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Nanoparticles with a multi-domain structure have been identified as a new class of highly potent nanocarriers with a dual transport mechanism for polar and non-polar guests. In this paper we present a detailed analysis of their spatial structure, which has been analyzed by small-angle neutron scattering (SANS) including contrast variation. The nanocarriers consist of a hyperbranched polyglycerol (hPG) core onto which di-block segments consisting of non-polar alkyl chains and hydrophilic poly(ethylene glycol) methyl ether (mPEG) has been grafted. The hPG cores have been analyzed separately for comparison. SANS demonstrates that the hPG-cores can be described as fractal structures. The nanocarriers form rather compact structures in the non-polar solvent toluene. A fractal structure with a correspondingly rough surface is found here as well, which is explained by the backfolding of the hydrophilic mPEG-chains in the non-polar environment. In water the nanocarriers associate to form well-defined nanoparticle clusters with an ellipsoidal shape. Contrast variation demonstrates that these particles have no distinct core–shell structure but the separation of the incompatible parts of the structure takes place on a much smaller length scale. [ABSTRACT FROM AUTHOR]

The water-soluble catalyst precursor [[(2,4,6-(3,5-(CF3)2C6H3)3-C6H2)-N═C(H)-(3-(9-anthryl)-2-O-C6H3)-κ2-N,O]Ni(CH3)(TPPTS)] (TPPTS = tri(sodiumphenylsulfonate)phosphine) polymerizes ethylene to aqueous dispersions of highly ordered nanoscale crystals (crystallinity χ(DSC) ≥ 90%) of strictly linear polyethylene (<0.7 methyl-branches/1000 carbon atoms, Mn = 4.2 × 105 g mol–1). SAXS in combination with cryo-TEM confirms this unusually high degree of order (χ(SAXS) = 82%) and shows the nanoparticles to possess a very thin amorphous layer on the crystalline lamella, just sufficient to accommodate a loop, but likely no entanglements. This ideal chain-folded structure is corroborated by annealing studies on the aqueous-dispersed nanoparticles, which show that the chain can move through the crystal as evidenced by lamella thickening without disturbing the crystalline order as concluded from an unaltered low thickness of the amorphous layers. These ideal chain-folded polyethylene nanocrystals arise from the crystallization in the confined environment of a nanoparticle and a deposition of the growing polymer chain on the crystal growth front as the chain is formed by the catalyst. [ABSTRACT FROM AUTHOR]

Artificial intelligences (AIs) are emerging in the field of medical informatics in many areas. They are mostly used for diagnosis support in medical imaging but have potential uses in many other fields of medicine where large datasets are available. To develop an artificial intelligence (AI) "ToxNet", a machine-learning based computer-aided diagnosis (CADx) system, which aims to predict poisons based on patient's symptoms and metadata from our Poison Control Center (PCC) data. To prove its accuracy and compare it against medical doctors (MDs). The CADx system was developed and trained using data from 781,278 calls recorded in our PCC database from 2001 to 2019. All cases were mono-intoxications. Patient symptoms and meta-information (e.g., age group, sex, etiology, toxin point of entry, weekday, etc.) were provided. In the pilot phase, the AI was trained on 10 substances, the AI's prediction was compared to naïve matching, literature matching, a multi-layer perceptron (MLP), and the graph attention network (GAT). The trained AI's accuracy was then compared to 10 medical doctors in an individual and in an identical dataset. The dataset was then expanded to 28 substances and the predictions and comparisons repeated. In the pilot, the prediction performance in a set of 8995 patients with 10 substances was 0.66 ± 0.01 (F1 micro score). Our CADx system was significantly superior to naïve matching, literature matching, MLP, and GAT (p < 0.005). It outperformed our physicians experienced in clinical toxicology in the individual and identical dataset. In the extended dataset, our CADx system was able to predict the correct toxin in a set of 36,033 patients with 28 substances with an overall performance of 0.27 ± 0.01 (F1 micro score), also significantly superior to naïve matching, literature matching, MLP, and GAT. It also outperformed our MDs. Our AI trained on a large PCC database works well for poison prediction in these experiments. With further research, it might become a valuable aid for physicians in predicting unknown substances and might be the first step into AI use in PCCs. [ABSTRACT FROM AUTHOR]

Background/Aims: Hepatocellular carcinomas (HCC) often show resistance to the effects of transforming growth factor-β (TGF-β). This study focuses on molecular mechanisms of this resistance to explore ways to overcome it. Methods: Transcription and protein expression of TGF-β type I and type II receptors (TGF-βRI/RII) were analyzed in clinical HCCs and the human hepatoma cell lines HuH-7 and HepG2. HuH-7 cells were transiently and stably transfected with a constitutively active TGF-βRI mutant (CA TGF-βRI). Resulting growth kinetics, integrin expression, invasiveness, TGF-β-mediated activation of human plasminogen activator inhibitor type-1 (PAI-1) promoter and Smad expression were determined. Results: In clinical HCCs, there was less TGF-βRII (6/10 cases) and more TGF-βRI (8/10 cases) protein expression detectable in tumor compared to adjacent liver tissue. In HuH-7 cells, TGF-βRII expression was likewise decreased. Cells transiently transfected with CA TGF-βRI exhibited strong TGF-β-related PAI-1 promoter activation. Stably transfected cells showed an attenuated response of the PAI-1 promoter, but increased Smad7 expression. Proliferation of stable clones was decreased. There was no change in integrin expression or invasiveness. Conclusions: Decreased TGF-βRII protein expression might cause TGF-β resistance in a subset of clinical HCCs. Stable transfection with CA TGF-βRI reverses this in HuH-7 cells without increasing invasiveness. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: It is not known whether the poor outcome of ventilated cirrhotic patients is related to the severity of the underlying liver disease or to the severity of the acute illness for which ICU care is required. This study examines parameters both of chronic liver disease and of acute illness with regard to their influence on outcome in mechanically ventilated cirrhotic patients.Design and Setting: Retrospective observational case series in a 9-bed medical ICU in an academic tertiary care center.Patients and Measurements: Seventy-six consecutive cirrhotic patients who received mechanical ventilation were identified. Clinical and laboratory parameters were compared between ICU survivors and ICU deaths.Results: There were 45/76 (59%) patients who died during their ICU stay. By univariate analysis, the Child-Pugh score, its components (serum bilirubin, prothrombin time), ALT, creatinine concentration, a clinical suspicion of infection, and the APACHE II score, but not the acute physiology score (APS), differed significantly between ICU survivors and ICU non-survivors. The Child-Pugh score was highly correlated to ICU mortality both in logistic regression analysis and receiver-operating characteristics analysis. Conversely, markers of acute illness, in particular the APS component of the APACHE II score, did not predict ICU survival.Conclusions: Markers of advanced chronic liver disease but not of the severity of acute illness are correlated to ICU outcome in ventilated cirrhotic patients. The outcome of advanced cases (Child-Pugh score of 12 and above) is poor. [ABSTRACT FROM AUTHOR]

Background and Aims: Adeno-associated virus (AAV) is the only known virus capable of site-specific genomic integration in human cells. Thus, AAV-based vectors may be an attractive option to achieve prolonged transgene expression in human cells. We therefore studied the minimal elements of gene therapy vectors necessary for stable integration and tested the effectiveness of this approach in hepatoma cells. Methods: Plasmids were constructed that contained a GFPneo fusion transgene with or without the AAV-inverted terminal repeats (ITRs). In addition, Rep protein was either encoded in cis or supplied in trans by co-transfections. Stable clones were analyzed by Southern blotting for site-specific integration. Results: The ITRs alone conferred neither stable nor site-specific transgene integration. Expression of Rep protein in cis or trans resulted in an increased frequency of integration regardless of the presence of ITRs. It was shown that in the absence of the ITRs, other Rep-binding site (RBS) like sequences such as the ColE1 sequence present in plasmid backbones can function as RBS. Site-specific integration was achieved in up to 26% of clones derived from hepatoma cells. Conclusion: Both expression of Rep proteins and inclusion of a RBS are necessary for enhanced and stable integration of AAV-based non-viral vectors. A novel two-plasmid system capable of achieving stable and site-specific gene transfer in hepatoma cells is introduced. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusionsTo independently validate the negative predictive value of the Tanta University risk model for intensive care requirements in poison center telephone consultations with other physicians.This study included 400 consecutive patients with acute poisoning. Clinical and laboratory parameters were recorded during the initial consultation with the poison center. Patients who were already ventilated or on vasopressors at the time of consultation were excluded. The Tanta University risk model score was calculated from the data according to the following equation: Tanta University risk model score = 1.966*Glasgow Coma Scale + 0.329*oxygen saturation (percent) + 0.212*diastolic blood pressure (mmHg) − 0.27*respiratory rate (breaths/minute) + 0.33*standard bicarbonate (mmol/L). Twenty-four hours later, the patients’ courses were followed up by telephone. The Tanta University risk model was then compared to a composite endpoint indicating the requirement for admission to an intensive care unit (vasopressors, need for intubation, or death).Four hundred patients with acute poisoning were included. Thirty-seven patients had a complicated clinical course as defined by the composite endpoint. Receiver operating characteristic analysis revealed the area under the curve to be 0.87 (95 percent confidence interval 0.83–0.90). An unfavorable Tanta University risk model score was defined as less than 73.46, using a cut-off derived from a previous study of an unrelated series of patients with acute poisoning admitted to our service. Thirty-one of 37 patients with complicated courses had an unfavorable Tanta University risk model score compared to six patients with complicated courses among 306 patients with a favorable Tanta University risk model score (P < 0.0002, Fisher’s exact test). Sixty-three patients had an unfavorable Tanta University risk model score but an uneventful course. The negative predictive value of the Tanta University risk model was 0.98 (95 percent confidence interval 0.96–0.99), sensitivity was 0.84, and specificity 0.83.In the present study of poison center telephone consultations, the Tanta University risk model was significantly related to the outcomes in patients with acute poisoning. Patients with a favorable Tanta University risk model score (greater than or equal to 73.46) were unlikely to need intensive care unit level of care. [ABSTRACT FROM AUTHOR]

Objective: To identify the psychiatric profile of patients hospitalized due to self-intoxication associated with suicide-related behavior (SRB). Methods: In this retrospective single-center study, records of consecutive patients treated for suicidal poisoning in our Clinical Toxicology unit between 1st January 2012 and 31st December 2016, who received at least one psychiatric exploration during their inpatient stay, were analyzed with regard to epidemiological data, ingested substances, psychiatric and somatic comorbidities, suicidal circumstances and follow-up therapy. Results: Out of 1289 hospitalized patients, 1090 patients with complete data were analyzed. Mean age was 40.5 ± 17.2 years, 66.7% were female. 32.0% of patients had previously engaged in SRB, in 76.3% intention was suicidal. 64.7% of patients had a pre-existing psychiatric disorder (PD). Patients with a pre-existing PD more often displayed prior SRB than those without PD (40.7% vs 15.3%; p < 0.001; Fisher′s exact test), used long-term/on demand medication (70.2% vs 38.9%; p < 0.001), distanced themselves from the current suicide attempt (65.9% vs 50.8%; p < 0.001) and had no detectable trigger (38.7% vs 18.1%; p < 0.001). Partnership conflict was the most commonly named trigger, and it was documented more often in patients without than in those with PD (41.6% vs 25.6%). After psychiatric reevaluation, most patients were diagnosed with mood disorders (29.7%) and stress disorders (17.0%); 32.8% of patients had a combination of two or more PDs. Conclusion: Hospitalization due to self-poisoning is associated with pre-existing PD, prior SRB and access to psychiatric medication. Detection of these risk factors could allow timely introduction of effective preventive measures tailored to particularly vulnerable subgroups and appropriate relief. However, lack of a detectable trigger in many cases may hamper the identification of those at risk. [ABSTRACT FROM AUTHOR]

Background: Although the total number of suicides decreased since the beginning of the 1980s, the number of suicide-related behaviors using self-intoxication increased. Therefore, research on the characteristics of individuals committing self-intoxication becomes of growing importance for risk assessments and the development of preventive measures. Methods: In this prospective, observational, monocentric cohort study, all incoming calls at our Poisons Control Centre reporting suicide-related behaviors through self-intoxication, were analyzed via a standardized questionnaire over 12 months. Both univariate and bivariate analyses were performed. Results: 1238 cases of deliberate intoxication were included in the study. The majority of cases occurred in the age group between 18 and 44 (n = 607/49%), two-thirds were female (n = 817/66%). The main substances used were antidepressants (n = 420/34%), peripheral analgesics (n = 322/26%) and neuroleptics (n = 282/23%). The majority of patients ingested substances from their prescribed medication (n = 640/82%) with the highest proportion in those aged over 64 years (n = 72/113; 91%, p < 0.001). Substance use was reported for the minority of patients (n = 175/23%). For 704 cases (79%), a psychiatric disorder was documented. Factors associated with recurrent suicide-related behaviors were an underlying psychiatric disorder (OR = 6.2; 95% CI 3.8–10.4), substance use (OR = 2.4; 95% CI 1.5–3.8), and ingestion of neuroleptics (OR = 2.1, 95% CI 1.4–3.0) or antidepressants (OR = 1.6; 95% CI 1.2–2.3). Conclusion: This study might contribute to identifying individuals with an increased risk of suicide-related behaviors by deliberate intoxication and to developing preventive strategies for future suicide attempt(s). [ABSTRACT FROM AUTHOR]

Background: Although the total number of suicides decreased since the beginning of the 1980s, the number of suicide-related behaviors using self-intoxication increased. Therefore, research on the characteristics of individuals committing self-intoxication becomes of growing importance for risk assessments and the development of preventive measures. Methods: In this prospective, observational, monocentric cohort study, all incoming calls at our Poisons Control Centre reporting suicide-related behaviors through self-intoxication, were analyzed via a standardized questionnaire over 12 months. Both univariate and bivariate analyses were performed. Results: 1238 cases of deliberate intoxication were included in the study. The majority of cases occurred in the age group between 18 and 44 (n = 607/49%), two-thirds were female (n = 817/66%). The main substances used were antidepressants (n = 420/34%), peripheral analgesics (n = 322/26%) and neuroleptics (n = 282/23%). The majority of patients ingested substances from their prescribed medication (n = 640/82%) with the highest proportion in those aged over 64 years (n = 72/113; 91%, p < 0.001). Substance use was reported for the minority of patients (n = 175/23%). For 704 cases (79%), a psychiatric disorder was documented. Factors associated with recurrent suicide-related behaviors were an underlying psychiatric disorder (OR = 6.2; 95% CI 3.8–10.4), substance use (OR = 2.4; 95% CI 1.5–3.8), and ingestion of neuroleptics (OR = 2.1, 95% CI 1.4–3.0) or antidepressants (OR = 1.6; 95% CI 1.2–2.3). Conclusion: This study might contribute to identifying individuals with an increased risk of suicide-related behaviors by deliberate intoxication and to developing preventive strategies for future suicide attempt(s). [ABSTRACT FROM AUTHOR]

Chlormequat chloride (2-chloro-N,N,N-trimethylethanaminium chloride) is a plant growth regulator. In subsequent serum samples, concentrations decreased rapidly, but chlormequat was still detectable at 0.15 mg/L about five days after ingestion, indicating an initial phase of fast elimination ( I t i SB ½ fast sb = 4.6 h) and a slower second phase ( I t i SB ½ slow sb = 88.6 h). This finding is also consistent with the long-lasting increased pulmonary secretion and paralysis in our patient, albeit the cardiac dysrhythmia occurred during the first hours after ingestion, when plasma levels of chlormequat were high. [Extracted from the article]

To independently validate the predictive value of the Tanta University Risk Model for intensive care requirement in unselected poisoned patients. Retrospective chart review of 293 poisoned patients. The Tanta University Risk Model was calculated as follows: Tanta University Risk Model = −1.966*Glasgow Coma Scale − 0.329*oxygen saturation − 0.212*diastolic blood pressure + 0.27*respiratory rate − 0.33*standard bicarbonate. It was then compared to a composite endpoint indicating an intensive care unit requirement (death in hospital, vasopressors, need for intubation). Nineteen of 293 patients had a complicated clinical course as defined by meeting the primary endpoint definition. Receiver operating characteristic analysis revealed the area under the curve to be 0.79 (95% confidence interval 0.73–0.83). A positive Tanta University Risk Model was defined >−73.46. Fifteen out of 84 patients with a positive Tanta University Risk Model had a complicated course, while four of 209 patients with a negative Tanta University risk model had a complicated course (P<0.0001, Fisher's exact test). The negative predictive value of the Tanta University Risk Model was 0.98 (95% confidence interval 0.95–0.99), the sensitivity was 0.79 and that specificity was 0.75. Poisoned patients with a negative Tanta University Risk Model score are unlikely to need an intensive care unit level of care. [ABSTRACT FROM AUTHOR]

Background:Valproic acid and its metabolites – particularly valproyl-CoA – are inhibitors of the enzymeN-acetylglutamate synthetase. The amino acidl-arginine can stimulateN-acetylglutamate synthetase activity and could be potentially used therapeutically to correct hyperammonemia caused by valproate therapy or overdose. Severely valproic-acid-poisoned patients are usually treated withl-carnitine or hemodialysis in order to decrease hyperammonemia. We herein report of five cases, in whichl-arginine was administered. Methods:Observational study on five cases. Patients with hyperammonemia (i.e., ammonia 80 > μg/dL) and symptoms consistent with valproate overdose (i.e., drowsiness, coma) were selected for treatment withl-arginine. Data was collected retrospectively. Results:l-Arginine decreased ammonia levels in a close temporal relation (case I ammonia in EDTA-plasma [μg/dL] decreased from 381 to 39; case II from 281 to 50; case III from 669 to 74; case IV from 447 to 56; case V from 202 to 60). In cases I and II, hemodialysis was performed andl-carnitine was given before the administration ofl-arginine. In case III, hemodialysis was performed after the administration ofl-arginine was already started. In cases IV and V, treatment withl-arginine was the sole measure to decrease ammonia levels in plasma. Conclusion:The results suggest thatl-arginine may be beneficial in selected cases of valproate overdose complicated by hyperammonemia.l-Arginine could extend our conventional treatment options for valproic acid overdose. [ABSTRACT FROM AUTHOR]

Prediction of clinical course of intoxication is essential for timely initiation of appropriate medical treatment in patients hospitalized due to suicidal self-poisoning. In this retrospective single-centre study in patients hospitalized due to suicidal poisoning in a specialized clinical toxicology unit, we aimed to identify predictive factors associated with severe or fatal course of self-poisoning. All patients underwent at least one psychiatric exploration during their inpatient stay. Severity of poisoning was assessed on admission and after 24 hours according to the Poison Severity Score index (PSS). Spearman's rank correlation coefficient was used to test the association of PSS with sociodemographic, anamnestic and (pre-)clinical parameters. Multivariable binomial logistic regression analysis was performed to determine predictive factors for severe and/or fatal self-poisoning. 1090 patients were included in the study. Median age was 39 years (range 13–91), 66.7% of patients were female. PSS was classified in the majority as "minor" (n = 558, 51.2%) or "moderate" (n = 264, 24.2%). 61 patients (5.6%) had PSS "severe"; 14 patients (1.3%) died. A higher severity of poisoning positively correlated with duration of inpatient therapy (p<0.001, Spearman's rho = 0.454) and duration of ventilation (p<0.001, rho = 0.474), and it inversely correlated with initial Glasgow Coma Scale (GCS) score (p<0.001, rho = -0.437). Multivariable analysis identified no alcohol co-ingestion (OR 3.23; 95%CI 1.3, 8.07; p = 0.012) and self-poisoning with non-medicinal substances (OR 5.4; 95%CI 1.78, 16.34; p = 0.003) as factors predictive for "severe" or "fatal" suicide outcome. In contrast, female gender (OR 0.4; 95%CI 0.2, 0.81; p = 0.011), not using an antidepressant as the method for self-poisoning (OR 0.27; 95%CI 0.12, 0.59; p = 0.001) and a higher initial GCS score (OR 0.79; 95%CI 0.73, 0.85; p<0.001) reduced the risk of a severe or fatal course of self-poisoning. The conclusion for clinical practice is that male patients hospitalized due to self-poisoning, with a low initial GCS score, who did not co-ingest alcohol, attempted suicide with non-pharmaceutical substances or antidepressants are at a higher risk of severe/fatal outcome of suicide. Determination of these risk factors at admission could be potentially used to guide treatment intensification in patients hospitalized due to deliberate self-poisoning. [ABSTRACT FROM AUTHOR]

The ternary system composed of theionic liquid surfactant (IL-S) 1-butyl-3-methylimidazolium dodecylsulfate([Bmim][DodSO4]), the room temperature ionic liquid (RTIL)1-ethyl-3-methylimidazolium ethylsulfate ([Emim][EtSO4]),and toluene has been investigated. Three major mechanisms guidingthe structure of the isotropic phase were identified by means of conductometricexperiments, which have been correlated to the presence of oil-in-IL,bicontinuous, and IL-in-oil microemulsions. IL-S forms micelles intoluene, which swell by adding RTIL as to be shown by dynamic lightscattering (DLS) and small-angle X-ray scattering (SAXS) experiments.Therefore, it is possible to form water-free IL-in-oil reverse microemulsions≤10 nm in size as a new type of nanoreactor. [ABSTRACT FROM AUTHOR]

Background: Treatment of multiple organ failure frequently requires enhanced hemodynamic monitoring. When renal replacement is indicated, it remains unclear whether transpulmonary thermodilution (TPTD) measurements are influenced by renal replacement therapy (RRT) and whether RRT should be paused for TPTD measurements. Our aim was therefore to investigate the effect of pausing RRT on TPTD results in two dialysis catheter locations.Materials and methods: In total, 62 TPTD measurements in 24 patients (APACHE: 32 ± 7 [mean ± standard deviation (SD)]) were performed using the PiCCO™ system (Pulsion, Germany). Patients were treated with sustained low efficiency dialysis (SLED; Genius™ system, Fresenius, Germany) as RRT. Measurements were taken during ongoing hemodialysis (HD, HDO), during paused HD (HDP) and immediately after termination of HD and blood restitution (HDT). Dialysis catheters were placed either in the superior vena cava (SVC, 19 times) or in the inferior vena cava (IVC, 5 times). Statistical analysis was performed to assess the effects of the measurement setting, SLED (blood flow rate) and the catheter location, on cardiac index (CI), global end-diastolic volume index (GEDVI) and extravascular lung water index (EVLWI) as measured by TPTD. Multilevel models were used for the analysis due to the triplicate measurements and due to 12 out of 19 SVC and 2 out of 5 IVC patients having more than one TPTD measured.Results: CI and GEDVI were significantly higher at time point HDP compared to both HDO and HDT. In contrast, values for EVLWI were lower at HDP when compared to HDO and HDT. These findings were independent of the site of dialysis catheter insertion and blood flow rate.Conclusions: PiCCO™ measurements assessed at paused SLED significantly deviate from ongoing and terminated SLED. Therefore, the dialysis system should not be paused for measurements. TPTD measurements in patients with PiCCO monitoring seem sufficiently reliable during ongoing SLED as well as after its termination. An effect of dialysis catheter location (SVC vs IVC) and blood flow rate on PiCCO™ measurements could not be shown. [ABSTRACT FROM AUTHOR]

Olanzapine is a second-generation antipsychotic drug which is generally considered safe with well therapeutic antipsychotic effects. We describe a patient suffering from bilateral intracerebral hemorrhage after severe olanzapine intoxication without underlying thrombocytopenia, arterial hypertension, or vascular malformation as cause of intracerebral hemorrhage. This raises the possibility of a direct side effect of high-dose olanzapine intake. So far, intracranial hemorrhage after olanzapine intoxication in such constellation has not been reported before. Given the high number of its prescription rates, our finding of intracranial hemorrhage after olanzapine intoxication is of high clinical relevance. [ABSTRACT FROM AUTHOR]

Objective:To define the demographics of German-speaking “bath salt” users. Design:Prospective web-based survey of volunteer users of “bath salts”. Subject recruitment/exclusion:Participation was solicited by posts in web forums frequented by users of synthetic cathinones. An invitation to participate was also disseminated via regional drug information centers. Responses were discarded if participants refused data analysis, provided incomplete surveys, were under 18 years of age (five cases), and in case of clearly improbable answers (i.e., two cases with profanity typed in free-form input fields). Overall 96 out of 180 participants provided complete questionnaires. These were further analyzed. Results and conclusions:74% of respondents were male. 41% were under the age of 30 and a further 38% between 30 and 39 years old. Cathinones were used on more than 10 days in the preceding year by 62% of study subjects. The nasal and intravenous routes of administration were most often used. About 80% of respondents reported binge use. There were frequent co-administrations of opioids and opiates. The most common complication was prolonged confusion (47%). 16% had been involuntarily confined. One third had thoughts of violence and 16% acted on these thoughts either against themselves or others. About 44% reported high-risk sexual activity under the influence of cathinones. About 31% had driven or ridden a bike while intoxicated. About 6% had problems with law-enforcement for selling cathinones and 16% for crimes committed under the influence of cathinones. In conclusion, cathinone users are typically young males in their twenties and thirties. Most are experienced drug users, particularly of alcohol and opiates/opioids. The impact on society is tremendous as evidenced by high rates of self-reported violence, high-risk sexual activity, crimes, and traffic violations. [ABSTRACT FROM PUBLISHER]

Objective:To define the characteristics of synthetic cathinone users admitted to hospital including clinical and laboratory parameters and the complications of use. Design:Retrospective single-center study of patients treated for acute cathinone intoxication and complications of cathinone use between January 2010 and January 2016. Setting:A specialized clinical toxicology unit at an academic tertiary care center in Southern Germany serving a population of about 4 million. Patients and methods:81 consecutive patients with laboratory-confirmed use of cathinones who presented for acute intoxication or complications of cathinone use were retrospectively analyzed. Results and conclusions:The patients were predominantly male (64%, 52/81) with a median age of 34 years. 60 were admitted for signs of acute intoxication while 21 suffered from complications of cathinone use. 70% of acutely intoxicated patients had an increased creatinine phosphokinase. Only a minority of patients presented with a sympathomimetic toxidrome. Three patients had infectious complications, 10 prolonged psychosis, 6 rhabdomyolyses and/or kidney failure, and two patients died. Based on presentations, cathinone use has increased with the first cases seen in 2010. Opiates/opioids are the main co-ingested drugs of abuse. The pattern of cathinone use shifted from methylone in 2010/2011 to 3,4-methylenedioxypyrovalerone (MDPV) and 3-methylmethcathinone (3-MMC) in 2014/2015. We conclude that in our setting “typical“ cathinone users are males in their thirties. They are seldom drug naïve and regularly co-ingest illicit drugs. Preventive measures have to be tailored to these difficult to reach patients. Present efforts to educate young clubbers in their late teens may fail to reach the pertinent demographic. [ABSTRACT FROM PUBLISHER]

Colchicine concentration was determined in serum, plasma and urine samples using a validated HPLC-MS/MS method after alkaline liquid extraction. Plasma exchange has been performed [[4]] in the hope of removing significant quantities of colchicine as up to 50% plasma protein binding has been reported. To the Editor, Colchicine inhibits microtubule assembly and cell division. [Extracted from the article]

Objective: To independently validate the predictive value of the intensive care requirement score (IRS) in unselected poisoned patients. Design: Retrospective chart review. Patients and methods: Five hundred and seventeen out of 585 admissions for acute intoxications could be analyzed. Eleven were excluded for a condition already requiring intensive care unit (ICU) support at admission (e.g., preclinical intubation). A further 57 admissions were excluded due to missing data. The IRS was calculated using a point-scoring system including age, Glasgow Coma Scale, heart rate, type of intoxication, and preexisting conditions. It was then compared to a composite endpoint indicating an ICU requirement (death in hospital, vasopressors, need for ventilation). The endpoint and the point-scoring system were identical to the original publication of the score. Results and conclusion: Twenty-three out of 517 patients had a complicated clinical course as defined by meeting the endpoint definition. Twenty-one out of 23 complicated courses had a positive IRS (defined as greater or equal 6 points), as compared to 255/494 patients with an uncomplicated clinical course (p < .001, Fisher’s exact test). One patient (with a positive IRS) died. The negative predictive value of the IRS was 0.99 (95% CI: 0.97-1), the sensitivity was 0.91 and the specificity 0.48. In conclusion, the IRS is significantly linked to outcome. While a negative IRS virtually excludes the need for ICU care, a positive IRS has a positive predictive value too low to be used for risk stratification. The IRS could also be applied to unselected admissions of poisoned patients. [ABSTRACT FROM AUTHOR]

Small-angle scattering methods have become routine techniques for the structural characterization of macromolecules and macromolecular assemblies like polymers, (block) copolymers or micelles in the spatial range from a few to hundreds of nanometres. Neutrons are valuable scattering probes, because they offer freedom with respect to scattering length density contrast and isotopic labelling of samples. In order to gain maximum benefit from the allotted experiment time, the instrumental setup must be optimized in terms of statistics of scattered intensity, resolution and accessible range in momentum transfer Q. The new small-angle neutron scattering instrument V16/VSANS at the Helmholtz-Zentrum in Berlin, Germany, augments neutron guide collimation and pinhole optics with time-of-flight data recording and flexible chopper configuration. Thus, the available Q range and the respective instrumental resolution in the intermediate and high momentum transfer regions can be adjusted and balanced to the individual experimental requirements. This renders V16/VSANS a flexible and versatile instrument for soft-matter research. [ABSTRACT FROM AUTHOR]

Small-angle scattering methods have become routine techniques for the structural characterization of macromolecules and macromolecular assemblies like polymers, (block) copolymers or micelles in the spatial range from a few to hundreds of nanometres. Neutrons are valuable scattering probes, because they offer freedom with respect to scattering length density contrast and isotopic labelling of samples. In order to gain maximum benefit from the allotted experiment time, the instrumental setup must be optimized in terms of statistics of scattered intensity, resolution and accessible range in momentum transfer Q. The new small-angle neutron scattering instrument V16/VSANS at the Helmholtz-Zentrum in Berlin, Germany, augments neutron guide collimation and pinhole optics with time-of-flight data recording and flexible chopper configuration. Thus, the available Q range and the respective instrumental resolution in the intermediate and high momentum transfer regions can be adjusted and balanced to the individual experimental requirements. This renders V16/VSANS a flexible and versatile instrument for soft-matter research. [ABSTRACT FROM AUTHOR]

Abstract: Organophosphate poisoning is associated with a high mortality rate due to respiratory failure, dysrhythmias, and multi-organ failure. We report two cases of survival after “in-the field” antidote treatment of very severe organophosphate poisonings. Two patients orally ingested large amounts of the organophosphorous agent oxydemeton-methyl in suicide attempts, resulting in the hypercholinergic syndrome in both. Resuscitation included early administration of antidote by emergency medical personnel as well as high-dose atropine. Plasma levels of pseudo cholinesterase were initially very low in both patients. Long-term mechanical ventilation was necessary, and both patients developed aspiration pneumonia. At discharge, no major neurological deficits were present. Prompt antidote treatment and aggressive supportive emergency and intensive care unit therapy contribute to improved survival after acute organophosphate poisoning. We believe that in cases of mass poisonings—for example, terrorist activity—therapy must be available on the scene as soon as possible. This also may require decentralized antidote storage. [Copyright &y& Elsevier]

Background/Aims: Large-volume paracentesis in patients with cirrhosis and ascites induces arterial vasodilatation and decreases effective arterial blood volume, termed paracentesis-induced circulatory dysfunction (PICD), which can be prevented by costly intravenous albumin. Vasoconstrictors, e.g. terlipressin, may also prevent PICD. The aim was to compare the less expensive vasoconstrictor midodrine, an α-adrenoceptor agonist, with albumin in preventing PICD. Methods: Twenty-four patients with cirrhosis and ascites were randomly assigned to be treated with either midodrine ( n=11) (12.5 mg three times per day; over 2 days) or albumin ( n=13) (8 g/L of removed ascites) after large-volume paracentesis. Effective arterial blood volume was assessed indirectly by measuring plasma renin and aldosterone concentration on days 0 and 6 after paracentesis; renal function and haemodynamic changes were also measured. PICD was defined as an increase in plasma renin concentration on day 6 by more than 50% of the baseline value. Results: PICD developed in six patients of the midodrine group (60%) and in only four patients (31%) of the albumin group. Six days after paracentesis, the aldosterone concentration increased significantly in the midodrine group, but not in the albumin group. Conclusions: This pilot study suggests that midodrine is not as effective as albumin in preventing circulatory dysfunction after large-volume paracentesis in patients with cirrhosis and ascites. [ABSTRACT FROM AUTHOR]

The addition of rituximab to chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) has been shown to improve outcome in first-line therapy. However, in patients with relapsed or refractory disease, the value of adding rituximab to salvage chemotherapy is less clearly defined. This study performed a matched-pair analysis of patients with relapsed or refractory DLBCL by comparing the combination of dexamethasone, high-dose cytarabine and cisplatin (DHAP) with rituximab to DHAP alone. Sixty-seven patients with relapsed or refractory DLBCL were collected from two prospective phase II trials from Germany and Italy. Twenty-three patient pairs treated with either DHAP in combination with rituximab or DHAP alone could be analysed after matching for important prognostic factors. The addition of rituximab to the DHAP regimen led to higher complete and similar overall remission rates. However, differences with regard to complete remission rates failed to reach statistical significance, thereby necessitating further evaluation of the role of combined immunochemotherapy in this patient population. [ABSTRACT FROM AUTHOR]

We designed a multicenter Phase II trial to prospectively evaluate the efficacy and safety of the combination of rituximab with the DHAP regimen (dexamethasone, high-dose cytarabine, cisplatin) in patients who relapsed after or were resistant to a CHOP-like regimen. A total of 53 patients with relapsed or resistant aggressive B-cell NHL were analyzed. The overall response rate was 62.3 percent. With a median follow-up of 24.9 months, median overall and progression-free survivals were 8.5 and 6.7 months, respectively. Immunochemotherapy with rituximab and DHAP proved to be feasible and effective in this patient population. [ABSTRACT FROM AUTHOR]

Background/Aims: The induction of liver fibrosis is difficult in mice. Here, we intended to improve fibrosis induction by combination of thioacetamide (TAA) injections and ethanol (EtOH) feeding and to characterize features of liver damage in this model. Most experimental therapeutic studies are performed in mice without pre-damaged livers. Methods: C3H mice were injected three times/week (0.15mg/g body weight) and fed with EtOH. Tissue and serum samples were collected and analysed. Results: Portal fibrosis was verified by van Gieson staining showing a mild fibrosis (score F2) in TAA-treated mice and liver fibrosis (score F4) in the combination group using TAA/EtOH. Consonant with the histological results, the fibrosis marker MMP-2 and alpha 1 procollagen (I) were elevated at week 10 and 15 after treatment initiation in the combination group, whereas tissue protective proteinase, TIMP-1, was 18.5-fold increased only at week 10 but normalized until week 15. Fibrosis development was associated with elevated ICAM-1 expression. Conclusions: Taken together, TAA/EtOH application was suitable to induce liver fibrosis characterized by typical bio-markers in C3H/He. [Copyright &y& Elsevier]

Background: Neutropenic enterocolitis is a life-threatening complication most frequently occurring after intensive chemotherapy in acute leukaemias. Gramnegative bacteria constitute the most important group of causative pathogens. Fungi have also been reported, but their practical relevance remains unclear. The guidelines do not address concrete treatment recommendations for fungal neutropenic enterocolitis. Methods: Here, we conducted a metaanalysis to answer the questions: What are frequency and mortality of fungal neutropenic enterocolitis? Do frequencies and microbiological distribution of causative fungi support empirical antimycotic therapy? Do reported results of antimycotic therapy in documented fungal neutropenic enterocolitis help with the selection of appropriate drugs? Following a systematic search, we extracted and summarised all detail data from the complete literature. Results: Among 186 articles describing patients with neutropenic enterocolitis, we found 29 reports describing 53 patients with causative fungal pathogens. We found no randomised controlled trial, no good quality cohort study and no good quality case control study on the role of antifungal treatment. The pooled frequency of fungal neutropenic enterocolitis was 6.2% calculated from all 860 reported patients and 3.4% calculated from selected representative studies only. In 94% of the patients, Candida spp. were involved. The pooled mortality rate was 81.8%. Most authors did not report or perform antifungal therapy. Conclusion: In patients with neutropenic enterocolitis, fungal pathogens play a relevant, but secondary role compared to bacteria. Evidence concerning therapy is very poor, but epidemiological data from this study may provide helpful clues to select empiric antifungal therapy in neutropenic enterocolitis. [ABSTRACT FROM AUTHOR]

Pseudomembranous and obstructive Aspergillus tracheobronchitis (PMATB/OATB) are still considered to be refractory to therapy and to have a fatal outcome. To evaluate the optimal diagnostic strategy and to describe factors affecting the outcome of PMATB and OATB. Retrospective analysis of four new cases of PMATB and OATB combined with 16 previously reported cases over a 10-year period (1995–2004). Among the four new cases reported and the 16 published cases, four patients survived their infection. The mortality rate was significantly higher in the group of ventilated patients [94% (15 of 16 patients)] than in the group of non-ventilated patients [25% (1 of 4 patients), P < 0.05, Fisher's exact test]. In all 20 patients, diagnosis was established by bronchoscopy. Culture examination of mucous plugs was positive in 8 of 10, culture of the tracheobronchial aspirate was positive in 8 of 12, and bronchoalveolar lavage was diagnostic in 7 of 13 patients. All bronchoscopic techniques were complementary in improving the yield of bronchoscopy. However, microscopy of mucous plugs and/or necrotic material was the best diagnostic modality [positive in 94% (17 of 18 patients)]. Prognosis of PMATB and OATB remains poor. Microscopy of respiratory specimens is the most sensitive tool to confirm the diagnosis. The characteristic appearance of the disease makes it possible to start antifungal therapy immediately. [ABSTRACT FROM AUTHOR]

Methods: We applied an experimental approach employing two recombinant adenoviral vectors (Ad) that express interleukin-12 (IL-12) and angiostatin-like molecule (K1-3) respectively to a subcutaneous hepatoma model in mice. Results: Injection of AdK1-3 into tumour nodules established by subcutaneous (s.c.) implantation of Hepa129 hepatoma cells in C3H mice resulted in a significant dose-dependent reduction in tumour growth by 57% in the high dosage group (5 x 109 plaque-forming units [pfu], n=8) 10 days after treatment initiation. Similar anti-tumoural effects were found for the intratumoural mono-therapy with IL- 12 (2.5 x 109 pfu, n=8) resulting in 60% tumour inhibition at the same time point. The survival rate was significantly (p=0.009) improved in the IL-12 but not in the K1-3 treatment group. A combination therapy of AdK1-3 and AdIL-12 was also effective, but did not further improve antitumour efficacy compared with the monotherapy. Conclusion: In conclusion, both mono- and combination therapy of K1-3 and IL-12 significantly inhibited tumour progression in this experimental tumour model. The co-administration of both compounds did not result in additive antitumour effects. We hypothesise that the lack of additive antitumour effects of the combination treatment might be attributed to partially counteracting antitumour effects and further studies are needed to illustrate the interference of tumour angiogenesis and tumour inflammation in this tumour model. [ABSTRACT FROM AUTHOR]

Background/Aims: Transgenic mice overexpressing hepatitis B x protein (HBx) show an increased susceptibility to mutations if exposed to mutagens. Also involved in HBx signalling, reactive oxygen intermediates (ROI) can induce DNA adducts such as 8-hydroxy-2′-deoxyguanosine that can in turn lead to G/T transversion mutations. Therefore, we investigated whether HBx expression increases the level of the mutational precursor 8-hydroxy-2′-deoxyguanosine in hepatocellular DNA. Methods: 8-hydroxy-2′-deoxyguanosine concentrations of DNA hydrolysates of HBx protein expressing HepG2 cells and livers of HBx transgenic mouse lines were determined electrochemically after HPLC fractionation. Results: 8-hydroxy-2′-deoxyguanosine concentrations in genomic DNA of HBx protein expressing cell lines correlated with the factor of transactivation. The 8-hydroxy-2′-deoxyguanosine levels were reduced after incubation of HBx recombinant cell lines with 0.1 or 1 mM of the antioxidant N-acetylcysteine. Hepatic 8-hydroxy-2′-deoxyguanosine concentrations in DNA of old transgenic mice were significantly, i.e. twofold, (p < 0.01) increased as compared to those of old nontransgenic or young transgenic controls and of control mice expressing a second HBV transactivator (MHBst76). Conclusion: HBx expression results in elevated DNA adduct levels. This could reflect a direct inhibitory interaction of HBx with cellular repair mechanisms. Alternatively, this may be an effect of an increased generation of reactive oxygen intermediates through HBx. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

: Background/AimsIn this study we established an orthotopic tumour model for hepatocellular carcinoma and evaluated a non-invasive high resolution ultrasound technique for diagnosis and follow-up of intrahepatic HCC.: MethodsOrthotopic liver tumours were induced by intrahepatic tumour cell injection of 105 Hepa129 hepatoma cells. Tumour establishment and growth were assessed by explorative laparotomy, ultrasound technique and hepatectomy one and two weeks after tumour cell implantation. Tumour establishment was confirmed histologically in liver sections.: ResultsOur results show that the Hepa129 hepatoma cell line is suitable for orthotopic tumour establishment and that tumours can be diagnosed correctly by ultrasound imaging in all cases as confirmed by explorative laparotomy, hepatectomy and cross-sections. Tumour diameters obtained by explorative laparotomy correlated significantly with diameters assessed by ultrasound (r=0.7; P<0.0001). Tumour burden was slightly overestimated (1.2-fold) by ultrasound one week after tumour induction and relative tumour extensions increased 1.7-fold and 1.8-fold within one week as determined by subsequent explorative laparotomy or ultrasound imaging, respectively.: ConclusionsThese data demonstrate in a systematic study that ultrasound imaging can be used as a reliable tool to detect and to follow up orthotopic liver tumours in this tumour model in mice. [Copyright &y& Elsevier]

Background/Aim: Kidney function and portal pressure have prognostic relevance in nonshunted patients with cirrhosis. Since insertion of a transjugular intrahepatic portosystemic shunt (TIPS) reduces portal pressure and may improve the renal function, the aim of the present study was to investigate the prognostic role of renal impairment and portal hemodynamics in patients with compensated cirrhosis electively shunted due to recurrent variceal hemorrhages. Methods: Data of 101 consecutive and prospectively followed patients with compensated cirrhosis (bilirubin <5 mg/dl) undergoing elective TIPS due to recurrent variceal bleeding (45 died, and 8 were transplanted during the follow-up period) were evaluated in a multivariate Cox model. Results: Creatinine and sodium were identified as the only independent predictors of survival in this model. The 90th percentile of creatinine (>1.7 mg/dl) defined a subgroup with a similar poor prognosis as the 90th percentile of the model for end-stage liver disease (MELD) score. Neither baseline nor post-TIPS portal pressure correlated with the long-term outcome. Conclusions: In compensated patients undergoing TIPS due to variceal bleeding, renal impairment indicates a poor prognosis. Portal hemodynamic parameters are not predictive of survival in TIPS patients.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Vasodilatation – despite activation of endogenous vasoconstrictors – is pronounced in portal hypertension. We therefore investigated the role of Urotensin II (U II), a newly described peptide reported to be a vasoconstrictor in the central arterial compartment and a vasodilator in the splanchnic vasculature.Methods: U II immunoreactivity was measured in 50 patients with cirrhosis and in 15 healthy controls. U II levels were compared in portal venous and central venous blood of 30 patients immediately before transjugular intrahepatic porto-systemic stent shunt implantation.Results: U II levels (median, range, ng/ml) were significantly increased in cirrhotics (12.3, 1.6–41.4) compared to controls (3.6, 0.1–12.0; P<0.001). In patients with cirrhosis, U II levels were significantly higher in central venous (12.9, 2.5–41.4) than in portal venous blood (11.0, 0.6–31.9; P<0.005). U II levels were higher in ascitic than in non-ascitic patients (P<0.02). They correlated positively with the wedged hepatic venous pressure gradient (ρ=0.34, P<0.005) and negatively with the mean arterial pressure (ρ=−0.41; P<0.001).Conclusions: Urotensin II formation is upregulated in patients with cirrhosis and portal hypertension. The transhepatic gradient suggests a hepatic production of this peptide. [Copyright &y& Elsevier]

Algae production is increasing to supply the growing demand for Omega-3 fatty acids for aquaculture, human food and pet food; co-products from the algae industry could be a suitable feed ingredient for cattle feeding. A safety study was conducted to evaluate feeding algal biomass to cattle. Crossbreed cattle (20 steers and 20 heifers, 255 kg initial BW, SD=14) were individually fed 4 inclusions of condensed algal residue solubles (CARS; 0, 2.5, 5, 7.5 % of diet DM) displacing dry rolled corn in a finishing diet (62.5 to 70% corn and 15% distillers grains) for a minimum of 97 d. At harvest, organs were weighed and sampled. Blood was collected every 30 d. Performance data were analyzed as a RCBD with treatment, gender, and treatment by gender interactions as fixed effects, BW block as a random effect and individual animal as the experimental unit. Orthogonal contrasts were used to test for linear, quadratic and cubic responses due to CARS inclusion. Increasing CARS in the diet quadratically increased DMI and ADG (P ≤ 0.01). A linear increase was observed for G:F, NEm,and NEg as CARS increased in the diet (P < 0.01). All organ weights measured were within expected ranges for cattle, with 6 out of 27 having differences in weight due to treatment (P ≤ 0.05). Histopathology analysis of organs revealed no differences due to treatment (P ≥ 0.24). Out of 21 blood chemistry measures, 8 were affected by treatment (P ≤ 0.02). Nearly all blood chemistry parameters were within expected ranges for cattle. No adverse effects of feeding CARS were observed in hematology, blood chemistry, or histopathology analyses. The feedstuff CARS demonstrated to be a safe and efficacious feed ingredient for cattle diets and maximized HCW, ADG, and DMI when fed at 2.5 or 5% of the diet. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Effect of hemoperfusion on flecainide serum concentration-a case report" published in the previous issue is presented.