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Humans are exposed via the environment and via food to Polycyclic Aromatic Hydrocarbons (PAH), mixtures considered carcinogenic by IARC. A quantitative cancer risk assessment for oral exposure is hampered by the absence of adequate data. The need for experimental data is substantiated by the fact that daily oral doses exceed inhaled doses for some potent carcinogenic PAH compounds, e.g. benzo[a]pyrene (B[a]P), by one order of magnitude, and the fact that epidemiological studies are not expected to provide useful data in this respect. For this reason we have performed a carcinogenicity study in rats; treatment (by gavage) for 2 years with the reference PAH B[a]P resulted in tumour-formation in a wide spectrum of organs and tissues, with liver and forestomach as major target-organs. Liver tumours in female rats were used for estimating a Virtually Safe Dose (VSD), i.e. the daily dose representing a one per million risk upon lifetime exposure, via methodology adopted by the Dutch Health Council (HCN, 1994-1996). Based on available data on occurrence and carcinogenic potency of PAH in Dutch diet it is suggested to apply a correction-factor of 10 for conversion to a VSD for B[a]P as indicator for all dietary PAH. With the resulting VSD of 0.5 ng B[a]P/kg bodyweight per day, cancer risks associated with PAH encountered in Dutch diet are estimated to be around acceptable risk levels. Parallel rat studies indicated that B[a]P-induced DNA adducts per se are not sufficient for tumour-development; induced local cell proliferation seems an additional critical factor. The possible implications of these findings are discussed.Polycyclische Aromatische Koolwaterstoffen (PAK) komen zowel wijdverbreid in het milieu als in voedsel voor, beide als gevolg van menselijk handelen. PAK worden beschouwd als kankerverwekkend voor de mens (IARC, 1983). Dit is gebaseerd op zowel dierexperimenteel werk als op epidemiologische studies. De mens staat continu bloot aan deze groep verbindingen via de inhalatoire alsook de orale route (via voedselconsumptie), en in sommige gevallen via de huid. Een kwantitatieve schatting van het risico op kanker als gevolg van de inhalatoire blootstelling aan PAK in het milieu laat zien dat deze de acceptabel geachte grens, 1 extra kankergeval per miljoen levenslang blootgestelden, ruimschoots overschrijdt. Schatting van het risico op kanker als gevolg van blootstelling aan PAK via het voedsel wordt belemmerd door gebrekkige dierexperimentele en epidemiologische gegevens. De noodzaak om dit risico te kwantificeren wordt ge6llustreerd door het feit dat de dagelijkse blootstelling via deze route in grootte een orde hoger geschat wordt dan die via inhalatoire blootstelling voor een aantal belangrijke carcinogene PAK, zoals benzo[a]pyreen (B[a]P). Omdat niet verwacht wordt dat epidemiologische studies hier op termijn uitkomst kunnen bieden, is grote behoefte aan goed uitgevoerd dierexperimenteel onderzoek. Om bovengenoemde reden is een carcinogeniteitsstudie uitgevoerd waarbij ratten levenslang oraal zijn blootgesteld aan B[a]P, algemeen beschouwd als een representatieve modelstof voor carcinogene PAK. De in het instituut gekweekte Wistar ratten (52 dieren per dosis en per sexe) zijn per maagsonde vijf dagen per week blootgesteld aan in soja-olie opgeloste B[a]P, in doseringen van 0 (kontrole), 3, 10 en 30 mg/kg lichaamsgewicht. Deze behandeling resulteerde in een dosis-gerelateerde toename in tumorincidentie in diverse organen en weefsels. Veruit de hoogste incidenties tumoren werden gevonden in lever en voormaag, beide organen met een lage spontane tumorincidentie in deze rattenstam. Levertumoren vormden daarnaast de belangrijkste doodsoorzaak in de hoogste dosis-groep in beide sexen. De tumorvorming in dit orgaan in vrouwtjes ratten is vervolgens gebruikt voor het berekenen van de carcinogene risico's volgens een door de Gezondheidsraad aanbevolen methode. Dit resulteerde in een "acceptabele dagelijkse dosis" (ADI) van 5 ng B[a]P per kg lichaamsgewicht, d.w.z. overeenkomend met 1 extra kankergeval per miljoen levenslang blootgestelden. Op basis van de beschikbare gegevens over de carcinogene potentie en het voorkomen van diverse PAK in het voedsel in Nederland wordt voorgesteld een conversie-factor van 10 te gebruiken voor totale PAK-belasting in voedsel, ofwel een ADI van 0.5 ng B[a]P per kg lichaamsgewicht, met B[a]P als indicator voor in voedsel voorkomende PAK. Dit 'onverwacht' lage risico, althans in vergelijking met de bovenvermelde risico's van PAK bij inhalatoire blootstelling, en de onzekerheden in de database en gebruikte methodiek, worden bediscussieerd. De vorming van DNA addukten door B[a]P is ook in deze species bestudeerd onder dezelfde blootstellings condities. DNA addukten (bepaald met de 32P-postlabelings-methodiek, die stabiele DNA addukten met grote gevoeligheid kan detecteren) konden in alle onderzochte organen en weefsels worden aangetoond. Omdat tumoren slechts in een beperkt aantal hiervan werden gevonden, kan worden geconcludeerd dat de vorming van stabiele DNA addukten op zichzelf niet voldoende is voor tumorvorming. Ook de totale hoeveelheid DNA addukten (ofwel de dichtheid), of de vorming van specifieke DNA addukten kon niet aan de localisatie van tumorvorming gerelateerd worden. Daarentegen suggereren waarnemingen in de range-finding en sub-chronische studies dat lokale celproliferatie een kritische additionele factor in tumor-vorming zou kunnen zijn. De mogelijke implicaties van deze bevindingen worden bediscussieerd

Gene Expression Changes Related to Endocrine Function and Decline in Reproduction in Fathead Minnow (Pimephales promelas) after Dietary Methylmercury Exposure

BACKGROUND: Methylmercury (MeHg) is a known neurotoxic agent, but the mechanisms by which MeHg may act on reproductive pathways are relatively unknown. Several studies have indicated potential changes in hormone levels as well as declines in vertebrates with increasing dietary MeHg exposure. OBJECTIVES: The purpose of this study was to identify alterations in gene expression associated with MeHg exposure, specifically those associated with previously observed changes in reproduction and reproductive biomarkers. Fathead minnows, Pimephales promelas, were fed one of three diets that were similar to documented concentrations of MeHg in the diets of wild invertivorous and piscivorous fish. We used a commercial macroarray in conjunction with quantitative polymerase chain reaction to examine gene expression in fish in relation to exposure to these environmentally relevant doses of MeHg. RESULTS: Expression of genes commonly associated with endocrine disruption was altered with Hg exposure. Specifically, we observed a marked up-regulation in vitellogenin mRNA in individual Hg-exposed males and a significant decline in vitellogenin gene expression in female fish with increasing Hg concentrations. Other genes identified by the macroarray experiment included those associated with egg fertilization and development, sugar metabolism, apoptosis, and electron transport. We also observed differences in expression patterns between male and female fish not related to genes specifically associated with reproduction, indicating a potential physiological difference in the reaction of males and females to MeHg. CONCLUSION: Gene expression data may provide insight into the mechanisms by which MeHg affects reproduction in fish and indicate how MeHg differs in its effect from other heavy metals and endocrine-disrupting compounds

Endoreplication Controls Cell Fate Maintenance

Cell-fate specification is typically thought to precede and determine cell-cycle regulation during differentiation. Here we show that endoreplication, also known as endoreduplication, a specialized cell-cycle variant often associated with cell differentiation but also frequently occurring in malignant cells, plays a role in maintaining cell fate. For our study we have used Arabidopsis trichomes as a model system and have manipulated endoreplication levels via mutants of cell-cycle regulators and overexpression of cell-cycle inhibitors under a trichome-specific promoter. Strikingly, a reduction of endoreplication resulted in reduced trichome numbers and caused trichomes to lose their identity. Live observations of young Arabidopsis leaves revealed that dedifferentiating trichomes re-entered mitosis and were re-integrated into the epidermal pavement-cell layer, acquiring the typical characteristics of the surrounding epidermal cells. Conversely, when we promoted endoreplication in glabrous patterning mutants, trichome fate could be restored, demonstrating that endoreplication is an important determinant of cell identity. Our data lead to a new model of cell-fate control and tissue integrity during development by revealing a cell-fate quality control system at the tissue level

Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease

In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice

Biology of human hair: Know your hair to control it

Hair can be engineered at different levels—its structure and surface—through modification of its constituent molecules, in particular proteins, but also the hair follicle (HF) can be genetically altered, in particular with the advent of siRNA-based applications. General aspects of hair biology are reviewed, as well as the most recent contributions to understanding hair pigmentation and the regulation of hair development. Focus will also be placed on the techniques developed specifically for delivering compounds of varying chemical nature to the HF, indicating methods for genetic/biochemical modulation of HF components for the treatment of hair diseases. Finally, hair fiber structure and chemical characteristics will be discussed as targets for keratin surface functionalization

Benign external hydrocephalus: a review, with emphasis on management

Benign external hydrocephalus in infants, characterized by macrocephaly and typical neuroimaging findings, is considered as a self-limiting condition and is therefore rarely treated. This review concerns all aspects of this condition: etiology, neuroimaging, symptoms and clinical findings, treatment, and outcome, with emphasis on management. The review is based on a systematic search in the Pubmed and Web of Science databases. The search covered various forms of hydrocephalus, extracerebral fluid, and macrocephaly. Studies reporting small children with idiopathic external hydrocephalus were included, mostly focusing on the studies reporting a long-term outcome. A total of 147 studies are included, the majority however with a limited methodological quality. Several theories regarding pathophysiology and various symptoms, signs, and clinical findings underscore the heterogeneity of the condition. Neuroimaging is important in the differentiation between external hydrocephalus and similar conditions. A transient delay of psychomotor development is commonly seen during childhood. A long-term outcome is scarcely reported, and the results are varying. Although most children with external hydrocephalus seem to do well both initially and in the long term, a substantial number of patients show temporary or permanent psychomotor delay. To verify that this truly is a benign condition, we suggest that future research on external hydrocephalus should focus on the long-term effects of surgical treatment as opposed to conservative management

Neutrinos

229 pages229 pages229 pagesThe Proceedings of the 2011 workshop on Fundamental Physics at the Intensity Frontier. Science opportunities at the intensity frontier are identified and described in the areas of heavy quarks, charged leptons, neutrinos, proton decay, new light weakly-coupled particles, and nucleons, nuclei, and atoms

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Histopathologische veranderingen, in het bijzonder nieuwvormingen, in de lever van de bot (Platichthys flesus) uit Nederlandse kustwateren en estuarien, en de relatie met milieufactoren

Dit rapport beschrijft het histopathologisch onderzoek van levers van platvis (bot, Platichthys flesus) afkomstig van de Nederlandse kustwateren en estuaria welke bemonsterd zijn in de periode 1985-89. Bemonstering vond plaats op een 10-tal lokaties waarbij 210 levers zijn verzameld met waarneembare knobbels (diameter > 2 mm); daarnaast zijn 315 ogenschijnlijke normale levers onderzocht. Van de 210 levers met waarneembare afwijkingen bleek 67% inderdaad tumoren te bevatten, de meeste waren goedaardig (hepatocellulair adenoom). Bij 13.6% bleek sprake van een kwaadaardig tumor (hepatocellulair carcinoom). De meeste overige afwijkingen bleken te bestaan uit zgn. "foci of cellular alteration" (fca). welke wel worden beschouwd als voorstadia van tumoren. Levertumoren komen het meest frequent voor bij bot langs de Hollandse en Zeeuwse kust, prevalenties kunnen hier oplopen tot 30% in vissen van 6 jaar en ouder. Verder werd de tumorziekte vaker bij vrouwelijke dan bij mannelijke botten waargenomen. Histopathologisch onderzoek van de ogenschijnlijk normale levers gaf niettemin een scala van veranderingen te zien, waaronder hepatocellulair adenoom, fca's, ontstekingen, vervalshaardjes, regeneratieve haardjes,hydropische degeneratie van lever- en galgangcellen en fibrillair veranderde levercellen waarvan de betekenis onduidelijk is. Daarnaast werd stapeling (vacuolisatie) van glycogeen en vet gezien, alsmede zgn. melanomacrofagen centra. De laatste twee veranderingen vallen binnen het normale beeld, maar werden gekwantificeerd (semikwantitatief). Uit de resultaten kan worden geconcludeerd dat een geringe fractie van de tumoren zou worden gemist als het onderzoek zich zou beperken tot alleen de zichtbare afwijkende levers. De verspreiding van de fca's kwam goed overeen met die van de tumoren hetgeen de hypothese ondersteund dat deze veranderingen tot hetzelfde proces behoren. Van de overige veranderingen en parameters vertoonde alleen de hydropische galgangdegeneratie ene overeenkomstige verspreiding. Gezien de ruimtelijke en temporele verdeling van de zichtbare afwijkingen over de diverse meetpunten en de gegevens van de histopathologische bevestiging kan geconcludeerd worden dat het voorkomen van levertumoren bij bot als integrale indicator van chemische vervuiling (potentiele carcinogene stoffen) kan dienen. Gezien de lange latentietijd echter zal er behoefte zijn aan vroege indicatoren (waaronder mogelijk fca's), hetgeen in verder laboratoriumonderzoek dient te worden uitgewerkt.This paper reports the detailed histopathological analysis of livers of flounder (Platichthys flesus) sampled in Dutch coastal and estuarine waters during 1985-89. In conjunction with an epidemiological study of grossly identifiable diseases at 10 sampling locations, 210 livers showing gross nodular lesions (diameter > 2 mm) and 315 livers showing no gross pathology were collected. Of the 210 livers with grossly observable nodules, 67% were diagnosed as having neoplasia. The majority of these neoplasms were identified as hepatocellular adenoma ; 13.1% were diagnosed as hepatocellular carcinoma. Most of the remaining modules were diagnosed as foci of cellular alteration, which are considered to be pre-neoplastic lesions. Routine histopathological examination of livers showing no gross pathology resulted in the identification of a range of lesions including hepatocellular adenoma, foci of cellular alteration, inflammatory lesions, focal necrosis, regenerative foci, hydropic vacuolated lesions of bile duct cells and hepatocytes, and fibrillar hepatocytes of unknown significance. In addition, indices were used to quantify the presence of storage vacuoles (glycogen and lipid) and the density of melanomacrophage centres. The results indicate that a small proportion of neoplasms would be missed if only livers with grossly detectable nodules were subjected to histological examination. The prevalence of foci of cellular alteration at the different sampling sites showed a good correspondence with that of neoplasia, providing support for the hypothesis that these conditions represent stages of the same process. Of the other lesions and quantitative indices, only bile duct vacuolization had a spatial distribution similar to that of neoplasia. The findings indicate that the occurrence of liver neoplasms in flounder represents a promising tool for monitoring exposure to potential carcinogens. However, because of the long latency period associated with tumour development, there will be a need to identify early markers preceding tumour formation (including possibly fca). This will be subject of future laboratory studies.RIV