A comparison of the chemo- and radiotoxicity of thorium and uranium at different enrichment grades.

Uranium and thorium are heavy metals, and all of their isotopes are radioactive, so it is impossible to study chemical effects entirely independent of the radiation effects. In the present study, we tried to compare the chemo- and radiotoxicity of both metals, taking into account deterministic radiation damages reflected by acute radiation sickness and stochastic radiation damages leading to long-term health impairments (e.g., tumor induction). We made at first a literature search on acute median lethal doses that may be expected to be caused by chemical effects, as even acute radiation sickness as a manifestation of acute radiotoxicity occurs with latency. By simulations based on the biokinetic models of the International Commission on Radiological Protection and using the Integrated Modules for Bioassay Analysis software, we determined the amounts of uranium at different enrichment grades and thorium-232 leading to a short-term red bone marrow equivalent dose of 3.5 Sv considered to cause 50% lethality in humans. Different intake pathways for incorporation were considered, and values were compared to the mean lethal doses by chemotoxicity. To assess stochastic radiotoxicity, we calculated the uranium and thorium amounts leading to a committed effective dose of 200 mSv that is often considered critical. Mean lethal values for uranium and thorium are in the same order of magnitude so that the data do not give evidence for substantial differences in acute chemical toxicity. When comparing radiotoxicity, the reference units (activity in Bq or weight in g) must always be taken into account. The mean lethal equivalent dose to the red bone marrow of 3.5 Sv is reached by lower activities of thorium compared to uranium in soluble compounds. However, for uranium as well as thorium-232, acute radiation sickness is expected only after incorporation of amounts exceeding the mean lethal doses by chemotoxicity. Thus, acute radiation sickness is not a relevant clinical issue for either metal. Concerning stochastic radiation damages, thorium-232 is more radiotoxic than uranium if incorporating the same activities. Using weight units for comparison show that for soluble compounds, thorium-232 is more radiotoxic than low-enriched uranium in the case of ingestion but even more toxic than high-enriched uranium after inhalation or intravenous administration. For insoluble compounds, the situation differs as the stochastic radiotoxicity of thorium-232 ranges between depleted and natural uranium. For acute effects, the chemotoxicity of uranium, even at high enrichment grades, as well as thorium-232 exceeds deterministic radiotoxicity. Simulations show that thorium-232 is more radiotoxic than uranium expressed in activity units. If the comparison is based on weight units, the rankings depend on the uranium enrichment grades and the route of intake.

Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Simulations of radioiodine exposure and protective thyroid blocking in a new biokinetic model of the mother-fetus unit at different pregnancy ages.

In the case of nuclear incidents, radioiodine may be released. After incorporation, it accumulates in the thyroid and enhances the risk of thyroidal dysfunctions and cancer occurrence by internal irradiation. Pregnant women and children are particularly vulnerable. Therefore, thyroidal protection by administering a large dose of stable (non-radioactive) iodine, blocking radioiodide uptake into the gland, is essential in these subpopulations. However, a quantitative estimation of the protection conferred to the maternal and fetal thyroids in the different stages of pregnancy is difficult. We departed from an established biokinetic model for radioiodine in pregnancy using first-order kinetics. As the uptake of iodide into the thyroid and several other tissues is mediated by a saturable active transport, we integrated an uptake mechanism described by a Michaelis-Menten kinetic. This permits simulating the competition between stable and radioactive iodide at the membrane carrier site, one of the protective mechanisms. The Wollf-Chaikoff effect, as the other protective mechanism, was simulated by adding a total net uptake block for iodide into the thyroid, becoming active when the gland is saturated with iodine. The model's validity was confirmed by comparing predicted values with results from other models and sparse empirical data. According to our model, in the case of radioiodine exposure without thyroid blocking, the thyroid equivalent dose in the maternal gland increases about 45% within the first weeks of pregnancy to remain in the same range until term. Beginning in the 12th pregnancy week, the equivalent dose in the fetal thyroid disproportionately increases over time and amounts to three times the dose of the maternal gland at term. The maternal and fetal glands' protection increases concomitantly with the amount of stable iodine administered to the mother simultaneously with acute radioiodine exposure. The dose-effect curves reflecting the combined thyroidal protection by the competition at the membrane carrier site and the Wolff-Chaikoff effect in the mother are characterized by a mean effective dose (ED50) of roughly 1.5 mg all over pregnancy. In the case of the fetal thyroid, the mean effective doses for thyroid blocking, taking into account only the competition at the carrier site are numerically lower than in the mother. Taking into account additionally the Wolff-Chaikoff effect, the dose-effect curves for thyroidal protection in the fetus show a shift to the left over time, with a mean effective dose of 12.9 mg in the 12th week of pregnancy decreasing to 0.5 mg at term. In any case, according to our model, the usually recommended dose of 100 mg stable iodine given at the time of acute radioiodine exposure confers a very high level of thyroidal protection to the maternal and fetal glands over pregnancy. For ethical reasons, the possibilities of experimental studies on thyroid blocking in pregnant women are extremely limited. Furthermore, results from animal studies are associated with the uncertainties related to the translation of the data to humans. Thus model-based simulations may be a valuable tool for better insight into the efficacy of thyroidal protection and improve preparedness planning for uncommon nuclear or radiological emergencies.

A comparison of thyroidal protection by iodine and perchlorate against radioiodine exposure in Caucasians and Japanese.

Radioactive iodine released in nuclear accidents may accumulate in the thyroid and by irradiation enhances the risk of cancer. Radioiodine uptake into the gland can be inhibited by large doses of stable iodine or perchlorate. Nutritional iodine daily intake may impact thyroid physiology, so that radiological doses absorbed by the thyroid as well as thyroid blocking efficacy may differ in Japanese with a very rich iodine diet compared to Caucasians. Based on established biokinetic-dosimetric models for the thyroid, we derived the parameters for Caucasians and Japanese to quantitatively compare the effects of radioiodine exposure and the protective efficacy of thyroid blocking by stable iodine at the officially recommended dosages (100 mg in Germany, 76 mg in Japan) or perchlorate. The maximum transport capacity for iodine uptake into the thyroid is lower in Japanese compared to Caucasians. For the same radioiodine exposure pattern, the radiological equivalent thyroid dose is substantially lower in Japanese in the absence of thyroid blocking treatments. In the case of acute radioiodine exposure, stable iodine is less potent in Japanese (ED50 = 41.6 mg) than in Caucasians (ED50 = 2.7 mg) and confers less thyroid protection at the recommended dosages because of a delayed responsiveness to iodine saturation of the gland (Wolff-Chaikoff effect). Perchlorate (ED50 = 10 mg in Caucasians) at a dose of 1000 mg has roughly the same thyroid blocking effect as 100 mg iodine in Caucasians, whereas it confers a much better protection than 76 mg iodine in Japanese. For prolonged exposures, a single dose of iodine offer substantially lower protection than after acute radioiodine exposure in both groups. Repetitive daily iodine administrations improve efficacy without reaching levels after acute radioiodine exposure and achieve only slightly better protection in Japanese than in Caucasians. However, in the case of continuous radioiodine exposure, daily doses of 1000 mg perchlorate achieve a high protective efficacy in Caucasians as well as Japanese (> 0.98). In Caucasians, iodine (100 mg) and perchlorate (1000 mg) at the recommended dosages seem alternatives in case of acute radioiodine exposure, whereas perchlorate has a higher protective efficacy in the case of longer lasting radioiodine exposures. In Japanese, considering protective efficacy, preference should be given to perchlorate in acute as well as prolonged radioiodine exposure scenarios.

Pregnancy care in Germany, France and Japan: an international comparison of quality and efficiency using structural equation modelling and data envelopment analysis.

OBJECTIVES: Healthcare systems in developed countries may differ in financing and organisation. Maternity services and delivery are particularly influenced by culture and habits. In this study, we compared the pregnancy care quality and efficiency of the German, French and Japanese healthcare systems. STUDY DESIGN: Comparative healthcare data analysis. METHODS: In an international comparison based mainly on Organisation for Economic Co-operation and Development (OECD) indicators, we analysed the health resources significantly affecting pregnancy care and quantified its quality using structural equation modelling. Pregnancy care efficiency was studied using data envelopment analysis. Pregnancy output was quantified overall or separately using indicators based on perinatal, neonatal or maternal mortality. RESULTS: The density of obstetricians, midwives, paediatricians and the average annual doctor's consultations were positively and the caesarean delivery rate negatively associated with pregnancy outcome. In the international comparison at an aggregate level, Japan ranked first for pregnancy care quality, whereas Germany and France were positioned in the second part of the ranking. Similarly, at an aggregate level, the Japanese system showed pure technical efficiency, whereas Germany and France revealed mediocre efficiency results. Perinatal, neonatal and maternal care quality and efficiency taken separately were quite similar and mediocre in Germany and France. In Japan, there was a marked difference between a highly effective and efficient care of the unborn and newborn baby, and a rather mediocre quality and efficiency of maternal care. CONCLUSION: Germany, France, and Japan have to struggle with quality and efficiency issues that are nevertheless different: in Germany and France, disappointing pregnancy care quality does not correspond to the high health care expenditures and lead to low technical efficiency. The Japanese system shows a high variability in outcomes and technical efficiency. Maternal care quality during delivery seems to be a particular issue that could possibly be addressed by legally implementing quality assurance systems with stricter rules for reimbursement in obstetrics.

The German and Japanese health care systems: an international comparison using an input-output model.

OBJECTIVES: The German and Japanese health care systems have common roots, but have evolved differently. Whereas the German system is often considered as expensive and poorly efficient, people in Japan are viewed as healthy and health care as comparatively cheap. In this study, we compared the quality, the effectiveness and efficiency of the German and Japanese health care systems. STUDY DESIGN: This study includes comparative health care data analysis. METHOD: The quality and effectiveness of the German and Japanese health care systems were analyzed using an input-output model including 12 countries based on health indicators published by the OECD. Besides the invested resources, a risk-related input dimension was used for risk adjustment. The efficiency of the systems was assessed by relating the average output to the health expenses per capita. RESULTS: Health risks seem qualitatively different in Germany and Japan, but at the aggregate level, lifestyle does not seem to be an outstanding explanatory factor for health outcome differences between both countries. For investments in health resources, Germany is in a top position, whereas in the international comparison, the outcome is rather poor. The resources invested in Japan are also high, but slightly less than in Germany, whereas on average, the outcome is better. However, in the international comparison, resources as well as results in Japan show a very high variability. Relating the average output to the health expenses per capita indicates that on the average, the health care system in Japan is more efficient than in Germany. CONCLUSION: Germany and Japan have a quality problem with their health care systems. In Germany there is a transmission failure from structural to outcome quality that might be related to coordination problems between the outpatient and inpatient sector. Japan shows an unbalanced system that may be suspected to have a quality problem as a whole. As the development of the remuneration system including quality requirements is under the direct responsibility and guidance of the Ministry of Health in Japan, the issue might however be more easily solved in Japan than in Germany. Although on average, health care seems more efficient in Japan than in Germany, taking into account health as well as long-term care expenses and uncertainties related to exchange rate adjustments, the higher efficiency of the Japanese system becomes questionable.

Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome.

Growth retardation resulting in short stature is a major concern for parents and due to its great variety of causes, a complex diagnostic challenge for clinicians. A major locus involved in linear growth has been implicated within the pseudoautosomal region (PAR1) of the human sex chromosomes. We have determined an interval of 170 kb of DNA within PAR1 which was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3. This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. We have isolated a homeobox-containing gene (SHOX) from this region, which has at least two alternatively spliced forms, encoding proteins with different patterns of expression. We also identified one functionally significant SHOX mutation by screening 91 individuals with idiopathic short stature. Our data suggest an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients.

Macrocephaly, obesity, mental (intellectual) disability, and ocular abnormalities: alternative definition and further delineation of MOMO syndrome.

MOMO syndrome, previously defined as Macrosomia, Obesity, Macrocephaly, and Ocular abnormalities (OMIM 157980) is a rare intellectual disability syndrome of unknown cause. We describe two further patients with MOMO syndrome. Reported data of patients with MOMO syndrome and our own findings indicate that overgrowth does not appear to be a specific feature. We propose to form the acronym "MOMO" from Macrocephaly, Obesity, Mental (intellectual) disability, and Ocular abnormalities, excluding macrosomia from the syndrome name. The combination of obesity, macrocephaly, and colobomas is unique, therefore these features can be used as major diagnostic criteria of MOMO syndrome.

A new autosomal dominant syndrome of distinctive face showing ptosis and prominent eyes associated with cleft palate, ear anomalies, and learning disability.

We report on three patients from two families with apparently a novel clinical entity. The main features of which include unusual craniofacial dysmorphism with ptosis, prominent eyes, flat midface, Cupid's bow configuration of the upper lip, low-set, posteriorly rotated small ears, as well as conductive hearing loss, cleft palate, heart defect, and mild developmental delay. We suggest that this entity is an autosomal dominant disorder given the occurrence in a mother and daughter as well as in an unrelated boy.

A quantitative comparison of the chemo- and radiotoxicity of uranium at different enrichment grades.

OBJECTIVE: The radiotoxic effects of uranium are often in the focus of the public fears but the chemical toxic effects of uranium are reported to surpass radiation effects. As there is no uranium isotope that is not radioactive, it is not possible to study chemical effects fully independently from radiation effects. In order to quantitate and compare radio- and chemotoxicity, we determined the median lethal doses of uranium due to its chemical toxicity and calculated the absorbed radiological doses resulting from the ingestion or inhalation of corresponding amounts depending on the isotopic enrichment grade. Committed effective doses over 50 years are related to the stochastic health effects like cancer occurrence and can be converted to a loss of statistical life time (mean loss 0.4 day / mSv). The equivalent doses absorbed within a short time frame permits conclusion on the induction of deterministic effects (e.g. acute radiation sickness). METHOD: Simulations were based on the biokinetic models of the International Commission for Radioprotection and performed using Integrated Modules for Bioassay Analysis software. Results were compared with the doses given by the calculator of the WISE uranium project. The fractions of the total doses absorbed within different time periods were derived from the respective areas under the activity-time curves in the whole body. RESULTS: The distribution of the total dose on the organs and tissues depends on the invasion pathway and the solubility of the compound. In the case of inhalation, the absorption of the total dose is more protracted than after ingestion. The incorporation of depleted or natural uranium in lethal amounts due to nephrotoxicity does not lead to deterministic radiation effects and is associated with committed effective doses reaching at most about 200 mSv (proposed possible threshold for therapeutic interventions after accidental radionuclide incorporation). The inhalation of low enriched uranium leads to higher effective doses up to 690 mSv, but they are still insufficient to cause acute deterministic effects. Even highly enriched uranium seems not to induce radiation nephropathy, but deterministic effects on the hematopoetic system cannot be excluded in particularly sensitive patients. But the equivalent doses to the lungs associated with the inhalation of poorly soluble compounds of highly enriched uranium are in a range that may induce radiation pneumonitis. CONCLUSION: Our findings give clear evidence that for depleted and natural uranium chemical toxicity is much more marked than radiotoxicity. However, this conclusion must not be drawn for enriched and in particular highly enriched compounds that besides stochastic effects may even cause deterministic radiation effects.

PUF60-SCRIB fusion transcript in a patient with 8q24.3 microdeletion and atypical Verheij syndrome.

Expression of the fusion genes is considered to be an important mechanism of tumorigenesis. However it is hardly ever discussed in relation to the neurodevelopmental disorders. Here we report on an 18-years-old female patient with 13.1 kb deletion of 8q24.3 fusing the 5'-portion of SCRIB with the 3'-portion of PUF60 and presenting with borderline intellectual disability, eye coloboma, short stature, scoliosis, heart defects and interestingly postnatal megalencephaly, in contrast to microcephaly, which is usually associated with 8q24.3 deletion (Verheij syndrome). Using next generation sequencing we mapped the breakpoints at nucleotide resolution and showed that the deletion preserved the reading frame. In contrast to the laborious techniques previously used for the precise mapping of deletion breakpoints, our approach identified an accurate interval very rapidly. We demonstrated the expression of the PUF60-SCRIB fusion gene in patient's cells and suggest that the fusion transcript might be a cause of the atypical clinical presentation.

Reconsidering Current Decorporation Strategies after Incorporation of Radionuclides.

In the case of a nuclear accident or a terrorist attack by a "dirty bomb," there is a risk of external and internal contamination with radionuclides in addition to external irradiation. Internal irradiation as a consequence of radionuclide incorporation is associated with a higher risk of stochastic radiation effects (e.g., tumors). Decorporation treatment will enhance the elimination of radionuclides and reduce the committed effective dose as a metric of stochastic health effects. Although treatment efficacy is better when started early, beginning the therapy without knowing the committed effective dose may unnecessarily expose the patient to the side effects of the medication. The question is: Delay the therapy to wait for the results of internal dosimetry or start the therapy promptly on spec? To prove insight into this question, a selective review of the literature was conducted. The importance of the initiation time of treatment in the efficacy of decorporation treatment can be explained with pharmacokinetic laws and first order processes determining the disposition of xenobiotics in the organism. Nevertheless, there is no internationally accepted standard on when to start a decorporation therapy (exception: iodide). The "precautionary approach," emphasizing the importance of the committed effective dose for the indication of treatment, is competing with the "urgent approach" advocating the administration of medication "a priori" within several hours. A review of the literature actually indicates that the most important drugs used for decorporation are well tolerated with few adverse effects. In consideration of the higher efficacy and the low side-effects of a short-term treatment, initiating decorporation therapy as soon as possible after internal contamination, even before the committed effective dose has been assessed, appears to be a reasonable approach. The decision of continuation or discontinuation of the therapy should be taken after internal dosimetry is completed on the basis of the committed effective dose.

The Impact of Time on Decorporation Efficacy After a "Dirty Bomb" Attack Studied by Simulation.

Background: In the case of a nuclear or radiological incident, there is a risk of external and internal contamination with radionuclides in addition to external irradiation. There is no consensus whether decorporation treatment should be initiated right away on spec or pending the results of internal dosimetry to determine the indication. Method: Based on biokinetic models for plutonium-239, americium-241 and cesium-137, the efficacy of a decorporation treatment using DTPA or Prussian blue was simulated depending on the initiation time and the duration of treatment for different invasion pathways and physicochemical properties of the inhaled compounds. Results: For the same level of radioactivity incorporated, the committed effective dose increases with the speed of the invasion process. The impact of the initiation time of a decorporation treatment is particularly important when the absorption of the radionuclide is fast. Even if started early after incorporation, the therapeutic efficacy is less for americium-241 or cesium-137 compared to plutonium-239. Therapeutic efficacy increases with treatment duration up to about 90 days for plutonium-239 and cesium-137, whereas a prolongation of the treatment over this limit may further enhance efficacy in the case of americium-241. Conclusion: In the case of a nuclear incident, several fractions with different but a priori unknown physicochemical properties may be inhaled. Thus, decorporation therapy should be started as soon as possible after the incorporation of the radionuclide(s), as a loss of efficacy caused by a delay of treatment initiation possibly cannot be compensated later on. Treatment should be pursued for several months.

Nucleotide sequence of a 24,206-base-pair DNA fragment carrying the entire nitrogen fixation gene cluster of Klebsiella pneumoniae.

The complete nucleotide sequence (24,206 base-pairs) of the Klebsiella pneumoniae gene region for nitrogen fixation (nif) is presented. Coding regions corresponding to the 19 known nif genes (including nifW and nifZ) could be identified. An additional open reading frame of 216 base-pairs, called nifT, was detected between nifK and nifY. Search for transcriptional signal structures revealed some unusual features: (1) several possible NifA-binding motifs are present in the intergenic regions between nifJ and nifH as well as between nifX and nifU; (2) a perfect NifA-binding motif, preceding the nifENX promoter, is located within an inverted repeat structure; (3) structures resembling the consensus nif promoter are found within the coding regions of nifW and nifZ and, together with a NifA-binding motif, in nifN. Typical rho-independent termination structures were detected only downstream from the nifHDKTY and the nifBQ operons. Analysis of the deduced amino acid sequences revealed the presence of two Cys-X2-Cys-X2-Cys-X3-Cys-Pro clusters in the pyruvate-flavodoxin oxidoreductase NifJ. This arrangement of cysteine residues is normally present only in ferredoxins. A high degree of homology between the two gene products (NifE and NifN) involved in iron-molybdenum cofactor biosynthesis and the two nitrogenase component I structural proteins (NifD and NifK) was found. All four proteins are characterized by the conserved motif His-Gly-X2-Gly-Cys, which may play a role in binding the iron-molybdenum cofactor.

Editing of GluR2 RNA in the gerbil hippocampus after global cerebral ischemia.

Postischemic delayed neuronal death (DND) in CA1 of the gerbil hippocampus is thought to be caused by an abnormal increase of Ca2+ influx into the cell, mediated by excessive activation of glutamate receptors. One subtype of glutamate receptors, the AMPA receptor, is not permeable to calcium ions as long as an edited form of its GluR2 subunit is present. It is possible that global ischemia interferes with the posttranscriptional editing of the GluR2 mRNA and thus leads to calcium influx via the AMPA receptor. In order to test this hypothesis, we examined the extent of GluR2 RNA editing in CA1 and CA3 microdissected from gerbil hippocampus after 5 min of global ischemia and various recirculation intervals. At each interval tested, quality and quantity of mRNA editing in the vulnerable CA1 region were the same as in CA3. Furthermore, postischemic mRNA editing in both hippocampal regions was indistinguishable from editing in untreated control animals. Our results clearly demonstrate that global ischemia does not cause impairment of GluR2 RNA editing, which is thus not responsible for the abnormal calcium permeability of the postischemic cell membrane.

Tandem arrangement of tRNA(Asp)-encoding genes in Phytophthora spp.

We have cloned a region of repetitive DNA from the phytopathogenic fungus, Phytophthora parasitica. The cloned region consists of 17 highly homologous units arranged in tandem. The consensus sequence is 562 bp long and carries the information for a tRNA(Asp). All sequence motifs required for efficient RNA polymerase III transcription are present, and the tRNA derived from the nucleotide sequence is able to form a complete cloverleaf structure with high homology to previously characterized tRNA(Asp) molecules. The isolated tRNA(Asp) gene cluster is located at a distance of 20 kb from the TRP1 gene of P. parasitica. It comprises about 0.1% of the total genomic DNA. Similar clusters were detected in four other Phytophthora species.

A quantitative comparison of functional and anti-ischaemic effects of the phosphodiesterase-inhibitors, amrinone, milrinone and levosimendan in rabbit isolated hearts.

1. The functional and anti-ischaemic effects of the phosphodiesterase (PDE)-inhibitors, amrinone, milrinone and levosimendan, a new agent combining PDE-inhibitory with calcium-sensitizing properties, were investigated in rabbit isolated hearts (Langendorff, constant pressure: 70 cmH2O, Tyrode solution, Ca2+ 1.8 mmol l-1, 37 degrees C). Anti-ischaemic effects were studied in electrically-driven hearts (200 beats min-1). Acute regional ischaemia was induced by ligature of a branch of the circumflex coronary artery and quantified from epicardial NADH-fluorescence photography. 2. Cumulative concentration-response curves in spontaneously beating hearts in the presence of isoprenaline (10(-10) M), showed a higher inotropic and coronary vasodilator potency for levosimendan (EC50: 7 x 10(-7) M) compared to milrinone (EC50: 7.7 x 10(-6) M) or amrinone (EC50: 2 x 10(-5) M). Although the maximal coronary dilator activity was similar for the three agents, the maximal inotropic and chronotropic effects were lower for levosimendan than for amrinone or milrinone (P < 0.05). 3. In regionally ischaemic hearts, milrinone (10(-5) M) or levosimendan (5 x 10(-6) M) similarly enhanced the left ventricular pressure (+15-20%) (P < 0.05) and the global coronary flow (+40-50%) (P < 0.05). The epicardial NADH-fluorescence area was significantly diminished by milrinone or levosimendan (-20-30%) (P < 0.05) and there was no significant difference between the anti-ischaemic effects of either agent (P > 0.05). 4. It is concluded that amrinone and milrinone possess similar functional profiles in rabbit isolated hearts and a higher inotropic and chronotropic efficacy than levosimendan. At functionally equieffective concentrations, milrinone and levosimendan show similar anti-ischaemic effects, related to an improvement of myocardial perfusion. The calcium-sensitizing properties seem not to be relevant for cardioprotection by levosimendan at the concentration used.

Controlled release of antibiotics from biomedical polyurethanes: morphological and structural features.

Polymer-associated infections are of increasing importance. Antistaphylococcal antimicrobial substances (ciprofloxacin, gentamycin, fosfomycin, flucloxacillin) were incorporated into polyurethanes by the solvent casting technique. Drug release rates, bacterial colonization and morphological features were evaluated to predict and understand the antimicrobial activity of these delivery systems. Drug release characteristics were investigated by standard bioassay and high-performance liquid chromatography (HPLC), and the physico-chemical mechanisms of the delivery were discussed. Ciprofloxacin hydrochloride showed a fast initial release rate, whereas gentamicin-base was characterized by a more continuous release type of behaviour. Bacterial colonization to the antibiotic-loaded polyurethanes was inhibited effectively by preparations showing a slower but more sustained antimicrobial delivery. Polyurethane-antibiotic combinations were most homogeneous for gentamicin-base and flucloxacillin as shown by scanning electron microscopy (SEM). In polymers loaded with fosfomycin and ciprofloxacin a granular structure of the crystallized drug embedded in the polyurethane matrix could be demonstrated. Physico-chemical similarity of the polymeric material and the antibiotics is important for the homogeneity of polymer-antibiotic combinations. High homogeneity is required for a sustained and prolonged release over time and effective inhibition of bacterial colonization.

Evaluation of an efavirenz-containing regimen: an open-label, multicenter study.

PURPOSE: Efavirenz (EFV) has been shown to be a highly effective HIV therapy in antiretroviral-naïve patients when used with nucleoside reverse transcriptase inhibitors. METHOD: The study participants were 314 patients, 45 of whom had not been previously treated with any antiretroviral medication. The other patients were heavily pretreated for about 3 years (1,047 days); 34 with two nucleoside reverse transcriptase inhibitors, 147 with triple therapy, and 88 with a quadruple regimen. RESULTS: Suppression of plasma HIV-1 RNA to <50 copies/mL and <500 copies/mL was achieved in 56% and 72% of the pretreated patients and in 82% and 91% of the naïve patients, respectively, at week 80 (intention-to-treat analysis: noncompleters = failure: 10% and 15% and 20% and 22%, respectively). The viral load reduction at week 80 was 0.7 log(10) for the pretreated patients and 2.6 log(10) for the naïve patients. CD4 cell counts increased from 386 to 474 cells/microL at week 80 in the pretreated group and from 264 to 431 in the naïve patients. 118 patients discontinued the treatment due to adverse events (37 patients due to nervous system symptoms and 15 patients because of exanthema). There were no AIDS-defining events in the group of antiretroviral-treated patients. CONCLUSION: EFV in combination with nucleoside reverse transcriptase inhibitors as antiretroviral therapy was potent and effective in reducing viral load, mainly in treating therapy-naïve patients and in preventing AIDS-defining events.

Cardioprotection by ramiprilat in isolated rabbit hearts.

The anti-ischemic properties of the ACE inhibitor ramiprilat (ram) were investigated in electrically driven Langendorff hearts from rabbits whose endogenous angiotensin-I content has been previously shown to be very low (constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l). Cumulative concentration-response curves showed that the reduction in global coronary flow (CF) by exogenous angiotensin-I was concentration dependently inhibited by ram (P < 0.05). Myocardial ischemia (MI) was induced by occlusion of a left coronary artery branch and MI was quantified by NADH surface fluorescence photography. MI was significantly enlarged (+23%) (P < 0.05) by exogenous angiotensin-I (6 x 10(-9) mol/l). Addition of ram (10(-8) mol/l) to the perfusion buffer simultaneously with angiotensin-I, completely prevented the reduction of CF by angiotensin-I (P > 0.05) and significantly diminished MI even below control values (-25%) (P < 0.05). In the absence of exogenous angiotensin-I, ram alone (10(-8) mol/l) did not significantly enhance CF (P > 0.05), supporting findings demonstrating a very low endogenous angiotensin-I content in isolated rabbit hearts. However, ram alone (10(-8) mol/l) significantly diminished MI (-24%) (P < 0.05). We conclude that ram does possess direct cardioprotective properties that are independent of the inhibition of angiotensin-II generation but that may be related to potentiation of the effects of bradykinin.