPB) particles in aqueous solution containing trivalent La3+ counterions. The particles consist of a monodisperse polystyrene core of 121 nm radius from which linear sodium poly(styrenesulfonate) (PSS) chains are densely grafted (contour length 48 nm). We determine the rate of coagulation by time-resolved simultaneous static and dynamic light scattering in the presence of LaCl3 (0.2 to 150 mM). Direct measurements of the repulsive force between macroscopic brush layers demonstrate that the potential is decaying exponentially with distance. This is in good agreement with a simple theoretical treatment that furthermore leads to the effective surface potential Psi0. The good agreement of data obtained by the novel microscopic method with direct macroscopic measurements underscores the general validity of our approach.


A comparison of covariance structure in wild and laboratory muroid crania.
Mutations have the ability to produce dramatic changes to covariance structure by altering the variance of covariance-generating developmental processes. Several evolutionary mechanisms exist that may be acting interdependently to stabilize covariance structure, despite this developmental potential for variation within species. We explore covariance structure in the crania of laboratory mouse mutants exhibiting mild-to-significant developmental perturbations of the cranium, and contrast it with covariance structure in related wild muroid taxa. Phenotypic covariance structure is conserved among wild muroidea, but highly variable and mutation-dependent within the laboratory group. We show that covariance structures in natural populations of related species occupy a more restricted portion of covariance structure space than do the covariance structures resulting from single mutations of significant effect or the almost nonexistent genetic differences that separate inbred mouse strains. Our results suggest that developmental constraint is not the primary mechanism acting to stabilize covariance structure, and imply a more important role for other mechanisms.


[Primary adrenal insufficiency in adults: 150 years after Addison].
Thomas Addison first described, 150 years ago, a clinical syndrome characterized by salt-wasting and skin hyperpigmentation, associated with a destruction of the adrenal gland. Even today, over a century after Addison's report, primary adrenal insufficiency can present as a life-threatening condition, since it frequently goes unrecognized in its early stages. In the 1850s, tuberculous adrenalitis was present in the majority of patients, but nowadays, autoimmune Addison's disease is the most common cause of primary adrenal insufficiency. In the present report, we show the prevalence of different etiologies, clinical manifestations and laboratorial findings, including the adrenal cortex autoantibody, and 21-hydroxylase antibody in a Brazilian series of patients with primary adrenal insufficiency followed at Divisão de Endocrinologia da Universidade Federal de São Paulo (UNIFESP) and at Faculdade de Medicina de Ribeirão Preto-USP (FMRP-USP).


Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging.
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and the limited available treatment options have not meaningfully impacted patient survival in the past decades. Such poor outcomes can be at least partly attributed to the inability of most drugs tested to cross the blood-brain barrier and reach all areas of the glioma. The objectives of these studies were to visualize and compare by matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry the brain and tumor distribution of the phosphatidylinositol 3-kinase (PI3K) inhibitors pictilisib (GDC-0941, 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine) and GNE-317 [5-(6-(3-methoxyoxetan-3-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine] in U87 and GS2 orthotopic models of GBM, models that exhibit differing blood-brain barrier characteristics. Following administration to tumor-bearing mice, pictilisib was readily detected within tumors of the contrast-enhancing U87 model whereas it was not located in tumors of the nonenhancing GS2 model. In both GBM models, pictilisib was not detected in the healthy brain. In contrast, GNE-317 was uniformly distributed throughout the brain in the U87 and GS2 models. MALDI imaging revealed also that the pictilisib signal varied regionally by up to 6-fold within the U87 tumors whereas GNE-317 intratumor levels were more homogeneous. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analyses of the nontumored half of the brain showed pictilisib had brain-to-plasma ratios lower than 0.03 whereas they were greater than 1 for GNE-317, in agreement with their brain penetration properties. These results in orthotopic models representing either the contrast-enhancing or invasive areas of GBM clearly demonstrate the need for whole-brain distribution to potentially achieve long-term efficacy in GBM.


Species-dependent variations in erythrocyte membrane skeletal proteins.
Two mammalian species (porcine and murine) have erythrocytes that are being widely used to study membrane protein synthesis and red cell aging. Erythrocytes of these species however, are significantly smaller than those of the human. Before results obtained from study of these red cells can be applied to human cells, the membrane skeleton of these species must be investigated to determine if the skeletal elements are equivalent. Both pig and mouse bands 4.1b were of lower molecular weight than human 4.1b, and the a/b ratio was lower. In each species, 4.1a and b were sequence-related phosphoproteins, and yielded substantially different one-dimensional peptide maps. Band 3 of pig and mouse erythrocytes had a higher molecular weight than human band 3 and also had differing one-dimensional peptide maps after limited proteolytic cleavage with three different enzymes. In each species, free band 3 and band 3 bound to the membrane skeleton had identical peptide maps. Other major membrane skeletal components (spectrin, actin, and bands 2.1 and 4.2) seem to be very similar in molecular weight in various species. These results demonstrate that the molecular weights and relative proportions of the membrane skeletal elements are species dependent.


Influence of pollutants in the magneto-dielectric response of silicon nanoparticles.
The influence of the degree of purity of a silicon nanoparticle on its resonances, either electric or magnetic, is assessed by using Mie theory as well as finite-element simulations. In particular, it is shown that the main effect of the increase of absorption due to the pollutants is observed in the magnetic resonances. Concerning Kerker's conditions for the directionality of the scattering [J. Opt. Soc. Am.73, 765 (1983)], it is found that both are strongly shifted when the material's purity is varied. Resistive losses confirm the quenching of magnetic resonances, showing that the region of influence in the magnetic dipole resonance is much larger than in the electric one, although it has been found that losses are not critical for silicon content over 99.50%.


Liquid fuel from waste tires: novel refining, advanced characterization and utilization in engines with ethyl levulinate as an additive.
Pyrolysis is a promising thermochemical strategy to convert scrap tires into diesel-like fuels. Crude tire pyrolysis oil (CTPO) was produced in a 10 ton rotating autoclave reactor by thermal depolymerization of the tire polymers. In this work, the prior-reported straightforward and inexpensive strategy of upgrading CTPO using a combination of silica gel (as adsorbent) and petroleum ether (as the solvent) has been scaled up with minimal loss in mass of oil and improved physicochemical characteristics (e.g., lowered acid value, low sulfur content). The upgraded TPO (StTPO) was characterized extensively to better understand their chemical compositions, physicochemical properties, and combustion characteristics. StTPO was mixed with diesel in different volumetric proportions and the blends were studied for performance and emission characteristics in a single-cylinder engine. The use of biomass-derived ethyl levulinate (EL) as a fuel oxygenate improved the cold-flow properties of StTPO-diesel blends as well as lowered the exhaust emissions (e.g., lower NO x ). A fuel blend consisting of 50% diesel, 40% StTPO, and 10% EL demonstrated the best fuel properties in the single-cylinder diesel engine.


[Update on eosinophilic airway disorders].
Eosinophilic disorders of the airways affect the nose and paranasal sinuses, the bronchi and the lungs. Involvement of the nose includes the well known non allergic rhinitis with eosinophilia syndrome and new disorders characterized by co-participation of mast cells and neutrophils. Eosinophilic bronchitis must be distinguished from asthma, on the basis of some functional findings and a different cytokine profile. Eosinophilic pneumonia comprises acute and chronic forms, Churg-Strauss syndrome, hypereosinophilic syndrome, and eosinophilic granuloma, as well as secondary pneumonia such as Loeffler's syndrome.The treatment is mainly based on corticosteroids and the prognosis is variable, depending upon the development of acute respiratory failure (acute eosinophilic pneumonia, eosinophilic granuloma) or of vasculitis with multi-organ organ involvement in Churg-Strauss syndrome.


Assessment of the mutagenic potency of sewage sludges contaminated with polycyclic aromatic hydrocarbons by an Ames sludges for fluctuation assay.
The mutagenicity of crude extracts and subfractions of two samples of a reference sewage sludge material and two sewage sludges from two wastewater treatment plants (WWTP), one urban and the other one urban mixed with industrial, was assessed using an Ames fluctuation assay based on 384-well microtiter plates with liquid cultures. Crude extracts of sludges were obtained by ultrasonic extraction with dichloromethane/methanol, and further column fractionation yielded two fractions, one of which containing mutagenic polycyclic aromatic hydrocarbons (PAHs). Quantitative analysis performed by gas chromatography-mass spectrometry gave sum concentrations of the 16 PAHs listed as priority pollutants by the U.S. Environmental Protection Agency at levels between 1,305 and 2,442 microg/kg. Subjecting crude extracts and column fractions to the mutagenicity assay with Salmonella strains TA98 and TA 100 provided good qualitative correlation between the presence of mutagenic PAH and the induction of gene mutations. In general, the crude extracts and the PAH-fractions induced positive responses in the assay with both bacterial strains on metabolic activation by S9 rat-liver homogenate, whereas direct-acting mutagens were not detectable. In the assay with the real sludge samples of two different WWTPs, TA98 proved to be more sensitive than TA100; however, similar sensitivities of the tester strains were observed for two reference sewage sludge materials of the same origin. The outcomes of the Ames fluctuation assay demonstrated its performance as a cost-effective and relatively rapid screening tool to assess the genotoxic potential of complex environmental samples.


Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease.
Despite the frequency of cerebellar hemangioblastomas in von Hippel-Lindau (VHL) disease, their optimum contemporary management has not been defined, and is made complex because of the multiple, progressive, and protean nature of the tumors found in patients with this disorder. To examine modern management and outcomes of cerebellar hemangioblastomas in VHL disease, the authors reviewed findings in patients with this disease who underwent resection of cerebellar hemangioblastomas. Consecutive patients with VHL disease who underwent surgery for cerebellar hemangioblastoma(s) at the National Institutes of Health were included. Eighty consecutive patients (44 female and 36 male patients) underwent 126 operations for removal of 164 cerebellar hemangioblastomas (age at surgery 37.8+/-10.3 years, follow-up duration 96.0+/-60.3 months). Serial clinical examinations, imaging studies, and operative records were analyzed. Symptoms and signs included headache (94 operations; 75%), ataxia (55%), dysmetria (29%), and hydrocephalus (28%). Although the primary objective of surgery was resection of the hemangioblastoma considered responsible for symptoms (136 of the hemangioblastomas [83%]), 28 additional hemangioblastomas (17%) were removed during the same surgeries. Tumors associated with symptoms were larger (diameter 1.8+/-1.9 cm; volume 2.8+/-3.4 cm3; p<0.05) and more likely to be associated with peritumoral edema or peritumoral cysts (100% associated with edema and/or cyst; p<0.05) than asymptomatic tumors (diameter 1.1+/-0.9 cm; volume 0.7+/-0.4 cm3; 18%). More tumors were located in the posterior (74%) compared with the anterior (26%) half of the cerebellum (p<0.05). Three months after resection, symptom improvement/stabilization had occurred following 124 of the operations (98%). Preoperative hydrocephalus resolved after tumor removal in 33 cases (94%) and did not require cerebrospinal fluid diversion. Long-term imaging follow-up (61.5+/-15.0 months) revealed no recurrences. Symptoms and signs caused by cerebellar hemangioblastomas in VHL disease are associated with edema and peritumoral cyst formation/propagation and are treated safely and effectively with resection. Cerebrospinal fluid diversion is rarely necessary after complete tumor removal in patients with preoperative hydrocephalus. Cerebellar hemangioblastomas are preferentially distributed in the posterior half of the cerebellum, as they are in the brainstem and spinal cord. Tumor recurrence is avoided by meticulous extracapsular resection.


Antifibrinolytic therapy: evidence, bias, confounding (and politics!).
Cardiac surgery can be complicated by postoperative bleeding and a need for blood transfusion and surgical reexploration. Anti-fibrinolytic drugs such as aprotinin and tranexamic acid may reduce bleeding risks but could possibly increase thrombotic complications. Aprotinin, in particular, has recently been implicated in at least two large observational studies, but this could be because it is more widely used in high-risk cardiac surgical patients. Observational studies are prone to several important sources of bias, in particular, confounding by indication (high-risk patients are more likely to receive aprotinin and more likely to have postoperative complications, irrespective of their exposure to aprotinin). Although multivariate adjustment and propensity score-matching can adjust for confounding, there is no certainty that it removes all such bias. For all anti-fibrinolytic drugs, it remains unclear as to whether the beneficial effect on reduced bleeding outweighs a possible increased risk of thrombotic complications. Debate will continue until we have the results of definitive large randomized trials powered to detect a clinically important effect on outcome.


Repeat-proteins films exhibit hierarchical anisotropic mechanical properties.
Complex hierarchical structures provide beneficial structure-property relationships that can be exploited for a variety of applications in engineering and biomedical fields. Here we report on molecular organization and resulting mechanical properties of self-assembled designed repeat-protein films. Wide-angle X-ray diffraction indicates the designed 18-repeat concensus tetratricopeptide repeat protein (CTPR18) orients normal to the casting surface, while small-angle measurements and electron microscopy show a through-plane transversely aligned laminar sheet-like morphology. Self-assembly is driven by the combination of CTPRs head-to-tail stacking and weak dipole-dipole interactions. We highlight the effect that this hierarchical structure has on the material's mechanical properties. We use nanoindentation and dynamic mechanical analysis to test the mechanical properties over multiple length scales, from the molecular level to the bulk. We find that morphology predictably affects the film's mechanics from the nano- to the macroscale, with the axial modulus values ranging from 2 to 5 GPa. The predictable nature of the structure-property relationship of CTPR proteins and their assemblies proves them a promising platform for material engineering.


Management of alcohol-related liver disease: the French Association for the Study of the Liver and the French Alcohol Society clinical guidelines.
Excessive alcohol consumption is the leading cause of liver diseases in Western countries, especially in France. Alcohol-related liver disease (ARLD) is an extremely broad context and there remains much to accomplish in terms of identifying patients, improving prognosis and treatment, and standardising practices. The French Association for the Study of the Liver wished to organise guidelines together with the French Alcohol Society in order to summarise the best evidence available about several key clinical points in ARLD. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe how patients with ARLD should be managed nowadays and discuss the main unsettled issues in the field.


Delivery of maternal health care in Indigenous primary care services: baseline data for an ongoing quality improvement initiative.
Australia's Aboriginal and Torres Strait Islander (Indigenous) populations have disproportionately high rates of adverse perinatal outcomes relative to other Australians. Poorer access to good quality maternal health care is a key driver of this disparity. The aim of this study was to describe patterns of delivery of maternity care and service gaps in primary care services in Australian Indigenous communities. We undertook a cross-sectional baseline audit for a quality improvement intervention. Medical records of 535 women from 34 Indigenous community health centres in five regions (Top End of Northern Territory 13, Central Australia 2, Far West New South Wales 6, Western Australia 9, and North Queensland 4) were audited. The main outcome measures included: adherence to recommended protocols and procedures in the antenatal and postnatal periods including: clinical, laboratory and ultrasound investigations; screening for gestational diabetes and Group B Streptococcus; brief intervention/advice on health-related behaviours and risks; and follow up of identified health problems. The proportion of women presenting for their first antenatal visit in the first trimester ranged from 34% to 49% between regions; consequently, documentation of care early in pregnancy was poor. Overall, documentation of routine antenatal investigations and brief interventions/advice regarding health behaviours varied, and generally indicated that these services were underutilised. For example, 46% of known smokers received smoking cessation advice/counselling; 52% of all women received antenatal education and 51% had investigation for gestational diabetes. Overall, there was relatively good documentation of follow up of identified problems related to hypertension or diabetes, with over 70% of identified women being referred to a GP/Obstetrician. Participating services had both strengths and weaknesses in the delivery of maternal health care. Increasing access to evidence-based screening and health information (most notably around smoking cessation) were consistently identified as opportunities for improvement across services.


Interleukin 10 in Helicobacter pylori associated gastritis: immunohistochemical localisation and in vitro effects on cytokine secretion.
Interleukin 10 (IL-10) is a counter-inflammatory peptide implicated in the downregulation of human intestinal immune responses. Enhanced secretion of IL-10 has been documented in gastric biopsy organ culture in Helicobacter pylori infection. This study aimed to define the cellular origins of IL-10 in H pylori associated gastritis, and to determine the effects of endogenous IL-10 on proinflammatory cytokine secretion in vitro. Endoscopic biopsies were obtained from the gastric antrum at endoscopy from patients with dyspepsia. Two pairs of antral biopsies were cultured in vitro for 24 hours, one pair in the presence of neutralising anti-IL-10 monoclonal antibody, the other pair as controls. The cytokine content of culture supernatants (tumour necrosis factor alpha (TNF-alpha), IL-6, and IL-8) was determined by enzyme linked immunosorbent assay and corrected for biopsy weight. Helicobacter pylori status was established by histology and biopsy urease test, and histopathology graded by the Sydney system. In a subgroup of patients, western blotting was used to establish CagA serological status. Immunohistochemistry for IL-10 was performed on formalin fixed tissues using a combination of microwave antigen retrieval and the indirect avidin-biotin technique. Immunoreactivity was scored semiquantitatively. In vitro culture was performed in 41 patients: 31 with H pylori positive chronic gastritis and 10 H pylori negative. In vitro secretion of TNF-alpha, IL-6, and IL-8 for "control" biopsies was significantly higher in H pylori positive versus negative samples, with values of TNF-alpha and IL-6 correlating with the degree of active and chronic inflammation and being higher in CagA seropositive cases. No evidence for enhanced cytokine secretion was seen in biopsies cocultured in the presence of anti-IL-10 monoclonal antibody. Immunohistochemistry was performed in 29 patients, of whom 13 were H pylori positive. IL-10 immunoreactivity was observed in the surface epithelium in all H pylori positive cases and in 13 of 16 negative cases, especially in areas of surface epithelial degeneration. Lamina propria mononuclear cells (LPMNCs) were positively stained in all H pylori positive cases and in 12 of 16 negative cases, with a significantly greater proportion of positive LPMNCs in the positive group. This study localised IL-10 protein to the gastric epithelium and LPMNCs. In vitro proinflammatory cytokine secretion was increased in H pylori infection (especially CagA positive infection), but blocking endogenous IL-10 secretion did not significantly increase cytokine secretion. IL-10 is implicated in H pylori infection and might "damp down" local inflammation. The role of gastric IL-10 secretion in determining the clinicopathological outcome of infection merits further study.


Relationship among LRP1 expression, Pyk2 phosphorylation and MMP-9 activation in left ventricular remodelling after myocardial infarction.
Left ventricular (LV) remodelling after myocardial infarction (MI) is a crucial determinant of the clinical course of heart failure. Matrix metalloproteinase (MMP) activation is strongly associated with LV remodelling after MI. Elucidation of plasma membrane receptors related to the activation of specific MMPs is fundamental for treating adverse cardiac remodelling after MI. The aim of current investigation was to explore the potential association between the low-density lipoprotein receptor-related protein 1 (LRP1) and MMP-9 and MMP-2 spatiotemporal expression after MI. Real-time PCR and Western blot analyses showed that LRP1 mRNA and protein expression levels, respectively, were significantly increased in peri-infarct and infarct zones at 10 and 21 days after MI. Confocal microscopy demonstrated high colocalization between LRP1 and the fibroblast marker vimentin, indicating that LRP1 is mostly expressed by cardiac fibroblasts in peri-infarct and infarct areas. LRP1 also colocalized with proline-rich tyrosine kinase 2 (pPyk2) and MMP-9 in cardiac fibroblasts in ischaemic areas at 10 and 21 days after MI. Cell culture experiments revealed that hypoxia increases LRP1, pPyk2 protein levels and MMP-9 activity in fibroblasts, without significant changes in MMP-2 activity. MMP-9 activation by hypoxia requires LRP1 and Pyk2 phosphorylation in fibroblasts. Collectively, our in vivo and in vitro data support a major role of cardiac fibroblast LRP1 levels on MMP-9 up-regulation associated with ventricular remodelling after MI.


Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3-Knockin Mice.
In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy. Here, we report the development and characterization of REGN3767, a fully human IgG4 antibody targeting LAG-3, another inhibitory receptor on T cells. REGN3767 binds human and monkey LAG-3 with high affinity and specificity and blocks the interaction of LAG-3 with its ligand, MHC class II. In an engineered T-cell/antigen-presenting cell bioassay, REGN3767 alone, or in combination with cemiplimab (REGN2810, human anti-PD-1 antibody), blocked inhibitory signaling to T cells mediated by hLAG-3/MHCII in the presence of PD-1/PD-L1. To test the in vivo activity of REGN3767 alone or in combination with cemiplimab, we generated human PD-1xLAG-3 knockin mice, in which the extracellular domains of mouse Pdcd1 and Lag3 were replaced with their human counterparts. In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in nonhuman primates, together with enhancement of antitumor efficacy of anti-PD-1 antibody in preclinical tumor models, support its clinical development.


Pharmacogenomic Challenges in Cardiovascular Diseases: Examples of Drugs and Considerations for Future Integration in Clinical Practice.
Even if cardiovascular disease (CVD) drugs are supported by high level proofs, the results of CVD treatment present great disparities: there are still patients dying with supposed optimal treatment, patients facing adverse events and CVD remains the primary cause of death in the world. Pharmacogenomics is the basis of personalisation of the treatment able to allow higher medication success rates. In this review, we will present detailed examples of CVD drugs to highlight the complexity of this challenging field and we will discuss novel concepts that should be considered for a fastest integration of pharmacogenomics in clinical practice of CVD. Areas Covered: The complexity of pharmacogenetics and pharmacogenomics of CVD drugs are presented though examples of medications such as statins, with a focus on their effectiveness and adverse effects. Expert Opinion: The application of personalised medicine in the CVD medical practice requires the study of human genome with regard to drugs pharmacokinetics, pharmacodynamics, interactions and tolerance profile. The existing state -of-the-art of CVD drugs gives hopes for a future revolution in the drug development that will maximise cardiovascular patients benefit while decreasing their risks for adverse effects. Article Highlights Box: • Coronary heart disease (CHD) remains the first cause of death worldwide. • Cardiovascular treatment has a significant percentage of insufficient efficacy, poor tolerance and compliance. • Predicting the response to therapy while diminishing the side effects is the basis of personalised medicine; pharmacogenomics is leading towards this direction. • The response to CVD therapy and side effects are in the heart of CVD pharmacogenomics and significant progress has been noted. • The application of pharmacogenomics in the CVD medical practice is facing many methodological, technical, ethical, behavioral and financial issues, while cost-effectiveness is the main prerequisite. • The consideration of gene × gene × environment interactions and the inclusion of "omics" data in pharmacogenomic studies of CVD drugs will facilitate the generation of reliable results and will promote tailored treatments and new strategies of drug research and development.


The clinical anatomy fellowship: A participants' perspective.
Kansas City University offers a Clinical Anatomy Fellowship which enrolls nine medical students during each academic year and provides training in research, teaching, and advanced anatomical topics. The Fellows practice as novice educators, working alongside Anatomy faculty to teach medical students in the Gross Anatomy laboratory. However, little has been reported related to Fellowship participation and success outcomes. This survey-based study was designed to explore (1) student motivation(s) for pursuing the Fellowship, (2) benefits of participation, and (3) the perceived impact on residency applications and career success. Three unique populations were surveyed. The most important factors driving application to the Fellowship were a desire to increase competitiveness in the residency application process (Likert mean score 4.7-5.0) and a passion for Anatomy (Likert mean score 4.3-4.7). Taking a year away from the College of Osteopathic Medicine curriculum (Likert mean score 4.4) and delaying clinical exposure (Likert mean score 4.2) were the most important deterrents to application. The most reported benefits after program completion included opportunities to build a strong residency application (44% and 50% of Fellows), conduct research (44% and 45% of Fellows), and participate in teaching (11% and 50% of Fellows). 73% of past Fellows matched into their top specialty of choice. Flexibility in the program allows participants to individualize their Fellowship experience to address their personal goals related to residency applications and careers as future physicians. As the results suggest, the Clinical Anatomy Fellowship benefits Fellows, signaling other medical institutions to consider adopting a similar program.


Neonatal cerebral sinovenous thrombosis: sifting the evidence for a diagnostic plan and treatment strategy.
Although cerebral sinovenous thrombosis (CSVT) is an uncommon disorder in neonates, the incumbent morbidity, mortality, and adverse neurodevelopmental sequelae highlight the importance of establishing an early diagnosis with an appropriate therapeutic plan. The clinical signs and symptoms of the condition are subtle and invariably masquerade under the umbrella of a broad spectrum of neonatal illnesses. A high index of diagnostic suspicion is essential for investigating and initiating treatment in a timely fashion before major complications ensue. Recent advances in accessible radiographic techniques with reduced radiation exposure have facilitated rapid diagnosis of thrombosis in both the superficial and deep plexuses of the cerebral venous systems. The absence of large-scale randomized trials and solid prospective smaller-sample-sized studies of neonates with CSVT has compromised our ability to develop efficacious treatment decisions. In this review of the scientific literature we offer understanding of the complex etiology of CSVT and inherent problems involved in the diagnosis and treatment of the disorder and focus on the limitations in current follow-up. An approach to neonatal CSVT is proposed on the basis of the available evidence from guidelines, registries, prospective and retrospective infant studies, and case series.


The role of object affordances and center of gravity in eye movements toward isolated daily-life objects.
The purpose of the current study was to investigate to what extent low-level versus high-level effects determine where the eyes land on isolated daily-life objects. We operationalized low-level effects as eye movements toward an object's center of gravity (CoG) or the absolute object center (OC) and high-level effects as visuomotor priming by object affordances. In two experiments, we asked participants to make saccades toward peripherally presented photographs of graspable objects (e.g., a hammer) and to either categorize them (Experiment 1) or to discriminate them from visually matched nonobjects (Experiment 2). Objects were rotated such that their graspable part (e.g., the hammer's handle) pointed toward either the left or the right whereas their action-performing part (e.g., the hammer's head) pointed toward the other side. We found that early-triggered saccades were neither biased toward the object's graspable part nor toward its action-performing part. Instead, participants' eyes landed near the CoG/OC. Only longer-latency initial saccades and refixations were subject to high-level influences, being significantly biased toward the object's action-performing part. Our comparison with eye movements toward visually matched nonobjects revealed that the latter was not merely the consequence of a low-level effect of shape, texture, asymmetry, or saliency. Instead, we interpret it as a higher-level, object-based affordance effect that requires time, and to some extent also foveation, in order to build up and to overcome default saccadic-programming mechanisms.


Treatment of acute gonococcal urethritis in men with simultaneous infection with Chlamydia trachomatis.
Each of 201 men with symptoms and signs of acute urethritis was randomly assigned to one of two treatment regimens: ampicillin (2g) plus probenecid (1g), or sulphamethoxazole-trimethoprim (SMX-TMP) (sulphamethoxazole 1600 mg plus trimethoprim 320 mg) four tablets twice daily for two days. Before treatment Neisseria gonorrhoeae was isolated from 162 patients, while coexistent Chlamydia trachomatis was recovered from 42 (26%) men. After treatment N gonorrhoeae persisted in 11 (14.3%) of the 77 patients treated with ampicillin and probenecid and in three (3.5%) of the 85 treated with SMX-TMP (p less than 0.05), while C trachomatis persisted in four (16%) of the 25 men treated with SMX-TMP and in all 17 patients treated with ampicillin and probenecid. SMX-TMP was thus more effective than ampicillin in treating acute gonorrhoea in men and in eradicating concurrent C trachomatis infection.


Oligonucleotide studies. Optical rotatory dispersion of five homodinucleotides.
1. The optical rotatory dispersion (ORD) of five homodinucleotides, ApAp(3'), CpCp(3'), GpGp(3'), IpIp(3') and UpUp(3') (where A, C, G, I and U represent adenosine, cytidine, guanosine, inosine and uridine respectively, and p to the left of a nucleoside symbol indicates a 5'-phosphate and to the right it indicates a 3'-phosphate), were measured as a function of pH, ionic strength and Mg(2+) concentration. 2. The ORD titrations of ApAp(3') and CpCp(3'), which were made by measuring the ORD curves at closely spaced pH intervals, exhibit a maximum at approx. pH5.0 and 5.7 for ApAp(3') and CpCp(3') respectively in the profile of the magnitude of the first Cotton effect versus pH. The results indicate that the conformational rigidity of these dinucleotides depends on the ionization state of a 3'-terminal phosphate group. 3. ApAp(3') was shown to exist as an approximately 1:1 equilibrium mixture of the two major ionic species represented by Ap((-1))Ap((-1)) and Ap((-1))Ap((-2)) at pH6.16, whereas at pH7.5 it exists exclusively as a form of Ap((-1))Ap((-2)). 4. To ascertain the effects of the presence of a terminal phosphate group and of the ionization of the secondary phosphate on the conformation of adenylate dimer, we measured the ORD of ApA, ApAp(3')CH(3) and ApAp(2'). The rotatory power of the first Cotton effect in the above series of dinucleotides decreased at 20 degrees in the order ApA> ApAp(3')CH(3) approximately ApAp(3')((-1))> ApAp(2') at pH7> ApAp(3') at pH7. 5. The pH-rotation profiles were also obtained for ApAp(2'), CpCp(2') and UpUp(3'), but no corresponding maximum was observed. Although simple nearest-neighbour calculations based on the ORD data of IpIp(3') and 5'-IMP account for the observed ORD spectrum of polyinosinic acid at low salt concentration, there were large discrepancies between calculated and experimental results of the polyguanylic acid ORD even at low ionic strength. 6. The extent to which the amplitude of the Cotton effects of IpIp(3') increases with salt concentration, especially by the addition of Mg(2+), was much greater than that observed for ApAp(3'). The implication of such salt effects on the ORD is considered.


Clinical spectrum of Kabuki-like syndrome caused by HNRNPK haploinsufficiency.
Kabuki syndrome is a genetically heterogeneous disorder characterized by postnatal growth retardation, skeletal abnormalities, intellectual disability, facial dysmorphisms and a variable range of organ malformations. In ~30% of affected individuals, the underlying genetic defect remains unknown. A small number of inactivating heterozygous HNRNPK mutations has recently been reported to be associated with a condition partially overlapping or suggestive of Kabuki syndrome. Here, we report on an 11-year-old girl with a complex phenotype in whom the diagnosis of KS was suggested but molecular testing for the known causative disease genes was negative. Whole-exome sequencing identified a previously undescribed de novo truncating mutation in HNRNPK as the molecular defect underlying the trait. Analysis of available records of patients with HNRNPK haploinsufficiency was performed to delineate the associated clinical phenotype and outline their distinguishing features in comparison with the KS clinical spectrum. The clinical profile associated with inactivating HNRNPK mutations supports the idea that the associated disorder should be considered as a distinct nosologic entity clinically related to KS, and that the condition should be considered in differential diagnosis with KS, in particular in subjects exhibiting brain malformation (nodular heterotopia), craniosynostosis, and polydactyly.


[Health care reform in Chile: 2005 to 2009].
Five years ago Chile implemented a Health Care Reform to reduce the great inequalities in health care provision that affects the low- income, high-risk segment of its population. A universal care plan ("AUGE") was designed to make medical coverage available to all Chilean citizens suffering from one of a specified, growing list of diseases (66 at present time). The diseases are prioritized by the Ministry of Health and its inclusion in the plan is revised periodically by an Advisory Committee according to four cardinal criteria: burden of disease, effectiveness of treatment, specific capacity of the health system and financial costs. The plan is funded by the state and enforced by law through a set of four specific guarantees: access, opportunity, quality and financial protection. This paper reviews the origin and development of the reform, the benefits and drawbacks of the application of the specific guarantees and the perception of the public regarding its strengths and weaknesses.


Intestinal parasitic infection among children and neonatus admitted to Ibn-Sina Hospital, Sirt, Libya.
A total of 350 stool samples from 196 males and 154 female children and neonatus admitted in Ibn-Sina hospital, Sirt, were examined from June 2001 to May 2002, to determine the prevalence of intestinal parasites. Intestinal parasitic infections were identified in 196 (56%) of children and neonates. No intestinal helminthic parasites were detected but 13 intestinal protozoan parasites were detected. The most prevalent protozoan was Entamoeba histolytica /E. dispar (36.57%); Blastocystis hominis (12.57%), Giardia lamblia (10.29%), Isospora belli (3.14%) and Balantidium coli (0.86%), the latter was detected in non-Libyan children. The non-pathogenic ones were Entamoeba coli (15.14%), Endolimax nana (13.71%), Entamoeba hartmanni (4.29%), Chilomastix mesnilli (4.29%), Retortamonas intestinalis (3.43%), Dientamoeba fragilis (2%), Iodamoeba butschlii (0.86%) and Trichomonas hominis (0.86%). The result showed a significant difference exists between the prevalence of pathogenic and non-pathogenic protozoan parasites (P < 0.05). High prevalence of E. histolytica/ E. dispar followed by E. coli, E. nana, B. hominis and G. lamblia in both sexes of children, while the prevalence of other intestinal parasites were low in both sexes, significantly different existed in the prevalence of intestinal parasites between males and females children (t = 24.68; P < 0.05). Age groups had no effect on the prevalence of intestinal parasites (F = 0.66; P < 0.05). Significant differences existed in the prevalence between single and multiple infections with pathogenic protozoa. The socio-economic status of children parents revealed that high prevalence in children from medium socio-economic status. The family size had no significant effect on the prevalence of the intestinal parasites.


Self-reported pelvic inflammatory disease in the United States, 1988.
--To assess any changes in the characteristics of women with self-reported pelvic inflammatory disease (PID) between 1982 and 1988 and to evaluate the role of additional behavioral factors. In 1982, PID was a frequent problem among American women of reproductive age, occurring in one in seven. It was also more common among older (greater than or equal to 30 years) than younger women, more common among blacks than among whites, and more common among formerly married women than among those currently married. --We analyzed data on self-reported PID from the cycle IV National Survey of Family Growth, conducted in 1988. --The survey was conducted with a multistage probability sample of 8450 women. --The findings from 1982 were all replicated. Additional variables available in 1988 show that PID is more common among women with multiple (two or more) sexual partners (10% to 22%) compared with those with only one lifetime partner (7%) and among women who report a history of sexually transmitted disease (STD) (26%) compared with those with no STD history (10%). Controlling for other variables, age, race, vaginal douching, age at first intercourse, STD history, and number of lifetime partners emerged as independent predictors of self-reported PID among American women of reproductive age. --PID is still a widely prevalent condition among American women, PID is associated with a variety of risk factors for STD. Prevention of lower genital tract infection is crucial to avoiding PID and its sequelae.


Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure.
Folliculin (FLCN) is an autosomal dominant tumor suppressor gene that modulates diverse signaling pathways required for growth, proliferation, metabolism, survival, motility, and adhesion. FLCN is an essential protein required for murine embryonic development, embryonic stem cell (ESC) commitment, and Drosophila germline stem cell maintenance, suggesting that Flcn may be required for adult stem cell homeostasis. Conditional inactivation of Flcn in adult hematopoietic stem/progenitor cells (HSPCs) drives hematopoietic stem cells (HSC) into proliferative exhaustion resulting in the rapid depletion of HSPC, loss of all hematopoietic cell lineages, acute bone marrow (BM) failure, and mortality after 40 days. HSC that lack Flcn fail to reconstitute the hematopoietic compartment in recipient mice, demonstrating a cell-autonomous requirement for Flcn in HSC maintenance. BM cells showed increased phosphorylation of Akt and mTorc1, and extramedullary hematopoiesis was significantly reduced by treating mice with rapamycin in vivo, suggesting that the mTorc1 pathway was activated by loss of Flcn expression in hematopoietic cells in vivo. Tfe3 was activated and preferentially localized to the nucleus of Flcn knockout (KO) HSPCs. Tfe3 overexpression in HSPCs impaired long-term hematopoietic reconstitution in vivo, recapitulating the Flcn KO phenotype, and supporting the notion that abnormal activation of Tfe3 contributes to the Flcn KO phenotype. Flcn KO mice develop an acute histiocytic hyperplasia in multiple organs, suggesting a novel function for Flcn in macrophage development. Thus, Flcn is intrinsically required to maintain adult HSC quiescence and homeostasis, and Flcn loss leads to BM failure and mortality in mice.


Differential control of abdominal muscles during multi-directional support-surface translations in man.
The current study aimed to understand how deep and superficial abdominal muscles are coordinated with respect to activation onset times and amplitudes in response to unpredictable support-surface translations delivered in multiple directions. Electromyographic (EMG) data were recorded intra-muscularly using fine-wire electrodes inserted into the right rectus abdominis (RA), obliquus externus (OE), obliquus internus (OI) and transversus abdominis (TrA) muscles. Twelve young healthy male subjects were instructed to maintain their standing balance during 40 support surface translations (peak acceleration 1.3 m s(-2); total displacement 0.6 m) that were counter-balanced between four different directions (forward, backward, leftward, rightward). Differences between abdominal muscles in EMG onset times were found for specific translation directions. The more superficial RA (backward translations) and OE (forward and leftward translations) muscles had significantly earlier EMG onsets compared to TrA. EMG onset latencies were dependent on translation direction in RA, OE and OI, but independent of direction in TrA. EMG amplitudes in RA and OE were dependent on translation direction within the first 100 ms of activity, whereas responses from the two deeper muscles (TrA and OI) were independent of translation direction during this interval. The current results provide new insights into how abdominal muscles contribute to postural reactions during human stance. Response patterns of deep and superficial abdominal muscles during support surface translations are unlike those previously described during upper-body perturbations or voluntary arm movements, indicating that the neural mechanisms controlling individual abdominal muscles are task-specific to different postural demands.


Teaching and Rehabilitation of Handwriting for Children in the Digital Age: Issues and Challenges.
Handwriting is a determining factor for academic success and autonomy for all children. Making knowledge accessible to all is a challenge in the context of inclusive education. Given the neurodevelopmental diversity within a classroom of children, ensuring that the handwriting of all pupils progresses is very demanding for education professionals. The development of tools that can take into account the variability of the profiles and learning abilities of children with handwriting difficulties offers a new potential for the development of specific and adapted remediation strategies. This narrative review aims to present and discuss the challenges of handwriting learning and the opportunities offered by new technologies involving AI for school and health professionals to successfully improve the handwriting skills of all children.


Prediction of alcohol-related harm from controlled drinking strategies and alcohol consumption trajectories.
To establish predictors of age 21 alcohol-related harm from prior drinking patterns, current levels of alcohol consumption and use of controlled drinking strategies. One thousand, five hundred and ninety-six students recruited from an initial sample of 3300 during their final year of high school in 1993. Longitudinal follow-up across five waves of data collection. Post high school in Victoria, Australia. Self-administered surveys examining a range of health behaviours, including alcohol consumption patterns and related behaviour. Drinking behaviours at age 21 were found to be strongly predicted by drinking trajectories established through the transition from high school. Multivariate regression analysis revealed that alcohol-related harms at age 21 were reduced where current levels of alcohol use fell within limits recommended in Australian national guidelines. After controlling for this effect it was found that the range of strategies employed by participants to control alcohol use maintained a small protective influence. Post-high-school drinking trajectories continued to demonstrate a significant effect after controlling for current behaviours. revealed that over one quarter of males and females drank alcohol, but on a less-than-weekly basis. This pattern of alcohol use demonstrated considerable stability through the post-school transition and was associated with a low level of subsequent harm at age 21. Future research should investigate whether encouraging more Australian adolescents to drink alcohol on a less-than-weekly basis may be a practical intervention target for reducing alcohol-related harms.


Cosmological element production.
Two recent observations appear to have provided critical information about the past history of the universe. The thermal character of the microwave background radiation suggests that the universe has expanded from a state of high temperature and density, and places constraints on such a big-bang cosmology. The observations of very weak helium lines in the spectra of certain stars in the halo of our galaxy are possibly due to a low primeval abundance of this element. However, the simplest model of a big-bang cosmology leads to much higher helium abundances, such as are observed in the solar system and in many stars. The production of helium can be reduced either by altering the early expansion rate or by introducing degenerate electron neutrinos. Observations of interstellar and intergalactic deuterium and He(4), and possibly even He(3) and Li(7), are needed to test the various models.


Narrow band imaging with magnification for the characterization of small and diminutive colonic polyps: pit pattern and vascular pattern intensity.
Narrow band imaging (NBI) can accurately characterize colonic polyps using microvascular appearances. We aimed to assess whether the Kudo pit pattern classification is accurate when used with NBI (without dye-spray), and if microvascular appearances or NBI pit patterns maintain accuracy for polyp characterization at sizes < 10 mm. 116 polyps < 10 mm in size were detected in 62 patients undergoing surveillance colonoscopy. The polyps were prospectively assessed using NBI and magnification for Kudo pit pattern (III-V neoplastic, I-II non-neoplastic) and vascular pattern intensity (VPI), a measure of microvascular density (strong VPI, neoplastic; normal or weak VPI, non-neoplastic). Sensitivity, specificity, and accuracy were calculated and compared with results from histopathology. The mean polyp size was 3.4 mm (range 1 - 9 mm). Overall, NBI pit pattern sensitivity, specificity, and accuracy were 0.88, 0.91, and 89.6 %, respectively. Equivalent values for VPI were 0.94, 0.89, and 91.4 %. Results were similar when polyps were subdivided into diminutive polyps (size <or= 5 mm) and flat polyps. Combining both pit pattern and VPI improved the sensitivity (0.98, P = 0.06 versus NBI pit pattern alone). There was very good agreement between NBI pit pattern and VPI for prediction of dysplasia (kappa = 0.83). No evidence of a learning curve for VPI was found. The NBI pit pattern was better than the VPI at subclassifying hyperplastic from other non-neoplastic polyps (sensitivity 0.79 versus 0.56, respectively, P = 0.02), but accuracy was poor. The NBI pit pattern and VPI are both highly accurate in characterizing neoplastic colonic polyps of < 10 mm, with VPI appearing to be simple to learn. NBI has the potential to replace conventional histology for small polyps.


Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma.
From 1980 through 1986, 119 patients with soft tissue sarcomas of the extremities were referred to our tumor center either before surgery (n = 78) or immediately after incisional biopsy or marginal excision (n = 41). The tumors were classified according to anatomic location at admittance as subcutaneous (n = 40), intramuscular (n = 30), and extramuscular tumors (n = 49). Open biopsy was omitted in 75 of the 78 patients referred before surgery; the preoperative diagnosis was based on physical and radiographic findings and fine-needle aspiration cytology. The surgical intention for subcutaneous tumor was to obtain a wide margin, which required a cuff of fat tissue around the tumor and inclusion of the deep fascia beneath the tumor. A wide margin for an intramuscular tumor implied no open biopsy and an unbroken muscle fascia or thick muscle cuff around the tumor (primary myectomy). The 70 patients with subcutaneous and intramuscular tumors were all treated by local surgery. A wide margin was obtained in 56 patients who were not given radiotherapy. During a median follow-up of 5 years (range, 3.5 to 10 years), four of these 56 patients--47 of whom had high-grade malignant tumors--had a local recurrence. We conclude that routine combination of limb-sparing surgery with adjuvant radiotherapy is not necessary in patients with soft tissue sarcoma. Two thirds of soft tissue sarcomas of the extremities are primarily subcutaneous or intramuscular tumors, the majority of which can be treated by local surgery without local adjuvant therapy with a local recurrence rate of less than 10%, irrespective of malignancy grade.


Thermodynamics of the interactions of positively charged cellulose nanocrystals with molecules bearing different amounts of carboxylate anions.
Negatively charged ions readily interact with the surface of positively charged pyridinium-grafted cellulose nanocrystals. In this work we investigated the thermodynamics of these interactions using isothermal titration calorimetry. We investigated the effect of the ionic charge, using carboxylate salts with different valence (1-4), and compared it with sodium sulfate as another delocalized ionic charge. Experiments performed using cellulose nanocrystals with three different degrees of substitution of pyridinium grafts showed that the number of ions adsorbed onto the surface of cellulose nanocrystals is directly linked to the number of grafted cationic functionalities. The adsorption of anions onto pyridinium-grafted nanocrystals was further found to be endothermic and driven by an increase in entropy upon adsorption of the anions due to the release of surface bound water. The association constant increased with the net charge of the anions from a low value for monovalent sodium acetate. Both entropy and enthalpy increased linearly with the net charge of the anions, demonstrating that a stronger depolarization occurred when anions of higher net charge were adsorbed. The values of the stoichiometric number determined were lower than the values relative to processes involving ions in solution, suggesting a more complex mode of interaction, involving hydrogen-bonding and bridge formation. However, the number of adsorbed ions was directly correlated with the amount of cationic surface grafts. This makes it possible to control the amount of surface interactions directly with the degree of substitution on the nanocrystal surfaces. Comparison with zeta potential measurements showed that zeta-potential measurements can be used as a direct method to determine the stoichiometry of binding between the positive surface grafts and the carboxylate salts.


Suppression by p38 MAP kinase inhibitors (pyridinyl imidazole compounds) of Ah receptor target gene activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the possible mechanism.
Cytochrome P-450 1A1 (CYP1A1) is known to be induced by aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), through activation of the aryl hydrocarbon receptor (AhR). We found that p38 MAP kinase inhibitors (SB203580 and SB202190; 40 microm each; pyridinyl imidazole compounds) suppressed CYP1A1-mRNA induction by TCDD (2 nm) in mouse hepatoma Hepa-1 cells and in human hepatoma HepG2 cells, and also suppressed CYP1B1-mRNA induction by TCDD (2 nm) in human breast adenocarcinoma MCF7 cells. An analogue compound, SB202474, which does not inhibit p38 MAP kinase, also suppressed CYP1A1-mRNA induction by TCDD. Moreover, overexpression of a dominant-negative gene for p38 MAP kinase in Hepa-1 cells did not suppress Cyp1a1 reporter gene induction by TCDD. Therefore, the suppression of Cyp1a1 transcription by pyridinyl imidazole compounds is not because of their inhibition of p38 MAP kinase activity. Because SB203580 did not inhibit in vitro AhR transformation by TCDD, this compound was not acting as a simple AhR antagonist. SB203580 decreased TCDD-induced histone acetylation levels in the region of the Cyp1a1 gene promoter, especially around the TATA box sequence. This result suggests the possibility that pyridinyl imidazole compounds suppress the recruitment of some co-activator that has the histone acetyltransferase activity necessary for CYP1A1-mRNA transcription.


Comparison of the in-vivo and in-vitro response to ragweed immunotherapy in children and adults with ragweed-induced rhinitis.
In order to compare results of allergen immunotherapy in paediatric and adult populations, 22 children with a history of ragweed hay fever were matched with an equal number of adults for skin sensitivity to ragweed and all were given a 1-year course of immunotherapy with a partially purified ragweed extract. Biological responses were measured by nasal challenges with ragweed before therapy was started, after 12 weekly injections and when the maintenance dose had been reached and also by methacholine bronchoprovocation tests before and after 12 months of therapy. Skin-test sensitivity to ragweed and control allergens, and ragweed-specific IgE and IgG antibody responses were measured at the same intervals as the challenges and at the end of the study. The effect of the therapy on clinical symptoms was not evaluated. Before therapy the groups of adults and children were comparable by all indices, except for TAME esterase activity in nasal washes during ragweed nasal challenge which was significantly lower in children. During treatment, mediators released during sequential nasal challenges declined to undetectable levels in most patients and changes in nasal ragweed sensitivity were comparable in both groups. Ragweed IgE increases after 12 weeks of therapy and IgG levels at maintenance therapy tended to be higher in the children, but neither difference was statistically significant. At the end of the study IgE and IgG antibody levels were comparable in both groups. Results of methacholine inhalation tests did not change significantly in either group. The decrease in skin sensitivity to ragweed was similar in both groups. We conclude that ragweed immunotherapy leads to immunological and biological consequences that are comparable in children and adults.


A Brief Review on the Neuroprotective Mechanisms of Vitexin.
The neural dysfunction is triggered by cellular and molecular events that provoke neurotoxicity and neural death. Currently, neurodegenerative diseases are increasingly common, and available treatments are focused on relieving symptoms. Based on the above, in this review we describe the participation of vitexin in the main events involved in the neurotoxicity and cell death process, as well as the use of vitexin as a therapeutic approach to suppress or attenuate neurodegenerative progress. Vitexin contributes to increasing neuroprotective factors and pathways and counteract the targets that induce neurodegeneration, such as redox imbalance, neuroinflammation, abnormal protein aggregation, and reduction of cognitive and/or motor impairment. The results obtained provide substantial evidence to support the scientific exploration of vitexin in these pathologies, since their effects are still little explored for this direction.


[Amiodarone-induced pulmonary fibrosis].
The most feared side-effect of long-term amiodarone therapy is progressive alveolitis/pneumonitis leading to pulmonary fibrosis. The case history of a patient is presented who received amiodarone unnecessarily in a high dose (600 mg/day) for 4 years: drug-induced dermatopathy, hypothyroidism and lung fibrosis developed. After cessation of amiodarone treatment the pulmonary complication did not disappear therefore glucocorticoid therapy was introduced. New-onset improductive cough, dyspnea, fever and/or enhanced erythrocyte sedimentation rate may suggest the presence of amiodarone pulmonary toxicity and may form the basis of indication of high-resolution computed tomography (HRCT). Amiodarone-induced pulmonary involvement can be shown by HRCT early, before the appearance of any considerable abnormality of chest radiography.


Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo.
Changes in the amounts of cellular eumelanin and pheomelanin have been associated with carcinogenesis. The goal of this work is to develop methods based on two-photon-excited-fluorescence (TPEF) for measuring relative concentrations of these compounds. We acquire TPEF emission spectra (λ(ex)=1000 nm) of melanin in vitro from melanoma cells, hair specimens, and in vivo from healthy volunteers. We find that the pheomelanin emission peaks at approximately 615 to 625 nm and eumelanin exhibits a broad maximum at 640 to 680 nm. Based on these data we define an optical melanin index (OMI) as the ratio of fluorescence intensities at 645 and 615 nm. The measured OMI for the MNT-1 melanoma cell line is 1.6 ± 0.22 while the Mc1R gene knockdown lines MNT-46 and MNT-62 show substantially greater pheomelanin production (OMI=0.5 ± 0.05 and 0.17 ± 0.03, respectively). The measured values are in good agreement with chemistry-based melanin extraction methods. In order to better separate melanin fluorescence from other intrinsic fluorophores, we perform fluorescence lifetime imaging microscopy of in vitro specimens. The relative concentrations of keratin, eumelanin, and pheomelanin components are resolved using a phasor approach for analyzing lifetime data. Our results suggest that a noninvasive TPEF index based on spectra and lifetime could potentially be used for rapid melanin ratio characterization both in vitro and in vivo.


Efficacy and safety of cyclooxygenase 2 inhibitors for desmoid tumor management: a systematic review.
The efficacy and safety of cyclooxygenase 2 (COX2) inhibitors for the treatment of desmoid-type fibromatosis (DF) are unclear. Therefore, we systematically reviewed related literature to assess the efficacy and safety of COX2 inhibitors for DF treatment. We searched pertinent literature between January 1999 and August 2017 to identify relevant studies using the keywords "Fibromatosis, aggressive" and "Cyclooxygenase inhibitors." Thereafter, we screened and determined the quality of the studies using the Grading of Recommendations Assessment, Development, and Evaluation system and extracted the article data. The critical outcomes selected were the efficacy and adverse effects of COX2 inhibitors. Efficacy was evaluated in terms of clinical benefit when patients showed complete response, partial response, and stable disease. Thirty-one articles were identified from the database search, and one was identified through the reviewers' manual search. Finally, we retrieved six studies, including three case reports, comprising 89 patients after the first and second screenings. Fifty-three patients were excluded because three studies were reported from the same institution; hence, in total, 36 patients were included. Clinical benefit was noted in 64% of the patients. Three adverse effects were identified from the records of the six extracted studies. The strategy of watchful waiting using COX2 inhibitors with few side effects is weakly recommended for DF, especially DF patients with pain.


Surface-induced optimal packing of two-dimensional molecular networks.
High-density packing in organic crystals is usually associated with an increase of the coordination between molecules. Such a concept is not necessarily extended to two-dimensional molecular networks self-assembled on a solid surface, for which we demonstrate the key role of the surface in inducing the optimal packing. By a combination of scanning tunneling microscopy experiments and multiscale computer simulations, we study the phase transition between two polymorphs. We find that, contrary to intuition, the structure with the lowest packing fraction corresponds to the highest molecular coordination number, due to the competition between surface and intermolecular forces. Having the lowest free energy, this structure spreads out as the most stable polymorph over a wide range of molecular concentrations.


Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44.
CD44 on lymphocytes binding to its carbohydrate ligand hyaluronan can mediate primary adhesion (rolling interactions) of lymphocytes on vascular endothelial cells. This adhesion pathway is utilized in the extravasation of activated T cells from the blood into sites of inflammation and therefore influences patterns of lymphocyte homing and inflammation. Hyaluronan is a glycosaminoglycan found in the extracellular matrix and is involved in a number of biological processes. We have shown that the expression of hyaluronan on the surface of endothelial cells is inducible by proinflammatory cytokines. However, the manner through which hyaluronan is anchored to the endothelial cell surface so that it can resist shear forces and the mechanism of the regulation of the level of hyaluronan on the cell surface has not been investigated. In order to characterize potential hyaluronan receptors on endothelial cells, we performed analyses of cell surface staining by flow cytometry on intact endothelial cells and ligand blotting assays using membrane fractions. Hyaluronan binding activity was detected as a major species corresponding to the size of CD44, and this was confirmed to be the same by Western blotting and immunoprecipitation. Moreover, alterations in the surface level of hyaluronan after tumor necrosis factor-alpha stimulation is regulated primarily by changes in the cell surface levels of the hyaluronan-binding form of CD44. In laminar flow assays, lymphoid cells specifically roll on hyaluronan anchored by purified CD44 coated on glass tubes, indicating that the avidity of the endothelial CD44/hyaluronan interaction is sufficient to support rolling adhesions under conditions mimicking physiologic shear forces. Together these studies show that CD44 serves to anchor hyaluronan on endothelial cell surfaces, that activation of CD44 is a major regulator of endothelial surface hyaluronan expression, and that the non-covalent interaction between CD44 and hyaluronan is sufficient to provide resistance to shear under physiologic conditions and thereby support the initial steps of lymphocyte extravasation.


[Eluding clinical medicine: a phenomenon that can be stopped].
A study published in this issue (Lotan et at.) reveals distressing data on the percentage of 4th year students, after their first clerkship, that regret their choice of medicine as a career and contemplate a non-clinical vocational path. This phenomenon, entitled "eluding clinical medicine", is analyzed in terms of early professional socialization of the students toward sciences and their difficulty to tolerate ambiguity and uncertainty, so typical to clinical medicine. Also discussed is the student's incapability to integrate acquired knowledge across disciplines and to interweave it into clinical reality. Rectification of this escape from clinical medicine" may require modification of the pattern of the students' professional socialization during their first years of studies by such measures as early clinical exposure, interdisciplinary integration and practice in decision-making and problem-solving throughout the so-called "preclinical phase". The alarming findings presented in the above-mentioned study call for immediate response.


Lineage-specific variation in intensity of natural selection in mammals.
The molecular clock hypothesis states that protein-coding genes evolve at an approximately constant rate. However, this is only expected to be true as long as the function and the tertiary structure of the molecule remain unaltered. An important implication of this statement is that significant deviations in the rate of evolution of a gene with respect to the species clock are likely to reflect functional and/or structural alterations. Here, we present a method to identify such deviations and apply it to a data set of 2,929 high-quality coding sequence alignments corresponding to one-to-one orthologous genes from six mammalian species--human, macaque, mouse, rat, cow, and dog. Deviated branches are defined as those that present significant alterations in both the rate of nonsynonymous substitutions (dN) and the selective pressure (dN/dS). Strikingly, we find that as many as 24.5% of the genes show branch-specific deviations in dN and dN/dS, though this is a relatively well-conserved set of genes. Around half of these genes show branch-specific acceleration of evolutionary rates. Positive selection (PS) tests based on divergence data only identify 17.7% of the accelerated branches. Failure to identify PS in accelerated branches with an excess of radical amino acid replacements suggests that these tests are conservative. Interestingly, genes with accelerated branches are significantly enriched in neural proteins, indicating that this type of protein might play a more important role than previously thought in species diversification, although they are generally not detected by PS tests. We discuss in detail several examples of genes that show lineage-specific evolutionary rate acceleration and are involved in synaptic transmission, chemosensory perception, and ubiquitination.


Mechanical stimulation promotes enthesis injury repair by mobilizing Prrx1+ cells via ciliary TGF-β signaling.
Proper mechanical stimulation can improve rotator cuff enthesis injury repair. However, the underlying mechanism of mechanical stimulation promoting injury repair is still unknown. In this study, we found that Prrx1+ cell was essential for murine rotator cuff enthesis development identified by single-cell RNA sequence and involved in the injury repair. Proper mechanical stimulation could promote the migration of Prrx1+ cells to enhance enthesis injury repair. Meantime, TGF-β signaling and primary cilia played an essential role in mediating mechanical stimulation signaling transmission. Proper mechanical stimulation enhanced the release of active TGF-β1 to promote migration of Prrx1+ cells. Inhibition of TGF-β signaling eliminated the stimulatory effect of mechanical stimulation on Prrx1+ cell migration and enthesis injury repair. In addition, knockdown of Pallidin to inhibit TGF-βR2 translocation to the primary cilia or deletion of Ift88 in Prrx1+ cells also restrained the mechanics-induced Prrx1+ cells migration. These findings suggested that mechanical stimulation could increase the release of active TGF-β1 and enhance the mobilization of Prrx1+ cells to promote enthesis injury repair via ciliary TGF-β signaling.


Co-occurrence of depression with chronic diseases among the older population living in low- and middle-income countries: A compound health challenge.
Few studies have examined the associations between mental and physical health conditions in low- and middle-income countries (LMICs). The aim of this study was to evaluate comorbidity of depression and other chronic diseases in community-dwelling older adults. Data were obtained from the World Health Organization Study on global AGEing and adult health (SAGE) implemented in 6 LMICs: China, Ghana, India, Mexico, the Russian Federation, and South Africa. A total of 33,508 participants age ≥50 were included in this analysis. Demographics, socioeconomic status, anthropometrics, depression, and chronic diseases status were collected using well-validated instruments in all countries. Multivariate analyses were used to examine the association between depression and comorbid conditions. Type 2 diabetes mellitus (odds ratio: 1.39 [95% confidence interval: 1.15, 1.68]), arthritis (1.82 [1.52, 2.18]), asthma (3.20 [2.56, 4.00]), chronic lung disease (3.77 [3.08, 4.62]), angina (2.48 [2.01, 3.05]), and stroke (2.74 [2.18, 3.45]) were positively associated with depression prevalence (all P < .001). Noting the strong association between depression and other chronic diseases in our sample of older adults from 6 LMICs, additional vigilance and screening through informal and formal health care systems would help to decrease the impact of comorbidity on the health and well-being of older populations.


Timing of complementary feeding is associated with gut microbiota diversity and composition and short chain fatty acid concentrations over the first year of life.
Early introduction of complementary foods has been associated with various immune disorders, oxidative stress, and obesity in childhood. The gut microbiota and the short chain fatty acids (SCFAs) they produce are postulated to be on the causal pathway. The objective of this study was to determine if early complementary feeding (i.e. consumption of solids or non-water/formula liquids at or before 3 months) is prospectively associated with infant gut microbiota composition, diversity and SCFAs at 3 and 12 months of age in the Nurture birth cohort. Mother-infant dyads in the early complementary feeding group (n = 18) had similar baseline characteristics to those in the later feeding group (n = 49). We assessed differential abundance of microbial taxa (measured by 16S rRNA gene sequencing of the V4 region) by timing of complementary feeding using beta-binomial regression models (considering a two-sided FDR corrected p-value of < 0.05 as significant), and we fittted linear regression models to assess the association between early complementary feeding and SCFA concentrations (quantified using gas chromatography). After multivariable adjustment for breastfeeding, delivery method, birth weight, and gestational age, there were 13 differentially abundant microbial amplicon sequence variants (ASVs) by timing of introduction to complementary foods at 3 months and 20 ASVs at 12 months. Infants introduced to complementary foods early (vs. later) had higher concentrations of the SCFA butyric acid (mean difference = 0.65, 95% CI: 0.27, 1.04, p < 0.01) and total SCFAs (mean difference = 38.8, 95% CI: 7.83, 69.7) at 12 months. Bilophila wadsworthia and Lachnospiraceae Roseburia were associated with early (vs. later) complementary feeding and with higher butyric acid concentrations at 3 and 12 months, respectively. Our findings are consistent with the hypothesis that early (vs. later) introduction to complementary foods is associated with altered gut microbiota composition and butyric acid concentrations measured in stool until at least 1 year of age. Further research is needed to determine if these changes mediate future development of metabolic and immune conditions.


Improving students' long-term knowledge retention through personalized review.
Human memory is imperfect; thus, periodic review is required for the long-term preservation of knowledge and skills. However, students at every educational level are challenged by an ever-growing amount of material to review and an ongoing imperative to master new material. We developed a method for efficient, systematic, personalized review that combines statistical techniques for inferring individual differences with a psychological theory of memory. The method was integrated into a semester-long middle-school foreign-language course via retrieval-practice software. Using a cumulative exam administered after the semester's end, we compared time-matched review strategies and found that personalized review yielded a 16.5% boost in course retention over current educational practice (massed study) and a 10.0% improvement over a one-size-fits-all strategy for spaced study.


Evidence of high expression of peptidylglycine alpha-amidating monooxygenase in the rat uterus: estrogen regulation.
In the present study, high levels of peptidylglycine alpha-amidating monooxygenase (PAM), which catalyzes the two-step formation of bioactive alpha-amidated peptides from their glycine-extended precursors, have been found in the uterus. Expression of PAM was evaluated in the uterus of intact cycling adult female rats and after experimental manipulation of the estrogen status of the rats. During the estrous cycle, PAM mRNA levels exhibited striking changes inversely related to the physiological variations of plasma estrogen levels. The levels of PAM transcripts changed markedly during the estrous cycle, reaching the highest levels at metestrus. There was a 15-fold increase in the abundance of PAM mRNA between metestrus and proestrus. Chronic treatment of ovariectomized rats with 17beta-estradiol decreased PAM mRNA levels to values comparable with those found in intact rats at proestrus. Progesterone was without effect on PAM mRNA levels, indicating that the effect was specific for estradiol. In situ hybridization studies were conducted to determine the tissue disposition and cell types expressing PAM. High levels of PAM mRNA were localized in the endometrium at the level of luminal and glandular cells. A weak signal was observed in stromal cells, and the myometrium cells were negative. 17beta-Estradiol treatment induced an overall decrease of the hybridization signal, as compared with ovariectomized rats. These results demonstrate the presence of high levels of PAM in the uterus and indicate that estrogens are involved in regulating the expression of the enzyme in this tissue. However, the present study provides no information regarding whether this regulation takes place at the level of transcription or influences mRNA stability.


C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma.
Chondroid lipoma, a rare benign adipose tissue tumor, may histologically resemble myxoid liposarcoma or extraskeletal myxoid chondrosarcoma, but is genetically distinct. In this study, an identical reciprocal translocation, t(11;16)(q13;p13), was identified in three chondroid lipomas, a finding consistent with previously isolated reports. A fluorescence in situ hybridization (FISH)-based positional cloning strategy using a series of bacterial artificial chromosome (BAC) probe combinations designed to narrow the 16p13 breakpoint revealed MKL2 as the candidate gene. Subsequent 5' RACE studies demonstrated C11orf95 as the MKL2 fusion gene partner. MKL/myocardin-like 2 (MKL2) encodes myocardin-related transcription factor B in a megakaryoblastic leukemia gene family, and C11orf95 (chromosome 11 open reading frame 95) is a hypothetical protein. Sequencing analysis of reverse transcription-polymerse chain reaction (RT-PCR) generated transcripts from all three chondroid lipomas defined the fusion as occurring between exons 5 and 9 of C11orf95 and MKL2, respectively. Dual-color breakpoint spanning probe sets custom-designed for recognition of the translocation event in interphase cells confirmed the anticipated rearrangements of the C11orf95 and MKL2 loci in all cases. The FISH and RT-PCR assays developed in this study can serve as diagnostic adjuncts for the identification of this novel C11orf95-MKL2 fusion oncogene in chondroid lipoma.


Dustborne fungi in large office buildings.
Fungi are ubiquitous in our daily environments. However, their effects on office workers' health are of great interest to many environmental health researchers. Dust has been considered an important reservoir of indoor fungi from which aerosolization and exposure could occur. We have examined the characteristics of dustborne fungal populations recovered from floors and chairs in office buildings. We investigated twenty-one offices in four office buildings in Boston, MA over a year beginning May 1997. We conducted intensive environmental sampling every six weeks to measure culturable dustborne fungi from floors and chairs, surface dust levels and water activity in carpeting. Carbon dioxide, temperature, and relative humidity were monitored continuously. Concentrations of total dustborne fungi recovered from floors were positively related to carbon dioxide (beta = 0.00064; p-value = 0.0002) and temperatures between 20 and 22.5 degrees C (p-value = 0.0026). Also, total fungal concentrations in floors gradually increased over the year (p-value = 0.0028). Total fungi recovered from chairs varied significantly by season (p-value < 0.0001), highest in September and lowest in March, and were positively correlated with dust loads in floors (beta = 0.25; p-value < 0.0001). We used principal component analysis (PCA) to reduce various observed fungal species to fewer factors. Six groups (PCA factors) were obtained for dustborne fungi recovered from both floors and chairs. The models of the first PCA factors for both floors and chairs were similar to those for total fungal concentrations. The results of this study provide essential information to further evaluate the effects of dustborne fungi on office workers' health.


Visual Working Memory Impairment in Premanifest Gene-Carriers and Early Huntington's Disease.
Working memory deficits have been found in Huntington's disease (HD) and in a small group of premanifest (PreHD) gene-carriers. However, the nature and extent of these deficits are unknown. In a large cross-sectional study, we aimed to determine the degree of visuospatial working memory dysfunction across multiple stages of HD. Specifically, visuospatial working memory capacity and response times across various degrees of difficulty were examined, as well as the relationship between visuospatial working memory and motor dysfunction. We examined 62 PreHD-A gene-carriers (>10.8 years from estimated disease onset), 58 PreHD-B gene-carriers (<10.8 years from estimated disease onset), 77 stage-1 HD patients (HD1), 44 stage-2 HD patients (HD2), and 122 healthy controls. Participants viewed coloured squares (in sets of 3, 5 and 7) on a screen and were to decide whether on a subsequent screen the encircled square has changed colour. Accuracy and response times were recorded. Compared to controls, significant group differences in visuospatial working memory capacity (accuracy) were seen in PreHD-B, HD1 and HD2 groups across the difficulty levels. Significant group differences on response times were found for all groups (PreHD-A to HD2) compared to controls; the most difficult level producing the only group difference in speed between PreHD-A and controls. Accuracy and speed were positively correlated only in the HD groups. These findings suggest that visuospatial working memory impairments are detectable in both premanifest and manifest HD; the manifest HD showed evidence for a "worse-worse phenomenon" whereby reductions were present in both motor speed and accuracy.


Controlling electron transfer in Acyl-CoA oxidases and dehydrogenases: a structural view.
Plants produce a unique peroxisomal short chain-specific acyl-CoA oxidase (ACX4) for beta-oxidation of lipids. The short chain-specific oxidase has little resemblance to other peroxisomal acyl-CoA oxidases but has an approximately 30% sequence identity to mitochondrial acyl-CoA dehydrogenases. Two biochemical features have been linked to structural properties by comparing the structures of short chain-specific Arabidopsis thaliana ACX4 with and without a substrate analogue bound in the active site to known acyl-CoA oxidases and dehydrogenase structures: (i) a solvent-accessible acyl binding pocket is not required for oxygen reactivity, and (ii) the oligomeric state plays a role in substrate pocket architecture but is not linked to oxygen reactivity. The structures indicate that the acyl-CoA oxidases may encapsulate the electrons for transfer to molecular oxygen by blocking the dehydrogenase substrate interaction site with structural extensions. A small binding pocket observed adjoining the flavin adenine dinucleotide N5 and C4a atoms could increase the number of productive encounters between flavin adenine dinucleotide and O2.


Crossmodal transfer of arousal, but not pleasantness, from the musical to the visual domain.
Arousal and valence (pleasantness) are considered primary dimensions of emotion. However, the degree to which these dimensions interact in emotional processing across sensory modalities is poorly understood. We addressed this issue by applying a crossmodal priming paradigm in which auditory primes (Romantic piano solo music) varying in arousal and/or pleasantness were sequentially paired with visual targets (IAPS pictures). In Experiment 1, the emotion spaces of 120 primes and 120 targets were explored separately in addition to the effects of musical training and gender. Thirty-two participants rated their felt pleasantness and arousal in response to primes and targets on equivalent rating scales as well as their familiarity with the stimuli. Musical training was associated with elevated familiarity ratings for high-arousing music and a trend for elevated arousal ratings, especially in response to unpleasant musical stimuli. Males reported higher arousal than females for pleasant visual stimuli. In Experiment 2, 40 nonmusicians rated their felt arousal and pleasantness in response to 20 visual targets after listening to 80 musical primes. Arousal associated with the musical primes modulated felt arousal in response to visual targets, yet no such transfer of pleasantness was observed between the two modalities. Experiment 3 sought to rule out the possibility of any order effect of the subjective ratings, and responses of 14 nonmusicians replicated results of Experiment 2. This study demonstrates the effectiveness of the crossmodal priming paradigm in basic research on musical emotions.


Determinants of butyrylcholinesterase inhibition among agricultural pesticide handlers in Washington State: an update.
Organophosphate (OP) and N-methyl-carbamate (CB) insecticides are used widely in agriculture to manage insect pests of economic importance. Agricultural workers are more likely to suffer exposure because of the widespread use of OP/CBs in agriculture, and pesticide-related illnesses among handlers may be more severe when compared to other farm workers. The goal of this study was to identify occupational and personal characteristics associated with butyrylcholinesterase (BuChE) inhibition in participants recruited from the Washington State Cholinesterase Monitoring Program from 2006 to 2011. We conducted a longitudinal study among agricultural pesticide handlers in Washington State during the OP/CB spray season (March-July) over a 6-year period (2006-2011). Linear mixed effects regression models were used to evaluate BuChE inhibition in relation to self-reported occupational and personal characteristics. Relative to pre-season baseline levels, the mean decrease in BuChE activity during the OP/CB spray season over all years of the study period was 3.77% (P < 0.001). Greater BuChE inhibition was observed among handlers who reported using multiple OP/CBs (β = -2.70, P = 0.045), mixed or loaded OP/CBs (β = -3.97, P = 0.002), did not store personal protective equipment (PPE) in a locker at work (β = -3.4, P = 0.014), or did not wear chemical-resistant boots (β = -16.6, P < 0.001). The Washington State Cholinesterase Monitoring Program has provided a valuable opportunity to evaluate potential sources of OP/CB exposure among agricultural pesticide handlers. Several previously reported associations were confirmed in the current analysis, which included a larger number of pesticide handlers enrolled over a longer time period. The use of multiple OP/CBs and mixing/loading activities were significant risk factors, and the use of chemical-resistant boots and lockers for PPE storage were protective factors. Our findings point toward logical interventions to reduce exposure such as the implementation of engineering controls for mixing/loading activities, requirements for appropriate footwear, and the regular use of lockers for PPE storage.


Comparison of high-order harmonic generation in uracil and thymine ablation plumes.
We present studies of high-order harmonic generation (HHG) in laser ablation plumes of the ribonucleic acid nucleobase uracil and its deoxyribonucleic acid counterpart thymine. Harmonics were generated using 780 nm, 30 fs and 1300 nm, 40 fs radiation upon ablation with 1064 nm, 10 ns or 780 nm, 160 ps pulses. Strong HHG signals were observed from uracil plumes with harmonics emitted with photon energies >55 eV. Results obtained in uracil plumes were compared with those from thymine, which did not yield signs of harmonic generation. The ablation plumes of the two compounds were examined by collection of the ablation debris on a silicon substrate placed in close proximity to the target and by time-of-flight mass spectrometry. From this evidence we conclude that the differences in HHG signal are due to the different fragmentation dynamics of the molecules in the plasma plume. These studies constitute the first attempt to analyse differences in structural properties of complex molecules through plasma ablation-induced HHG spectroscopy.


[Electrophoretic karyotypes and genomic DNA restriction fragment analysis: their usefulness as tools in the epidemiological study of Candid parapsilosis].
During the past decades, several studies have reported an increase in the incidence of nosocomial candidosis. In a prospective study, performed at the Departamento de Micología, INEI, ANLIS Dr. C. G. Malbrán and the Servicio de Neonatología and Microbiología, Hospital de Niños Sor María Ludovica, from October 1995 to December 1996, 167 patients with candidosis were detected. Candida species isolated were C. albicans (53.1%), C. parapsilosis (26.5%) and C. tropicalis (14.8%). The aim of this work was to characterize the clinical C. parapsilosis isolates from pediatric patients hospitalized in two neonatal intensive care units from the same hospital and to evaluate the usefulness of electrophoretic karyotype (EK) and restriction endonuclease analysis of genomic DNA (REAG) using a low frequency digestion enzyme. EK of all isolates disclosed 12 banding patterns and REAG with endonuclease Sfi I showed only 5 groups. However, isolates from the control group could not be separated from the clinical isolates. The isolates within each dendogram group for EK or REAG were apparently unrelated. Our results show that EK yields better results than REAG, but that it falls short of the desired discrimination, which suggests that these techniques do not seem to be useful for studying nosocomial C. parapsilosis outbreaks.


BC-02 eradicates liver cancer stem cells by upregulating the ROS-dependent DNA damage.
Cancer stem cells (CSCs) are responsible for chemoresistance, tumor recurrence and metastasis. Reportedly, aminopeptidase N (APN, also known as CD13) is a marker for semi-quiescent CSCs and a therapeutic target in human liver CSCs. In the present study, the effect of BC-02, a compound obtained by conjugating a CD13 inhibitor bestatin and fluorouracil (5-FU), was investigated toward liver CSCs. Tumor spheres formed in serum-free culture conditions have been successfully used to enrich CSCs. In this study, the sphere cells were shown to have several characteristics of CSCs, including drug resistance, high tumorigenicity, epithelial-mesenchymal transition (EMT) phenotype, lower reactive oxygen species (ROS) levels, greater colony-forming efficiency and increased proliferation capacity in vitro. Furthermore, BC-02 effectively suppressed self-renewal and malignant proliferation of CSCs compared with 5-FU, bestatin, and even the combination of 5-FU and bestatin. In addition, cell proliferation was effectively suppressed when exposed to 5-FU plus CD13-neutralizing antibody (CD13 Ab) compared with 5-FU alone. BC-02 can effectively inhibit the activity of CD13. Results demonstrated that CD13 inhibitor BC-02 impaired the properties of liver CSCs by targeting CD13 and upregulating the intracellular ROS and ROS-induced DNA damage. BC-02 might be a potential therapeutic agent for eradicating the liver CSCs and overcoming chemoresistance in liver cancer.


[Bladder lithiasis secondary to intrauterine device migration. Case report].
To report one clinical case of bladder lithiasis secondary to the migration of an intrauterine device, its symptoms, diagnostic tests employed and treatment. 30-year-old female patient who presented lower urinary tract irritative symptoms. One year before she underwent insertion of an intrauterine device (copper T) after endometrial curettage for pregnancy interruption. She received treatment for infection cystitis over two years, with various antibiotic cycles. The persistence of symptoms led her to the urology clinics, and a 5 x 3 cm intravesical lithiasis with a copper T inside was detected by ultrasound and pelvic anterior-posterior x-ray Suprapubic cystolithotomy was performed with a good outcome and disappearance of the symptoms. The migration of an intrauterine device to the bladder is an unfrequent cause of bladder lithiasis secondary to foreign body. Nevertheless, we must consider this possibility in front of chronic lower urinary tract irritative symptoms in every female using this birth control method.


Novel Frog Skin-Derived Peptide Dermaseptin-PP for Lung Cancer Treatment: In vitro/vivo Evaluation and Anti-tumor Mechanisms Study.
Lung cancer is the major cause of cancer deaths worldwide, and it has the highest incidence and mortality rate of any cancer among men and women in China. The first-line therapy for lung cancer treatment is platinum-based chemotherapy drugs such as cisplatin. However, the application of present chemotherapies is limited by severe side effects, which stimulates the discovery of new drugs with new anti-tumor mechanisms and fewer side effects. Beneficially, many antimicrobial peptides (AMPs) from frog skin have been reported to exhibit potent anti-cancer activities with low toxicity, high selectivity and a low propensity to induce resistance. In this study, we first reported an AMP named Dermaseptin-PP, from a rarely studied frog species, Phyllomedusa palliata. Dermaseptin-PP exhibited selective cytotoxicity on H157, MCF-7, PC-3, and U251 MG cancer cells instead of normal HMEC-1 cells with low hemolytic effect. Furthermore, on subcutaneous H157 tumor model of nude mice, Dermaseptin-PP was found to display potent in vivo anti-tumor activity in a dose-related manner without obvious hepatopulmonary side effects. It is widely accepted that AMPs usually work through a membrane disruptive mode, and the confocal laser microscope observation confirmed that Dermaseptin-PP could destroy H157 cell membranes. Further investigation of mechanisms by flow cytometry assay and immunohistochemical analysis unraveled that Dermaseptin-PP also exerted its anti-tumor activity by inducing H157 cell apoptosis via both endogenous mitochondrial apoptosis pathway and exogenous death receptor apoptosis pathway. Herein, we emphasize that the membrane disrupting and the apoptosis activation effects of Dermaseptin-PP both depend on its concentration. Overall, a novel frog skin-derived AMP, named Dermaseptin-PP, was identified for the first time. It possesses strong antimicrobial activity and effective anti-tumor activity by distinct mechanisms. This study revealed the possibility of Dermaseptin-PP for lung cancer treatment and provided a new perspective for designing novel AMP-based anti-tumor candidates with low risk of cytotoxicity.