Adverse eVects Research Articles

Use of proteomics in radiobiological research: current state of the art

Biological systems are complex, variable and to a great extent adaptive to environmental and occupational challenge such as ionising radiation, making the mathematical modelling of their behaviour a diYcult task. The required models need to be based on useful experimental data describing global eVects on a cellular, tissue and organ level. High-throughput technologies such as proteomics have been shown to be powerful tools on many areas of modern biology. In radiation biology, especially facing the question of possible adverse health eVects following exposures to low doses of ionising and non-ionising radiation, new and sensitive approaches are slowly gaining support. Epidemiological studies suggest that doses of ionising radiation much lower than previously assumed may cause adverse eVects on human health. However, the epidemio

Toxicology at the interface of basic, applied, and clinical sciences

Toxicology, the study of the adverse eVects of chemicals on living organisms, represents an interdisciplinary science that requires both expertise on the chemical nature of the studied compounds and precise knowledge of the normal cellular mechanisms that can be compromised by toxic substances. In the clinical context, the contribution of toxicology is primarily the identiWcation of adverse eVects, ideally at an early stage of pharmaceutical drug development. In this context, it can be helpful if toxicologists also identify the mechanisms responsible for such adverse eVects. This knowledge can be particularly relevant when therapeutic and adverse eVects are due to diVerent mechanisms and can therefore contribute to a rational design of safer drugs. Editors of a toxicological journal, such as the Archives of Toxicology, sometimes Wnd themselves in the diYcult situation of deciding whether articles on basic cellular or physiological mechanisms remain within the focus of the journal. This is not a trivial matter as a clear demarcation line does not exist. Almost all critical control mechanisms of cells may become targets of toxic substances. For this reason, in previous years the editors have invited several articles focussing primarily on mechanisms. Examples are the recent reviews on mechanisms of telomere maintenance (Liew and Norbury 2009) and genomic instability (Florl and Schulz 2008). On the other hand, it is clear that articles concentrating on chemicals and their interactions with cellular mechanisms will stay a focus of the Archives of Toxicology. In order to address the Weld of tension between Toxicology, basic and clinical sciences, the editors are happy to announce a new cooperation with an interdisciplinary online journal named Experimental and Clinical Sciences (EXCLI Journal). EXCLI Journal includes mechanisms and clinical research relevant for Toxicology, but with a primary focus toward basic mechanisms and clinical aspects. EXCLI J is a relatively new journal and ongoing development is required to continuously improve its quality. However, EXCLI J is already evaluated by ISI Web of Knowledge and has been added to both the Directory of Open Access Journals (DOAJ) and the Electronic Journals Library (EZB), and will hopefully soon be included into PubMed. In order to give our readers an impression, we summarize below the take-home messages of selected articles of EXCLI J (Table 1).

Considerations on prostate cancer: diagnosis and treatment decisions

Discussion on the accuracy of PSA and biopsy for the selection of tailored treatment has been generated from several Welds. The inherent variability of total, free and complex PSA has been demonstrated. Analytical sample handling, laboratory processing, assay performance, and standardisation as well as biological variation are factors inXuencing its impact. Bogermann and colleagues from the University of Essen, Germany draw attention to the fact that diVerent pre-analytic timetables of blood samples in inpatient and out-patient setups lead to subsequent diVerent fPSA degradation, thereby shedding light on the need for diVerent cut-oV values for biopsy indication in these clinical settings. Prostate biopsy has evolved from a paradigm of a small number of random biopsies to a systematic, numerically standardised, and anatomically controlled strategy. Over the past several years, data have demonstrated the need for deWned biopsy strategies for detecting, accurately grading, and staging prostate cancer in varying patient populations. Saturation biopsy schemes have proven beneWcial in repeat biopsy and active surveillance protocols. Ploussard and colleagues from Creteil, Paris, France, report on how to follow-up prostate cancer detection with repeated biopsies after high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) following their initial 21-core extended biopsy scheme. Proving the sensitivity and speciWcity of artiWcial neuronl networks (ANN) for prostate cancer in a diVerent “statistical environment” is a necessary part of the evaluation of any ANN. Meijer and colleagues from Hertogenbosch, The Netherlands, report on their results on prostate biopsy predicting model of the ANN Prostataclass of the Universitatsklinikum Charite, Berlin, Germany, from their database. Trifecta (continence, potency and oncological result) has been the issue of discussions in recent years but lacking single center data for intra-institutional comparisons. Drouin and colleagues from Pitie-Salpetriere, University of Paris, France, compared the oncological midterm outcome over 50 months of patients treated during the same period in a single institution. Gilberti and colleagues from Savona, Italy present a prospective randomised trial including the mid-term follow-up data comparing brachytherapy with radical prostatectomy with regard to Trifecta. As with any other surgical treatment option, laparoscopy carries the risk of major surgical complications. Teber and colleagues from Heilbronn, Germany, present their experience with identifying and treating ureteral injury during laparoscopic radical prostatectomy in their institutions series of more than 2,100 patients. Rinnab and colleagues from the University of Ulm, Germany have been involved in detection methods for patients with biochemical recurrence after treatment of prostate cancer, which remains a diagnostic and therapeutic challenge. Here, they display their results on [(11)C] choline PET/CT in patients with biochemical recurrence after radical prostatectomy. Androgen-deprivation therapy is associated with important adverse eVects which have an impact on quality of life, especially in men over 70 years of age. A further disadvantages of continuous application is the cost consideration. Numerous phase II trials have shown the eYcacy of intermittent androgen withdrawal with a reduction in inter-treatment intervals. Prapotnich and colleagues from Montsouris, Paris, France, report their oncological results over a period T. R. W. Herrmann (&) · A. S. Merseburger · M. Burchardt Department of Urology and Urologic Oncology, Hannover Medical School, Carl-Neuberg-Strase 1, 30625 Hannover, Germany e-mail: Herrmann.Thomas@mh-hannover.de

Alternative methods to safety studies in experimental animals

During the next few years two major decisions of the European Commission will have great consequences for the use of animals to evaluate the adverse eVects of chemicals on human health and the environment. The Wrst is the implementation of REACH. It requests safety assessment of a large number of chemicals, which according to the legislation should be based preferentially on alternatives to animal testing. The second is the phasing out date for studies in animals, March 2013, of the 7th amendment of the Cosmetics Guideline 76/768/EEC for repeated dose toxicity, reproductive toxicity and carcinogenicity. In contrast to these expectations or even regulations, Lilienblum et al. (2008) recently concluded that both a signiWcant reduction of animal testing for REACH and the phasing out of in vivo testing for cosmetics in a few years appear unrealistic. Consequently, the authors recommended that established in vivo tests at least at present should be considered indispensable as basic tools for hazard and risk assessment and that development of alternative methods should be more directed towards the reWnement or reduction of animal testing. The publication of this conclusion is of utmost importance because the perception and understanding of the role of in vitro tests and other alternative methods for hazard identiWcation and risk assessment of chemical substances diVers extremely between the scientiWc community and stakeholders such as animal welfare groups, parlamentarians and the public. Whereas the non-biased scientiWc community has repeatedly stressed that there are principle obstacles to completely avoiding animal studies (e.g. Greim et al. 2006), others, including politicians, assume that suYcient availability of research funding will easily overcome these obstacles. The scientiWc community has repeatedly addressed such intrinsic pitfalls. The goal of REACH and other programs is to evaluate the risk of human or environmental exposure to chemical compounds. Risk assessment follows the generally accepted methodology comprising hazard identiWcation, exposure assessment, and the assessment of the risk at a given exposure. Hazard identiWcation requires identiWcation of all relevant endpoints of adverse eVects (e.g. organ-speciWc toxicity, carcinogenicity, genotoxicity, reproductive toxicity or teratogenicity), their dose responses, thresholds and the NOEL of the prominent eVect. Toxicokinetic data clarify the metabolic fate of the chemical under assessment and can provide a scientiWc basis for this extrapolation. Based on our current understanding of biological complexity, it is very unlikely that a few selected cell culture models could mimic the multitude of potential target cells with respect to physiology, biochemistry, pathogenesis, capacity for biotransformation of chemicals and hence the sensitivity to toxic eVects. Many chemicals show target organ-speciWc responses in animal toxicity studies arising from a combination of a number of processes. These include the accumulation of the chemical in the target organ, speciWc capacity of the target organ for biotransformation of the chemical, speciWc sensitivity of the target cells to the toxic eVects, and the complex and often poorly understood interactions of cells and their mediators in diVerent tissues and organs that are regulated by complex systems of the organism such as the neuroendocrine and immune systems. Without such understanding, an estimation of the risk of human exposure cannot be performed. The various eVects and the critical H. A. Greim (&) Institute of Toxicology and Environmental Hygiene, Technical University, Munich, Germany e-mail: helmut.greim@lrz.tum.de

Reply to the comments of Preuss and Wittekindt on our article: “Management and prognostic factors of recurrent pleomorphic adenoma of the parotid gland: personal experience and review of the literature”

Sir, First of all, we would like to thank Drs. Preuss and Wittekindt for their comments [1] on our paper: “Management and prognostic factors of recurrent pleomorphic adenoma (RPA) of the parotid gland: personal experience and review of the literature” [2]. Of course, we agree with our colleagues on the need for surgical extirpation of RPA of the parotid gland. However, as to the kind of surgery we performed, we do not consider “exceptionally radical parotidectomy” to be an accurate characterization of the surgical procedures that we applied. As is known from collective experience, RPA is uninodular in a minority of patients and may develop following incomplete excision of the tumor at the initial surgery. In such cases, surgical removal of RPA must be proportionate to the volume and site (superWcial or deep lobe), ranging from limited removal to total parotidectomy. The probability of further relapses is very low. However, in the majority of RPAs the recurrence is multinodular and widely disseminated in the parotid gland and space (sometimes also in the parapharyngeal space), with tumor nodules in the overlying skin (especially the scar), in subcutaneous tissue, in muscle, and in sheets of the facial nerve trunk and branches. Indeed, although hypothetical and diYcult to test, the distribution of the recurring tumor seems to reXect the extent of growth of neoplastic cells in the parotid space and its walls at the time of the Wrst surgical excision. In such cases of widespread tumor dissemination there are two choices for surgical removal: total parotidectomy or, better, clearance of the parotid space, of course with preservation of the facial nerve tree. Even so, in multinodular and extended recurrences, one can be almost certain, on the grounds of literature and personal experience, that microscopic remnants of the tumor will often remain at the end of the procedure, even in an apparently clean surgical Weld, resulting in further relapses. The rationale for postoperative radiotherapy, when it can be applied without undue risk to the patient (contraindicated mainly in young patients), is to try to slow (or halt) the growth of those microscopic tumor remnants. We agree that the literature results are not unanimous on the advantages of postoperative radiotherapy [2–8]. On the other hand, there are also reports of adverse eVects of radiotherapy in RPA [6]. As to management of the facial nerve, 4 of the 26 patients who received initial surgery elsewhere presented with deWnitive hemifacial paralysis prior to our RPA treatment. In one of these latter patients the facial trunk was found to be encased by the recurring tumor and was excised with no attempt to restore nerve continuity (clearly, such an attempt would have been futile). Out of the seven patients who were initially treated at our department, none had facial paralysis. In the whole group, i.e., 33 patients, we found facial nerve branches enveloped by the tumor in 9: the marginal mandibular nerve in 7, a midface branch to the orbicular oris muscle in 1 and a branch to the frontalis muscle in 1. In these patients a piece of the involved nerve branch was excised, with no attempt to reconstruct nerve continuity, Wrst because of the usually poor functional results, at least in our hands, after grafting the marginal mandibular or the temporal nerve branch, and second because of the existing “redundancy” of the motor nerve supply to the muscles of L. O. Redaelli de Zinis (&) · M. Piccioni · A. R. Antonelli · P. Nicolai Department of Otorhinolaryngology-Head Neck Surgery, University of Brescia, Piazzale Spedali Civili, 1, 25123 Brescia, Italy e-mail: redaelli@med.unibs.it

DISTRIBUTION AND EXCRETION OF FLUOXETINE AND NORFLUOXETINE IN HUMAN MILK.

Aims To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants. Methods Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg kg ’1 day ’1 ) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. Results Mean M/P values of 0.68 (95% CI 0.52‐0.84) and 0.56 (95% CI 0.35‐0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15‐12%) of the weight-adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal. Fluoxetine (range 20‐252 m gl ’1 ) was detected in five of the nine infants from whom samples were collected, and norfluoxetine (range 17‐187 m gl ’1 ) was detected in seven of the nine infants. The highest of these concentrations was about 70% of the maternal plasma concentrations. Conclusions The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% notional level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse eVects have been observed in breast-fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse eVects.

A comparison of benthic biodiversity in the North Sea, English Channel, and Celtic Seas

Two complementary surveys of the benthos around the United Kingdom coastline and oVshore are described. The first sampled the macroinfauna by day grab at several stations around the England and Wales coastline as part of a wider interdisciplinary assessment of environmental quality by the regulatory authorities. The second sampled the epifauna with a small beam trawl at the grab stations, and at several additional stations, most of which were in the central and southern North Sea. Similar infaunal assemblages were encountered on both the eastern and western UK coasts in comparable environmental conditions. Tidal current velocity and sediment characteristics accounted for a significant amount of the observed variability in species richness and densities. There was no evidence of any adverse eVects on these measures of assemblage structure arising from trace metal contamination of sediments. Coastal influences (proximity to large estuaries), depth, tidal current velocity, and temperature all helped to explain the distribution of epifaunal assemblages. However, sediment type appeared to be the main structuring force, with a coarser component to samples collected from the north and west of the survey area, i.e. especially around the UK coastline, supporting a much wider variety of sessile taxa. Grab samples provide unambiguously quantitative data which can be easily linked with sediment type within the small unit area of the sample. Trawls provide integrated samples of the fauna over a much larger area. However, both the design of the trawl, and inherent uncertainties over its sampling eYciency, determine that the survey results are ‘‘operationally defined’’, and consistency in sampling procedures is essential, especially for the analysis of temporal trends. There is a need to provide better working descriptions of the environment along trawl tows where sediments are variable; a combination of acoustic methods and underwater photograpy may be most suitable.

How to assess an article on economic evaluation.

As a London based consultant in genitourinary medicine you are approached by your colleagues in the neighbouring obstetrics department who are concerned about the prevalence of HIV infection in their...