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.

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.

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.

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.

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.

Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations.

ACTB and ACTG1 mutations have recently been reported to cause Baraitser-Winter syndrome (BRWS) - a rare condition characterized by ptosis, colobomata, neuronal migration disorder, distinct facial anomalies and intellectual disability. One of the patients carrying an ACTB mutation was previously diagnosed with Fryns-Aftimos syndrome (FAS), which is a rare and severe, multiple congenital anomaly (MCA) syndrome whose symptoms partially overlap with that of BRWS. However, several patients with Fryns-Aftimos were considered not to fit into the ACTB and ACTG1 spectrum because of their severe impairment and additional malformations. We report on three patients who had been diagnosed with FAS. All three patients carry a mutation in the ACTB gene. On the basis of the ACTB mutations and analysis of the clinical findings, we reclassify the diagnosis of these patients as severe BRWS. We suggest that mutations in ACTB cause a distinctly more severe phenotype than ACTG1 mutations, despite the structural similarity of beta- and gamma-actins and their overlapping expression pattern. We expand the spectrum of BRWS and confirm that FAS is not a separate entity but an early and severe manifestation of BRWS.

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.

[The prehospital use of antibiotics in military operations]. / L'usage préhospitalier d'antibiotiques en milieu militaire.

War wounds usually show abundant devitalized tissue and often contain foreign material (environmental matter, shrapnels, and bullets). Thus, they are particularly prone to infection. Moreover, evacuation to a medical treatment facility and surgical debridement are often delayed due to tactical constraints. Thus, the early administration of an antibiotic on the ground in a prehospital setting seems justified to slow bacterial growth and the development of early infection. However, antibiotics are never a substitute for surgical treatment. The mix of microorganisms expected in war wounds is highly variable and determines the choice of the antibacterial agent. In a prehospital setting and in the absence of medical or paramedical personnel, the antibiotic must be administered orally (combat pill pack). In view of the antibacterial activity as well as pharmacokinetic and pharmaceutical properties, a combination of a fluoroquinolone active against Pseudomonas and a lincomycine with a high oral bioavailability at high doses seems to be a rational choice (ciprofloxacine 750 mg or alternatively levofloxacine 500 mg+clindamycine 600 mg tablets). If oral administration is excluded (unconsciousness, penetrating abdominal trauma, shock), the parenteral administration will be delayed until the patient has been taken in charge by medical or paramedical personnel. In that case, the intravenous administration of an association of an ureidopenicilline with antibacterial activity against Pseudomonas and a ß-lactamase-inhibitor at high doses could be a rational choice (piperacilline 4 g+tazobactam 0.5 g) (Tazocilline®). An antibiotic treatment beyond the time of surgery may become necessary in individual patients depending on the local features of the wound and should be prescribed by the medical officer in charge of the patient on a case-by-case basis.

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.

Cerebral autoregulation is temporarily disturbed in the early recovery phase after dynamic resistance exercise.

AIM: To determine cerebral blood-flow velocity (CBFV) and parameters of dynamic cerebral autoregulation (CA) during and after exhausting resistance exercise. METHODS: Strength endurance (23 repetitions) and maximal strength training (8 repetitions) in 16 female and 16 male athletes on a leg curler (m. quadriceps training; approx. 2 s contraction) in the upright position. Registration of ECG, blood pressure by Finapres, CBFV by transcranial Doppler (TCD), and breathing by a Zak breathing-belt. Additional repetitive ergospirometry (O2-uptake, CO2-elimination, ventilation) and blood gas analyses were performed in a subgroup of seven athletes. From BP and CBFV cerebrovascular resistance (CVR), pulsatility index (PI) as well as LF-power, gain and phase-angle (frequency analysis) were derived. RESULTS: All athletes showed significant (p<0.01) 15 % to 30 % increases in CBFV during both training sets without signs of flow depression due to Valsalva maneuvers. In the early recovery, when blood pressure rapidly decreased, CBFV amplitude significantly (p<0.01) increased for 60-80 seconds with mean flow (Vm) at the exercise level, while CVR and PI showed conflicting results, similar to a presyncopal reaction. Ergospirometry and blood gas analyses revealed no evidence of major changes in pCO2, but phase angle was reduced (p<0.001) after exercise, together with an LF power increase (p<0.001). CONCLUSION: An unexpected increase in CBFV amplitude and in Vm occurs directly after dynamic resistance exercise without increased pCO2, which is comparable to a maximum leg press with hypercapnia. CVR and PI results as well as data from frequency analysis show similarities to presyncopal reactions, on the one hand, and point towards a temporarily disturbed cerebral autoregulation, on the other.

[Special aspects of implant-associated infection in orthopedic surgery. From the pathophysiology to custom-tailored prevention strategies]. / Besonderheiten der implantatassoziierten Infektion in der orthopädischen Chirurgie. Von der Pathophysiologie zu massgeschneiderten Präventionsstrategien.

One of the most important risk factors in orthopedic surgery is implant-associated infection. Adhesion and colonization mediated implant infections are extremely resistant to antibiotics and host defences and frequently persist until the biomaterial or foreign body is removed, which is standard therapy. Tissue damage caused by surgery and foreign body implantation increases the susceptibility to infections, activates host defences and stimulates the generation of inflammatory mediators including radicals that are further aggravated by bacterial activity and toxins. Nearly one third of implant-related infections can be prevented by strictly following established infection control guidelines. However, a significant number of implant-associated infections remains. The escape of bacteria from host defence and antibiotic therapy makes the development of infection-resistant materials as anti-microbial drug delivery systems feasible. This concept consists of the sustained delivery of antimicrobial drugs into the local microenvironment of implants avoiding systemic side effects exceeding usual systemic concentrations by magnitudes of order.

Evaluation of a didanosin-containing regimen including genotypic resistance testing: an open-label, multicenter study.

PURPOSE: To show Didanosin in a new formulation as a once-a-day capsula as a well-tolerated and effective HIV-therapy when used in a protease sparing regimen including genotypic resistance pattern in blood, semen and cerebrospinal fluid before and during treatment. METHOD: Two groups of 58 patients, each containing 9 patients who had not been previously treated with any antiretroviral medication, and 49 patients heavily pretreated for 3,7 (DDI group) and 2,8 (non-DDI group) years, have been followed up for at least half a year. A group of 24 patients taking a special combination of Didanosin plus Efavirenz and Stavudine have been analysed with genotypic resistance testing concerning viral load response and resistance pattern under therapy. RESULTS: Suppression of plasma HIV-1 RNA to <50 copies/mL and <500 copies/mL in the DDI group was achieved in 74% and 84% of the pretreated patients, respectively, and in 100% of the naive patients after 24 weeks. In the non-DDI group suppression was achieved in 59% and 69% of the pretreated patients, respectively, and in also 100% of the naive patients. The viral load reduction in the DDI containing regimen at week 24 was 1.7 log subset 10 for the pretreated and 3,4 log subset 10 for the naive patients. In the non-DDI group, the reduction was 1.5 for the pretreated and 4,0 for the naive patients. CD4 cell counts increased from 440 to 517 cells/microL at week 24 for the pretreated, and from 171 to 289 for the naive patients in the DDI containing regimen. In the other group, cells increased from 396 to 406 for the pretreated and from 155 to 321 for the naive patients. In each group, 12 patients discontinued treatment; 4 patients in the DDI group and 7 patients in the non-DDI group because of adverse events. There were no AIDS-defining events in the antiretroviral-treated patients in both groups. 16 patients of the special combination group (DDI, D4T and EFV) were evaluated for more than 24 weeks. Suppression of HIV-1 RNA to <50 copies /mL were found in 75% of the naive and 43% of the pretreated patients. No relevant mutations were found during treatment. CONCLUSION: The new formulation of Didanosin as a once-a-day capsula in a protease sparing regimen was well-tolerated, effective in reducing viral load and in preventing AIDS-defining events. The combination of DDI, D4T and EFV proved to be a potent therapy without developing relevant mutations.

Pharmacokinetics of the antimicrobial agents rifampicin and miconazole released from a loaded central venous catheter.

The time course of rifampicin and miconazole concentrations after insertion of a polyurethane catheter loaded with these antibiotics were studied. Data from controlled release experiments in vitro were used, and the concentration time courses of the antimicrobials in serum were calculated by pharmacokinetic simulations. Systemic therapy using typical dosages (rifampicin 600 mg/day iv, miconazole 3 x 200 mg/day iv) results in rifampicin concentrations between 54 and 8424 microg/L, and miconazole concentrations between 3567 and 4676 microg/L. After insertion of a polyurethane catheter loaded with these antibiotics, the maximal concentrations after catheter placement were determined as 6 microg/L at 10.7h for rifampicin, and 13 microg/L at 28.6 h for miconazole. Assuming that the total amount of antibiotics incorporated in the catheter matrix were bioavailable ('worst case'), the resulting maximal concentrations calculated by simulation are 10 microg/L for rifampicin and 65 microg/L for miconazole. Maximal concentrations of rifampicin or miconazole resulting from the insertion of a polyurethane catheter loaded with these antibiotics are, therefore, far below the concentrations resulting from a systemic therapy with the same antimicrobial agents. Even in the worst case, the danger of selecting resistant bacterial strains seems remote because the systemic drug levels are magnitudes of order below subinhibitory concentrations.

Pharmacokinetics of intra-arterial mitomycin C in the chemoembolization treatment of liver metastases with polyvinylalcohol or degradable starch microspheres.

OBJECTIVES: In cancer treatment, arterial blood flow reduction by embolization combined with intra-arterial chemotherapy may be advantageous by achieving high and prolonged drug concentrations in the tumor, and lower systemic drug exposure. The pharmacokinetics of intra-arterial mitomycin C (MMC) was investigated in patients with liver metastases undergoing chemoembolization treatment. METHODS: The chemoembolization treatment consisted of the use of polyvinylalcohol microspheres (ITC-Contour, diameter 150-250 micro m, irreversible vessel occlusion, 20 mg MMC, 15 patients) followed by sealing of the supplying artery with Ethibloc. Alternatively, starch microspheres (Spherex, diameter 45 micro m, biologically degradable, 10 ml of suspension containing 60 mg starch/ml, 20 mg MMC in 7 patients, 15 mg/m2 body surface in 3 patients) were used. MMC was infused over 6 min into the artery supplying the tumor. Serum MMC concentrations were determined from peripheral venous blood samples [protein precipitation with acetonitrile, reverse-phase HPLC with ultraviolet detection (C18 column, elution with 0.01 M, pH 6.5 phosphate buffer/methanol, v/v 70:30, 365 nm)]. The pharmacokinetic parameters were computed assuming an open two-compartment model and linear kinetics. RESULTS: The disposition parameters for MMC in patients treated with polyvinylalcohol microspheres were comparable to data from the literature (C(max)=913+/-98 ng/ml, T(max)=7.7+/-0.3 min, V(c)=0.27+/-0.03 l/kg, V(ss)=0.59+/-0.07 l/kg, Cl=757+/-67 ml/min, T(1/2 alpha)=5.8+/-0.8 min, T(1/2 beta)=50.4+/-4.1 min). There was no significant difference in the disposition parameters for MMC between patients treated with polyvinylalcohol microspheres and those treated with starch microspheres ( P>0.05). In particular, there was no significant difference in the standardized AUC between the groups; this implies that the systemic toxicity of MMC is comparable when polyvinylalcohol microspheres and ethibloc (AUC 1472+/-123 microg min/l per 1 mg MMC) or starch microspheres (AUC: 1448+/-172 microg min/l per 1 mg MMC) are used. CONCLUSION: The AUC values found in this study do not indicate a reduction in the systemic toxicity of MMC if applied intra-arterially in combination with embolizing microspheres, when compared to the AUC values in the literature for intra-arterial application without embolization, or intravenous MMC application. The amount of starch microspheres may have been too small to cause marked effects. On the other hand, there is a very wide range of AUC values reported in the literature for different application modes, and the use of such historical controls is not adequate for detecting more subtle advantages of the chemoembolization procedure, which may, however, exist.

Antiinfective and encrustation-inhibiting materials--myth and facts.

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.