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"text": "\n2401\nSpecific cutaneous infiltrates in patients with myelogenous leukemia: a clinicopathologic study of 26 patients with assessment of diagnostic criteria.\n\nKaddu, S\n\nZenahlik, P\n\nBeham-Schmid, C\n\nKerl, H\n\nCerroni, L\n\nBeiträge in Fachzeitschriften\nISI:000080638700012\n10365929.0\n10.1016/S0190-9622(99)70086-1\nNone\nBACKGROUND: Few recent studies have analyzed the clinicopathologic features of specific cutaneous manifestations of myelogenous leukemia in a large number of patients. OBJECTIVE: We characterize the clinical and histopathologic spectrum of specific cutaneous manifestations in acute (AML) and chronic (CML) myelogenous leukemia, ascertain further diagnostic criteria, and examine current prognosis. METHODS: Thirty-six lesions of specific cutaneous infiltrates from 26 patients with myelogenous leukemia (AML: 17 patients; M:F = 1:2.4; mean age: 52.6 years; AML-French-American-British [FAB] classification subtypes:M1 = 1, M2 = 3, M4 = 8, M5 = 5. CML = 9 patients; M:F = 4.5:1; mean age: 60.6 years) were retrospectively collected for the study. RESULTS: Cutaneous manifestations presented as solitary or multiple reddish to violaceous papules, plaques, and nodules (17 lesions), or as a generalized erythematous maculopapular eruption (9 lesions). Concurrent extramedullary involvement in other peripheral sites (eg, gums, pharynx, orbits) was observed in 10 patients. Histopathologically, lesions revealed nodular/diffuse infiltrates, often with perivascular and periadnexal accentuation, sparing of the upper papillary dermis, and prominent single arraying of neoplastic cells between collagen bundles. Extension to the subcutis was noted in all deep biopsy specimens (26 lesions). Cytomorphologically, medium to large-sized mononuclear cells (myeloblasts and atypical myelocytes) predominated in AML-M1 and M2, whereas M4 and M5 mainly showed small, medium-sized, or large mononuclear cells with slightly eosinophilic cytoplasm and indented, bi-lobular, or kidney-shaped nuclei (atypical monocytoid cells). In CML, either a variable mixture of mature and immature cells of the granulocytic series (myelocytes, metamyelocytes, eosinophilic metamyelocytes, and neutrophils) or a rather monomorphous infiltrate of mononuclear cells were found. Staining for naphthol AS-D chloroacetate-esterase (NASD) was positive in 24 of 36 lesions (66.6%; AML: 16; CML: 8). Immunohistochemical analysis on paraffin sections using a large panel of antibodies (16 lesions: AML: 13; CML: 3) showed strong reactivity for LCA (CD45), lysozyme, myeloperoxidase (MPD), LN2 (CD74), HLA-DR, and MT1 (CD43) in the majority of cases, and variable staining for monocyte/macrophage markers (KP1/CD68, PGM1/CD68, Mac387, Ki-M1p). The neuronal cell adhesion molecule (NCAM) marker CD56 was reactive in 2 cases of CML, but negative in all cases of AML. MIB1(Ki67) stained 20% to 80% of neoplastic cells. CD34, CD15, CD20, and CD3 were negative in all cases. No correlation between histochemical/immunohistochemical features with type of leukemia or FAB-subtype of AML was observed. All patients with CML and AML with adequate follow-up died within 24 months after onset of skin lesions (mean survival, AML: 7.6 months; CML: 9.4 months). CONCLUSION: Specific cutaneous lesions in AML and CML show distinctive clinicopathologic features that allow diagnosis in most cases. Immunohistochemistry on routinely fixed, paraffin-embedded tissue sections provides useful adjunctive information. Simultaneous expression of lysozyme, MPD, CD45, CD43, and CD74 militates in favor of a diagnosis of specific cutaneous infiltrate of myelogenous leukemia. Pitfalls in immunohistologic diagnosis mainly include lack of expression of some myeloid markers (lysozyme, MPD), and aberrant expression of T-cell markers (eg, CD45RO). Regardless of type of myelogenous leukemia, onset of specific skin manifestations correlates with an aggressive course and short survival.\n\nBeham-Schmid, Christine\n\nCerroni, Lorenzo\n\nKaddu, Steven\n\nKerl, Helmut\n\n\n"
},
{
"text": "\n3798\nThe carcinostatic and proapoptotic potential of 4-hydroxynonenal in HeLa cells is associated with its conjugation to cellular proteins.\n\nSovic, A\n\nBorovic, S\n\nLoncaric, I\n\nKreuzer, T\n\nZarkovic, K\n\nVukovic, T\n\nWäg, G\n\nHrascan, R\n\nWintersteiger, R\n\nKlinger, R\n\nZurak, N\n\nSchaub, RJ\n\nZarkovic, N\n\nBeiträge in Fachzeitschriften\nISI:000170276600045\n11497289.0\nNone\nNone\nBACKGROUND: Previous studies have shown that the lipid peroxidation product 4-hydroxynonenal (HNE) acts as a cell growth modulator if used at low, physiological concentrations being strongly cytotoxic at higher concentrations for a number of cells. These effects of HNE also appeared to be mutually dependent on the effects of serum growth factors. The aim of this investigation was to study the concentration-dependent response of human cervical carcinoma (HeLa) cells in vitro with respect to the intracellular uptake of exogenous HNE, the cellular energy metabolism, DNA synthesis, overall gene expression and susceptibility to apoptosis. MATERIALS AND METHODS: MTT assay was applied as an index of energy metabolism and the replicative activity was quantitated by the 3H-thymidine incorporation assay. The occurence and intracellular distribution was studied with monoclonal antibodies directed against HNE-protein conjugates. Binding of HNE to serum proteins was determined with the same antibodies by Western blotting. Differential gene expression was studied by differential display RT-PCR while a novel photometric assay, denoted Titer-TACS, was used for in situ detection and quantitation of apoptosis in monolayer cell cultures. RESULTS: A physiological concentration of HNE (1 microM) had hardly any effect on the parameters of the replicative activity and the energy metabolism. No morphological changes were observed and the number of HNE-positive cells was not significantly different when compared to the untreated control cells, while most of the aldehyde appeared to be bound to serum proteins (albumin fraction). A ten-fold higher concentration (10 microM) was found to be cytostatic. Spindle-shaped cells with a picnotic nucleus were observed occasionally, as well as membrane blebs, which were HNE-positive. The number of HNE-positive cells was significantly increased compared both to the control cells and cells treated with 1 microM HNE, but in the presence of serum the effects of 10 microM HNE were negated due to its binding to the serum proteins. Finally, 100 microM HNE was cytotoxic for the HeLa cells. Most of the cells were picnotic, together with a few spindle-shaped or oval cells. The staining for HNE was diffuse and strong (90% of the cells were HNE-positive) while even binding of the aldehyde to serum proteins did not prevent its cytotoxic effects. This concentration of HNE caused acute stress response of the cells resulting in the decreased expression of several as yet unidentified genes. The altered pattern of gene expression was followed by programmed cell death, i.e. an increased number of apoptotic cells after treatment with low (1 and 10 microM) concentrations of HNE. A rebound effect was observed, i.e. a decrease of apoptotic cells after 24 hours followed by an overshooting increase after 48 hours. CONCLUSIONS: For HeLa carcinoma cells there appears to be a concentration range of HNE where it does not cause necrosis but preferentially apoptosis. At this concentration range HNE is cytochemically detectable within the cells as a protein conjugate. It is proposed that a possible differential sensitivity of cancer cells and their normal counterparts to the cytostatic activity of HNE should be explored.\n\n\n"
},
{
"text": "\n111393\nFirst-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial.\n\nPENPACT-1 (PENTA 9/PACTG 390) Study Team\n\nBabiker, A\n\nCastro nee Green, H\n\nCompagnucci, A\n\nFiscus, S\n\nGiaquinto, C\n\nGibb, DM\n\nHarper, L\n\nHarrison, L\n\nHughes, M\n\nMcKinney, R\n\nMelvin, A\n\nMofenson, L\n\nSaidi, Y\n\nSmith, ME\n\nTudor-Williams, G\n\nWalker, AS\n\nBeiträge in Fachzeitschriften\nISI:000289275600015\n21288774.0\n10.1016/S1473-3099(10)70313-3\nPMC3111069\nChildren with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children.\n In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30, 00 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385.\n Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30, 00 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30, 00 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups.\n Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low.\n Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).\n Copyright © 2011 Elsevier Ltd. All rights reserved.\n\nZenz, Werner\n\n\n"
},
{
"text": "\n157118\nTachykinin receptor inhibition and c-Fos expression in the rat brain following formalin-induced pain.\n\nBaulmann, J\n\nSpitznagel, H\n\nHerdegen, T\n\nUnger, T\n\nCulman, J\n\nBeiträge in Fachzeitschriften\nISI:000084664100019\n10670449.0\nNone\nNone\nRecent pharmacological evidence has implicated substance P and neurokinin A, natural ligands for neurokinin-1 and neurokinin-2 receptors, respectively, as neurotransmitters in brain neuronal circuits activated upon noxious stimulation. The expression of the inducible transcription factor, c-Fos, was used to identify areas in the brain activated by a noxious stimulus (the subcutaneous injection of formalin), and to investigate the effects of intracerebroventricular administration of selective, nonpeptide antagonists for neurokinin-1 and neurokinin-2 tachykinin receptors on the neural activity in these areas and on the behavioural response to formalin-induced pain. Formalin (5%, 50 microl), injected subcutaneously through a chronically implanted catheter in the region of the lower hindlimb, increased c-Fos expression in a number of brain areas related to nociceptive transmission or the integration of stress responses. Grooming behaviour, licking and biting directed to the injected site, was the most frequent behavioural response. Intracerebroventricular pretreatment of rats with either RP 67580 (500 pmol), the active enantiomer of a neurokinin-1 receptor antagonist, or with SR 48968 (500 pmol), the active enantiomer of a neurokinin-2 receptor antagonist, reduced the formalin-induced c-Fos staining in the prefrontal cortex, dorsomedial and ventromedial nuclei of the hypothalamus, the locus coeruleus and the periaqueductal gray. The neurokinin-1, but not the neurokinin-2, receptor antagonist attenuated the formalin-induced activation of c-Fos in the paraventricular nucleus of the hypothalamus. Simultaneous intracerebroventricular pretreatment with both neurokinin-1 and neurokinin-2 receptor antagonists did not produce any additional inhibitory effect on the post-formalin c-Fos expression. None of the tachykinin receptor antagonists had an effect on the formalin-induced c-Fos expression in the septohypothalamic nucleus, medial thalamus, parabrachial nucleus and central amygdaloid nucleus, indicating that neurotransmitters other than neurokinins are most probably responsible for the activation of these areas in response to noxious stimulation. While both tachykinin receptor antagonists reduced the grooming behaviour to formalin, the neurokinin-1 receptor antagonist was clearly more effective than the neurokinin-2 receptor antagonist. Intracerebroventricular pretreatment of rats with the inactive enantiomers of the tachykinin receptor antagonists, RP 68651 and SR 48965, was without effect. Our results show that (i) the modified formalin test elicited an intense grooming behaviour and expression of c-Fos in numerous forebrain and brainstem areas, (ii) both tachykinin receptor antagonists were able to attenuate the behavioural response to pain and to reduce the formalin-induced c-Fos expression in some, but not all, brain areas, and (iii) the neurokinin-1 antagonist, RP 67580, was more effective in inhibiting the behavioural response to formalin and the pain-induced activation of c-Fos than the antagonist for neurokinin-2 receptors, SR 48968, indicating that neurokinin-1 receptors are preferentially activated in neurokinin-containing pathways responding to noxious stimuli. Our results demonstrate that blockade of brain tachykinin receptors, especially of the neurokinin-1 receptor, reduces the behavioural response to pain and the pain-induced c-Fos activation in distinct brain areas which are intimately linked with nociceptive neurotransmission and the initiation and integration of central stress responses. Together with the previous findings of the inhibition of hypertensive and tachycardic responses to pain, the present data indicate that tachykinin receptor antagonists can effectively inhibit the generation of an integrated cardiovascular and behavioural response pattern to noxious stimuli.\n\n\n"
},
{
"text": "\n163384\nHow frequent is osteogenesis imperfecta in patients with idiopathic osteoporosis?: Case reports (vol 96, e7863, 2017)\n\nWindpassingers, C\n\nBeiträge in Fachzeitschriften\nISI:000410887400070\n28858097.0\n10.1097/MD.0000000000008141\nPMC5585491\nThe term idiopathic osteoporosis itself is quite a non-specific disease label, which fails to address the etiological understanding. Bone mineral density alone is not a reliable parameter to detect patients at high risk of fracture. The diversity of the clinical phenotypes of discolored teeth, blueness of the sclera, back and joint pain, cardiovascular disease, Diabetes type II, hearing problems and a long list of orthopedic problems are have to be considered.\n Our study has been designed in accordance with the clinical and radiological phenotype of eleven index cases with the provisional diagnosis of OI, which was followed by genotypic confirmation. This was followed by the invitation of siblings, parents, grandparents and other relatives to participate in the interviews, and to discuss the impact of the diagnosis. Proper collaboration with these families facilitated the process to identify other subjects with a history of fractures and other deformities/disabilities which were seemingly correlated to heritable connective tissue disorder. In total, 63 patients (27 children and 36 parents/grandparents and relatives) were enrolled in the study. Two groups of children were not included in our study. We excluded children with incomplete documentation and children who manifested de novo mutation. The term idiopathic osteoporosis (IOP) has been given to these families in other Institutes and was considered as a definite diagnosis. IOP was solely based on T scores, BMD and certain laboratory tests. Surprisingly, no single adult patient underwent clinical and or radiological phenotypic characterization.\n A constellation of significant disease associations with osteoporotic fracture risk have been encountered. The index cases showed mutations in COL1A1 (17q21.31.q22) and COL1A2 (7q22.1), the genes encoding collagen type I. The phenotype/genotype confirmation in 11 children was the key factor to boost our research and to re-consult each family. Comprehensive clinical and radiological phenotypic documentation has been applied to most of other family subjects who principally received the diagnosis of IOP.\n All adult patients had normal serum calcium and only three patients showed an average of low serum phosphate of 0.7-0.61 mmol/l. Serumcrosslaps in six parents was in the average of (2.9-3.8 nM) and PTH levels were normal in all patients (the average showed 8.73 pg/ml).\n Our efforts to minimize and constrain the usage of the term idiopathic osteoporosis and to understand the sequence of pathological events that occurred in these families were emphasized. These efforts evolved into a remarkable and unique constellation of clinical findings. Strikingly, fracture represented a portion in a series of skeletal and extra-skeletal deformities and abnormalities which are all correlated to connective tissue disorder. This was achieved mainly through comprehensive phenotype/genotype confirmation, followed by scrutinizing the records of each family, clinical examination of the adults and revising the archives of our Hospitals and other Institutes.\n The sequence of diverse pathological events recorded within each family would be almost incomprehensible without a proper etiological understanding of the natural history of each child/family deformity that led to their occurrences. We wish to stress that, our current study is just an attempt to cover only a tiny fraction of the tip of the iceberg and to profoundly explore one of the most under-estimated causes of idiopathic osteoporosis.\n\nWindpassinger, Christian\n\n\n"
},
{
"text": "\n183628\nThe burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017.\n\nDeuschl, G\n\nBeghi, E\n\nFazekas, F\n\nVarga, T\n\nChristoforidi, KA\n\nSipido, E\n\nBassetti, CL\n\nVos, T\n\nFeigin, VL\n\nBeiträge in Fachzeitschriften\nISI:000576842600012\n33007212.0\n10.1016/S2468-2667(20)30190-0\nNone\nNeurological disorders account for a large and increasing health burden worldwide, as shown in the Global Burden of Diseases (GBD) Study 2016. Unpacking how this burden varies regionally and nationally is important to inform public health policy and prevention strategies. The population in the EU is older than that of the WHO European region (western, central, and eastern Europe) and even older than the global population, suggesting that it might be particularly vulnerable to an increasing burden of age-related neurological disorders. We aimed to compare the burden of neurological disorders in the EU between 1990 and 2017 with those of the WHO European region and worldwide.\n The burden of neurological disorders was calculated for the year 2017 as incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability for the countries in the EU and the WHO European region, totally and, separately. Diseases analysed were Alzheimer's disease and other dementias, epilepsy, headache (migraine and tension-type headache), multiple sclerosis, Parkinson's disease, brain cancer, motor neuron diseases, neuroinfectious diseases, and stroke. Data are presented as totals and by sex, age, year, location and socio-demographic context, and shown as counts and rates.\n In 2017, the total number of DALYs attributable to neurological disorders was 21·0 million (95% uncertainty interval 18·5-23·9) in the EU and 41·1 million (36·7-45·9) in the WHO European region, and the total number of deaths was 1·1 million (1·09-1·14) in the EU and 1·97 million (1·95-2·01) in the WHO European region. In the EU, neurological disorders ranked third after cardiovascular diseases and cancers representing 13·3% (10·3-17·1) of total DALYs and 19·5% (18·0-21·3) of total deaths. Stroke, dementias, and headache were the three commonest causes of DALYs in the EU. Stroke was also the leading cause of DALYs in the WHO European region. During the study period we found a substantial increase in the all-age burden of neurodegenerative diseases, despite a substantial decrease in the rates of stroke and infections. The burden of neurological disorders in Europe was higher in men than in women, peaked in individuals aged 80-84 years, and varied substantially with WHO European region and country. All-age DALYs, deaths, and prevalence of neurological disorders increased in all-age measures, but decreased when using age-standardised measures in all but three countries (Azerbaijan, Turkmenistan, and Uzbekistan). The decrease was mostly attributed to the reduction of premature mortality despite an overall increase in the number of DALYs.\n Neurological disorders are the third most common cause of disability and premature death in the EU and their prevalence and burden will likely increase with the progressive ageing of the European population. Greater attention to neurological diseases must be paid by health authorities for prevention and care. The data presented here suggest different priorities for health service development and resource allocation in different countries.\n European Academy of Neurology.\n Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.\n\nFazekas, Franz\n\n\n"
},
{
"text": "\n170051\nFUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease.\n\nNovak, P\n\nSchmidt, R\n\nKontsekova, E\n\nKovacech, B\n\nSmolek, T\n\nKatina, S\n\nFialova, L\n\nPrcina, M\n\nParrak, V\n\nDal-Bianco, P\n\nBrunner, M\n\nStaffen, W\n\nRainer, M\n\nOndrus, M\n\nRopele, S\n\nSmisek, M\n\nSivak, R\n\nZilka, N\n\nWinblad, B\n\nNovak, M\n\nBeiträge in Fachzeitschriften\nISI:000448240400001\n30355322.0\n10.1186/s13195-018-0436-1\nPMC6201586\nNeurofibrillary pathology composed of tau protein is closely correlated with severity and phenotype of cognitive impairment in patients with Alzheimer's disease and non-Alzheimer's tauopathies. Targeting pathological tau proteins via immunotherapy is a promising strategy for disease-modifying treatment of Alzheimer's disease. Previously, we reported a 24-week phase 1 trial on the active vaccine AADvac1 against pathological tau protein; here, we present the results of a further 72 weeks of follow-up on those patients.\n We did a phase 1, 72-week, open-label study of AADvac1 in patients with mild to moderate Alzheimer's disease who had completed the preceding phase 1 study. Patients who were previously treated with six doses of AADvac1 at monthly intervals received two booster doses at 24-week intervals. Patients who were previously treated with only three doses received another three doses at monthly intervals, and subsequently two boosters at 24-week intervals. The primary objective was the assessment of long-term safety of AADvac1 treatment. Secondary objectives included assessment of antibody titres, antibody isotype profile, capacity of the antibodies to bind to AD tau and AADvac1, development of titres of AADvac1-induced antibodies over time, and effect of booster doses; cognitive assessment via 11-item Alzheimer's Disease Assessment Scale cognitive assessment (ADAS-Cog), Category Fluency Test and Controlled Oral Word Association Test; assessment of brain atrophy via magnetic resonance imaging (MRI) volumetry; and assessment of lymphocyte populations via flow cytometry.\n The study was conducted between 18 March 2014 and 10 August 2016. Twenty-six patients who completed the previous study were enrolled. Five patients withdrew because of adverse events. One patient was withdrawn owing to noncompliance. The most common adverse events were injection site reactions (reported in 13 [50%] of vaccinated patients). No cases of meningoencephalitis or vasogenic oedema were observed. New micro-haemorrhages were observed only in one ApoE4 homozygote. All responders retained an immunoglobulin G (IgG) antibody response against the tau peptide component of AADvac1 over 6 months without administration, with titres regressing to a median 15.8% of titres attained after the initial six-dose vaccination regimen. Booster doses restored previous IgG levels. Hippocampal atrophy rate was lower in patients with high IgG levels; a similar relationship was observed in cognitive assessment.\n AADvac1 displayed a benign safety profile. The evolution of IgG titres over vaccination-free periods warrants a more frequent booster dose regimen. The tendency towards slower atrophy in MRI evaluation and less of a decline in cognitive assessment in patients with high titres is encouraging. Further trials are required to expand the safety database and to establish proof of clinical efficacy of AADvac1.\n The studies are registered with the EU Clinical Trials Register and ClinicalTrials.gov : the preceding first-in-human study under EudraCT 2012-003916-29 and NCT01850238 (registered on 9 May 2013) and the follow-up study under EudraCT 2013-004499-36 and NCT02031198 (registered 9 Jan 2014), respectively.\n\nRopele, Stefan\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n183404\nPatient-reported outcome of surgical treatment for lumbar spinal epidural lipomatosis.\n\nFerlic, PW\n\nMannion, AF\n\nJeszenszky, D\n\nPorchet, F\n\nFekete, TF\n\nKleinstück, F\n\nHaschtmann, D\n\nBeiträge in Fachzeitschriften\nISI:000387483500022\n27363757.0\n10.1016/j.spinee.2016.06.022\nNone\nSpinal epidural lipomatosis (SEL) is a rare condition characterized by an excessive accumulation of fat tissue in the spinal canal that can have a compressive effect, leading to clinical symptoms. This condition has a distinct pathology from spinal stenosis associated with degeneration of the intervertebral discs, ligaments, and facet joints. Several different conservative and surgical treatment strategies have been proposed for SEL, but its treatment remains controversial. There is a lack of evidence documenting the success of surgical decompression in SEL, and no previous studies have reported the postoperative outcome from the patient's perspective.\n The aim of the present study was to evaluate patient-rated outcome after surgical decompression in SEL.\n A retrospective analysis of prospectively collected data was carried out.\n A total of 22 patients (19 males; age: 68.2±9.9 years) who had undergone spine surgery for SEL were identified from our local Spine Surgery Outcomes Database, which includes a total of 10, 28 spine surgeries recorded between 2005 and 2012. Inclusion criteria were epidural lipomatosis confirmed by preoperative magnetic resonance imaging (MRI) scans and subsequent decompression surgery without spinal fusion.\n The Core Outcome Measures Index (COMI) was used to assess patient-rated outcome. The COMI includes the domains pain (separate 0-10 scales for back and leg pain), back-specific function, symptom-specific well-being, general quality of life (QOL), work disability, and social disability.\n The questionnaires were completed preoperatively and at 3, 12, and 24 months postoperatively. Surgical data were retrieved from the patient charts and from our local Spine Surgery Outcomes Database, which we operate in connection with the International Spine Tango Registry. Differences between pre- and postoperative scores were analyzed using paired t tests and repeated measures analysis of variance.\n At 3-months follow-up, the COMI score and scores for leg pain and back pain had improved significantly compared with their preoperative values (p<.005). The mean decrease in COMI score after 3 months was 2.6±2.4 (range: -1.3 to 6.5) points: from 7.5±1.7 (range: 3.5-10) to 4.9±2.5 (range: 0.5-9.6). A total of 11 patients (50%) had an improvement of the COMI of more than the minimal clinically important change (MCIC) score of 2.2 points. The mean decrease in leg pain after 3 months was 2.4±3.5 (-5 to 10) points. Overall, 17 patients (77.3%) reported a reduced leg pain, 12 (54.6%) of whom by at least the MCIC score of 2 points. The significant reductions from baseline in COMI and leg and back pain scores were retained up to 2 years postoperatively (p<.02). The general QOL item of the COMI improved significantly after surgery (p<.0001). Over 80% of the cohort rated their preoperative QOL as bad (n=13) or very bad (n=5), whereas 3 months after surgery, only 7 patients rated their QOL as bad, and one as very bad (36%).\n The present study is the first to demonstrate that surgical decompression is associated with a statistically significant improvement in patient-rated outcome scores in patients with symptomatic SEL, with a clinically relevant change occurring in approximately half of them. Surgical decompression hence represents a reasonable treatment option for SEL, although the reason behind the less good response in some patients needs further investigation.\n Copyright © 2016 Elsevier Inc. All rights reserved.\n\nFerlic, Peter\n\n\n"
},
{
"text": "\n176095\nEuropean Society of Coloproctology Core Outcome Set for haemorrhoidal disease: an international Delphi study among healthcare professionals.\n\nvan Tol, RR\n\nKimman, ML\n\nMelenhorst, J\n\nStassen, LPS\n\nDirksen, CD\n\nBreukink, SO\n\nMembers of the Steering Group\n\nBeiträge in Fachzeitschriften\nISI:000471299500009\n30628177.0\n10.1111/codi.14553\nNone\nThere is considerable heterogeneity in outcomes in studies reporting on the treatment of haemorrhoidal disease (HD). The aim of this study was to develop a Core Outcome Set (COS) for HD in cooperation with the European Society of Coloproctology.\n A Delphi study was performed according to the Outcome Measures in Rheumatology (OMERACT) methodology. In total 38 healthcare professionals and 30 patients were invited to the panel. Previously, 10 outcome domains and 59 outcomes were identified through a systematic literature review. In this study, these domains and outcomes were formed into one questionnaire for healthcare professionals and a separate questionnaire for patients. Sequential questionnaire rounds prioritizing the domains and outcomes were conducted. Panel members were asked to rate the appropriateness of each domain and outcome on a nine-point Likert scale. During a face-to-face meeting, healthcare professionals agreed on the primary and secondary end-points of the COS for HD. Finally, a short survey was sent to the healthcare professionals in order to reach consensus on how the chosen end-points should be assessed and at which time points.\n The response rate in questionnaire round 1 for healthcare professionals was 44.7% (n = 17). Sixteen out of 17 healthcare professionals also completed the questionnaire in round 2. The response rate for the patient questionnaire was 60% (n = 18). Seventeen healthcare professionals participated in the face-to-face meeting. The questionnaire rounds did not result in a clear-cut selection of primary and secondary end-points. Most domains and outcomes were considered important, and only three outcomes were excluded. During the face-to-face meeting, agreement was reached to select the domain 'symptoms' as primary end-point, and 'complications', 'recurrence' and 'patient satisfaction' as secondary end-points in the COS for HD. Furthermore, consensus was reached that the domain 'symptoms' should be a patient reported outcome measure and should include the outcomes 'pain' and 'prolapse', 'itching', 'soiling' and 'blood loss'. The domain 'complications' should include the outcomes 'incontinence', 'abscess', 'urinary retention', 'anal stenosis' and 'fistula'. Consensus was reached to use 'reappearance of initial symptoms' as reported by the patient to define recurrence. During an additional short survey, consensus was reached that 'incontinence' should be assessed by the Wexner Fecal Incontinence Score, 'abscess' by physical examination, 'urinary retention' by ultrasonography, 'anal stenosis' by physical examination, and 'fistula' by physical examination and MR imaging if inconclusive. During follow-up, the outcome 'symptoms' should be assessed at baseline, 7 days, 6 weeks and 1 year post-procedure. The outcomes 'abscess' and 'urinary retention' should be assessed 7 days post-procedure and 'incontinence', 'anal stenosis' and 'fistula' 1 year post-procedure.\n We developed the first European Society of Coloproctology COS for HD based on an international Delphi study among healthcare professionals. The next step is to incorporate the patients' perspective in the COS. Use of this COS may improve the quality and uniformity of future research and enhance the analysis of evidence.\n Colorectal Disease © 2019 The Association of Coloproctology of Great Britain and Ireland.\n\nLemmerer, Martina\n\n\n"
},
{
"text": "\n164072\nIncomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis\n\nArbyn, M\n\nRedman, CWE\n\nVerdoodt, F\n\nKyrgiou, M\n\nTzafetas, M\n\nGhaem-Maghami, S\n\nPetry, KU\n\nLeeson, S\n\nBergeron, C\n\nNieminen, P\n\nGondry, J\n\nReich, O\n\nMoss, EL\n\nBeiträge in Fachzeitschriften\nISI:000417001900044\n29126708.0\n10.1016/S1470-2045(17)30700-3\nNone\nIncomplete excision of cervical precancer is associated with therapeutic failure and is therefore considered as a quality indicator of clinical practice. Conversely, the risk of preterm birth is reported to correlate with size of cervical excision and therefore balancing the risk of adequate treatment with iatrogenic harm is challenging. We reviewed the literature with an aim to reveal whether incomplete excision, reflected by presence of precancerous tissue at the section margins, or post-treatment HPV testing are accurate predictors of treatment failure.\n We did a systematic review and meta-analysis to assess the risk of therapeutic failure associated with the histological status of the margins of the tissue excised to treat cervical precancer. We estimated the accuracy of the margin status to predict occurrence of residual or recurrent high-grade cervical intraepithelial neoplasia of grade two or worse (CIN2+) and compared it with post-treatment high-risk human papillomavirus (HPV) testing. We searched for published systematic reviews and new references from PubMed-MEDLINE, Embase, and CENTRAL and did also a new search spanning the period Jan 1, 1975, until Feb 1, 2016. Studies were eligible if women underwent treatment by excision of a histologically confirmed CIN2+ lesion, with verification of presence or absence of CIN at the resection margins; were tested by cytology or HPV assay between 3 months and 9 months after treatment; and had subsequent follow-up of at least 18 months post-treatment including histological confirmation of the occurrence of CIN2+. Primary endpoints were the proportion of positive section margins and the occurrence of treatment failure associated with the marginal status, in which treatment failure was defined as occurrence of residual or recurrent CIN2+. Information about positive resection margins and subsequent treatment failure was pooled using procedures for meta-analysis of binomial data and analysed using random-effects models.\n 97 studies were eligible for inclusion in the meta-analysis and included 44 446 women treated for cervical precancer. The proportion of positive margins was 23·1% (95% CI 20·4-25·9) overall and varied by treatment procedure (ranging from 17·8% [12·9-23·2] for laser conisation to 25·9% [22·3-29·6] for large loop excision of the transformation zone) and increased by the severity of the treated lesion. The overall risk of residual or recurrent CIN2+ was 6·6% (95% CI 4·9-8·4) and was increased with positive compared with negative resection margins (relative risk 4·8, 95% CI 3·2-7·2). The pooled sensitivity and specificity to predict residual or recurrent CIN2+ was 55·8% (95% CI 45·8-65·5) and 84·4% (79·5-88·4), respectively, for the margin status, and 91·0% (82·3-95·5) and 83·8% (77·7-88·7), respectively, for high-risk HPV testing. A negative high-risk HPV test post treatment was associated with a risk of CIN2+ of 0·8%, whereas this risk was 3·7% when margins were free.\n The risk of residual or recurrent CIN2+ is significantly greater with involved margins on excisional treatment; however, high-risk HPV post-treatment predicts treatment failure more accurately than margin status.\n European Federation for Colposcopy and Institut national du Cancer (INCA).\n Copyright © 2017 Elsevier Ltd. All rights reserved.\n\nReich, Olaf\n\n\n"
},
{
"text": "\n131352\nCommon variants in Mendelian kidney disease genes and their association with renal function.\n\nParsa, A\n\nFuchsberger, C\n\nKöttgen, A\n\nO'Seaghdha, CM\n\nPattaro, C\n\nde Andrade, M\n\nChasman, DI\n\nTeumer, A\n\nEndlich, K\n\nOlden, M\n\nChen, MH\n\nTin, A\n\nKim, YJ\n\nTaliun, D\n\nLi, M\n\nFeitosa, M\n\nGorski, M\n\nYang, Q\n\nHundertmark, C\n\nFoster, MC\n\nGlazer, N\n\nIsaacs, A\n\nRao, M\n\nSmith, AV\n\nO'Connell, JR\n\nStruchalin, M\n\nTanaka, T\n\nLi, G\n\nHwang, SJ\n\nAtkinson, EJ\n\nLohman, K\n\nCornelis, MC\n\nJohansson, A\n\nTönjes, A\n\nDehghan, A\n\nCouraki, V\n\nHolliday, EG\n\nSorice, R\n\nKutalik, Z\n\nLehtimäki, T\n\nEsko, T\n\nDeshmukh, H\n\nUlivi, S\n\nChu, AY\n\nMurgia, F\n\nTrompet, S\n\nImboden, M\n\nKollerits, B\n\nPistis, G\n\nHarris, TB\n\nLauner, LJ\n\nAspelund, T\n\nEiriksdottir, G\n\nMitchell, BD\n\nBoerwinkle, E\n\nSchmidt, H\n\nHofer, E\n\nHu, F\n\nDemirkan, A\n\nOostra, BA\n\nTurner, ST\n\nDing, J\n\nAndrews, JS\n\nFreedman, BI\n\nGiulianini, F\n\nKoenig, W\n\nIllig, T\n\nDöring, A\n\nWichmann, HE\n\nZgaga, L\n\nZemunik, T\n\nBoban, M\n\nMinelli, C\n\nWheeler, HE\n\nIgl, W\n\nZaboli, G\n\nWild, SH\n\nWright, AF\n\nCampbell, H\n\nEllinghaus, D\n\nNöthlings, U\n\nJacobs, G\n\nBiffar, R\n\nErnst, F\n\nHomuth, G\n\nKroemer, HK\n\nNauck, M\n\nStracke, S\n\nVölker, U\n\nVölzke, H\n\nKovacs, P\n\nStumvoll, M\n\nMägi, R\n\nHofman, A\n\nUitterlinden, AG\n\nRivadeneira, F\n\nAulchenko, YS\n\nPolasek, O\n\nHastie, N\n\nVitart, V\n\nHelmer, C\n\nWang, JJ\n\nStengel, B\n\nRuggiero, D\n\nBergmann, S\n\nKähönen, M\n\nViikari, J\n\nNikopensius, T\n\nProvince, M\n\nColhoun, H\n\nDoney, A\n\nRobino, A\n\nKrämer, BK\n\nPortas, L\n\nFord, I\n\nBuckley, BM\n\nAdam, M\n\nThun, GA\n\nPaulweber, B\n\nHaun, M\n\nSala, C\n\nMitchell, P\n\nCiullo, M\n\nVollenweider, P\n\nRaitakari, O\n\nMetspalu, A\n\nPalmer, C\n\nGasparini, P\n\nPirastu, M\n\nJukema, JW\n\nProbst-Hensch, NM\n\nKronenberg, F\n\nToniolo, D\n\nGudnason, V\n\nShuldiner, AR\n\nCoresh, J\n\nSchmidt, R\n\nFerrucci, L\n\nvan Duijn, CM\n\nBorecki, I\n\nKardia, SL\n\nLiu, Y\n\nCurhan, GC\n\nRudan, I\n\nGyllensten, U\n\nWilson, JF\n\nFranke, A\n\nPramstaller, PP\n\nRettig, R\n\nProkopenko, I\n\nWitteman, J\n\nHayward, C\n\nRidker, PM\n\nBochud, M\n\nHeid, IM\n\nSiscovick, DS\n\nFox, CS\n\nKao, WL\n\nBöger, CA\n\nBeiträge in Fachzeitschriften\nISI:000328817300021\n24029420.0\n10.1681/ASN.2012100983\nPMC3839542\nMany common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74, 54 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56, 46 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.\n\nHofer, Edith\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n187071\nAutomatic real-time analysis and interpretation of arterial blood gas sample for Point-of-care testing: Clinical validation.\n\nRodríguez-Villar, S\n\nPoza-Hernández, P\n\nFreigang, S\n\nZubizarreta-Ormazabal, I\n\nPaz-Martín, D\n\nHoll, E\n\nPérez-Pardo, OC\n\nTovar-Doncel, MS\n\nWissa, SM\n\nCimadevilla-Calvo, B\n\nTejón-Pérez, G\n\nMoreno-Fernández, I\n\nEscario-Méndez, A\n\nArévalo-Serrano, J\n\nValentín, A\n\nDo-Vale, BM\n\nFletcher, HM\n\nLorenzo-Fernández, JM\n\nBeiträge in Fachzeitschriften\nISI:000627854700067\n33690724.0\n10.1371/journal.pone.0248264\nPMC7946183\nPoint-of-care arterial blood gas (ABG) is a blood measurement test and a useful diagnostic tool that assists with treatment and therefore improves clinical outcomes. However, numerically reported test results make rapid interpretation difficult or open to interpretation. The arterial blood gas algorithm (ABG-a) is a new digital diagnostics solution that can provide clinicians with real-time interpretation of preliminary data on safety features, oxygenation, acid-base disturbances and renal profile. The main aim of this study was to clinically validate the algorithm against senior experienced clinicians, for acid-base interpretation, in a clinical context.\n We conducted a prospective international multicentre observational cross-sectional study. 346 sample sets and 64 inpatients eligible for ABG met strict sampling criteria. Agreement was evaluated using Cohen's kappa index, diagnostic accuracy was evaluated with sensitivity, specificity, efficiency or global accuracy and positive predictive values (PPV) and negative predictive values (NPV) for the prevalence in the study population.\n The concordance rates between the interpretations of the clinicians and the ABG-a for acid-base disorders were an observed global agreement of 84, % with a Cohen's kappa coefficient 0.81; 95% CI 0.77 to 0.86; p < 0.001. For detecting accuracy normal acid-base status the algorithm has a sensitivity of 90.0% (95% CI 79.9 to 95.3), a specificity 97.2% (95% CI 94.5 to 98.6) and a global accuracy of 95.9% (95% CI 93.3 to 97.6). For the four simple acid-base disorders, respiratory alkalosis: sensitivity of 91.2 (77.0 to 97.0), a specificity 100.0 (98.8 to 100.0) and global accuracy of 99.1 (97.5 to 99.7); respiratory acidosis: sensitivity of 61.1 (38.6 to 79.7), a specificity of 100.0 (98.8 to 100.0) and global accuracy of 98.0 (95.9 to 99.0); metabolic acidosis: sensitivity of 75.8 (59.0 to 87.2), a specificity of 99.7 (98.2 to 99.9) and a global accuracy of 97.4 (95.1 to 98.6); metabolic alkalosis sensitivity of 72.2 (56.0 to 84.2), a specificity of 95.5 (92.5 to 97.3) and a global accuracy of 93.0 (88.8 to 95.3); the four complex acid-base disorders, respiratory and metabolic alkalosis, respiratory and metabolic acidosis, respiratory alkalosis and metabolic acidosis, respiratory acidosis and metabolic alkalosis, the sensitivity, specificity and global accuracy was also high. For normal acid-base status the algorithm has PPV 87.1 (95% CI 76.6 to 93.3) %, and NPV 97.9 (95% CI 95.4 to 99.0) for a prevalence of 17.4 (95% CI 13.8 to 21.8). For the four-simple acid-base disorders and the four complex acid-base disorders the PPV and NPV were also statistically significant.\n The ABG-a showed very high agreement and diagnostic accuracy with experienced senior clinicians in the acid-base disorders in a clinical context. The method also provides refinement and deep complex analysis at the point-of-care that a clinician could have at the bedside on a day-to-day basis. The ABG-a method could also have the potential to reduce human errors by checking for imminent life-threatening situations, analysing the internal consistency of the results, the oxygenation and renal status of the patient.\n\nFreigang, Sascha\n\nHoll, Etienne\n\n\n"
},
{
"text": "\n184719\nPREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.\n\nTrebicka, J\n\nFernandez, J\n\nPapp, M\n\nCaraceni, P\n\nLaleman, W\n\nGambino, C\n\nGiovo, I\n\nUschner, FE\n\nJansen, C\n\nJimenez, C\n\nMookerjee, R\n\nGustot, T\n\nAlbillos, A\n\nBañares, R\n\nJarcuska, P\n\nSteib, C\n\nReiberger, T\n\nAcevedo, J\n\nGatti, P\n\nShawcross, DL\n\nZeuzem, S\n\nZipprich, A\n\nPiano, S\n\nBerg, T\n\nBruns, T\n\nDanielsen, KV\n\nCoenraad, M\n\nMerli, M\n\nStauber, R\n\nZoller, H\n\nRamos, JP\n\nSolé, C\n\nSoriano, G\n\nde Gottardi, A\n\nGronbaek, H\n\nSaliba, F\n\nTrautwein, C\n\nKani, HT\n\nFrancque, S\n\nRyder, S\n\nNahon, P\n\nRomero-Gomez, M\n\nVan Vlierberghe, H\n\nFrancoz, C\n\nManns, M\n\nGarcia-Lopez, E\n\nTufoni, M\n\nAmoros, A\n\nPavesi, M\n\nSanchez, C\n\nPraktiknjo, M\n\nCurto, A\n\nPitarch, C\n\nPutignano, A\n\nMoreno, E\n\nBernal, W\n\nAguilar, F\n\nClària, J\n\nPonzo, P\n\nVitalis, Z\n\nZaccherini, G\n\nBalogh, B\n\nGerbes, A\n\nVargas, V\n\nAlessandria, C\n\nBernardi, M\n\nGinès, P\n\nMoreau, R\n\nAngeli, P\n\nJalan, R\n\nArroyo, V\n\nPREDICT STUDY group of the EASL-CLIF CONSORTIUM\n\nBeiträge in Fachzeitschriften\nISI:000640696100013\n33227350.0\n10.1016/j.jhep.2020.11.019\nNone\nAcute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes.\n The multicenter, prospective, observational PREDICT study (NCT03056612) included 1, 73 non-electively hospitalized patients with AD (No ACLF = 1, 71; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome.\n Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality.\n This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis.\n Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.\n Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.\n\nStauber, Rudolf\n\n\n"
},
{
"text": "\n89324\nComparison of two insole materials using subjective parameters and pedobarography (pedar-system).\n\nPawelka, S\n\nKopf, A\n\nZwick, E\n\nBhm, T\n\nKranzl, A\n\nBeiträge in Fachzeitschriften\nNone\n11415703.0\nNone\nNone\nINTRODUCTION:: The objective of this trial was to investigate two commonly used insole materials prescribed for shock-absorption and cushioning concerning subjective and pedobarographic parameters. The design was prospective, controlled, randomized and single-blinded. MATERIAL AND METHODS:: A convenient sample of six healthy male adults without any history of leg or foot injury or pain wore -- in random order -- the custom-made insoles for one week. For both insoles the same base material (TEPEFON(R)) was used, insole 1 was covered with PLASTAZOTE(R) I, 3 mm, insole 2 with PPT, 3 mm. Both insoles had a metatarsal pad. After one week of wearing, in-shoe plantar pressures, measured at the same time of day and within the same type of indoor tennis shoes (sockliner removed), were obtained using the PEDAR-System(R) (Novel GmbH, Munich, Germany). Before each measurement the PEDAR-insoles were calibrated and the subject walked around for 5 minutes to get aquainted with the device. Three trials were performed for three different conditions and average values were determined: PEDAR-insole alone, with PLASTAZOTE(R) insole, with PPT(R) insole. Data were collected at self selected speed, gait velocity was determined using two optical switches on a 10 m walkway. Pressures were normalized to body weight. Main outcome parameters were 'Maximal Peak Pressure' (MPP) and 'Pressure Time Integral' (PTI). These parameters were determined for the whole footsole, medial and lateral heel, medial and lateral midfoot, medial, middle and lateral forefoot, hallux and toes II-V. Additionally the subjects filled in a questionnaire including: time wearing the insoles daily (in hours), sweating (visual analogue scale -- VAS), wearing comfort (VAS), perceived discomfort (location). Three months after the trial they were asked via telephone call whether they were still using the insoles. RESULTS:: 1. The overall MPP and PTI values did not differ significantly between the PEDAR-insole alone and the investigated inserts. There was a tendency for both insoles towards lower MPP and PTI values in all regions except for the toes, especially for the PPT(R) insole. 2. The questionaire showed a significantly higher wearing comfort for the PPT(R) insole in contrast to the PLASTAZOTE(R) insole, though all subjects sweated more with the PPT(R) material. Four of the six subjects experienced discomfort due to the metatarsal pad within the PLASTAZOTE(R) insole, only one within the PPT(R) insole. 3. None of the subjects continued to use the PLASTAZOTE(R) insole, but three continued to use the PPT(R) insoles. DISCUSSION:: Despite the significant differences in the subjective parameters, especially wearing comfort, no statistical significant difference for the overall MPP and PTI values between the PEDAR-insole alone and the investigated insoles or in between the insoles tested could be obtained. Yet there was a tendency for both insoles to lower MPP and PTI values in all regions except for the toes. This might be due to the thickness of the insoles and the reduced space within the toe box. The subjectively better tolerated PPT(R) insole tended to lower MPP and PTI more than the PLASTAZOTE(R) insole. CONCLUSION:: Wearing comfort and pedobarographic outcome measurements did not correlate significantly in this trial. Yet there was a tendency for the subjectively better tolerated PPT(R) insole to lower MPP and PTI more.\n\n\n"
},
{
"text": "\n175615\nDiagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis.\n\nBridel, C\n\nvan Wieringen, WN\n\nZetterberg, H\n\nTijms, BM\n\nTeunissen, CE\n\nand the NFL Group\n\nAlvarez-Cermeño, JC\n\nAndreasson, U\n\nAxelsson, M\n\nBäckström, DC\n\nBartos, A\n\nBjerke, M\n\nBlennow, K\n\nBoxer, A\n\nBrundin, L\n\nBurman, J\n\nChristensen, T\n\nFialová, L\n\nForsgren, L\n\nFrederiksen, JL\n\nGisslén, M\n\nGray, E\n\nGunnarsson, M\n\nHall, S\n\nHansson, O\n\nHerbert, MK\n\nJakobsson, J\n\nJessen-Krut, J\n\nJanelidze, S\n\nJohannsson, G\n\nJonsson, M\n\nKappos, L\n\nKhademi, M\n\nKhalil, M\n\nKuhle, J\n\nLandén, M\n\nLeinonen, V\n\nLogroscino, G\n\nLu, CH\n\nLycke, J\n\nMagdalinou, NK\n\nMalaspina, A\n\nMattsson, N\n\nMeeter, LH\n\nMehta, SR\n\nModvig, S\n\nOlsson, T\n\nPaterson, RW\n\nPérez-Santiago, J\n\nPiehl, F\n\nPijnenburg, YAL\n\nPyykkö, OT\n\nRagnarsson, O\n\nRojas, JC\n\nRomme Christensen, J\n\nSandberg, L\n\nScherling, CS\n\nSchott, JM\n\nSellebjerg, FT\n\nSimone, IL\n\nSkillbäck, T\n\nStilund, M\n\nSundström, P\n\nSvenningsson, A\n\nTortelli, R\n\nTortorella, C\n\nTrentini, A\n\nTroiano, M\n\nTurner, MR\n\nvan Swieten, JC\n\nVågberg, M\n\nVerbeek, MM\n\nVillar, LM\n\nVisser, PJ\n\nWallin, A\n\nWeiss, A\n\nWikkelsø, C\n\nWild, EJ\n\nBeiträge in Fachzeitschriften\nISI:000486895500008\n31206160.0\n10.1001/jamaneurol.2019.1534\nPMC6580449\nNeurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.\n To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.\n PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.\n Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.\n Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.\n The cNfL levels adjusted for age and sex across diagnoses.\n Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.\n These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.\n\nKhalil, Michael\n\n\n"
},
{
"text": "\n131918\nUltra-long pharmacokinetic properties of insulin degludec are comparable in elderly subjects and younger adults with type 1 diabetes mellitus.\n\nKorsatko, S\n\nDeller, S\n\nMader, JK\n\nGlettler, K\n\nKoehler, G\n\nTreiber, G\n\nUrschitz, M\n\nWolf, M\n\nHastrup, H\n\nSøndergaard, F\n\nHaahr, H\n\nPieber, TR\n\nBeiträge in Fachzeitschriften\nISI:000329232200005\n24263619.0\n10.1007/s40266-013-0138-0\nPMC3880476\nManagement of diabetes in elderly subjects is complex and careful management of glucose levels is of particular importance in this population because of an increased risk of diabetes-related complications and hypoglycaemia.\n The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a basal insulin with an ultra-long duration of action, in elderly subjects with type 1 diabetes compared with younger adults.\n This trial was a randomised, double-blind, two-period, crossover trial conducted in a single centre and included both inpatient and outpatient periods. Subjects were men and women aged 18-35 years inclusive (younger adult group) or ≥65 years (elderly group) with type 1 diabetes who received IDeg (0.4 U/kg) via subcutaneous injection in the thigh once-daily for six days. Following 6-day dosing, a 26-hour euglycaemic glucose clamp procedure was conducted to evaluate the steady-state pharmacodynamic effects of IDeg. Blood samples were taken for pharmacokinetic analysis up to 120 h post-dose. Pharmacokinetic endpoints included the total exposure of IDeg, ie the area under the IDeg serum concentration curve during one dosing interval at steady state (AUC(IDeg, , S)) (τ = 0-24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (C(max, Deg, S)). Pharmacodynamic endpoints included the total glucose-lowering effect of IDeg, ie the area under the glucose infusion rate (GIR) curve at steady state (AUC(GIR, , S)), and the maximum GIR at steady state (GIR(max, Deg, S)).\n Total exposure (AUC(IDeg, , S)) and maximum concentration (C(max, Deg, S)) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUC(IDeg, , S) and C(max, Deg, S) and corresponding two-sided 95 % confidence intervals (CIs) were 1.04 (95 % CI 0.73-1.47) and 1.02 (95 % CI 0.74-1.39), respectively. Mean AUC(IDeg, -12h, S)/AUC(IDeg, , S) was 53 % in both younger adult and elderly subjects, showing that in both age groups IDeg exposure was evenly distributed across the first and second 12 h of the 24-hour dosing interval. No statistically significant differences were observed between younger adult and elderly subjects with regard to AUC(GIR, , S) (the primary endpoint of this study) and GIR(max, Deg, S). Estimated mean age group ratios (elderly/younger adult) for AUC(GIR, , S) and GIR(max, Deg, S) and corresponding two-sided 95 % CIs were 0.78 (95 % CI 0.47-1.31) and 0.80 (95 % CI 0.54-1.17), respectively. Duration of action was beyond the clamp duration of 26 h in all subjects.\n The exposure of IDeg at steady state during once-daily dosing was similar in younger adult and elderly subjects. The glucose-lowering effect of IDeg was numerically lower in elderly subjects compared with younger adults, but no significant differences were observed between age groups. The ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in younger adults were preserved in elderly subjects with type 1 diabetes. Clinical trials.gov number: NCT00964418.\n\nDeller, Sigrid\n\nKöhler, Gerd\n\nKorsatko, Stefan\n\nMader, Julia\n\nPieber, Thomas\n\nTreiber, Gerlies\n\nUrschitz, Martina\n\nWolf, Michael\n\n\n"
},
{
"text": "\n168987\nTargeted therapy with a localised abluminal groove, low-dose sirolimus-eluting, biodegradable polymer coronary stent (TARGET All Comers): a multicentre, open-label, randomised non-inferiority trial.\n\nLansky, A\n\nWijns, W\n\nXu, B\n\nKelbæk, H\n\nvan Royen, N\n\nZheng, M\n\nMorel, MA\n\nKnaapen, P\n\nSlagboom, T\n\nJohnson, TW\n\nVlachojannis, G\n\nArkenbout, KE\n\nHolmvang, L\n\nJanssens, L\n\nOchala, A\n\nBrugaletta, S\n\nNaber, CK\n\nAnderson, R\n\nRittger, H\n\nBerti, S\n\nBarbato, E\n\nToth, GG\n\nMaillard, L\n\nValina, C\n\nBuszman, P\n\nThiele, H\n\nSchächinger, V\n\nBaumbach, A\n\nTARGET All Comers Investigators\n\nBeiträge in Fachzeitschriften\nISI:000445968800026\n30190206.0\n10.1016/S0140-6736(18)31649-0\nNone\nThe FIREHAWK is a drug-eluting stent with a fully biodegradable sirolimus-containing polymer coating localised to recessed abluminal grooves on the stent surface. We investigated clinical outcomes with this targeted, low-dose, biodegradable polymer, sirolimus-eluting stent compared with XIENCE durable polymer, everolimus-eluting stents in an all-comers population.\n The TARGET All Comers study was a prospective, multicentre, open-label randomised non-inferiority trial done at 21 centres in ten European countries. Patients with symptomatic or asymptomatic coronary artery disease and objective evidence of myocardial ischaemia who qualified for percutaneous coronary intervention were randomised 1:1 to undergo implantation of a FIREHAWK or XIENCE. Randomisation was web-based, with random block allocation and stratification by centre and ST elevation myocardial infarction. Outcome assessors were masked to treatment allocation, but treating physicians and patients were not. The primary endpoint was target lesion failure at 12 months, a composite of cardiac death, target vessel myocardial infarction, or ischaemia-driven target lesion revascularisation. The control event rate for XIENCE was assumed to be 7%, the non-inferiority margin was 3.5%, and the primary analysis was in the intention-to-treat population, censoring patients who did not have either an event before 365 days or contact beyond 365 days. Late lumen loss was the primary endpoint of an angiographic substudy designed to investigate the non-inferiority of the FIREHAWK compared with the XIENCE stent. This trial is registered with ClinicalTrials.gov, number NCT02520180.\n From Dec 17, 2015, to Oct 14, 2016, 1653 patients were randomly assigned to implantation of the FIREHAWK (n=823) or XIENCE (n=830). 65 patients in the FIREHAWK group and 66 in the XIENCE group had insufficient follow-up data and were excluded from the analyses. At 12 months, target lesion failure occurred in 46 (6·1%) of 758 patients in the FIREHAWK group and in 45 (5·9%) of 764 patients in the XIENCE group (difference 0·2%, 90% CI -1·9 to 2·2, pnon-inferiority=0·004, 95% CI -2·2 to 2·6, psuperiority=0·88). There were no differences in ischaemia-driven revascularisation or stent thrombosis rates at 12 months. 176 patients were included in the angiographic substudy, in which in-stent late lumen loss was 0·17 mm (SD 0·48) in the FIREHAWK group and 0·11 mm (0·52) in the XIENCE group (p=0·48), with an absolute difference of 0·05 mm (95% CI -0·09 to 0·18, pnon-inferiority=0·024).\n In a broad all-comers population of patients requiring stent implantation for myocardial ischaemia, the FIREHAWK was non-inferior to the XIENCE as assessed with the primary endpoint of target lesion failure at 12 months and in-stent late lumen loss at 13 months. The FIREHAWK is a safe and effective alternative stent to treat patients with ischaemic coronary artery disease in clinical practice.\n Shanghai Microport Medical.\n Copyright © 2018 Elsevier Ltd. All rights reserved.\n\nToth-Gayor, Gabor\n\n\n"
},
{
"text": "\n182634\nPulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry.\n\nKaemmerer, H\n\nGorenflo, M\n\nHuscher, D\n\nPittrow, D\n\nApitz, C\n\nBaumgartner, H\n\nBerger, F\n\nBruch, L\n\nBrunnemer, E\n\nBudts, W\n\nClaussen, M\n\nCoghlan, G\n\nDähnert, I\n\nD'Alto, M\n\nDelcroix, M\n\nDistler, O\n\nDittrich, S\n\nDumitrescu, D\n\nEwert, R\n\nFaehling, M\n\nGermund, I\n\nGhofrani, HA\n\nGrohé, C\n\nGrossekreymborg, K\n\nHalank, M\n\nHansmann, G\n\nHarzheim, D\n\nNemes, A\n\nHavasi, K\n\nHeld, M\n\nHoeper, MM\n\nHofbeck, M\n\nHohenfrost-Schmidt, W\n\nJurevičienė, E\n\nGumbienè, L\n\nKabitz, HJ\n\nKlose, H\n\nKöhler, T\n\nKonstantinides, S\n\nKöestenberger, M\n\nKozlik-Feldmann, R\n\nKramer, HH\n\nKropf-Sanchen, C\n\nLammers, A\n\nLange, T\n\nMeyn, P\n\nMiera, O\n\nMilger-Kneidinger, K\n\nNeidenbach, R\n\nNeurohr, C\n\nOpitz, C\n\nPerings, C\n\nRemppis, BA\n\nRiemekasten, G\n\nScelsi, L\n\nScholtz, W\n\nSimkova, I\n\nSkowasch, D\n\nSkride, A\n\nStähler, G\n\nStiller, B\n\nTsangaris, I\n\nVizza, CD\n\nVonk Noordegraaf, A\n\nWilkens, H\n\nWirtz, H\n\nDiller, GP\n\nGrünig, E\n\nRosenkranz, S\n\nBeiträge in Fachzeitschriften\nISI:000540223800213\n32414075.0\n10.3390/jcm9051456\nPMC7290703\nPulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension.\n To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data.\n COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients´ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status.\n In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.\n\nKoestenberger, Martin\n\n\n"
},
{
"text": "\n128390\nLoci influencing blood pressure identified using a cardiovascular gene-centric array.\n\nGanesh, SK\n\nTragante, V\n\nGuo, W\n\nGuo, Y\n\nLanktree, MB\n\nSmith, EN\n\nJohnson, T\n\nCastillo, BA\n\nBarnard, J\n\nBaumert, J\n\nChang, YP\n\nElbers, CC\n\nFarrall, M\n\nFischer, ME\n\nFranceschini, N\n\nGaunt, TR\n\nGho, JM\n\nGieger, C\n\nGong, Y\n\nIsaacs, A\n\nKleber, ME\n\nMateo Leach, I\n\nMcDonough, CW\n\nMeijs, MF\n\nMellander, O\n\nMolony, CM\n\nNolte, IM\n\nPadmanabhan, S\n\nPrice, TS\n\nRajagopalan, R\n\nShaffer, J\n\nShah, S\n\nShen, H\n\nSoranzo, N\n\nvan der Most, PJ\n\nVan Iperen, EP\n\nVan Setten, J\n\nVan Setten, JA\n\nVonk, JM\n\nZhang, L\n\nBeitelshees, AL\n\nBerenson, GS\n\nBhatt, DL\n\nBoer, JM\n\nBoerwinkle, E\n\nBurkley, B\n\nBurt, A\n\nChakravarti, A\n\nChen, W\n\nCooper-Dehoff, RM\n\nCurtis, SP\n\nDreisbach, A\n\nDuggan, D\n\nEhret, GB\n\nFabsitz, RR\n\nFornage, M\n\nFox, E\n\nFurlong, CE\n\nGansevoort, RT\n\nHofker, MH\n\nHovingh, GK\n\nKirkland, SA\n\nKottke-Marchant, K\n\nKutlar, A\n\nLacroix, AZ\n\nLangaee, TY\n\nLi, YR\n\nLin, H\n\nLiu, K\n\nMaiwald, S\n\nMalik, R\n\nCARDIOGRAM, METASTROKE\n\nMurugesan, G\n\nNewton-Cheh, C\n\nO'Connell, JR\n\nOnland-Moret, NC\n\nOuwehand, WH\n\nPalmas, W\n\nPenninx, BW\n\nPepine, CJ\n\nPettinger, M\n\nPolak, JF\n\nRamachandran, VS\n\nRanchalis, J\n\nRedline, S\n\nRidker, PM\n\nRose, LM\n\nScharnag, H\n\nSchork, NJ\n\nShimbo, D\n\nShuldiner, AR\n\nSrinivasan, SR\n\nStolk, RP\n\nTaylor, HA\n\nThorand, B\n\nTrip, MD\n\nvan Duijn, CM\n\nVerschuren, WM\n\nWijmenga, C\n\nWinkelmann, BR\n\nWyatt, S\n\nYoung, JH\n\nBoehm, BO\n\nCaulfield, MJ\n\nChasman, DI\n\nDavidson, KW\n\nDoevendans, PA\n\nFitzgerald, GA\n\nGums, JG\n\nHakonarson, H\n\nHillege, HL\n\nIllig, T\n\nJarvik, GP\n\nJohnson, JA\n\nKastelein, JJ\n\nKoenig, W\n\nLifeLines Cohort Study\n\nMärz, W\n\nMitchell, BD\n\nMurray, SS\n\nOldehinkel, AJ\n\nRader, DJ\n\nReilly, MP\n\nReiner, AP\n\nSchadt, EE\n\nSilverstein, RL\n\nSnieder, H\n\nStanton, AV\n\nUitterlinden, AG\n\nvan der Harst, P\n\nvan der Schouw, YT\n\nSamani, NJ\n\nJohnson, AD\n\nMunroe, PB\n\nde Bakker, PI\n\nZhu, X\n\nLevy, D\n\nKeating, BJ\n\nAsselbergs, FW\n\nBeiträge in Fachzeitschriften\nISI:000316965400016\n23303523.0\n10.1093/hmg/dds555\nPMC3657476\nBlood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.\n\nMärz, Winfried\n\nScharnagl, Hubert\n\n\n"
},
{
"text": "\n129998\nAntimicrobial Activity of Copper (II) Complex with 1,2-bis [(1,3-diphenylpyrazol-4-yl)methyl] Diaminoethane.\n\nSuvajdzic, L\n\nLeovac, V\n\nJoksovic, M\n\nBogdanovic, G\n\nKojic, V\n\nVujic, N\n\nMrdja, T\n\nKocic, B\n\n\n\nBeiträge in Fachzeitschriften\nISI:000320937200008\nNone\nNone\nNone\nBackground: Multi-resistant strains multiply daily, populate farms, hospitals and other ecological niches around the world, and cause serious infections in animals and humans, often leading to a fatal outcome. Researchers of all profiles are investigating intensively to find new substances with antimicrobial activity. In the period between 1981 and 2002, 163 new chemical compounds were approved for use as drugs. Synthesized compounds have become much more interesting than the natural ones in the production of new antimicrobial agents. Some of these synthesized compounds are Copper (II) complex. The antimicrobial properties of copper were known in ancient Egypt (2000 BC), where it was used to sterilize water and wounds. Copper is still interesting for today's research. Materials, Methods & Results: Antimicrobial activity was tested using a microdilution method according to Clinical and Laboratory Standards Institute. The percentage of surviving bacteria was calculated in comparison to the number of bacteria placed in each well. Based on these results, using the Excel software package from Microsoft Office 2007, graphs were generated that showed the percentage of surviving bacteria depending on the corresponding effective concentrations of the tested substance. The function, which was used to approximate the experimental results, was determined using the Power Trendline supplement from the Microsoft Excel program. Cytotoxicity (growth inhibition) was evaluated by tetrazolium colorimetric MTT assay, after exposure of cells to the tested compound for 48 h. Inhibition of growth was expressed as a percentage of cytotoxicity and calculated according to the following equation: (1-A test/A control) x 100. MBC99.9 and MIC99 of the test substance were lowest for Arcanobacterium haemolyticum being 0.2 mg/L and 0.0054 mg/L, respectively. The highest values were obtained for Arcanobacterium pyogenes and methicillin-resistant Staphylococcus aureus (MRSA) 488.002 mg/L and 20.2 mg/L. MIC80 for all four strains ranged from 0.00002 to 0.0023 mg/L. Measured values for MIC99 are 0.00545 mg/L for A. haemolyticum, 0.0443199 mg/L for R. equi, 0.0520712 mg/L for S. aureus and 2.36378 mg/L for A. pyogenes. Values for MIC99.9 ranged from 0.236134 to 488, 02 mg/L. Most of the MIC values obtained in this study are significantly lower than those reported by other researchers. The values we obtained were lower as compared to MIC values for standard antibiotics, which were considered acceptable by the relevant institutions. This speaks in favor of a stronger antibacterial effect of our tested substances. In regards to cytotoxicity, the obtained MIC80 doses were lower than toxic, whereas MIC90 could be classified as low-toxic (less than 0.0625 mu M), except of Arcanobacterium pyogenes only. According to the IC50 values, the compound Cu (L) Br2 center dot MeOH was 6.4-fold and 4.8-fold more potent against HCT116 cells compared to normal lung fibroblasts and SW620 cells, respectively. Discussion: Copper (II) complex with an arylpyrazole ligand exhibits strong antibacterial properties, and it shows bacteriostatic effect at concentrations where there is no cytotoxic effect in normal human cells. The emergence of multi-resistant strains of pathogenic bacteria is a growing problem worldwide. Therefore, each new compound with potential antimicrobial activity, especially if it is not cytotoxic in effective dosage, deserves the attention of the scientific community. In this paper, we presented a newly synthesized substance with such properties.\n\nVujic, Nemanja\n\n\n"
}
]
}