[Constitution of a New Specialised Pediatric Home Care Team - First Year Experience]. / Aufbau eines Palliativteams für Kinder und Jugendliche (SAPV-KJ).

BACKGROUND: Since the amendment of the Social Law V in Germany in 2007 the financial basis for a Specialised Home Palliative Care for Children (SHPC) for children was established. In Hesse 3 different SHPC teams entered into collective negotiations with health insurance companies. In 2014, the team of the University Children's Hospital in Giessen started to treat the first patient with a lead time of two months. METHODS: Thus in this paper the development of a SHPC team is described. After the first year anonymized patients data were retrospectively analyzed. RESULTS: Within 12 months 35 patients, 24 females and 11 males, were treated. All of the 6 patients who died, died at home. Calculated 48 weeks survival was 78%. 45% of the patients suffered from malignancies, 34% of malformations and 34% had metabolic disorders. 51% needed crisis intervention and 51% infusion therapy. Only 26% of parents denied cardiopulmonary resuscitation (CPR). Only 10% of the patients or their families received professional psychological care. CONCLUSION: Formation of a SHPC is feasible within a short time period once a financial basis is established. So, empathic guidance of families to help decision making for emergency situations are considered to be important. Analysis of patient's data after one year could help to improve the quality of care. Our data provides information for developing a palliative care team und could motivate colleagues to start the job.

[Testicular cancer: a model to optimize the radiological follow-up]. / Cancer testicutaire: un modèle pour optimiser le suivi radiologique.

Despite being rare cancers, testicular seminoma and non-seminoma play an important role in oncology: they represent a model on how to optimize radiological follow-up, aiming at a lowest possible radiation exposure and secondary cancer risk. Males diagnosed with testicular cancer undergo frequently prolonged follow-up with CT-scans with potential toxic side effects, in particular secondary cancers. To reduce the risks linked to ionizing radiation, precise follow-up protocols have been developed. The number of recommended CT-scanners has been significantly reduced over the last 10 years. The CT scanners have evolved technically and new acquisition protocols have the potential to reduce the radiation exposure further.

[Recent advances in the treatment of adrenocortical carcinomas]. / Avancées recentes dans le traitement des carcinomes corticosurrénaliens.

Adrenocortical carcinomas are rare and aggressive malignant tumors, with an incidence of 1 to 2 cases per million inhabitants. Their diagnosis is made in three clinical situations: during the work up of a syndrome of hormonal hypersecretion, during the work up of locoregional symptoms, or incidentally during an unrelated radiological procedure. Surgery is usually indicated except in situations of advanced metastatic disease. Adjuvant chemotherapy with mitotane is associated with a significant increase in disease-free survival when the drug is administered at adequate therapeutic dosage. Novel anti-mitotic therapies have recently been described for treating recurrent adrenocortical carcinoma under mitotane treatment, but their overall efficacy remains unsatisfactory.

Finasteride-related Leydig cell tumour: report of a case and literature review.

Leydig cell tumours (LCTs) of the testis are rare. Their origin is still unknown. This case report describes a potential relationship between LCT and prolonged exposure to Finasteride.

Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement.

With six targeted agents approved (sorafenib, sunitinib, temsirolimus, bevacizumab [+interferon], everolimus and pazopanib), many patients with metastatic renal cell carcinoma (mRCC) will receive multiple therapies. However, the optimum sequencing approach has not been defined. A group of European experts reviewed available data and shared their clinical experience to compile an expert agreement on the sequential use of targeted agents in mRCC. To date, there are few prospective studies of sequential therapy. The mammalian target of rapamycin (mTOR) inhibitor everolimus was approved for use in patients who failed treatment with inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) based on the results from a Phase III placebo-controlled study; however, until then, the only licensed agents across the spectrum of mRCC were VEGF(R) inhibitors (sorafenib, sunitinib and bevacizumab + interferon), and as such, a large body of evidence has accumulated regarding their use in sequence. Data show that sequential use of VEGF(R) inhibitors may be an effective treatment strategy to achieve prolonged clinical benefit. The optimal place of each targeted agent in the treatment sequence is still unclear, and data from large prospective studies are needed. The Phase III AXIS study of second-line sorafenib vs. axitinib (including post-VEGF(R) inhibitors) has completed, but the data are not yet published; other ongoing studies include the Phase III SWITCH study of sorafenib-sunitinib vs. sunitinib-sorafenib (NCT00732914); the Phase III 404 study of temsirolimus vs. sorafenib post-sunitinib (NCT00474786) and the Phase II RECORD 3 study of sunitinib-everolimus vs. everolimus-sunitinib (NCT00903175). Until additional data are available, consideration of patient response and tolerability to treatment may facilitate current decision-making regarding when to switch and which treatment to switch to in real-life clinical practice.

[Active surveillance in prostate cancer]. / Surveillance active du cancer de la prostate.

Active surveillance in prostate cancer The spread of PSA in the screening of prostate cancer has almost doubled the incidence of this disease in the last twenty years. An improved understanding of the natural history of this cancer allows for risk stratification of the disease and to better predict insignificant prostate cancer. Active surveillance has recently been proposed as a new option to delay or avoid a radical treatment for patients with low-risk disease. The principle, results and future perspectives of this treatment modality are discussed in this review.

[Prostate cancer screening: an update]. / Dépistage du cancer de la prostate: actualité.

Prostate cancer screening using PSA is controversial because of a low specificity and detection of non clinically relevant cancer. Two important studies have been published recently. One of two studies suggests a 20% lowering in specific prostate cancer mortality due to PSA screening. This benefit is relevant but implies at a high risk of overtreatment and treatment-related complications. Currently PSA screening is only proposed as an individual screening for informed patients.

[Active surveillance for early-stage prostate cancer]. / La surveillance active dans la prise en charge du cancer de la prostate précoce.

Diagnostic and treatment management of prostate cancer at its initial stage continues to raise important debates within the involved medical community. To establish a protocol for active surveillance, a validated option in specific conditions of localised prostate cancer management for eight years, is a unique opportunity to gather different specialists in this field. This paper presents this concept.

Survival and PSA response of patients in the TAX 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa.

BACKGROUND: The TAX 327 study compared 3-weekly docetaxel, weekly docetaxel or 3-weekly mitoxantrone, each with prednisone, for 1006 patients with metastatic hormone-refractory prostate cancer. Survival and symptom control were superior following 3-weekly docetaxel as compared with mitoxantrone. At progression, many patients were treated with the other drug. Here, we provide a retrospective report of survival and prostate-specific antigen (PSA) response after second-line therapy. METHODS: The TAX 327 database provided information about treatment after progression on first-line therapy, and survival has been updated. Investigators were asked to provide information about crossover treatment and serial PSA values. RESULTS: We identified 232 crossover patients. Median survival after crossover was 10 months and did not depend on direction of crossover. Data on PSA response are available for 96 patients: PSA response (> or =50% reduction) occurred in 15% of 71 men receiving mitoxantrone after docetaxel and in 28% of 25 men receiving docetaxel after mitoxantrone. Median PSA progression-free survival was 3.4 months for mitoxantrone after docetaxel and 5.9 months for docetaxel after mitoxantrone. CONCLUSIONS: One quarter of men received crossover therapy and survival was similar in the crossover groups. The PSA response rate to docetaxel after mitoxantrone was higher than that for mitoxantrone after docetaxel.

A new member of the family of di-iron carboxylate proteins. Coq7 (clk-1), a membrane-bound hydroxylase involved in ubiquinone biosynthesis.

Ubiquinone (UQ) is an essential cofactor for respiratory metabolism. In yeast, mutation of the COQ7 gene results in the absence of UQ biosynthesis and demonstrates a role for this gene in the step leading to the hydroxylation of 5-demethoxyubiquinone. Intriguingly, the disruption of the corresponding gene in Caenorhabditis elegans, clk-1, results in a prolonged life span and a slowing of development. Because of the pleiotropic effect of this disruption, the small size of the protein, and the lack of obvious homology to other known hydroxylases, it has been suggested that Coq7 may be a regulatory or structural component in UQ biosynthesis, rather than acting as the hydroxylase per se. Here we identify Coq7 as belonging to a family of a di-iron containing oxidases/hydroxylases based on a conserved sequence motif for the iron ligands, supporting a direct function of Coq7 as a hydroxylase. We have cloned COQ7 from Pseudomonas aeruginosa and Thiobacillus ferrooxidans and show that indeed this gene complements an Escherichia coli mutant that lacks an unrelated 5-demethoxyubiquinone hydroxylase. Based on the similarities to other well studied di-iron carboxylate proteins, we propose a structural model for Coq7 as an interfacial integral membrane protein.

New insight into the structure and function of the alternative oxidase.

The alternative oxidase is a ubiquinol oxidase found in plant mitochondria, as well as in the mitochondria of some fungi and protists. It catalyzes a cyanide-resistant reduction of oxygen to water without translocation of protons across the inner mitochondrial membrane, and thus functions as a non-energy-conserving member of the respiratory electron transfer chain. The active site of the alternative oxidase has been modelled as a diiron center within a four-helix bundle by Siedow et al. (FEBS Lett. 362 (1995) 10-14) and more recently by Andersson and Nordlund (FEBS Lett. 449 (1999) 17-22). The cloning of the Arabidopsis thaliana IMMUTANS (Im) gene, which encodes a plastid enzyme distantly related to the mitochondrial alternative oxidases (Wu et al. Plant Cell 11 (1999) 43-55; Carol et al. Plant Cell 11 (1999) 57-68), has now narrowed the range of possible ligands to the diiron center of the alternative oxidase. The Im protein sequence suggests a minor modification to the recent model of the active site of the alternative oxidase. This change moves an invariant tyrosine into a conserved hydrophobic pocket in the vicinity of the active site, in a position analogous to the long-lived tyrosine radical at the diiron center of ribonucleotide reductase, and similar to the tyrosines near the diiron center of bacterioferritin and rubrerythrin. The Im sequence and modified structural model yield a compelling picture of the alternative oxidase as a diiron carboxylate protein. The current status of the relationship of structure to function in the alternative oxidase is reviewed.

A single amino acid change in the plant alternative oxidase alters the specificity of organic acid activation.

The alternative oxidase is a quinol oxidase of the respiratory chain of plants and some fungi and protists. Its activity is regulated by redox-sensitive disulphide bond formation between neighbouring subunits and direct interaction with certain alpha-ketoacids. To investigate these regulatory mechanisms, we undertook site-directed mutagenesis of soybean and Arabidopsis alternative oxidase cDNAs, and expressed them in tobacco plants and Escherichia coli, respectively. The homologous C99 and C127 residues of GmAOX3 and AtAOX1a, respectively, were changed to serine. In the plant system, this substitution prevented oxidative inactivation of alternative oxidase and rendered the protein insensitive to pyruvate activation, in agreement with the recent results from other laboratories [Rhoads et al. (1998) J. Biol. Chem. 273, 30750-30756; Vanlerberghe et al. (1998) Plant Cell 10, 1551-1560]. However, the mutated protein is instead activated specifically by succinate. Measurements of AtAOX1a activity in bacterial membranes lacking succinate dehydrogenase confirmed that the stimulation of the mutant protein's activity by succinate did not involve its metabolism. Examples of alternative oxidase proteins with the C to S substitution occur in nature and these oxidases are expected to be activated under most conditions in vivo, with implications for the efficiency of respiration in the tissues which express them.

Anaerobic expression of Escherichia coli succinate dehydrogenase: functional replacement of fumarate reductase in the respiratory chain during anaerobic growth.

Succinate-ubiquinone oxidoreductase (SQR) from Escherichia coli is expressed maximally during aerobic growth, when it catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid cycle and reduces ubiquinone in the membrane. The enzyme is similar in structure and function to fumarate reductase (menaquinol-fumarate oxidoreductase [QFR]), which participates in anaerobic respiration by E. coli. Fumarate reductase, which is proficient in succinate oxidation, is able to functionally replace SQR in aerobic respiration when conditions are used to allow the expression of the frdABCD operon aerobically. SQR has not previously been shown to be capable of supporting anaerobic growth of E. coli because expression of the enzyme complex is largely repressed by anaerobic conditions. In order to obtain expression of SQR anaerobically, plasmids which utilize the PFRD promoter of the frdABCD operon fused to the sdhCDAB genes to drive expression were constructed. It was found that, under anaerobic growth conditions where fumarate is utilized as the terminal electron acceptor, SQR would function to support anaerobic growth of E. coli. The levels of amplification of SQR and QFR were similar under anaerobic growth conditions. The catalytic properties of SQR isolated from anaerobically grown cells were measured and found to be identical to those of enzyme produced aerobically. The anaerobic expression of SQR gave a greater yield of enzyme complex than was found in the membrane from aerobically grown cells under the conditions tested. In addition, it was found that anaerobic expression of SQR could saturate the capacity of the membrane for incorporation of enzyme complex. As has been seen with the amplified QFR complex, E. coli accommodates the excess SQR produced by increasing the amount of membrane. The excess membrane was found in tubular structures that could be seen in thin-section electron micrographs.

Isolation of mutants of the Arabidopsis thaliana alternative oxidase (ubiquinol:oxygen oxidoreductase) resistant to salicylhydroxamic acid.

The plant-type ubiquinol:oxygen oxidoreductase, commonly called the alternative oxidase, is a respiratory enzyme thought to contain non-heme iron at its active site. To explore the structure of the enzyme by identifying amino acids involved in inhibitor-binding, a library of random mutants of the Arabidopsis thaliana alternative oxidase was constructed using error-prone polymerase chain reaction and expressed in the heme-deficient Escherichia coli SASX41B. Selection for resistance to salicylhydroxamic acid (SHAM) resulted in the recovery of four mutations. Three of these, F215L, M219I, and M219V, confer a small, but measurable resistance to SHAM of between 1.4- and 1.7-fold relative to the wild type alternative oxidase. These changes are located in a putative amphipathic helix following the second transmembrane helix. The fourth mutation, G303E, is found three residues from the C-terminus of the protein, and results in 4. 6-fold resistance to SHAM. None of the mutations have any effect on the sensitivity of the alternative oxidase to propyl gallate. The identification of distant residues involved in SHAM resistance suggests that the poorly conserved C-terminal region is in spatial proximity to the amphipathic helix, and thus located in the vicinity of the iron-binding motif.

[Windmill principle versus clockwork principle--tradition and interaction in academic lectures. A. N. S. A. Radiologica]. / Windmühlenprinzip versus Uhrwerkprinzip--Tradition und Interaktion in der akademischen Vorlesung. A. N. S. A. Radiologica.

In reply to depersonalization of teaching, students hiding behind anonymity and their decreasing effective presence in campus life, academic teaching has to become practice-oriented, attractive and at least more effective. The traditional teacher-based lecture competes with student-centered and issue-related academic events like problem-based learning, thus, concerning student-teacher interaction. The model of a clockwork represents the components of a traditional lecture. The model of a windmill is suitable for explaining synergistic effects in scope and experience during an interaction concerned lecture. An example of student-teacher interaction and students' activation even in a preclinical course of lectures on anatomy and radiology is given. A high response and acceptance of the lecture is assured by structure-and process-oriented features.

The deletion of petG in Chlamydomonas reinhardtii disrupts the cytochrome bf complex.

The 4-kDa protein encoded by chloroplast petG copurifies with the cytochrome bf complex of spinach and is found in a number of other photosynthetic organisms, including the eukaryotic alga Chlamydomonas reinhardtii. To determine whether petG is involved in the function or assembly of the cytochrome bf complex, the gene was cloned from C. reinhardtii, excised from the DNA fragment, and replaced with a spectinomycin resistance cassette. A petG deletion strain of C. reinhardtii was then obtained by biolistic transformation. The resulting homoplasmic petG deletion strains are unable to grow photosynthetically, and immunoblot analysis shows markedly decreased levels of cytochrome b6, cytochrome f, the Rieske iron-sulfur protein, and subunit IV. To verify that this phenotype was due to the removal of petG, we also constructed a strain with a deletion in the open reading frame (ORF56), which is found 25 base pairs downstream of petG. The ORF56 deletion strain grew photosynthetically and had wild-type levels of the four major cytochrome bf subunits. We conclude that the absence of the PetG protein affects either the assembly or stability of the cytochrome bf complex in C. reinhardtii.

Partial purification of the cyanide-resistant alternative oxidase of skunk cabbage (Symplocarpus foetidus) mitochondria.

A partial purification of the cyanide-resistant, alternative oxidase from skunk cabbage (Symplocarpus foetidus L.) spadix mitochondria is described. Skunk cabbage mitochondria were solubilized in N,N-bis-(3-D-glucon-amido-propyl)deoxycholamide and the alternative oxidase was purified using a batch DEAE-cellulose treatment, followed by precipitation with Extracti-Gel and chromatography on Sephadex G-200. Following pooling and concentrating of the most active fractions from the gel filtration column, a 20- to 30-fold purification of the alternative oxidase was obtained, with no evidence of contamination by cytochrome c oxidase (complex IV) or cytochrome c reductase (complex III). Polyacrylamide gel electrophoresis of the partially purified oxidase showed major polypeptides at 36 and 29 kD, both of which react with monoclonal antibodies raised against the Sauromatum guttatum alternative oxidase. The purified oxidase fraction showed no absorbance in the visible spectral region, and addition of sodium borohydride induced no absorbance changes in the ultraviolet region. The purified alternative oxidase catalyzed the four-electron reduction of oxygen to water in the absence of citrate, but catalyzed an apparent two-electron reduction of oxygen to hydrogen peroxide in the presence of 0.7 M citrate.

Determination of molecular mass of the aroid alternative oxidase by radiation-inactivation analysis.

The functional molecular mass of the cyanide-resistant salicylhydroxamate-sensitive duroquinol oxidase activity from Sympocarpus foetidus (skunk cabbage) and Sauromatum guttatum spadix mitochondria was determined by radiation-inactivation analysis. The functional molecular mass for the oxidase activity was found to be 26,700 Da for skunk cabbage and 29,700 Da for Sauromatum guttatum mitochondria frozen at -70 degrees C. Irradiation of dried mitochondrial samples resulted in a larger target size of 38,000 Da, and in some cases, a stimulation of activity at low dose of radiation. The functional molecular mass of cytochrome c oxidase activity from skunk-cabbage and bovine heart mitochondria was also investigated. Dried and frozen mitochondrial samples from both species yielded similar target sizes, in the range 70,900-73,400 Da. Purified bovine heart cytochrome c oxidase was also irradiated, and yielded a functional molecular mass of 66,400 Da. The target size of cytochrome c oxidase agrees with literature values insofar as the target size is considerably smaller than the molecular mass of the entire complex.