The IUR Forum: Worldwide Harmonisation of Networks to Support Integration of Scientific Knowledge and Consensus Development in Radioecology.

During the past decades, many specialised networks have formed to meet specific radioecological objectives, whether regional or sectorial (purpose-oriented). Regional networks deal with an array of radioecological issues related to their territories. Examples include the South Pacific network of radioecologists, and the European network of excellence in radioecology. The latter is now part of the European platform for radiation protection. Sectorial networks are more problem-oriented, often with wider international representativeness, but restricted to one specific issue, (e.g. radioactive waste, low-level atmospheric contamination, modelling). All such networks, while often working in relative isolation, contribute to a flow of scientific information which, through United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR's) efforts of synthesis, feeds into the radiation protection frameworks of protecting humans and the environment. The IUR has therefore prompted a co-construction process aimed at improving worldwide harmonisation of radioecology networks. An initiative based on an initial set of 15 networks, now called the IUR FORUM, was launched in June 2014. The IUR Forum agreed to build a framework for improved coordination of scientific knowledge, integration and consensus development relative to environmental radioactivity. Three objectives have been collectively assigned to the IUR FORUM: (1) coordination, (2) global integration and construction of consensus and (3) maintenance of expertise. One particular achievement of the FORUM was an improved description and common understanding of the respective roles and functions of the various networks within the overall scene of radioecology R&D. It clarifies how the various networks assembled within the IUR FORUM interface with UNSCEAR and other international regulatory bodies (IAEA, ICRP), and how consensus on the assessment of risk is constructed. All these agencies interact with regional networks covering different geographical areas, and with other networks which address specific topics within radiation protection. After holding its first Consensus Symposium in 2015, examining the possible ecological impact of radiation from environmental contamination, the IUR FORUM continues its work towards improved radiation protection of humans and the environment. We welcome new members.

mRNA Transcript abundance during plant growth and the influence of Li(+) exposure.

Lithium (Li) toxicity in plants is, at a minimum, a function of Li(+) concentration, exposure time, species and growth conditions. Most plant studies with Li(+) focus on short-term acute exposures. This study examines short- and long-term effects of Li(+) exposure in Arabidopsis with Li(+) uptake studies and measured shoot mRNA transcript abundance levels in treated and control plants. Stress, pathogen-response and arabinogalactan protein genes were typically more up-regulated in older (chronic, low level) Li(+)-treatment plants and in the much younger plants from acute high-level exposures. The gene regulation behavior of high-level Li(+) resembled prior studies due to its influence on: inositol synthesis, 1-aminocyclopropane-1-carboxylate synthases and membrane ion transport. In contrast, chronically-exposed plants had gene regulation responses that were indicative of pathogen, cold, and heavy-metal stress, cell wall degradation, ethylene production, signal transduction, and calcium-release modulation. Acute Li(+) exposure phenocopies magnesium-deficiency symptoms and is associated with elevated expression of stress response genes that could lead to consumption of metabolic and transcriptional energy reserves and the dedication of more resources to cell development. In contrast, chronic Li(+) exposure increases expression signal transduction genes. The identification of new Li(+)-sensitive genes and a gene-based "response plan" for acute and chronic Li(+) exposure are delineated.

Whole-organism concentration ratios for plutonium in wildlife from past US nuclear research data.

Whole-organism concentration ratios (CRwo-media) for plutonium (Pu) in wildlife were calculated using data from the broad range of organism types and environmental settings of the US nuclear research program. Original sources included site-specific reports and scientific journal articles typically from 1960s to 80s research. Most of the calculated CRwo-media values are new to existing data sets, and, for some wildlife categories, serve to fill gaps or add to sparse data including those for terrestrial reptile; freshwater bird, crustacean and zooplankton; and marine crustacean and zooplankton. Ratios of Pu concentration in the whole-organism to that in specific tissues and organs are provided here for a range of freshwater and marine fish. The CRwo-media values in fish living in liquid discharge ponds were two orders of magnitude higher than those for similar species living in lakes receiving Pu from atmospheric fallout, suggesting the physico-chemical form of the source Pu can dominate over other factors related to transfer, such as organism size and feeding behavior. Small rodent data indicated one to two order of magnitude increases when carcass, pelt, and gastrointestinal tract were included together in the whole-organism calculation compared to that for carcass alone. Only 4% of Pu resided in the carcass of small rodents compared to 75% in the gastrointestinal tract and 21% in the pelt.

Site transfer and process validation in case of Herceptin API.

The manufacturing process for Herceptin Active Pharmaceutical Ingredient (API) was successfully transferred from Genentech to Roche, Penzberg site. Although the transferred process in principle remained the same, some changes had to be introduced mainly due to the different equipment installed in the Penzberg facility. As a consequence, a thorough (re-)validation of the process was performed. At the downscale level, the lifetime of the chromatography columns as well as the capacity of the purification process for virus removal and virus inactivation were examined. At the production scale, the consistency of the Roche process was investigated. As a result of the process validation, the Genentech and the Roche process were found to be comparable. In particular, the analytical comparability of the Roche and Genentech API could be demonstrated.

[Immunohistochemical determination of cell cycle regulatory proteins. No prognostic significance in advanced squamous epithelial carcinomas of the head-neck area]. / Immunhistochemische Bestimmung von ZellzykluskomponentenFehlende prognostische Bedeutung bei fortgeschrittenen Plattenepithelkarzinomen des Kopf-Hals-Bereichs.

BACKGROUND: In recent years, a number of molecular markers have been tested for their potential to predict the outcome after radiotherapy or radiochemotherapy in patients with advanced head and neck squamous cell carcinomas (HNSCC). These studies have produced controversial results. PATIENTS AND METHODS: The expression patterns of the proteins p53, pRb, cyclinD1, cdk4, p21(CIP1/WAF1), p16(INK4a), bcl-2, and mib-1/ki-67 were analyzed in pretreatment tumor biopsies of 53 patients with advanced nonresectable head and neck squamous cell carcinomas (mainly UICC IV). The patterns obtained were compared with clinical outcome after accelerated radiochemotherapy with carboplatin and 5-fluorouracil or accelerated fractionated radiotherapy alone, respectively. RESULTS: The expression patterns of the proteins examined did not correlate with response to therapy or with further clinical course. CONCLUSION: In patients with advanced head and neck squamous cell carcinomas, the prognostic relevance of pretreatment expression patterns of the proteins investigated in this study, particularly p53, cyclinD1, and cdk4, has to be questioned.

Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus.

AIMS: Limited data are available on determinants of diabetic neuropathy as its pathogenesis is multifactorial. Since homocysteine exhibits toxic effects on vascular endothelial cells, the association between homocysteine and the prevalence of neuropathy in Type 2 diabetes mellitus was investigated. METHODS: A total of 65 Type 2 diabetic patients were consecutively enrolled into the study. Neuropathy was diagnosed according to clinical symptoms, clinical examination, electrophysiological sensory testing and autonomic function testing. With regard to homocysteine-related parameters, plasma homocysteine, folate, vitamin B12, vitamin B6 and renal function (creatinine, ceratinine clearance, cystatin C) were measured, and the C677T polymorphism of the methylenetetrahydrofolate reductase gene was determined. RESULTS: Forty-three of the Type 2 diabetic patients were classified as suffering from neuropathy. Both patient groups were comparable with regard to demographic data, blood pressure, glucose metabolism, renal function and homocysteine-related vitamins. In contrast, homocysteine levels (P = 0.04) and the frequency of hyperhomocysteinemia (>or= 15 micromol/l) (P = 0.01) were significantly increased in neuropathic patients. In a logistic regression model with neuropathy as dependent variable, homocysteine (adjusted for creatinine, homocysteine-related vitamins, HbA1c and duration of diabetes) was the only significant variable associated with the prevalence of neuropathy (odds ratio for homocysteine per 5 micromol/l increase: 2.60 (95% confidence interval 1.07-6.33)). CONCLUSION: The data indicate that homocysteine is independently associated with the prevalence of diabetic neuropathy in a collective of Type 2 diabetic patients. A larger, prospective study would be desirable to clarify the role of homocysteine in the pathogenesis of diabetic neuropathy.

[Prognostic significance of cell-cycle regulatory proteins for outcome after primary radiochemotherapy in patients with advanced head and neck cancer]. / Expression von Zellzykluskomponenten in fortgeschrittenen Kopf-Hals-Karzinomen.Bedeutung für die Prognose nach primärer akzelerierter Radiochemotherapie.

BACKGROUND: Primary radiochemotherapy is gaining increasing importance for the treatment of advanced head and neck squamous cell carcinomas. However, there is a lack of clinical factors concerning prognostic information in relation to treatment. In this pilot study, we examined whether molecular factors can provide such information. PATIENTS AND METHODS: The expression patterns and their possible prognostic relevance of the cell cycle regulatory proteins p53, p21(WAF/CIP1), Rb, p16(INK4A), CDK4 and Cyclin D1, MIB1 (Ki-67) and BCL-2 were analysed in pretreatment tumor biopsies from 43 patients with advanced carcinomas of the oropharynx (n = 26), hypopharynx (n = 10) and larynx (n = 7) by applying immunohistochemistry to paraffin sections of tumor specimens. All patients were treated by the same method of an accelerated "concomitant boost" radiochemotherapy with carboplatin in a phase II study. Median followup time was 56 months. RESULTS: No correlation was found between any of the markers and the remission rate, T-stage, N-stage, rate of loco-regional recurrences and distant metastases. However, independent of the tumor stage, patients with CDK4/cyclin-D1 overexpressing tumors had a significantly shortened overall survival (P = 0.014 and 0.026, respectively). CONCLUSION: The results of this pilot study indicate that CDK4 and cyclin D1 over-expression provide useful prognostic information about clinical outcome after primary radiochemotherapy of head and neck cancer patients.

[The role of oncogenic human papillomaviruses in tonsillar squamous cell carcinomas with functional inactivation of the retinoblastoma protein]. / Onkogene humane Papillomaviren.Schlüsselrolle bei Plattenepithelkarzinomen der Tonsillen mit Defekt im Retinoblastomprotein.

In order to identify squamous cell carcinomas of the head and neck (HNSCC) with common biological and clinical features, we investigated the incidence and properties of carcinomas lacking retinoblastoma protein (pR6) cell cycle control. Of 208 HNSCC investigated, 23 (11%) showed a lack of pRb expression. The majority of these tumors (65%) were tonsillar carcinomas. The pRb-negative tonsillar tumors were all stage IV, had metastasized to lymph nodes at the time of diagnosis and were in general poorly differentiated or undifferentiated. Very significantly, the pRb-negative phenotype was strongly associated with the presence of oncogenic human papilloma viruses, implying a viral etiology and functional inactivation of pRb by the viral E7 oncoprotein. Despite the very adverse histopathological factors, patients with pRb-negative tonsillar carcinomas had a better clinical outcome, which was consistent with a uniform favorable responsiveness of these tumors to postoperative radiation therapy.

Disintegration of cytoskeletal structure of actin filaments in energy-depleted endothelial cells.

In a previous study [Watanabe, H., W. Kuhne, R. Spahr, P. Schwartz, and H. M. Piper. Am. J. Physiol. 260 (Heart Circ. Physiol. 29): H1344-H1352, 1991] metabolic inhibition (5 mM KCN + 5 mM 2-deoxy-D-glucose, for 2 h) was found to cause disintegration of F-actin filaments, cell retraction, and augmented paracellular macromolecule permeability in monolayer cultures of porcine aortic endothelial cells after a rapid depletion of ATP stores (90% in 5 min). These changes were reversible. In the present study, the nature of this cytoskeletal disintegration was investigated. 1) Disintegration of F-actin filaments within 2-h incubation under metabolic inhibition was accompanied by appearance of F-actin clumps in the cells, but total contents of F-actin remained unaltered. 2) Cytosolic Ca2+ levels rapidly rose in metabolically inhibited cells; after 2 h a 10-fold increase was observed. 3) Presence of the Ca2+ ionophore A23187 (10 microM) mimicked the reversible effect of metabolic inhibition on F-actin filaments and monolayer permeability but not the extensive depletion of ATP stores. 4) Existence of the Ca(2+)-activatable actin-severing protein gelsolin in endothelial cells was demonstrated. The results show that during the reversible phase of endothelial energy depletion disintegration of F-actin filaments is only partial, since it is based on their fragmentation and not depolymerization. Increase in cytosolic Ca2+ levels seems to be the primary cause for the fragmentation, possibly through the activation of gelsolin.

Cytosolic Ca2+ overload and macromolecule permeability of endothelial monolayers.

It was investigated how cytosolic Ca2+ overload affects the cytoskeletal structure and macromolecule permeability (for albumin) of monolayers of endothelial cells (from porcine aorta). States of cytosolic Ca2+ overload were produced either 1. by metabolic inhibition (5 mM KCN plus 5 mM 2-deoxyglucose) or 2. by increasing membrane permeability with the use of a Ca2+ ionophore (10 microM A 23187). The effects of cytosolic Ca2+ overload on the structure of F-actin filaments and monolayer permeability were monitored. ATP stores were rapidly degraded (> 90% in 15 minutes) in the presence of metabolic inhibitors, but only partially reduced in the presence of A 23187 (30%) in two hours). Concomitantly with ATP loss, cytosolic Ca2+ levels were increased in metabolically inhibited cells. Two-hour exposure to the Ca2+ ionophore A 23187 mimicked the effect of two-hour metabolic inhibition on F-actin filaments and monolayer permeability, in spite of the divergence in energy metabolism. Disintegration of F-actin filaments in presence of metabolic blockers or ionophore was accompanied by appearance of F-actin clumps in the cells, but total contents of F-actin remained unaltered. Within three hours after removal of these agents, a normal F-actin structure and normal macromolecule permeability were re-established in the monolayers. The results show that cytosolic Ca2+ overload causes disintegration of F-actin filaments and a subsequent increase in macromolecule permeability. These changes are readily reversible as long as the dis-integration is based on fragmentation and not depolymerization of F-actin filaments.

[Transesophageal atrial stimulation in 168 patients]. / Estimulacion auricular transesofagica. Experiencia en 168 pacientes.

Transesophageal atrial stimulation was performed in 168 patients, 95 males and 73 males, 20 to 81 years of age. The indication for atrial stimulation was the study of some bradyarrhythmia in 109 and ischemic heart disease in 59. An esophageal catheter was introduced through the nose and placed at a spot where a bimodal P wave was obtained. Stimulation was performed using a baby Medtronic stimulator coupled to a Vygon amplifier delivering an output of 30 volt. Sinus node recovery time was measured after 2 to 3 min of stimulation at different rates. Wenckebach and 2:1 A-V block as well as ST deviation were determined. Sick sinus syndrome was diagnosed in 41 cases through altered sinus node recovery time and/or secondary pauses; 35 patients showed Wenckebach rhythm at a stimulation rate over 120 per min; 2: 1 A-V block appeared in 22. Ischemic ST-T changes were produced in 20 subjects. No complications were observed, confirming this approach as a simple and effective way to achieve atrial stimulation for diagnostic purposes.

A2-adenosine receptor stimulation increases macromolecule permeability of coronary endothelial cells.

The effect of the A2-adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA) on macromolecule permeability (PM; indicator fluorescein isothiocyanate-labeled albumin) of endothelial cells was investigated using confluent monolayers of rat coronary microvascular endothelial cells (CEC) and porcine aortic macrovascular endothelial cells (AEC). In CEC, NECA (10(-7) M) increased PM by 39%. Similar results were obtained by isoproterenol (10(-6) M) and forskolin (10(-5) M). The effect of NECA could be antagonized by 8-phenyltheophylline (8-PT; 10(-5) M). In AEC, NECA (10(-7) M) caused an opposite effect in that it decreased PM by 26% as did isoproterenol (10(-6) M) and forskolin (10(-5) M). The response to NECA was abolished in the presence of 8-PT (10(-5) M). In AEC but not CEC, NECA could reduce the rise in PM caused by endothelial energy depletion (in the presence of 5 mM KCN and 5 mM 2-deoxy-D-glucose). It was common to AEC and CEC that NECA (10(-7) M), isoproterenol (10(-6) M), and forskolin (10(-5) M) stimulated production of adenosine 3',5'-cyclic monophosphate (cAMP). The stimulatory effect of NECA on production of cAMP could be antagonized by 8-PT (10(-5) M). In summary, the results indicate that in AEC and CEC PM is modulated by an A2-adenosine receptor-mediated stimulation of adenylate cyclase. The secondary effects of stimulation of adenylate cyclase are different in CEC and AEC, however, since it caused a reduction of PM in AEC, but an increase in CEC.

[The problems of early diagnosis of diffuse malignant mesothelioma from the pathologo-anatomic view]. / Zur Problematik der Frühdiagnose diffuser maligner Mesotheliome aus pathologisch-anatomischer Sicht.

An account is given in this paper of particular problems associated with early detection of mesotheliomatous alterations and differential diagnosis for their distinction from reactive mesothelial cell proliferations. Reference is made, in that context, to pathologico-anatomic experience obtained from postmortem and biopsy samples of human malignant mesotheliomas and animal experiments, following exposure to various asbestos-containing dusts. Diagnoses, such as "premesotheliomatous alteration" or "early mesothelioma", in other words, differentiation between benign and malignant, consequently, appear to be unjustified.

Macromolecule permeability of coronary and aortic endothelial monolayers under energy depletion.

The dependence of macromolecule permeability (MP; indicator fluorescein isothiocyanate-labeled albumin) of endothelial cells on their energetic state was investigated using confluent monolayers of rat coronary microvascular endothelial cells and porcine aortic macrovascular endothelial cells. When oxidative and glycolytic energy productions were inhibited (5 mM KCN plus 5 mM 2-deoxy-D-glucose) 90% of the endothelial ATP contents were lost within 15 min, followed by a progressive increase of MP, disintegration of the actin cytoskeleton, and the opening of intercellular gaps. Elution of the blocker and a subsequent 3-h incubation in complete culture medium reversed the effects of 2-h metabolic blockade, completely for MP and partially for ATP levels. Coronary microvascular and aortic macrovascular endothelial cells responded similarly to energy depletion and repletion, the microvascular cells being more sensitive. The results demonstrate that 1) energetic inhibition augments endothelial macromolecule permeability when both oxidative and glycolytic energy production are inhibited, 2) increased macromolecule permeability in energy-depleted endothelial monolayers is caused by the opening of intercellular gaps, and 3) endothelial cells reversibly tolerate up to 2 h of almost complete ATP depletion.

Familial Alzheimer disease: a large, multigeneration German kindred.

A German family with 21 members affected by Alzheimer disease (AD) was studied clinically and genetically. The diagnosis was histologically verified in three affected family members. Ancestors were traced through seven generations to a couple residing in East-Westfalia during the middle of the 19th century. Dementia was often accompanied by extrapyramidal features and myoclonus. No cases of Down syndrome or hematologic malignancy occurred in this family. Clinical manifestations, temporal progression, neurological testing, and neuropathological features do not differ from the more common sporadic form of AD. The inheritance pattern is most consistent with autosomal-dominant transmission.

[Differentiated thyroid cancer. Their peculiarities in typing and assessment of invasiveness]. / Differenzierte Schilddrüsenkarzinome. Ihre Besonderheiten bei der Typisierung und Dignitätseinschätzung.

Differentiated thyroid carcinomas (follicular and papillary) were found to differ, for several biological behaviours, from carcinomas of other organs and even from anaplastic carcinomas of the thyroid. These peculiarities are quite often morphologically characterised by mature, organ-like histological appearances, long-time encapsulation from adjacent thyroid tissue, and delayed metastasation. Proper judgement of need for surgery and operability, consequently, can be quite difficult. Any tumour, therefore, should be individually assessed, and caution may be appropriate when it comes to therapeutic decision-making. These tumours are briefly typed in this paper by their histological patterns. The unique nature is mentioned of follicular and papillary carcinomas. Reference is made to factors of relevance to prognosis.

[An unusual benign hamartomatous tumor of the lung]. / Uber einen ungewöhnlichen benignen hamartomatösen Tumor der Lunge.

About a rare benign tumor of the lung of a fifty-nine years old woman is reported. The possible relation to the group of the pulmonary hamartomas is discussed. The tumor was benoted as "Benign angiohamartomatous tumor".