Identification of a common neurobiological substrate for mental illness.
Psychiatric diagnoses are currently distinguished based on sets of specific symptoms. However, genetic and clinical analyses find similarities across a wide variety of diagnoses, suggesting that a common neurobiological substrate may exist across mental illness. To conduct a meta-analysis of structural neuroimaging studies across multiple psychiatric diagnoses, followed by parallel analyses of 3 large-scale healthy participant data sets to help interpret structural findings in the meta-analysis. PubMed was searched to identify voxel-based morphometry studies through July 2012 comparing psychiatric patients to healthy control individuals for the meta-analysis. The 3 parallel healthy participant data sets included resting-state functional magnetic resonance imaging, a database of activation foci across thousands of neuroimaging experiments, and a data set with structural imaging and cognitive task performance data. Studies were included in the meta-analysis if they reported voxel-based morphometry differences between patients with an Axis I diagnosis and control individuals in stereotactic coordinates across the whole brain, did not present predominantly in childhood, and had at least 10 studies contributing to that diagnosis (or across closely related diagnoses). The meta-analysis was conducted on peak voxel coordinates using an activation likelihood estimation approach. We tested for areas of common gray matter volume increase or decrease across Axis I diagnoses, as well as areas differing between diagnoses. Follow-up analyses on other healthy participant data sets tested connectivity related to regions arising from the meta-analysis and the relationship of gray matter volume to cognition. Based on the voxel-based morphometry meta-analysis of 193 studies comprising 15 892 individuals across 6 diverse diagnostic groups (schizophrenia, bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety), we found that gray matter loss converged across diagnoses in 3 regions: the dorsal anterior cingulate, right insula, and left insula. By contrast, there were few diagnosis-specific effects, distinguishing only schizophrenia and depression from other diagnoses. In the parallel follow-up analyses of the 3 independent healthy participant data sets, we found that the common gray matter loss regions formed a tightly interconnected network during tasks and at resting and that lower gray matter in this network was associated with poor executive functioning. We identified a concordance across psychiatric diagnoses in terms of integrity of an anterior insula/dorsal anterior cingulate-based network, which may relate to executive function deficits observed across diagnoses. This concordance provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology, despite likely diverse etiologies, which is currently not an explicit component of psychiatric nosology.


Complex formation and function of estrogen receptor α in transcription requires RIP140.
RIP140 is a transcriptional coregulator involved in energy homeostasis, ovulation, and mammary gland development. Although conclusive evidence is lacking, reports have implicated a role for RIP140 in breast cancer. Here, we explored the mechanistic role of RIP140 in breast cancer and its involvement in estrogen receptor α (ERα) transcriptional regulation of gene expression. Using ChIP-seq analysis, we demonstrate that RIP140 shares more than 80% of its binding sites with ERα, colocalizing with its interaction partners FOXA1, GATA3, p300, CBP, and p160 family members at H3K4me1-demarcated enhancer regions. RIP140 is required for ERα-complex formation, ERα-mediated gene expression, and ERα-dependent breast cancer cell proliferation. Genes affected following RIP140 silencing could be used to stratify tamoxifen-treated breast cancer cohorts, based on clinical outcome. Importantly, this gene signature was only effective in endocrine-treated conditions. Cumulatively, our data suggest that RIP140 plays an important role in ERα-mediated transcriptional regulation in breast cancer and response to tamoxifen treatment.


[Confidentiality as ethical responsibility and legal duty].
The article analyzes the challenge that the health professionals encounter when trying to protect their patient's confidentiality, considering the increasing demand for globalization of the information. It discusses the importance that confidentiality has for the therapeutic alliance and how the government has protected it throughout time. It identifies weak areas in the protection of confidentiality, especially in the psychiatry field. Finally, it invites the reader to consider the real benefits of sharing patient's information when deciding whether to brake or not the patient's confidentiality.


Glutamatergic enteric neurons.
We tested the hypothesis that glutamate, the major excitatory neurotransmitter of the CNS, is also an excitatory neurotransmitter in the enteric nervous system (ENS). Glutamate immunoreactivity was found in cholinergic enteric neurons, many of which were identified as sensory by their co-storage of substance P and/or calbindin. Glutamate immunoreactivity was concentrated in terminal varicosities with a majority of small clear synaptic vesicles. The immunoreactivities of both AMPA and NMDA receptor subunits were also detected on neurons in both submucosal and myenteric plexuses. The immunoreactivity of the EAAC1 neuronal glutamate transporter was widespread in both plexuses. Glutamate evoked depolarizing responses in myenteric neurons that had fast and slow components. The fast component was mimicked by AMPA, and the slow component was mimicked by NMDA. The fast component and the response to AMPA mimicked fast EPSPs evoked in 2/AH neurons; moreover, fast EPSPs as well as fast glutamate and AMPA responses were blocked by selective AMPA antagonists and potentiated by the glutamate uptake inhibitor L-(-)-threo-3-hydroxyaspartic acid. These observations demonstrate, for the first time, the presence of glutamatergic neurons and glutamate-mediated neurotransmission in the ENS.


Laplace-Beltrami Eigenvalues and Topological Features of Eigenfunctions for Statistical Shape Analysis.
This paper proposes the use of the surface based Laplace-Beltrami and the volumetric Laplace eigenvalues and -functions as shape descriptors for the comparison and analysis of shapes. These spectral measures are isometry invariant and therefore allow for shape comparisons with minimal shape pre-processing. In particular, no registration, mapping, or remeshing is necessary. The discriminatory power of the 2D surface and 3D solid methods is demonstrated on a population of female caudate nuclei (a subcortical gray matter structure of the brain, involved in memory function, emotion processing, and learning) of normal control subjects and of subjects with schizotypal personality disorder. The behavior and properties of the Laplace-Beltrami eigenvalues and -functions are discussed extensively for both the Dirichlet and Neumann boundary condition showing advantages of the Neumann vs. the Dirichlet spectra in 3D. Furthermore, topological analyses employing the Morse-Smale complex (on the surfaces) and the Reeb graph (in the solids) are performed on selected eigenfunctions, yielding shape descriptors, that are capable of localizing geometric properties and detecting shape differences by indirectly registering topological features such as critical points, level sets and integral lines of the gradient field across subjects. The use of these topological features of the Laplace-Beltrami eigenfunctions in 2D and 3D for statistical shape analysis is novel.


Specific expression of PAD4 and citrullinated proteins in lung cancer is not associated with anti-CCP antibody production.
Anti-citrullinated protein antibodies (ACPAs), produced against citrullinated proteins, are diagnostic and prognostic markers of rheumatoid arthritis (RA). The underlying mechanism that explains the connection of smoking, citrullination [catalyzed by peptidyl arginine deiminases (PADs)] and ACPAs is still unclarified in RA. Thus, we searched for a non-arthritic model in which an increased cell death allows the formation of autoantibodies. Data supporting that lung cancer might be a good candidate are as follows: (i) smoking plays a role in its pathogenesis, (ii) the disease is frequently accompanied by paraneoplastic syndrome, (iii) smoking increases citrullination in the lung, (iv) various types of malignancies are associated with increased citrullination and (v) lung cancer tissue shows similarities with RA synovium. Serum PAD4, rheumatoid factor (RF) and ACPA levels were measured in 42 lung cancer patients; expression of cytokeratin 7 (CK7), PAD4 and citrullinated proteins was visualized in 113 lung cancer tissues. All parameters were analyzed in correlation with smoking history. None of the patients had polyarthritis or autoimmune disease. Significantly increased RF levels were associated with higher PAD4 levels in smoker lung cancer patients compared with non-smokers. Both PAD4 and citrullination immunostaining strongly correlated with that of CK7 in lung cancer, however, did not differ according to smoking history. Two of 30 smoker lung cancer patients had high anti-cyclic citrullinated peptide levels. In conclusion, PAD4 and citrullination may be helpful in distinguishing lung cancer from healthy tissue. Smoking, abnormal serum PAD4 and RF levels may not be sufficient for the production of ACPAs and development of autoimmunity.


Oxygen incorporation in rubrene single crystals.
Single crystal rubrene is a model organic electronic material showing high carrier mobility and long exciton lifetime. These properties are detrimentally affected when rubrene is exposed to intense light under ambient conditions for prolonged periods of time, possibly due to oxygen up-take. Using photoelectron, scanning probe and ion-based methods, combined with an isotopic oxygen exposure, we present direct evidence of the light-induced reaction of molecular oxygen with single crystal rubrene. Without a significant exposure to light, there is no reaction of oxygen with rubrene for periods of greater than a year; the crystal's surface (and bulk) morphology and chemical composition remain essentially oxygen-free. Grand canonical Monte Carlo computations show no sorbtion of gases into the bulk of rubrene crystal. A mechanism for photo-induced oxygen inclusion is proposed.


Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: comparison of toxicities of 10 fluoroquinolones and effects of anti-inflammatory compounds.
Fluoroquinolone antibacterial agents have been reported to induce tendon lesions in juvenile rats. In the present study, we characterized fluoroquinolone-induced Achilles tendon lesions by comparing the effects of 10 fluoroquinolones and examining the potential of one of these antimicrobial agents, pefloxacin, to induce tendon lesions when coadministered with one of nine anti-inflammatory compounds. Among the 10 fluoroquinolones tested, fleroxacin and pefloxacin were the most toxic, inducing lesions at a dose of 100 mg/kg of body weight or more, while lomefloxacin, levofloxacin, and ofloxacin or sparfloxacin and enoxacin induced lesions at 300 mg/kg or more and 900 mg/kg, respectively. In contrast, norfloxacin, ciprofloxacin, and tosufloxacin had no effect even at the high dose of 900 mg/kg. The severity of the Achilles tendon lesions appeared to correlate with the structure of the substituent at the seventh position. Furthermore, pefloxacin-induced tendon lesions were inhibited by coadministration with dexamethasone and N-nitro-L-arginine methyl ester. Phenidone (1-phenyl-3-pyrazolidinone) and 2-(12-hydroxydodeca-5,10-diynyl)3,5,6-trimethyl-1,4-benzoqui none (AA861) also decreased the incidence of tendon lesions. In contrast, catalase, dimethyl sulfoxide, indomethacin, pyrilamine, and cimetidine did not modify these tendon lesions. These results suggest that nitric oxide and 5-lipoxigenase products partly mediate fluoroquinolone-induced tendon lesions.


Numerous asymptomatic dermal cysts: Diagnosis and treatment of steatocystoma multiplex.
To provide family physicians with the information needed to recognize, diagnose, and discuss available treatment options for steatocystoma multiplex (SM). A comprehensive PubMed search using steatocystoma multiplex as either a text word or a MeSH term was conducted, and articles reporting on treatment outcomes were included. Steatocystoma multiplex is a benign disorder often characterized by numerous asymptomatic dermal cysts on the trunk, arms, axillae, face, thighs, and scalp. Psychological distress due to these undesirable lesions is not uncommon for this condition. A literature review identified the following SM treatments, all of which were associated with limitations: carbon dioxide laser, modified surgical techniques, cryotherapy, and medical management. Steatocystoma multiplex is challenging to treat and, at this time, effective management is most often achieved through patient education. Family physicians play a critical role in the early diagnosis and management of SM. Education about treatment options and managing patient expectations might greatly alleviate the psychosocial implications of this disease.


Estrogen enhances growth hormone receptor expression and growth hormone action in rat osteosarcoma cells and human osteoblast-like cells.
Postmenopausal bone loss is primarily due to estrogen deficiency. Recent clinical observation demonstrate that GH increases bone mass in GH deficient patients. The present study investigates whether estrogen regulates GH action and GH receptor expression in osteoblasts. 17 beta-estradiol or GH added to the culture medium as single substances did not influence rat osteosarcoma cell proliferation nor human osteoblast-like (hOB) cell proliferation. However, together they synergistically induced osteoblast proliferation (rat osteosarcoma cells 160.1 +/- 15.5% of control cells; human osteoblast-like cells 159.6 +/- 5.1% of control cells). 17 beta-estradiol stimulated 125I-GH binding and GH receptor (GHR) mRNA levels in rat osteosarcoma cells. The stimulatory effect of estradiol was time dependent, reaching a peak after 8 h of incubation with 17 beta-estradiol (binding 216.9 +/- 27.8% and mRNA 374.6 +/- 30.8% of control). The finding that estradiol stimulated 125I-GH binding was confirmed in human osteoblast-like cells. In these cells, 17 beta-estradiol (10(-12) M) increased 125I-GH binding to 203.8 +/- 3.6% of control levels. We conclude that estrogen stimulates GH activity as well as GH binding and GHR mRNA levels in osteoblasts. These findings indicate that estrogen potentiates the effect of GH at the receptor level.


Airborne Bacterial Interactions: Functions Out of Thin Air?
Bacteria produce and release a large diversity of small molecules including organic and inorganic volatile compounds, hereafter referred to as bacterial volatile compounds (BVCs). Whereas BVCs were often only considered as wasted metabolic by-product sometimes perceived by animal olfactory systems, it is increasingly clear that they can also mediate cross-kingdom interactions with fungi, plants and animals. Recently, in vitro studies also reported the impact of BVCs on bacterial biology through modulation of antibiotic resistance, biofilm formation and virulence. Here, we review BVCs influence on bacterial adaptation to their environment and discuss the biological relevance of recently reported inter- and intra-species bacterial interactions mediated by BVCs.


Person-centered planning: analysis of research and effectiveness.
Person-centered planning is a well known and widely used approach to individual program planning in the field of intellectual and developmental disabilities. Its purpose is to develop collaborative supports focused on community presence, community participation, positive relationships, respect, and competence. Because there is little research on its effectiveness, our purpose here was to (a) review the current status of effectiveness research; (b) describe its effectiveness in terms of outcomes or results; and (c) discuss the effectiveness of person-centered planning in relation to evidence-based practices. Analyzed studies suggest that, overall, this planning has a positive, but moderate, impact on personal outcomes for this population. The body of evidence provided in this review is weak with regard to criteria for evidence-based research.


Staff nurse financial management committees--the nurse manager's guide to effective financial performance.
As Cohen states (1991, p. 25), "The future role that nursing will play in the health care delivery system is one of many major issues faced by contemporary nursing... Nursing must be able to determine realistically the cost of and evaluate the effectiveness of nursing care provided to its patients." A unit-based financial management committee is one very effective way of teaching the skills needed for the professional nurse to advance the practice in financial management. This will help nursing gain the professional status that they have always worked for. But beyond these very lofty ideals, a staff nurse managed financial management committee can make the nurse manager's life much easier. Staff nurses need to understand and accept the importance of managing the financial as well as the quality side of patient care. When this happens, the budget becomes theirs. Nurses develop a sense of ownership of the budget and learn how to effectively manage the unit's finances. Much staff nurse brain power is not used. Systems must be developed to access nurses' effective ideas for financial management--first in a financial management committee and then on the unit. Not only will this develop the professional status that nurses need and deserve, but it will also impact the cost of health care. In a society where the cost of an appendectomy requires Dayton Hudson to sell 39,000 Ninja Turtle action figures, Atlantic Richfield to sell 192,000 gallons of gas a day, Anheuser-Busch to sell 11,627 6-packs of 12 oz.(ABSTRACT TRUNCATED AT 250 WORDS)


[Surface antigens of Haemophilus influenzae non-typed strains].
H. influenzae non-typed strains cause diseases of respiratory organs, otitis, sinusitis and conjunctivitis. H. influenzae surface antigens play an important role in the vital activity of bacteria and the pathogenesis of diseases. A large number of antigens with similar functions and different structure, as well as the variability of their structure, determine the strain specificity of immune response and facilitate the development of chronic diseases. Modern data on the structure and functions of surface antigens of H. influenzae non-typed strains are presented.


Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia.
Hypoxia is one of the most frequently encountered stresses in health and disease. The duration, frequency, and severity of hypoxic episodes are critical factors determining whether hypoxia is beneficial or harmful. Adaptation to intermittent hypoxia has been demonstrated to confer cardiovascular protection against more severe and sustained hypoxia, and, moreover, to protect against other stresses, including ischemia. Thus, the direct and cross protective effects of adaptation to intermittent hypoxia have been used for treatment and prevention of a variety of diseases and to increase efficiency of exercise training. Evidence is mounting that nitric oxide (NO) plays a central role in these adaptive mechanisms. NO-dependent protective mechanisms activated by intermittent hypoxia include stimulation of NO synthesis as well as restriction of NO overproduction. In addition, alternative, nonenzymic sources of NO and negative feedback of NO synthesis are important factors in optimizing NO concentrations. The adaptive enhancement of NO synthesis and/or availability activates or increases expression of other protective factors, including heat shock proteins, antioxidants and prostaglandins, making the protection more robust and sustained. Understanding the role of NO in mechanisms of adaptation to hypoxia will support development of therapies to prevent and treat hypoxic or ischemic damage to organs and cells and to increase adaptive capabilities of the organism.


Xylem wall collapse in water-stressed pine needles.
Wall reinforcement in xylem conduits is thought to prevent wall implosion by negative pressures, but direct observations of xylem geometry during water stress are still largely lacking. In this study, we have analyzed the changes in xylem geometry during water stress in needles of four pine species (Pinus spp.). Dehydrated needles were frozen with liquid nitrogen, and xylem cross sections were observed, still frozen, with a cryo-scanning electron microscope and an epifluorescent microscope. Decrease in xylem pressure during drought provoked a progressive collapse of tracheids below a specific threshold pressure (P(collapse)) that correlates with the onset of cavitation in the stems. P(collapse) was more negative for species with smaller tracheid diameter and thicker walls, suggesting a tradeoff between xylem efficiency, xylem vulnerability to collapse, and the cost of wall stiffening. Upon severe dehydration, tracheid walls were completely collapsed, but lumens still appeared filled with sap. When dehydration proceeded further, tracheids embolized and walls relaxed. Wall collapse in dehydrated needles was rapidly reversed upon rehydration. We discuss the implications of this novel hydraulic trait on the xylem function and on the understanding of pine water relations.


Charnley low-friction arthroplasty in young patients with osteoarthritis: outcomes at a minimum of twenty-two years.
We previously reported the outcomes at a minimum of twelve years after eighty-four Charnley low-friction arthroplasties performed in patients with osteoarthritis who were less than fifty-six years old at the time of the surgery. We now update the results of that cohort at a minimum of twenty-two years postoperatively. Eighty-four hips (in sixty-nine patients) with osteoarthritis, which was secondary to congenital hip disease in sixty-four (76%) of them, were followed prospectively with use of the Merle D'Aubigné and Postel scoring system as modified by Charnley and with serial radiographs. At the time of the latest follow-up, thirty-seven hips (44%) had failed. Twenty-eight acetabular and thirty femoral components, in a total of thirty-two hips, had been revised because of aseptic loosening; six of the loose femoral components were broken. Three hips were infected and were converted to a resection arthroplasty. A periprosthetic femoral fracture occurred in two additional hips, three and ten years postoperatively, and both were treated with internal fixation. Thirty-seven original acetabular components and thirty-six original femoral components were in place for an average of twenty-nine years. The probability of survival for both components, with failure for any reason as the end point, was 0.51 (95% confidence interval, 0.39 to 0.62) at twenty-five years. These long-term results can be used as a benchmark with which to compare outcomes of different designs when total hip arthroplasty is performed in young patients when the majority have congenital hip disease.


Safety evaluation of the food enzyme α-amylase from the genetically modified Bacillus licheniformis strain DP-Dzb52.
The food enzyme α-amylase (1,4-α-d-glucan glucanohydrolase; EC 220.127.116.11) is produced with the genetically modified Bacillus licheniformis strain DP-Dzb52 by Danisco US Inc. The production strain contains multiple copies of an antimicrobial resistance gene. However, based on the absence of viable cells and DNA from the production organism in the food enzyme, this is not considered to be a risk. The α-amylase is intended to be used in starch processing for the production of glucose syrups, brewing processes and distilled alcohol production. Since residual amounts of the food enzyme are removed by the purification steps applied during the production of glucose syrups and distillation, no dietary exposure was calculated. Based on the maximum use levels recommended for the brewing processes and individual data from the EFSA Comprehensive European Food Consumption Database, dietary exposure to the enzyme-total organic solids (TOS) was estimated to be up to 0.145 TOS/kg body weight per day in European populations. The toxicity studies were carried out with another α-amylase from B. licheniformis strain DP-Dzb54, considered by the Panel as a suitable substitute. Toxicological tests indicated that there was no concern with respect to genotoxicity or systemic toxicity. A no observed adverse effect level was identified in rats which, compared with the dietary exposure, results in a margin of exposure of at least 750. A search for similarity of the amino acid sequence to known allergens was made and one match was found. The Panel considered that, under the intended conditions of use, the risk of allergic sensitisation and elicitation reactions can be excluded in distilled alcohol production and is considered low when the enzyme is used in starch processing and brewing. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.


Nephrocalcinosis formation by soy isoflavones in male rats.
Isoflavones (IFs), found in the form of both aglycones and glucosides in soybean foods, induce weak estrogenic activities. Although IFs have a number of health benefits, it was previously reported that IFs cause nephrocalcinosis (NC) in the kidney of male Fischer 344 (F344) rats. The present study aims to elucidate the safety of IFs by focusing on IF-induced NC formation in rats. Fermented soybean extract (FSE) containing 420 mg/g isoflavone aglycones was orally administered to male F344 and Sprague-Dawley (SD) rats for 28 days. FSE induced NC formation in the kidney of F344 rats, but not in SD rats. However, absorption of IFs did not differ between F344 and SD rats. NC formation and its severity of FSE were histologically compared with those of soybean extract (SE) containing 518 mg/g isoflavone glucosides in F344 rats. There were no differences in the number of NC formations and the extent of calcium deposit between FSE and SE groups. To examine the dose effect of FSE on NC formation, doses of 20, 140, or 1000 mg/kg FSE were administered to F344 rats for 90 days. NC formation was observed in the 140 and 1000 mg/kg groups. These results indicated that a high dose of oral administration of IFs induced NC formation depending on the strain of rat.


Investigation on the properties of methoxy poly(ethylene glycol)/chitosan graft co-polymers.
Methoxy poly(ethylene glycol)/chitosan graft co-polymers (CS-g-mPEGs) with different degrees of substitution were synthesized by reductive N-alkylation of chitosan with poly(ethylene glycol) aldehyde. The crystalline and thermal properties of CS-g-mPEGs were characterized by wide-angle X-ray diffraction (XRD), differential scanning calorimetry (DSC) and thermogravimetry (TG). The results indicate that CS-g-mPEG solids represent microphase separation morphology with mPEG crystal and CS domains coexistence and the introduction of PEG on CS improves the thermal decomposition. The hydrodynamic behavior of CS-g-mPEGs in aqueous solution and the influence of NaCl were investigated. The results indicate that the hydrodynamic behavior of CS-g-mPEGs in aqueous solution is significantly affected by the degree of substitution and the concentration of NaCl, which are quite different from that of CS. The results of this paper also certify that CS-g-mPEGs keep the property of complexation with a counter-ion, such as tripolyphosphate, to form nanoparticles through the electrostatic interaction.


Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.
The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs). Seven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA. All patients had drug-resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI-negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure-free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation. Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a "2-hit" mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable.


[Effect of several plant growth regulators on various prokaryotes and their viruses].
26 plant growth regulators including herbicides were investigated in their effect on the multiplication of Escherichia coli, Bacillus subtilis, and the blue-green alga Plectonema boryanum as well as the RNA phages M 12 and Qbeta and the DNA phages lambda, phi 105, and LPP-1 employing the agar diffusion method. Nearly all of the compounds inhibited and/or stimulated one or some of the prokaryotes tested. The most frequent and strongest effects occurred in Pl. boryanum, the least effects in E. coli. The multiplication of phages was also influenced by plant growth regulators leading to increase, decrease or non-appearance of plaques. The investigations with the temperate phages lambda and phi 105 suggested part of the compounds to be able to interfere with the process of lysogenization. The results are discussed comparatively involving correspondent findings referred to in literature.


Sexuality and fertility in long-term survivors of testicular cancer.
We assessed the impact of different treatment modalities on sexuality and fertility in long-term survivors of testicular cancer. The sample consisted of 85 testicular cancer patients, of whom 19 had undergone chemotherapy with retroperitoneal lymph node dissection (RPLND), 15 had received chemotherapy only, 42 had received infradiaphragmatic radiotherapy, and nine had received surveillance therapy. The questionnaire reported sexual function, marital status, and issues related to fertility and childbearing. One fourth to one half reported some type of sexual impairment in each group. The only significant difference was that approximately 70% of men with RPLND reported inability of ejaculation and a greater decline in semen volume, which is expected. The most striking finding is that the rates and nature of sexual dysfunction of surveillance patients were similar to other treatment groups, except for ejaculatory function. The highest rates of infertility distress were observed in chemotherapy patients. These data suggest that sexual dysfunction and infertility represent the major persisting side effects, even years after diagnosis. The hypothesis that surveillance patients have fewer sexual problems is not upheld in this study.


Person-centred medicine and mental health.
This paper discusses an integrated approach to person-centred medicine and its role in the future of mental health care. The origins and current status of this emerging field are revised with special attention to the contributions made from psychiatry and to the implications for psychiatric diagnosis and evaluation of the three pillars of the Person-centred Integrative Diagnosis (PID) model: its conceptual domains (health status, experiences and contributors to ill and good health), the related evaluative procedures, the partnerships needed and the existing links and differences with people-centred care and personalised medicine. In spite of their striking complementarities person-centred medicine and personalised medicine do not yet have substantial bridges built between them. Knowledge transfer and coordination should be established between these two models which will cast medical evaluation and care in the upcoming future.


High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle.
Myc (c-Myc) counteracts p27 effects, and low p27 usually correlates with high Myc expression in human cancer. However there is no information on the co-expression of both genes in chronic lymphocytic leukemia (CLL). We found a lack of correlation between RNA and protein levels of p27 and Myc in CLL cells, so we determined the protein levels by immunoblot in 107 cases of CLL. We observed a high p27 protein expression in CLL compared to normal B cells. Ectopic p27 expression in a CLL-derived cell line resulted in cell death resistance. Surprisingly, Myc expression was very low or undetectable in most CLL cases analyzed, with a clear correlation between high p27 and low Myc protein levels. This was associated with low Skp2 expression, which is consistent with the Skp2 role in p27 degradation and with SKP2 being a Myc target gene. High Myc expression did not correlate with leukemia progression, despite that cell cycle-related Myc target genes were upregulated. However, biochemical analysis showed that the high p27 levels inhibited cyclin-Cdk complexes even in Myc expressing CLL cells. Our data suggest that the combination of high p27 and low Myc is a marker of CLL cells which is mediated by Skp2.


Nonstoichiometric Phases of Two-Dimensional Transition-Metal Dichalcogenides: From Chalcogen Vacancies to Pure Metal Membranes.
Two-dimensional (2D) membranes consisting of a single layer of Mo atoms were recently manufactured [ Adv. Mater. 2018 , 30 , 1707281 ] from MoSe2 sheets by sputtering Se atoms using an electron beam in a transmission electron microscope. This is an unexpected result as formation of Mo clusters should energetically be more favorable. To get microscopic insights into the energetics of realistic Mo membranes and nonstoichiometric phases of transition-metal dichalcogenides (TMDs) MaXb, where M = Mo and W and X = S, Se, and Te, we carry out first-principles calculations and demonstrate that the membranes, which can be referred to as metallic quantum dots embedded into a semiconducting matrix, can be stabilized by charge transfer. We also show that an ideal neutral 2D Mo or W sheet is not flat but a corrugated structure, with a square lattice being the lowest-energy configuration. We further demonstrate that several intermediate nonstoichiometric phases of TMDs are possible as they have lower formation energies than pure metal membranes. Among them, the orthorhombic metallic 2D M4X4 phase is particularly stable. Finally, we study the properties of this phase in detail and discuss how it can be manufactured by the top-down approaches.


Prediction of glucose intolerance at 24-28 weeks of gestation by glucose and insulin level measurements in the first trimester.
Gestational diabetes is the second common disorder in pregnancy period, which is detected in 24-28 weeks of gestational age through screening tests in low-risk women. The women with gestational diabetes are prone to prenatal mortality and development of future diabetes. Therefore, detection of these individuals in the first trimester and conducting preventive interventions is of great importance. This study aimed to define the predictive value of fasting plasma glucose (FPG) and fasting plasma insulin (FPI) test in first trimester concerning the positive result of oral glucose challenge test (OGCT). This is a prospective and observational study conducted on 88 pregnant women in Tehran. After FPG and FPI measurements in these women in the first trimester, a screening test of GCT with 50 g oral glucose was conducted in 24-28 weeks of gestational age. Diagnostic value of FPG and in these two groups of positive and normal GCT results was evaluated through receiver operator characteristic (ROC) curve. P < 0.05 was considered significant. In this study, 15 subjects (17%) were detected with a positive GCT result. The sub-curve area of ROC diagram for FPG and FPI was calculated to be 0.573and 0.592, respectively, which reveals that FPG and FPI cannot have a proper predictive value for the positive result of GCT. Based on the results, the best cutoff points for FPG and FPI are 79.5 mg/dl and 7.55 μIU/ml, with accuracy of 60-67% and specificity of 45.2-47%. Only higher fasting glucose levels in early pregnancy, within the normoglycemic range, would predict the development of glucose intolerance with limited sensitivity and specificity.


An investigation of the expression of G1-phase cell cycle proteins in focal cortical dysplasia type IIB.
Balloon cells (BCs) are the pathologic hallmark of focal cortical dysplasia type IIB, a common cause of pharmacoresistent epilepsy. Expression of markers of cell immaturity and of the proliferation marker minichromosome maintenance protein 2 (mcm2) have been previously shown in BCs, suggesting that these cells might represent a pool of less-differentiated cells licensed for replication. An alternative explanation is that these cells are the remnants of early cortical plate cells that have failed to differentiate or to be eliminated during development and are arrested in the cell cycle, a hypothesis that this study aims to explore. Using immunohistochemical methods and semiquantitative analysis in 19 cases of focal cortical dysplasia (ages 1-81 years), we studied the expression of cell cycle proteins important either in regulating progression through the G1 phase or inducing cell arrest and promoting premature senescence. Only a small fraction of BCs expressed geminin, suggesting that few BCs enter the S phase or complete the cell cycle. Variable expression of nonphosphorylated retinoblastoma protein (Rb), cdk4, and p53 was noted in BCs. Cyclin E, D1, cdk2, phosphorylated Rb (795 and 807/811), and checkpoint 2 expression levels were low in BCs. These findings suggest early rather than late G1 arrest. Cell senescence could be induced by an undefined cerebral insult during development or alternatively represent a physiologic replicative senescence. These findings also suggest that dysregulation of cell cycle pathways may occur in focal cortical dysplasia, which opens further areas for exploration as potential new treatment avenues.


Requirement for host transcription in the replication of Sindbis virus.
Host cell involvement in Sindbis virus (SB) replication was examined in cells which had been treated with either actinomycin D (AMD) or alpha-amanitin (alpha-A). Treatment with these inhibitors of host transcription before infection reduced the ability of cells to support SB growth by 1 to 2 orders of magnitude, while having little or no effect on the replication of vesicular stomatitis virus. SB replication was sensitive to alpha-A in wild-type Chinese hamster ovary (CHO) cells but was resistant to alpha-A in CHOama-1 cells, a line which contains an alpha-A-resistant RNA polymerase II. A mutant of SB, SBamr, was isolated by mutagenesis followed by selection in cells which had been treated with AMD. SBamr grew normally not only in cells treated with AMD but also in alpha-A-treated cells. Our results suggest (i) that the synthesis of cellular mRNA (and presumably protein) is required for replication of SB, (ii) that prior treatment with either drug affects the same aspect of SB replication, and (iii) that mutations in the SB genome allow the virus to overcome the effect of inhibitors of host transcription.


Lower urinary tract symptoms (LUTS) as a risk factor for depressive symptoms in elderly men: results from a large prospective study in Southern Chinese men.
A cross-sectional relationship between lower urinary tract symptoms (LUTS) and depressive symptoms was previously reported among Southern Chinese men; however, the temporal relationship was unclear. Our objective is to evaluate the temporal relationship between moderate to severe lower urinary tract symptoms and clinically significant depressive symptoms in elderly Chinese men aged 65 in a prospective manner. In a prospective cohort of 2,000 Chinese men aged 65 to 92 years in Hong Kong, we studied the association of having moderate to severe LUTS at baseline and having clinically relevant depressive symptoms at year 2 follow-up. After excluding men with prostate or bladder cancer or surgery (n = 20) and lost to follow-up (n = 254), data on 1,726 subjects were analyzed. LUTS were measured by the International Prostate Symptom score; and clinically relevant depressive symptoms were measured by the Geriatric Depression Scale. The multiple logistic regressions showed that the presence of moderate-to-severe LUTS at baseline were significantly associated with increased risk for being depressed at two-year follow-up, with adjustments for demographic, lifestyle, medical factors, weight status and stressful life events (OR = 2.97; CI: 1.70-5.20). Association remained significant with additional adjustments for baseline GDS score (OR = 1.88; CI: 1.03-3.41). LUTS are important risk factors in predicting the presence of clinically relevant depressive symptoms. In elderly men, increased awareness and possible screening are needed to detect the increased risk of clinically relevant depressive symptoms.


Modulation of tumor angiogenesis by conditional expression of fibroblast growth factor-2 affects early but not established tumors.
Fibroblast growth factor-2 (FGF2) is a pleiotropic heparin-binding growth factor endowed with a potent angiogenic activity in vitro and in vivo. To investigate the impact of the modulation of FGF2 expression on the neovascularization at different stages of tumor growth, we generated stable transfectants (Tet-FGF2) from the human endometrial adenocarcinoma HEC-1-B cell line in which FGF2 expression is under the control of the tetracycline-responsive promoter (Tet-off system). After transfection, independent clones were obtained in which FGF2 mRNA and protein were up-regulated compared with parental cells. Also, the conditioned medium of Tet-FGF2 transfectants caused proliferation, urokinase-type plasminogen activator up-regulation, migration, and sprouting of cultured endothelial cells. A 3-day treatment of Tet-FGF2 cell cultures with tetracycline abolished FGF2 overexpression and the biological activity of the conditioned medium without affecting their proliferative capacity. Tet-FGF2 cells formed tumors when nude mice received s.c. injections. The administration of 2.0 mg/ml tetracycline in the drinking water before cell transplantation, continued throughout the whole experiment, inhibited FGF2 expression in Tet-FGF2 tumor lesions. This was paralleled by a significant decrease in the rate of tumor growth and vascularization to values similar to those observed in lesions generated by parental HEC-1-B cells. Tetracycline administration 20 days after tumor cell implant, although equally effective in reducing FGF2 expression and inhibiting tumor vascularity, only minimally impaired the growth of established Tet-FGF2 tumors. The results indicate that FGF2 expression deeply affects the initial tumor growth and neovascularization of HEC-1-B human endometrial adenocarcinoma in nude mice. On the contrary, the growth of established tumors appears to be independent of the inhibition of FGF2 expression and decreased vascular density. The possibility that a significant reduction of angiogenesis may not affect the progression of large tumors points to the use of antiangiogenic therapy in early tumor stage.


Two methods compared for measuring LD-1/total LD activity in serum.
We present evidence for the utility of an improved assay for the activity of lactate dehydrogenase (EC 22.214.171.124) isoenzymes 1 and 2 in serum, involving inhibition of the H-subunit of LD by pyruvate at pH 7.1. Results correlate well with the LD-1/total LD ratio as evaluated by immunological assay and, as an index to infarct, the method is superior to either the change in CK-MB activity or to the LD-1 activity or to a combination of these tests, as is the percentage of LD-1 to total LD activity. Moreover, the percentage inhibition of LD activity by pyruvate may have an advantage over other methods of isoenzyme fractionation because of its smaller population CV for patients with acute myocardial infarction than is true of other methods. We also demonstrate how, using a linear discriminant analysis, we compared this method with alternative methods. We determined that evaluation of CK-MB isoenzyme contributes no information in addition to that obtained from the LD-1 isoenzyme.


Amount of the two major Ag-NOR proteins, nucleolin, and protein B23 is cell-cycle dependent.
To know the biological basis allowing the use of Ag-NOR protein expression as proliferation marker in human malignancies, the relationship between cell cycle and amount of Ag-NOR protein was analyzed. The quantification of the two major Ag-NOR proteins, nucleolin and protein B23, was performed in exponentially growing, serum-deprived, and cell-cycle stimulated cells. Expression of nucleolin was low in serum-deprived cells and increased mostly in S phase during cell-cycle stimulation. Conversely, expression of protein B23 was slightly repressed in serum-deprived cells, and increased progressively until G2 phase during cell-cycle stimulation. The accumulation of nucleolin and protein B23 in G2 compared to G1 was demonstrated using sorted phase-specific cells. In G0, cells sorted according to their very low RNA content, and the amount of Ag-NOR proteins was half of that found in G1 cells, nucleolin being only weakly detectable. Therefore, the expression of nucleolin increased between G0-G1 and G1-S phases. These data support the hypothesis that quantification of Ag-NOR proteins is an estimation of the percentage of cells in each cell cycle phase because their amount is high in S-G2 and low in G1 phases.


Introduction of a 50 kbp DNA fragment into the plastid genome.
Plastid transformation technology has been used for the analysis and improvement of plastid metabolism. To create a transplastomic plant with a complicated and massive metabolic pathway, it is necessary to introduce a large amount of DNA into the plastid. However, to our knowledge, the largest DNA fragment introduced into a plastid genome was only 7 kbp long and consisted of just three genes. Here we report the introduction of foreign DNA of 23-50 kbp into the tobacco plastid genome with a bacterial artificial chromosome (BAC)-based plastid transformation vector. It was confirmed that the introduced DNA was passed on to the next generation. This is the first description of plastid transformation with a large amount of foreign DNA.


Absence of SV40 antibodies or DNA fragments in prediagnostic mesothelioma serum samples.
The rhesus monkey virus Simian Virus 40 (SV40) is a member of the polyomavirus family. It was introduced inadvertently to human populations through contaminated polio vaccine during the years 1956-1963, can induce experimental tumors in animals and transform human cells in culture. SV40 DNA has been identified in mesothelioma and other human tumors in some but not all studies. We tested prediagnostic sera from 49 mesothelioma cases and 147 matched controls for antibodies against the viral capsid protein VP1 and the large T antigen of SV40 and of the closely related human polyomaviruses BK and JC, and for SV40 DNA. Cases and controls were identified among donors to the Janus Serum Bank, which was linked to the Cancer Registry of Norway. Antibodies were analyzed by recently developed multiplex serology based on recombinantly expressed fusions of glutathione-S transferase with viral proteins as antigens combined with fluorescent bead technology. BKV and JCV specific antibodies cross- reactive with SV40 were preabsorbed with the respective VP1 proteins. Sera showing SV40 reactivity after preabsorption with BKV and JCV VP1 were further analyzed in SV40 neutralization assays. SV40 DNA was analyzed by SV40 specific polymerase chain reactions. The odds ratio for being a case when tested positive for SV40 VP1 in the antibody capture assay was 1.5 (95% CI 0.6-3.7) and 2.0 (95% CI 0.6-7.0) when only strongly reactive sera where counted as positive. Although some sera could neutralize SV40, preabsorption with BKV and JCV VP1 showed for all such sera that this neutralizing activity was due to cross-reacting antibodies and did not represent truly SV40-specific antibodies. No viral DNA was found in the sera. No significant association between SV40 antibody response in prediagnostic sera and risk of mesothelioma was seen.


The Utility of In-Office Ultrasound in the Diagnosis of Parotid Lesions.
Objective To determine whether the use of in-office ultrasound (US) by a head and neck surgeon is a useful adjunct to clinical assessment of parotid lesions and decrease the need of additional imaging, such as magnetic resonance imaging (MRI) or computed tomography (CT). Study Design Case series with chart review. Setting Tertiary care academic center. Subjects Seventy patients presenting with a parotid lesion who obtained an in-office US and ultrasound-guided fine-needle aspiration (USGFNA) from a head and neck surgeon from 2006 to 2015. Methods US images were retrospectively reviewed for 70 patients and characterized by a radiologist and a head and neck surgeon. Results Of the 70 patients, 6 had US characteristics that demonstrated a statistically significant association with a benign/malignant diagnosis: depth from surface; irregular borders; presence of calcifications, which included either micro- or macro-calcifications; posterior echogenicity enhancement; irregular shape; and homogeneous/heterogeneous echotexture. Imaging was performed prior to referral in 25 cases (35.7%); of those, 17 (68%) were for superficial, small (<2 cm) tumors where prereferral imaging studies did not provide additional information to that obtained with US. Of the 55 patients without MRI or CT performed prior to referral, MRI or positron emission tomography-CT scan was obtained in only 4 patients (7.3%) in cases involving recurrent parotid lesions, large tumors, or workup of a malignant neoplasm. Conclusions Several US characteristics individually assist in lesion characterization. In-office US and USGFNA are an appropriate first-line modality in the assessment of parotid lesions, can allow for immediate parotid lesion assessment, and can decrease the need for additional imaging.


Primary Epithelioid Angiosarcoma of the Uterus: A Rare Tumor with Very Aggressive Behavior.
Angiosarcoma is a high-grade vascular tumor arising from endothelial cells of blood vessels. It represents less than 1% of the mesenchymal tumors. Uterine angiosarcoma is an extremely rare tumor with less than 25 cases reported in the literature. It usually presents in postmenopausal women as uterine mass and rarely can arise in a leiomyoma. It is included in the group of tumors of aggressive behavior and poor prognosis. Herein, we present a case of primary uterine angiosarcoma in a 56-year-old female patient with a history of fibroids presenting with pelvic pain and weight loss. Abdominal CT scan showed a large uterine mass and enlarged pelvic lymph nodes. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed, and on histopathologic examination, it was found to be primary epithelioid angiosarcoma of the uterus. Immunohistochemical stains for CD31, keratin MAK-6, and keratin AE1/AE3 confirmed the diagnosis. In conclusion, uterine angiosarcoma should be suspected in any rapidly growing hemorrhagic uterine mass, and appropriate sampling and immunohistochemical stains should be considered.


[Studies on chemical constituents of Liriope platyphylla].
Seven chemical constituents were isolated from the CHCl3 fraction and n-BuOH fraction from EtOH ext. of Liriope platyphylla Wang et Tang. Their structures were elucidated as lupenone (I), lupeol (II), ursolic acid (III), beta-sitosterol (IV), diosgenin (V), LP-A (VI) and LP-B (VII) respectively. Compound I, II and V were isolated from this genus of Liriope for the first time. Compound III and IV were isolated from this plant for the first time.


Mitochondria-mediated oxidative stress induced by desert dust in rat alveolar macrophages.
Exposure to ambient particulate matter (PM), including PM from resuspension of soils and dusts, increases the risk for respiratory diseases. However, the exact mechanism of PM-mediated damage to the lungs remains unclear. Due to recent increases in the frequency of dust storms in many areas, we examined the cytotoxic effects of soil-dust samples collected in an arid zone in Israel on rat lung macrophages. The desert soil contains soil crusts and low levels of toxic metal content. Exposure of cells to water extracts from the dust samples caused significant reduction in the concentration of live cells and overall cell viability. The dust samples induced cell death through apoptosis, mitochondrial dysfunction, and increased mitochondrial lipid peroxidation. The dust samples generated more reactive oxygen species (ROS) compared to control-treated samples and National Institute of Standards and Technology San Joaquin Valley standard reference material. To assess whether the oxidative imbalance induced by dust extract also interferes with the antioxidant defense, we evaluated phase II detoxifying and antioxidant enzymes, which are Nrf2 classical targets. The Nrf2 transcription factor is a master regulator of cellular adaptation to stress. The dust extracts produced a significant increase in phase II detoxifying genes. This work suggests that the health-related injury observed in rat lung cells exposed to dust extracts is associated with ROS generation, mitochondrial dysfunction, mitochondrial lipid peroxidation, and cellular antioxidant imbalance. Damage to lung mitochondria may be an important mechanism by which dust-containing bacterial material induces lung injury upon inhalation.


Public preferences for responsibility versus public preferences for reducing inequalities.
In cost-utility analysis, the numbers of quality-adjusted life years (QALYs) gained are aggregated by placing the same weight on each QALY. Deviations from this rubric have been proposed on a number of grounds, including the degree to which persons might be deemed responsible for the illness faced, and inequality in lifetime health between groups. Most research has looked at these factors in isolation. This paper analyses public preferences about the relative importance of these factors. Over 500 members of the general public in the UK are interviewed in their homes. Where "blameworthy" groups experience a moderate drop in quality of life due to their behaviour, they appear to receive higher priority than an otherwise "trustworthy" group if they also experience poorer health prospects because the latter is weighted more heavily than the former.


Time-domain SFG spectroscopy using mid-IR pulse shaping: practical and intrinsic advantages.
Sum-frequency generation (SFG) spectroscopy is a ubiquitous tool in the surface sciences. It provides infrared transition frequencies and line shapes that probe the structure and environment of molecules at interfaces. In this article, we apply techniques learned from the multidimensional spectroscopy community to SFG spectroscopy. We implement balanced heterodyne detection to remove scatter and the local oscillator background. Heterodyning also separates the resonant and nonresonant signals by acquiring both the real and imaginary parts of the spectrum. We utilize mid-IR pulse shaping to control the phase and delay of the mid-IR pump pulse. Pulse shaping allows phase cycling for data collection in the rotating frame and additional background subtraction. We also demonstrate time-domain data collection, which is a Fourier transform technique, and has many advantages in signal throughput, frequency resolution, and line shape accuracy over existing frequency domain methods. To demonstrate time-domain SFG spectroscopy, we study an aryl isocyanide on gold, and find that the system has an inhomogeneous structural distribution, in agreement with computational results, but which was not resolved by previous frequency-domain SFG studies. The ability to rapidly and actively manipulate the mid-IR pulse in an SFG pules sequence makes possible new experiments and more accurate spectra.


Bringing rigor to evaluations of large-scale programs to improve infant and young child feeding and nutrition: the evaluation designs for the Alive & Thrive initiative.
The evidence base on the impact of large-scale infant and young child feeding (IYCF) and nutrition programs is limited, partly due to the challenges of rigorously evaluating complex programs including multiple interventions. To describe the process used to design Alive & Thrive's impact evaluations in the three target countries and discuss the feasibility of developing contextually relevant designs adapted to the country-specific programmatic context. The evaluation designs for Alive & Thrive needed to address several challenges. These included the selection of intervention components to evaluate rigorously; the identification of appropriate comparison groups in the context of rapidly scaling-up programs; the choice of impact indicators; addressing measurement challenges related to evaluating the impact of interventions targeted during the first 2 years of life on stunting; and developing methods and tools to assess implementation, utilization, and program impact pathways within evolving program portfolios. In Bangladesh and Vietnam, cluster-randomized probability designs are used for the impact evaluations; in Ethiopia, the impact evaluation uses an adequacy design. In all three countries, repeated cross-sectional surveys, 4 years apart, are used to measure impact, and appropriate age groups are sampled separately to capture change in the main impact indicators. In addition, theory-driven process evaluations are used to study factors that facilitate or prevent achievement of impact and scale. We conclude that robust impact and process evaluations of complex, large-scale nutrition programs are feasible, but that early implementer-evaluator engagement and shared vision and motivation to establishing meaningful evaluations are essential.


CA19-9: a pedictor of response in pancreatic cancer treated with gemcitabine and cisplatin.
The question was asked whether kinetics of CA19-9 would serve as a predictor of chemotherapeutic outcome in advanced pancreatic cancer treated with gemcitabine and cisplatin. Twenty one patients, 5 females and 16 males (median age 56 yrs, range 36-71 yrs) suffering from adenocarcinoma of the exocrine pancreas were analysed. Chemotherapy was applied for a median of 6 courses (range 2-21). Four patients achieved a complete remission, four a partial remission (OR = 38%), while stable disease was documented in 8 and progressive disease in 5 patients. Among 4 CR patients, all demonstrated a significant decline of CA 19-9 levels during the initial three treatment courses with apparent half-lifes of 15, 18, 24, and 33 days. At a cut-off level of 37 U/mL, all CR patients reached normal values in the course of treatment. All patients achieving PR showed a decrease of CA 19-9 values at apparent half-lifes of 9, 16, 88 and 89 days. Among patients with stable disease, CA19-9 transiently decreased in 7/8 patients and remained stable in 1 patient. However, values increased later in all patients after a median of 3 treatment courses (range 2-9). In patients with disease progression, CA 19-9 initially increased in 4/5 patients, while a further patient did so only beyound 100 days of treatment. In conclusion, kinetics of CA19-9 serum concentration may serve as an early indicator of response to gemcitabine/cisplatin chemotherapy in advanced pancreatic cancer.


Mechanisms of glucagon secretion during insulin-induced hypoglycemia in man. Role of the beta cell and arterial hyperinsulinemia.
To elucidate the mechanisms controlling the response of glucagon to hypoglycemia, a vital component of the counterregulatory hormonal response, the role of intraislet insulin was studied in seven normal subjects and five subjects with insulin-dependent diabetes mellitus (IDDM) (of less than 15-mo duration). In the normal subjects, hypoglycemia (arterial plasma glucose [PG] 53 +/- 3 mg/dl) induced by an intravenous insulin infusion (30 mU/m2 X min for 1 h, free immunoreactive insulin [FIRI] 58 +/- 2 microU/ml) elicited a 100% fall in insulin secretion and an integrated rise in glucagon of 7.5 ng/ml per 120 min. When endogenous insulin secretion was suppressed by congruent to 50 or congruent to 85% by a hyperinsulinemic-euglycemic clamp (FIRI 63 +/- 1.5 or 147 +/- 0.3 microU/ml, respectively) before hypoglycemia, the alpha cell responses to hypoglycemia were identical to those of the control study. When the endogenous insulin secretion was stimulated by congruent to 100% (hyperinsulinemic-hyperglycemic clamp, FIRI 145 +/- 1.5 microU/ml, PG 132 +/- 2 mg/dl) before hypoglycemia, the alpha cell responses to the hypoglycemia were also superimposable on those of the control study. Finally, in C-peptide negative diabetic subjects made euglycemic by a continuous overnight intravenous insulin infusion, the alpha cell responses to hypoglycemia were comparable to those of normal subjects despite absent beta cell secretion, and were not affected by antecedent hyperinsulinemia (hyperinsulinemic-euglycemic clamp for 2 h, FIRI 61 +/- 2 microU/ml). These results indicate that the glucagon response to insulin-induced hypoglycemia is independent of the level of both endogenous intraislet and exogenous arterial insulin concentration in normal man, and that this response may be normal in the absence of endogenous insulin secretion, in contrast to earlier reports. Thus, loss of beta cell function is not responsible for alpha cell failure during insulin-induced hypoglycemia in IDDM.


Segment number threshold determines juvenile onset of germline cluster expansion in Platynereis dumerilii.
Development of sexual characters and generation of gametes are tightly coupled with growth. Platynereis dumerilii is a marine annelid that has been used to study germline development and gametogenesis. P. dumerilii has germ cell clusters found across the body in the juvenile worms, and the clusters eventually form the gametes. Like other segmented worms, P. dumerilii grows by adding new segments at its posterior end. The number of segments reflect the growth state of the worms and therefore is a useful and measurable growth state metric to study the growth-reproduction crosstalk. To understand how growth correlates with progression of gametogenesis, we investigated germline development across several developmental stages. We discovered a distinct transition period when worms increase the number of germline clusters at a particular segment number threshold. Additionally, we found that keeping worms short in segment number, by manipulating environmental conditions or via amputations, supported a segment number threshold requirement for germline development. Finally, we asked if these clusters in P. dumerilii play a role in regeneration (as similar free-roaming cells are observed in Hydra and planarian regeneration) and found that the clusters were not required for regeneration in P. dumerilii, suggesting a strictly germline nature. Overall, these molecular analyses suggest a previously unidentified developmental transition dependent on the growth state of juvenile P. dumerilii leading to substantially increased germline expansion.


Impact of a modified Valsalva manoeuvre in the termination of paroxysmal supraventricular tachycardia.
Paroxysmal supraventricular tachycardia (SVT) is a relatively common problem presented to the emergency department. Most sources advocate the use of vagal manoeuvres as first-line management, including Valsalva manoeuvre. Despite this, there is lack of standardisation as to how the technique is performed. There is currently no 'gold standard' Valsalva manoeuvre. We propose a modified Valsalva manoeuvre, based on techniques described in small-scale electrophysiological studies, but no large clinical trials. The study was designed to assess the impact of introducing this modified Valsalva manoeuvre as the departmental standard for non-pharmacological reversion of SVT. A retrospective audit reviewing the preceding 6-month presentations of SVT was performed, and a questionnaire assessing techniques used and anticipated success rates was completed by a representative sample of emergency department doctors. Finally, a prospective trial of the impact of the modified Valsalva manoeuvre on patients presenting in SVT to the emergency department was performed. After meeting the study criteria and giving consent, the patients were instructed to perform the modified Valsalva manoeuvre, that is, while lying supine on the bed in a Trendelenberg position, they forcefully expire into a section of suction tubing and pressure gauge for at least 15 s and at a pressure of at least 40 mm Hg. The retrospective 6-month audit revealed only one successful reversion with Valsalva from a sample of 19 patients. Thirty-two doctors completed the questionnaire describing a variety of different Valsalva techniques highlighting a lack of consensus. 27 patients were recruited to the prospective trial, of whom 19 were correctly diagnosed as having paroxysmal SVT. Of these 19 patients, 6 reverted with the modified Valsalva manoeuvre. Our findings support previous observations that there is lack of standardisation as to how Valsalva is performed, and an apparent reliance on adenosine. The impact of introducing this technique as our departmental standard was a raise in non-pharmacological reversion from 5.3% to 31.7% with no reported significant adverse effects.


Reduction of needlestick injuries in healthcare personnel at a university hospital using safety devices.
Healthcare personnel (HCP) is exposed to bloodborne pathogens through occupational risk factors. The objective of this study was to compare the incidence of needlestick injuries (NSIs) before and after the introduction of safety devices in all departments of our hospital. Data was extracted from mandatory needlestick report forms of the hospital's Occupational Health Service. Serological results of patients and healthcare personnel (HCP) were reviewed in the laboratory information system. In 2007, the year before the introduction of safety devices, 448 needlestick injuries were self-reported, corresponding to an annual rate of 69.0 NSIs per 1 000 full-time HCP. The highest incidence was observed among medical staff in the surgery department and internal medicine with 152 (33.9%) and 79 (17.6%) NSIs, respectively. Of all occupational groups, nurses (36.2%) had the highest risk to sustain NSIs. In 2008 safety devices were introduced across the hospital, e.g. peripheral venous catheter, hypodermic needle and stapling system for wound sealing providing active or passive protection. In 2009, the year after introduction of safety devices, only 350 NSIs were reported, the annual rate of NSIs decreased to 52.4 per 1 000 full-time HCP. Thus an overall reduction of 21.9% for NSIs was achieved when safer devices were applied. The number of NSIs was reduced by even 50% for blood withdrawal, for use of peripheral venous catheters and application of hypodermic needles. The application of safety devices led to a reduction of NSIs and significantly reduces the risk of bloodborne infections.


Effect of pacing mode on health-related quality of life in the Canadian Trial of Physiologic Pacing.
Both "physiologic" (dual-chamber or atrial only) or ventricular-pacing-only permanent pacemakers provide chronotropic competence, with unknown health-related quality of life (QOL) differences between these options. The QOL studies within the Canadian Trial of Physiologic Pacing were performed to assess whether QOL differences exist in patients randomized to these 2 pacing modes. Two QOL protocols were performed: 1) a substudy of 269 patients with detailed QOL measures (The Medical Outcomes Study, Short-Form [SF-36], the Pacemaker Syndrome Scale, an activity scale, and a pacemaker-specific scale) at baseline and 6 months after implantation; and 2) a parent study assessment of QOL in 1721 patients with a 12-item QOL instrument package (SF-6, "ladder of life," and pacemaker syndrome scale) given 6 months after implantation only. In the substudy, pacing was associated with an average significant (P <.05) 0.36 SD unit improvement in QOL across all domains (SF-36: 38 +/- 9 to 41 +/- 11 for physical scores, 47 +/- 11 to 52 +/- 9 for mental health scores, both P <.001). Similar improvements were seen with the pacemaker-specific scales. There were no significant differences in the absolute or relative improvement in QOL between assigned pacing modes. The parent study similarly showed no differences in QOL between pacing modalities. Presyncope occurred in 31% of patients in the physiological pacing group, compared with 38% of the patients in the ventricular pacing group (P <.01). No other symptoms were different between the 2 groups. Pacemaker dependency, defined as an escape heart rate <50 beats per minute, did not influence the lack of difference in QOL scores between the 2 assigned pacing modes. In this largest randomized assessment of QOL in patients with pacemakers, with the instruments used, there was no significant health-related QOL difference seen between "physiologic" pacing and ventricular pacing.


Effect of recombinant human fibroblast interferon and mezerein on growth, differentiation, immune interferon binding and tumor associated antigen expression in human melanoma cells.
The combination of recombinant human fibroblast interferon (INF-delta) and the antileukemic compound mezerein (MEZ) results in a synergistic suppression in the growth of human melanoma cells and a concomitant increase in melanin synthesis. In the present study we have further analyzed this synergistic interaction and have also evaluated the effect of IFN-delta and MEZ, alone and in combination, on recombinant human gamma interferon (IFN-gamma) binding and Class I HLA and melanoma associated antigen (MAA) expression in the HO-1 human melanoma cell line. Single cell clones isolated from the HO-1 cell line varied in their sensitivity to the antiproliferative effects of IFN-delta and MEZ. With all twelve clones, however, the combination of IFN-delta plus MEZ was more growth inhibitory than either agent used alone, even in HO-1 subclones displaying relative resistance to IFN-delta. By continuous growth in gradually increasing concentrations of IFN-delta, a variant population of HO-1 cells, HO-1 delta R-D, was generated which was more resistant to the antigrowth effects of IFN-delta than the original HO-1 parental cell line. In the IFN delta R-D cell line the combination of IFN-delta plus MEZ synergistically suppressed growth. Exposure of HO-1 cells to 2500 units/ml IFN-delta or 50 ng/ml MEZ for 96 hr resulted in no change or an increase in the binding of labelled IFN-gamma to surface receptors, whereas the combination of IFN-delta plus MEZ increased IFN-gamma binding 2-to-4-fold in HO-1 cells. This increase was the result of an increase in the number of receptors on treated cells coupled with a protection against a decrease in receptors observed for confluent untreated cells. Changes in IFN-gamma binding resulting from treatment with IFN-delta plus MEZ were not associated with alterations in the binding affinity of INF-gamma to its receptor. Changes were also observed in the expression of HLA Class I antigens and MAAs following treatment of HO-1 cells with IFN-delta, MEZ or IFN-delta plus MEZ. IFN-delta and MEZ increased the expression of HLA Class I antigens a 96 kd MAA defined by MoAb CL203, a 100 kd MAA defined by MoAb 376.96 and a 115 kd MAA defined by MoAb 345.134 but decreased the expression of a high molecular weight-melanoma associated antigen (HMW-MAA) defined by MoAb 325.28S.(ABSTRACT TRUNCATED AT 400 WORDS)


Targeting vaccinia to solid tumors with local hyperthermia.
We have previously demonstrated that mutant vaccinia viruses target tumors in vivo after systemic delivery, and they have potential as vectors for tumor-directed gene therapy. We hypothesized that hyperthermia may augment vaccinia delivery to tumors after systemic injection, as hyperthermia increases the permeability of the endothelial vasculature to nanoparticles. In our in vitro experiments, we have shown that hyperthermia does not alter tumor cells' susceptibility to the intrinsic cytopathogenicity of the vaccinia virus compared with normothermic controls. Hyperthermia also does not change the viral infectivity or the level of viral marker gene expression when compared with normothermia. In an in vitro model of endothelial cell monolayer permeability, we have demonstrated that hyperthermia increases the permeability of the monolayer to vaccinia virus and that this phenomenon is completely reversible. In vivo we have demonstrated that the tumors that were treated with systemic vaccinia under conditions of hyperthermia (41.5 degrees C for 30 min) had significantly higher levels of vaccinia marker gene activity (>100-fold) than those treated under normothermic conditions (p < 0.05) and that this effect was specific to tumor. We also demonstrated that mice with 1 cm subcutaneous tumors treated with a systemically delivered, conditionally replicating vaccinia under conditions of hyperthermia had complete tumor regression in 50% and significantly improved antitumor response, compared with normothermic viral-treated controls (mean tumor volume of 110 mm(3) vs 3169 mm(3), 13 days after treatment) and compared with hyperthermic, nonvirally treated control animals (p < 0.0001). Regional hyperthermia improves vaccinia targeting to tumors, and thereby enhances the antitumor response.


Lack of an association between CYP1A1 gene Ile462Val polymorphism and polycystic ovary syndrome in Chinese.
Polycystic ovary syndrome (PCOS) is a complex multi-factorial disorder involving a number of genetic and environmental factors. CYP1A1 (Cytochrome P450, family 1, subfamily A, polypeptide 1) gene, which belongs to Cytochrome P450 (CYP) super family, encodes a phase I cytochrome P450 enzyme, involved in the oxidative metabolism of estrogens. A recent study suggested that a common polymorphism Ile462Val of the CYP1A1 gene might be associated with PCOS development in Turkish women. To investigate a possible association between the CYP1A1 Ile462Val polymorphism and PCOS in Chinese women, we examined 205 PCOS patients and 177 healthy controls. All subjects were genotyped for CYP1A1. There was no statistical difference in CYP1A1 genotype and allele frequencies between PCOS cases and controls (chi(2) = 0.956, df = 2, P = 0.089 by genotype; chi(2) = 0.005, df = 1, P = 0.941 by allele). Compared with controls, there were no statistical difference in Val/Val genotype and Val allele frequency in the PCOS cases (4.9% vs. 5.1% by genotype; 51.7% vs. 52.0% by allele) (chi(2) = 0.009, df = 1, P = 0.926 by genotype; chi(2) = 0.005, df = 1, P = 0.941 by allele). Moreover, no association between CYP1A1 Ile462Val genotypes and metabolic parameters was observed in PCOS women. Our findings clearly indicated that this polymorphism does not represent an additional genetic risk factor for PCOS in Chinese women.


Consistent delayed unilateral neuronal death after modified transient focal cerebral ischemia in mice that mimics neuronal injury after transient global cerebral ischemia.
Numerous studies have attempted to reveal the pathophysiology of ischemic neuronal injury using a representative transient global cerebral ischemia (tGCI) model in rodents; however, most of them have used gerbil or rat models. Recent advances in transgene and gene-knockout technology have enabled the precise molecular mechanisms of ischemic brain injury to be investigated. Because the predominant species for the study of genetic mutations is the mouse, a representative mouse model of tGCI is of particular importance. However, simple mouse models of tGCI are less reproducible; therefore, a more complex process or longer duration of ischemia, which causes a high mortality rate, has been used in previous tGCI models in mice. In this study, the authors aimed to overcome these problems and attempted to produce consistent unilateral delayed hippocampal CA1 neuronal death in mice. C57BL/6 mice were subjected to short-term unilateral cerebral ischemia using a 4-mm silicone-coated intraluminal suture to obstruct the origin of the posterior cerebral artery (PCA), and regional cerebral blood flow (rCBF) of the PCA territory was measured using laser speckle flowmetry. The mice were randomly assigned to groups of different ischemic durations and histologically evaluated at different time points after ischemia. The survival rate and neurological score of the group that experienced 15 minutes of ischemia were also evaluated. Consistent neuronal death was observed in the medial CA1 subregion 4 days after 15 minutes of ischemia in the group of mice with a reduction in rCBF of < 65% in the PCA territory during ischemia. Morphologically degenerated cells were mostly positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and cleaved caspase 3 staining 4 days after ischemia. The survival rates of the mice 24 hours (n = 24), 4 days (n = 15), and 7 days (n = 7) after being subjected to 15 minutes of ischemia were 95.8%, 100%, and 100%, respectively, and the mice had slight motor deficits. The authors established a model of delayed unilateral hippocampal neuronal death in C57BL/6 mice by inducing ischemia in the PCA territory using an intraluminal suture method and established inclusion criteria for PCAterritory rCBF monitored by laser speckle flowmetry. This model may be useful for investigating the precise molecular mechanisms of ischemic brain injury.


Dynamin phosphorylation controls optimization of endocytosis for brief action potential bursts.
Modulation of synaptic vesicle retrieval is considered to be potentially important in steady-state synaptic performance. Here we show that at physiological temperature endocytosis kinetics at hippocampal and cortical nerve terminals show a bi-phasic dependence on electrical activity. Endocytosis accelerates for the first 15-25 APs during bursts of action potential firing, after which it slows with increasing burst length creating an optimum stimulus for this kinetic parameter. We show that activity-dependent acceleration is only prominent at physiological temperature and that the mechanism of this modulation is based on the dephosphorylation of dynamin 1. Nerve terminals in which dynamin 1 and 3 have been replaced with dynamin 1 harboring dephospho- or phospho-mimetic mutations in the proline-rich domain eliminate the acceleration phase by either setting endocytosis at an accelerated state or a decelerated state, respectively. DOI:http://dx.doi.org/10.7554/eLife.00845.001.


[The validity and reliability of the Brief-Hypomanic Attitudes and Positive Predictions Inventory-Turkish version].
There has been a great deal of interest in specific dysfunctional beliefs that may be associated with susceptibility to mania. The Hypomanic Attitudes and Positive Predictions Inventory (HAPPI) was developed by Mansell (2006) to identify such beliefs. The present study aimed to measure the psychometric properties of the Turkish version of the brief version of the HAPPI (Brief-HAPPI-TR). The study sample consisted of 115 outpatients with bipolar disorder (BD) and 103 healthy controls. Participants were administered the Brief-HAPPI-TR, Mood Disorder Questionnaire (MDQ), and Dysfunctional Attitudes Scale (DAS). The reverse-scored HAPPI items lowered the alpha coefficient and were therefore excluded from the total score. The remaining items had high internal consistency for the entire sample (r = 0.84), for the BD group (r = 0.83), and for the control group (r = 0.86). The test-retest reliability coefficient was moderately high (r = 0.41). Brief-HAPPI-TR scores were significantly correlated with MDQ and DAS scores. Finally, Brief-HAPPI-TR was able to differentiate between the BD patients and controls. Brief-HAPPI-TR was observed to be valid and reliable for assessing hypomanic attitudes in Turkish BD patients in remission. In addition, we think that within the cognitive-behavioral paradigm this scale can be used to identify and treat dysfunctional cognitions in Turkish BD patients.


Synthesis, antielastase, antioxidant and radical scavenging activities of 4-(aza substituted) methylene substituted dihydroxy coumarines.
A series of some 4-(aza substituted) methylene substituted dihydroxy coumarines were evaluated for their antioxidant and antielastase activities. Different in vitro methodologies such as total reducing power, 1,1-diphenyl-2-picryl-hydrazil (DPPH·) free radical scavenging, ABTS radical scavenging activity were used as antioxidant activity. All the tested compounds exhibited potent free radical scavenging ability and antielastase activites.


Ethics and Privacy Implications of Using the Internet and Social Media to Recruit Participants for Health Research: A Privacy-by-Design Framework for Online Recruitment.
The Internet and social media offer promising ways to improve the reach, efficiency, and effectiveness of recruitment efforts at a reasonable cost, but raise unique ethical dilemmas. We describe how we used social media to recruit cancer patients and family caregivers for a research study, the ethical issues we encountered, and the strategies we developed to address them. Drawing on the principles of Privacy by Design (PbD), a globally recognized standard for privacy protection, we aimed to develop a PbD framework for online health research recruitment. We proposed a focus group study on the dietary behaviors of cancer patients and their families, and the role of Web-based dietary self-management tools. Using an established blog on our hospital website, we proposed publishing a recruitment post and sharing the link on our Twitter and Facebook pages. The Research Ethics Board (REB) raised concern about the privacy risks associated with our recruitment strategy; by clicking on a recruitment post, an individual could inadvertently disclose personal health information to third-party companies engaged in tracking online behavior. The REB asked us to revise our social media recruitment strategy with the following questions in mind: (1) How will you inform users about the potential for privacy breaches and their implications? and (2) How will you protect users from privacy breaches or inadvertently sharing potentially identifying information about themselves? Ethical guidelines recommend a proportionate approach to ethics assessment, which advocates for risk mitigation strategies that are proportional to the magnitude and probability of risks. We revised our social media recruitment strategy to inform users about privacy risks and to protect their privacy, while at the same time meeting our recruitment objectives. We provide a critical reflection of the perceived privacy risks associated with our social media recruitment strategy and the appropriateness of the risk mitigation strategies that we employed by assessing their alignment with PbD and by discussing the following: (1) What are the potential risks and who is at risk? (2) Is cancer considered "sensitive" personal information? (3) What is the probability of online disclosure of a cancer diagnosis in everyday life? and (4) What are the public's expectations for privacy online and their views about online tracking, profiling, and targeting? We conclude with a PbD framework for online health research recruitment. Researchers, REBs, ethicists, students, and potential study participants are often unaware of the privacy risks of social media research recruitment and there is no official guidance. Our PbD framework for online health research recruitment is a resource for these wide audiences.


Developmental cascade model for adolescent substance use from infancy to late adolescence.
A developmental cascade model for adolescent substance use beginning in infancy was examined in a sample of children with alcoholic and nonalcoholic parents. The model examined the role of parents' alcohol diagnoses, depression and antisocial behavior in a cascading process of risk via 3 major hypothesized pathways: first, via parental warmth/sensitivity from toddler to kindergarten age predicting higher parental monitoring in middle childhood through early adolescence, serving as a protective pathway for adolescent substance use; second, via child low self-regulation in the preschool years to a continuing externalizing behavior problem pathway leading to underage drinking and higher engagement with substance using peers; and third, via higher social competence from kindergarten age through middle childhood being protective against engagement with delinquent and substance using peers, and leading to lower adolescent substance use. The sample consisted of 227 intact families recruited from the community at 12 months of child age. Results were supportive for the first 2 pathways to substance use in late adolescence. Among proximal, early adolescent risks, engagement with delinquent peers and parent's acceptance of underage drinking were significant predictors of late adolescent alcohol and marijuana use. The results highlight the important protective roles of maternal warmth/sensitivity in early childhood to kindergarten age, parental monitoring in middle childhood, and of child self-regulation in the preschool period as reducing risk for externalizing behavior problems, underage drinking, and engagement with delinquent peers in early adolescence. Specific implications for the creation of developmentally fine-tuned preventive intervention are discussed. (PsycINFO Database Record


Corrosive oesophageal injuries: a preventable menace.
Potentially catastrophic presentations and lifelong complications resulting from corrosive ingestions in humans is one of the most challenging situations encountered in clinical medical practice. This study reviewed pattern, mechanisms and associated socio-medical challenges with ingestion of corrosive agents as seen in a tertiary health institution in South-western Nigeria. A retrospective review of all patients that were managed for corrosive ingestion at Ladoke Akintola University of Technology Teaching Hospital, Osogbo, Osun State, Nigeria, over a seven year period. A total of 28 patients M:F: 1.6:1. There were 7 children and 21 adults. Majority (78.6%) of the patients ingested alkaline substances. Accidental ingestion occurred in 28.6% while 71.4% resulted from deliberate self harm especially among adults (66.7%). Almost two thirds (64.3%) of the patients presented after 48hrs of ingestion. Patients who presented early were managed conservatively. Most patients (64.3%) who presented late had nutritional and fluid rehabilitation. Two patients died from oesophageal perforation and resulting septicaemia. Psychiatric evaluation revealed that seven adults (25%) had psychotic illness while (42.9%) of the patients developed oesophageal strictures. Short segment strictures were managed with oesophageal dilatation with good outcome while long and multiple segment strictures were referred to cardiothoracic surgeons for management. Corrosive oesophageal injuries remain a prevalent and preventable condition in the developing countries. Preventive strategies should include regulation and packaging of corrosive substances, organization of psychiatric services, and education of the population on corrosive ingestion.


Differential influences of the aryl hydrocarbon receptor on Th17 mediated responses in vitro and in vivo.
The aryl hydrocarbon receptor (AhR) has been attributed with anti-inflammatory effects in the development of pathological immune responses leading to experimental autoimmune encephalomyelitis (EAE) via the induction of regulatory T cells. In agreement with previously published findings, we find that TCDD administration confers protection from EAE, however, this immuno-modulatory effect was not the consequence of de novo Treg generation, but the inhibition of Th17 cell differentiation. Systemic application of FICZ at the time of immunization also reduced EAE pathology albeit to a lesser degree than TCDD. In vitro Th17 differentiation in the presence of AhR agonists, including TCDD, promoted IL-17 and IL-22 expression, but did not induce Treg differentiation. AhR affinity influenced the amounts of IL-17 and IL-22 protein that was secreted by Th17 cells, but did not seem to affect susceptibility to EAE in vivo. Making use of conditional AhR-deficient mice, we show that the anti-inflammatory effect of TCDD depends on AhR activation in both T cells and dendritic cells, further emphasising the ability of TCDD to interfere with T effector cell differentiation in vivo. The dichotomy between the in vivo and in vitro effects of AhR reveals the complexity of the AhR pathway, which has the capacity of affecting different AhR-expressing cell types involved in mounting immune responses, thus participating in defining their outcome.


[Postoperative percutaneous endoscopic gastrostomy/jejunostomy].
In order to cure complications appeared in the postoperative period two patients were treated with percutaneous endoscopic gastrostomy/jejunostomy (PEG, PEGJ) with the purpose of long-lasting enteral feeding and decompression. The indications of PEG/PEGJ were the following: external gastric fistula in one case and anastomotic leakage in one case. In the patients the PEG was located by intraoperative X-ray examination, this method was not published earlier. Regarding complications of the early postoperative period the PEG and the PEGJ are considered useful and expedient procedures with the aim of lasting enteral feeding and decompression.


Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis.
Epithelial-mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E-M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance into and continued residence in these various states, and which of these states favour the process of metastasis. Here we characterize a layer of EMT-regulating machinery that governs E-M plasticity (EMP). This machinery consists of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, which operate as critical regulators to maintain a stable epithelial state. Interestingly, loss of these two complexes unlocks two distinct EMT trajectories. Dysfunction of PRC2, but not KMT2D-COMPASS, yields a quasi-mesenchymal state that is associated with highly metastatic capabilities and poor survival of patients with breast cancer, suggesting that great caution should be applied when PRC2 inhibitors are evaluated clinically in certain patient cohorts. These observations identify epigenetic factors that regulate EMP, determine specific intermediate EMT states and, as a direct consequence, govern the metastatic ability of carcinoma cells.


[Thoracal insufficiency syndrome in congenital scoliosis].
We analyzed literature data and our own experience with treatment of 180 patients under 7 years of age during the period of 1990-2010. To demonstrate the resources of surgical correction of spinal and thoracic deformities in children with severe deformities of the spinal column and thoracic cage we propose a rational strategy of operative correction and postoperative management for children of early age depending on the variations of malformation.


PROGRAMMED CELL DEATH LIGAND 1 (PD-L1) EXPRESSION IN TRIPLE NEGATIVE BREAST CANCER CASES IN BENIN CITY.
Triple-negative breast cancers (TNBC) have been particularly challenging to manage due to their lack of intrinsic cellular receptors, with the resultant relatively higher morbidity and mortality. Recently, the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD- L1) immune checkpoint pathway has become the focus of immunotherapy, especially for TNBCs. This study aimed to determine the pattern of expression of PD-L1 in TNBC cases in Benin City. It was a 3-year retrospective study that involved the PD-L1 immunostaining of the TNBC cases that were diagnosed in the Department of Anatomical Pathology, University of Benin Teaching Hospital, Benin City, from January 1, 2017 to December 31, 2019. Ninety-two cases of TNBC were tested for PD-L1 expression. Thirteen (14.1%) of the TNBC cases were PDL1 positive to varying degrees on tumour and immune cells. Diffuse tumoural PD-L1 staining was seen in 4 (30.8%) of the PD-L1 positive cases. PD-L1 expression was significantly associated with increasing age up to the fifth decade (p =0.030). All the PD-L1 positive TNBC were invasive breast carcinoma of no special type and mostly grade 2 tumours; however, there was no significant association between PD-L1 expression and histological subtype or grade. PD-L1 expression was shown to occur at a relatively low rate among TNBC cases in this environment and was significantly associated with increasing age. This study has shown that 14.1% (1 in 7) of our TNBC patients could benefit from immune checkpoint inhibitor therapy.


IL-6 amplifier, NF-κB-triggered positive feedback for IL-6 signaling, in grafts is involved in allogeneic rejection responses.
The IL-6-amplifier first was discovered as a synergistic activation mechanism for NF-κB/STAT3 in type 1 collagen(+) cells. This process is marked by the hyperinduction of chemokines and subsequent local inflammation that leads to autoimmune diseases. In this study, we show that IL-6 amplifier activation in grafts plays important roles in allogeneic graft rejection by using a tracheal heterotopic transplantation model that includes bronchiolitis obliterans, a pathological marker for chronic rejection. IL-6, epidermal growth factor, and IFN-γ all stimulate IL-6 amplifier activation, whereas CCL2, a chemotactic factor for Th1 cells, was one of the amplifier's main targets. Interestingly, IFN-γ hyperinduced CCL2 in type 1 collagen(+) cells via the IL-6 amplifier at least in vitro. In addition, we detected IL-6, CCL2, phospho-STAT3, and phospho-NF-κB in epithelial type 1 collagen(+) cells of allogeneic tracheal grafts. These results show that IL-6 amplifier activation in grafts plays a critical role for graft rejection responses after allogeneic transplantation, including chronic rejection. From these results, we consider whether the IL-6 amplifier in grafts might be a valuable therapeutic target for the prevention of transplant rejection, including chronic rejection.


Likes Attract: The Sociopolitical Groupthink of (Social) Psychologists.
Inbar and Lammers (2012, this issue) contribute to the growing empirical evidence of discrimination against conservative (i.e., right-of-center) people and ideas not only in social and personality psychology, but within the academy generally. Because sociopolitical values are often a core component of self-identity that significantly impact our interpersonal relationships, sociopolitical discrimination is difficult to overcome. There is a tendency to marginalize the sociopolitical "other," along with a groupthink that implicitly presupposes that this form of discrimination is acceptable (e.g., because conservatives are self-interestedly motivated, conservative ideas are incorrect, or conservatism is well represented elsewhere in society and thus need not be in the academy). Yet discrimination must be overcome because sociopolitical diversity is vital for scholarly inquiry, pedagogy, and for ethical professional practice. Recent research suggests that the assumptions underlying psychology's value system of promoting racial, ethnic, gender, or sexual orientation diversity-that is, that doing so recognizes people's personal identities, ameliorates discrimination, and has educational benefits-may be all the more compelling with respect to sociopolitical ideas.


A cost analysis of web-enhanced training to reduce alcohol sales to intoxicated bar patrons.
The purpose of this study was to document the development and testing costs of the Enhanced Alcohol Risk Management (eARM) intervention, a web enhanced training program to prevent alcohol sales to intoxicated bar patrons and to estimate its implementation costs in a "real world", non-research setting. Data for this study were obtained retrospectively from a randomized controlled trial of the eARM intervention, which was conducted across 15 communities in a Midwestern metropolitan area. Inputs and their costs were obtained from records maintained during the randomized controlled trial. Total development and testing costs were computed, and implementation costs were estimated with input from the research team. The average implementation cost per establishment was calculated by dividing the total estimated implementation cost by the number of establishments that participated in the study. This provides an estimate of the resources needed to support a broader dissemination of interventions such as eARM. Direct development and testing costs were $484,904. Including the University's overhead cost rate of 51 percent, total development and testing costs were $732,205. Total estimated implementation costs were $179,999 over a 12 month period. The average cost per establishment was $1,588. Given the large damage liability awards faced by establishments that serve alcohol to drunk drivers, establishments or their insurance companies may be willing to pay the $1,588 estimated implementation cost in order to limit their exposure to these large damage awards. Therefore, making interventions such as eARM available could be an effective and sustainable policy for reducing alcohol-related incidents.