From Table 4, it is evident that the

immunoassays from la

From Table 4, it is evident that the

immunoassays from laboratory 7 are giving lower estimated potencies for all three samples A – C. Laboratory 2 has estimates that are higher than other laboratories for samples A and B, but for sample C they are in agreement with the other laboratories. Apart from these results, all laboratories appear to be giving consistent results and are in reasonable agreement. The within-laboratory, between-assay, variability is shown in Table 4, as %GCVs. These represent good within laboratory repeatability, with all GCVs less than 10%, and the majority being less than 5%. There was greater variability between estimates from individual plates within Panobinostat datasheet assays in some laboratories (data not shown). This appeared to result from possible plate effects (variation in response across different rows or columns of the plate). Because a balanced layout was used, varying the position of the samples across different plates, consistent results were obtained when the individual plate estimates were combined to give single assay estimates. However, it does emphasise the need to be aware of potential plate effects, and the importance PLX-4720 manufacturer of using a suitable experimental layout across plates. Samples A and B are duplicates of the same material (86/500). The average within-assay % differences in potency

estimates between duplicates are shown in Table 5. All but one of the laboratories are achieving average agreement within 10%, with the majority being within 5%. The overall geometric means of the laboratory means, along with between-laboratory %GCVs and the range of potency estimates are shown in Table 4. The overall trimmed mean (excluding the highest

and lowest laboratory estimates) are shown in Table 6. For the candidate standard 86/500, there is very little difference between the overall mean and the trimmed mean. The effects of the low results from laboratory 7 and the high results from laboratory 2 Ibrutinib solubility dmso on the overall mean cancel each other out. The combined overall mean for samples A and B is 202 IU based on all laboratories, or 203 IU based on the trimmed mean of the central 8 laboratories. For sample C, the potency estimates are around 20% higher than for A and B, at 236 IU and 242 IU for the overall and trimmed means respectively. Table 7 shows the overall means based on the 6 laboratories performing bioassay only. For the candidate standard 86/500 the mean is a little higher at 211 IU compared to the 201 or 203 IU from the overall or trimmed means of all laboratories. This is because restricting the calculation to the bioassays alone has the effect of removing the low results from the immunoassay of laboratory 7, but including the high results from the bioassay of laboratory 2. For sample C, there is little difference between the trimmed mean of all laboratories and the overall mean of the bioassays alone.

In summary, we find that low-level image features drove

In summary, we find that low-level image features drove GDC-0199 chemical structure the fixations performed

by the monkeys that actively explore the natural scenes if the images did not show faces of primates. For the remaining images, most of the eye movements relate to faces, i.e., regions that are typically of low saliency value and thus have a low bottom–up impact. Our analysis of the fixation positions (Section 2.1) revealed that these are not evenly distributed across the images, but rather tend to occur clustered in space (Fig. 3). Our interpretation was that these clusters represent ROIs. Thus, our next aim is to gain insight on the temporal sequences of visiting these ROIs. Therefore we explored the scanpaths of the image explorations by applying a Markov chain (MC) analysis to the eye movement trajectories

(see details in Section 4.5). Thereby we assume each of the significantly identified Stem Cell Compound Library screening fixation clusters on a particular image as a Markov state, and estimate the probabilities for consecutive fixations to either stay in the same cluster, to switch to a different cluster, or end up in the background. In this analysis the assumption of a MC enters in that the next state will be reached only depending on the current state, but does not depend on past states (see details in Section 4.5). The cluster analysis of the fixation positions typically revealed 3 to 5 significant clusters per image for monkeys D and M, however, not a single significant cluster could be extracted for monkey S. Thus this monkey seems not to express subjective ROIs, and we had to conclude that this monkey is not actively exploring the images. Since the MC analysis is based on ROIs, monkey S had to be excluded from the subsequent analysis of the sequence of fixation positions. Fig. 5A shows examples of eye movement sequences (4 out of 33) of monkey

D during presentations of the same image. The fixation positions L-gulonolactone oxidase of monkey D on the image during all its presentations were grouped into three significant clusters (Fig. 5B, color coded). Fixation positions that do not belong to any identified cluster (small blue dots) are pooled together and assigned to the background cluster (see Sections 4.6 and 4.7). The result of the MC analysis on these data is shown in Fig. 5C as a transition graph. Each identified significant cluster, as well as the background cluster, represents a state of the model, whereas the transitions between the states (whose probabilities are indicated in black) are marked by directed arrows. The statistical significance was evaluated by comparing the transition probabilities of the empirical data to uniform probabilities (Fig. 5C, numbers in gray; details see Section 4.7). The probabilities (across all images) of staying within the significant clusters are 87% (40/46) for monkey D and 95% (19/20) for monkey M, thus significantly higher than expected by chance (Fig. 5D). In contrast, the probabilities of moving between significant clusters (Fig.

Fig  1 shows the in vitro antioxidant results for evaluated essen

Fig. 1 shows the in vitro antioxidant results for evaluated essential oil.

Radonic and Milos (2003), using the same methodology as this study (TBARS), and Ćavar et al. (2008), using the DPPH (1,1-diphenyl-2-picrylhydrazyl) method, confirmed the antioxidant effect of winter savory EO in vitro. These authors also attributed the antioxidant activity of the EO to its thymol and carvacrol contents. Moreover, other components present in the S. montana L. EO evaluated in this study ( Table 1) have antioxidant activity that has been reported in the literature. Ruberto and Baratta (2000) evaluated about 100 purified constituents of various essential oils and found pronounced antioxidant effects in the compounds α and γ-terpinene, myrcene, limonene, p-cymene and PLX3397 purchase α-thujene; at high concentrations, their effects were comparable

to those of phenolic compounds. In the samples manufactured with sodium nitrite, however, the interaction between EO and nitrite should be considered. First, without added EO, TBARS values were significantly (p ≤ 0.05) lower across all storage times in samples with nitrite added than without nitrite (control sample). The antioxidant effect of nitrite in cured meats is related to the formation of stable compounds with myoglobin, which make Fe unavailable to act as active catalyst of oxidation reactions ( Karl-Otto, 2008). Al-Shuibi and Al-Abdullah (2002), in a study in which mortadella was produced with different levels of nitrite Ku-0059436 molecular weight and stored for 14 weeks at 4 and 25 °C, also found lower TBARS values in samples with nitrite added. Moreover, these authors observed that 40 and 80 mg/kg nitrite, with TBARS values ranging from 0.53 to 0.59 mg MDA/kg, have a greater antioxidant effect than 120 mg/kg nitrite (TBARS value 0.65 mg MDA/kg). This result was also observed

in this study because the antioxidant effect was more pronounced (p ≤ 0.05) in sausages manufactured with 100 mg/kg of nitrite than with 200 mg/kg. According to Lücke (2000), the nitrite concentrations required for the antioxidant effect vary between 20 and 50 mg/kg, depending on the type of meat product. ZD1839 research buy In this study, all samples manufactured with nitrite and EO had TBARS values below 3.1 mg MDA/kg sample. Melton (1983) reported detectable oxidized flavor with TBARS values in the range of 0.3–1.0 for pork and beef, 1.0–2.0 for chicken and above 3.0 for turkey meat. However, these TBARS values should not be considered thresholds of rancid odors in meat because they were influenced by several factors. Spicy meat products seem to mask the effects of off flavors. Although treatment with sodium nitrite and savory EO all significantly (p ≤ 0.05) inhibited lipid oxidation, the antioxidant effect was only synergistic with the combination of 100 ppm nitrite and 15.60 μl/g EO. This combination showed lower (p ≤ 0.05) TBARS values than other treatments after the 10th day of storage.

Some of the biologic attributes of nonpolypoid adenomas in humans

Some of the biologic attributes of nonpolypoid adenomas in humans can be demonstrated Selleckchem Panobinostat in laboratory animals. Amandeep K. Shergill and Francis A. Farraye Surveillance colonoscopy in patients with inflammatory bowel disease (IBD) with colonic involvement is recommended by multiple national and international gastrointestinal societies. Recommendations differ on the timing of initial screening colonoscopy, recommended surveillance intervals, optimal technique for dysplasia detection, and management of endoscopically visible and nonvisible

dysplasia. This article reviews current society guidelines, highlighting similarities and differences, in an attempt to summarize areas of consensus on surveillance protocols in IBD, while drawing attention to controversial areas in need of further research. Roy Soetikno, Silvia Sanduleanu, and Tonya Kaltenbach The role of endoscopy in the management of patients with inflammatory bowel disease (IBD) is well established. However, recent data have shown significant limitations in the effectiveness of colonoscopy in preventing colorectal cancer (CRC) in patients with IBD colitis. The current standard random biopsy seemed largely ineffective in detecting nonpolypoid

colorectal neoplasms. Data using chromoendoscopy with targeted biopsy, however, showed a significant improvement when used to detect dysplasia, Oligomycin A manufacturer the best predictor of CRC risk. This article

provides a useful and organized series of images of the detection, diagnosis and management of the superficial elevated, flat, and depressed colorectal neoplasms in IBD patients, and provides a technical guide for the use of chromoendoscopy with targeted biopsy. Index 521 “
“Charles J. Lightdale, MD, Consulting Editor Dr Roy Soetikno and Dr Tonya Kaltenbach are the editors for this issue of Gastrointestinal Endoscopy Clinics of North Montelukast Sodium America, which is devoted to the improved detection and management of early neoplasia in inflammatory bowel disease. An important aspect of Dr Soetikno’s outstanding career has been the bridging of endoscopic methods between Japan and the United States. Endoscopists in Japan have a better record of detecting subtle flat GI lesions. From the earliest days of endoscopy, it is fair to say that Japanese endoscopists have emphasized visual identification, analysis, and photo documentation of small GI lesions. The colon has been no exception. Dr Soetikno has incorporated these techniques, which have become increasingly feasible with steady improvement in modern digital endoscopes. Identifying small flat premalignant lesions and early cancers in patients with colitis can be lifesaving.

Ciężki przebieg kliniczny tych chorób i niepomyślne rokowanie sta

Ciężki przebieg kliniczny tych chorób i niepomyślne rokowanie stanowią trudny problem medyczny. Mutacje w genach PEX GSK2118436 kodujących białka peroksysomalne wchodzące w skład macierzy i odpowiadające za import białek błonowych (membrane protein import) prowadzą do zaburzenia powstawania (biogenezy) peroksysomów. Do tej pierwszej grupy chorób – zalicza się zespół Zellwegera (Zellweger syndrome, ZS), noworodkową

adrenoleukodystrofię (neonatal adrenoleukodystrophy, NALD), postać niemowlęcą choroby Refsuma (infantile Refsume disease, IRD) i rizomeliczną chondrodystrofię (rhizomelic chondrodysplasia punctata, RCDP) [9]. Najcięższą postać stanowi zespół Zellwegera, nazywany początkowo zespołem mózgowo-wątrobowo-nerkowym. Charakteryzuje się dysmorfią twarzowo-czaszkową (wysokie czoło, fałd mongolski), zaburzeniami

rozwojowymi ośrodkowego układu nerwowego, zaburzeniem mielinizacji w układzie nerwowym, głębokim upośledzeniem psychoruchowym, hepatomegalią. Noworodki urodzone z tym zespołem prezentują głęboką wiotkość, drgawki, zaćmę, retinopatię, mają trudności z jedzeniem. Charakterystyczne „centkowanie” kości widoczne w obrazie rentgenowskim, zwłaszcza w rzepce, stwierdza się u ∼ 50% pacjentów. W podstawowych parametrach biochemicznych obserwuje się wysoki poziom żelaza, transaminaz wątrobowych i kwasów żółciowych. Dzieci umierają click here najczęściej przed upływem pierwszego roku życia [7, 8, 11]. Noworodkowa adrenoleukodystrofia i postać niemowlęca choroby Refsuma przypominają zespół Zellwegera, ale o łagodniejszym przebiegu i dłuższym okresie przeżycia. Uważa się, że choroby te różnią się jedynie stopniem nasilenia objawów klinicznych. W NALD dysmorfia twarzowo-czaszkowa jest podobna do ZS, lecz nie tak wyrazista, napady padaczkowe mogą wystąpić dopiero po okresie noworodkowym. Większość dzieci

wykazuje wiotkość, ale w przeciwieństwie do zespołu Zellwegera mogą osiągnąć pewien stopień rozwoju psychomotorycznego, a nawet samodzielnie chodzić. W bardzo rzadkich wypadkach rozwijają funkcję mowy w stopniu odpowiednim GPX6 do wieku. Najbardziej charakterystycznym objawem w tej grupie jest utrata słuchu i zwyrodnienie barwnikowe siatkówki. Dzieci umierają w późnym okresie niemowlęcym. Ze względu na obserwowaną niewydolność nadnerczy początkowo sądzono, że NALD jest niemowlęcą formą X-ALD, dalsze badania udowodniły jednak, że są to dwie różne jednostki chorobowe. Pacjenci z niemowlęcą postacią choroby Refsuma (IRD) demonstrują najłagodniejszy fenotyp ZS spektrum, często dożywają powyżej 20 r. ż. 11., 12. and 13.. Chondrodystrofia rhizomeliczna klinicznie różni się od wcześniej opisanych chorób. Charakteryzuje się skróceniem proksymalnych części kończyn, zaburzeniami kostnienia, silnie zaznaczonymi cechami dysmorficznymi oraz obustronną zaćmą. Większość dzieci jest głęboko upośledzonych.

Since the physiological in vivo environment, although from a diff

Since the physiological in vivo environment, although from a different species, mimics the original tumor conditions much better than a plastic dish, success rates of establishing PDTX are higher than for cell lines and genetic divergence is less common [ 15]. Importantly, biological stability of PDTX from a variety of primary tumors including colon, lung, breast, pancreas, prostate, and ovarian cancer has been established [ 16 and 17]. Xenografted colon tumors, for example, preserve their original genetic and histological profiles for up

to 14 passages [ 18]. In addition, several sub-clones grow in parallel and partially conserve parental tumor heterogeneity ( Figure 1). These benefits make PDTX a valid preclinical Talazoparib price model and allow meaningful biological assays including drug efficacy and predictive biomarker development studies

[ 17]. To this end, PDTX have been used to functionally verify rationally predicted drug response scores [ 19], develop predictive biomarkers for standard and novel anticancer drugs [ 17], and identify effective treatment regimens for patients [ 20••]. Even though PDTX bear great promise as preclinical model for human cancer, there are several caveats. First, tumor take is unsatisfactory with aggressive tumors engrafting best. In some instances, the ability to xenograft even serves as a negative predictor

of the patients’ GSK J4 clinical trial disease free survival [21]. Second, although similarities between PDTX and parental tumors are common, they cannot be assumed and must be rigorously tested [17]. Third, tumor-host interactions are not always Erlotinib purchase conserved across species (e.g. HGF-MET) and tumor immunity is entirely absent [3]. Fourth, the use of animals is labor intense, time consuming, and ethically problematic. Consequently, PDTX are no substitute for in vitro cultures with respect to initial high throughput drug screens. This is particularly relevant since altered signaling pathways often crosstalk to others which requires combinatorial therapy of many drug candidates for optimal treatment [ 22]. Recently established organoid cultures from primary tumors [ 23••] may expand the repertoire of available preclinical tumor models by bridging this gap between cancer cell lines and xenografts. The past years have seen unprecedented developments in the use of human tissue surrogates in vitro. Adult stem cells are embedded in a three-dimensional matrix and allowed to self-organize into epithelia of the respective organ of origin. The resulting organoids represent the physiology of native epithelia much better than traditional cell lines. Mini-guts, for example, reproduce the epithelial architecture of small intestine and colon [ 23•• and 24•].

We therefore conducted a replication of our prior behavioral expe

We therefore conducted a replication of our prior behavioral experiment using conceptual and repetition primes in an R/K paradigm (Taylor and Henson, in press) in combination with fMRI. For the fMRI data, differences between the various trial-types (as a function of R/K/New judgments and prime-type) were explored in a whole-brain analysis. Second, as a more sensitive test of the hypothesis

above, we identified functional regions of interest (fROIs) sensitive to recollection (R > K contrast) or to familiarity (K > Correct Rejections (CR) contrast), and tested for (orthogonal) priming LBH589 research buy effects in those fROIs. Participants were recruited from the volunteer panel of the MRC Cognition and Brain Sciences Unit, or from the student population Selleck Everolimus of Cambridge University; all participants had normal or corrected to normal vision and were right-handed (self-report). Experiments were of the type approved by a local research ethics committee (Local Research Ethics Committee reference 05/Q0108/401). A total

of 22 participants (15 female) gave informed consent to participate in the fMRI experiment, with a mean age of 25.77 (SD = 4.57) years. The stimuli (identical to those used in Taylor and Henson, in press) consisted of 480 word-pairs (“prime”-“TARGET”) that were conceptually related but not lexically associated according to word-generation norms (both forward and backward association probabilities <.10 in the University of South Florida norms; Nelson et al., 1998: Conceptual relatedness was defined on the basis of taxonomic

category (e.g., piano–GUITAR, horse–COW), attributes or functions (e.g., silver–COIN, teapot–BOIL), typical context (e.g., pond–FROG, wedding–BRIDE), part-whole relationship (e.g., tobacco–CIGAR, camera–LENS), or lexical interchangeability (e.g., biscuit–COOKIE, shop–BOUTIQUE). All primes and targets were between three and eight letters long (primes: M = 5.26, Osimertinib solubility dmso SD = 1.12; targets M = 5.44, SD = 1.38) and had written frequencies between 1 and 150 per million (primes: M = 33.97, SD = 26.00; targets M = 34.14, SD = 36.08; Kučera and Francis, 1967). These conceptually related prime-target pairs comprised the Primed condition for Conceptual Priming trials; two further lists were created by re-pairing each target with itself (Primed condition, Repetition Priming trials) or with an unrelated prime via a pseudo-random shuffle (Unprimed conditions for both Conceptual and Repetition Priming trials). These lists were each further sub-divided into four Sets (A–D), to be used in the counterbalancing described in Procedure, below. The main experiment consisted of two trial types, Study and Test. On Study trials, participants made “interestingness” judgments (based on our previous studies, e.g., Woollams et al.

Walking is a critical functional

activity for mobility, i

Walking is a critical functional

activity for mobility, is important for maintaining health and function, and is essential for performance of many activities of daily living (Kerrigan et al., 1998 and Prince et al., 1997). Abnormal gait is predictive of falls and institutionalization (Verghese et al., 2002) and early identification of gait impairment might help identify older adults who are at risk of functional limitation, falls and injuries (Verghese et al., 2006). Similarly, rising from a chair is a precursor to several mobility activities including walking and is important for independent living (Hughes et al., 1994, Ikeda Lumacaftor mouse et al., 1991, Laporte et al., 1999 and Rodosky et al., 1989). When compared to CR, the CSt phase has received little attention (Durward et al., 1999 and Kerr et al., 1997). Among mobility-based tasks, stair negotiation is a physically challenging activity and peak knee flexion moments during SA have been reported to be three times greater than those of level walking (Andriacchi et al., 1980 and Startzell et al., 2000). Stairs pose a serious falls risk to older people with over 60% of accidents occurring on stairs (DTI, 2010). Diminishing physiological reserves selleck inhibitor and a decline in physical capacity with increasing age predispose

the older person to an increased risk of falls. Biomechanical analysis aimed at evaluating the demand placed on lower extremity Telomerase joints during everyday activities could enhance our understanding of the requirements of various tasks and help inform development

of suitable clinical interventions to address functional deficits. In addition, profiles of “FD” generated by different daily living tasks is of interest to clinicians, bioengineers, patients and their carers so as to set targets for rehabilitation (Macdonald et al., 2007). To date, few studies have evaluated the biomechanical demand placed on lower extremity muscles and joints and these have involved small sample sizes with a limited range of activities being investigated (Costigan et al., 2002, Livingston et al., 1991, McFadyen and Winter, 1988 and Protopapadaki et al., 2007). Previous investigations (Reeves et al., 2006 and Reeves et al., 2008) have suggested that older adults operated at a higher proportion of their maximum capacity when compared to young adults with a high loading placed on knee and ankle joints during stair negotiation (Hortobágyi et al., 2003, Reeves et al., 2006 and Reeves et al., 2009). While earlier biomechanical studies have highlighted a range of issues relating to task performance, these have involved small participant numbers ranging between 5 and 23 older adults and hence have limited inferential ability (Alexander et al., 1991, Hughes et al., 1996, Mourey et al., 1998, Schenkman et al., 1990 and Schultz, 1992).

, 2009) Soil and water conservation programs in China were first

, 2009). Soil and water conservation programs in China were first legislated in the 1950s following concern about local agricultural and industrial productivity and flooding downstream (Shi and Shao, 2000). Implementation at large spatial scales (e.g. 0.92 M km2 of land terracing, tree and grass planting, and construction of this website sediment trapping dams), mostly in the Yellow and Yangtze basins, has reduced sediment fluxes to coastal waters by an estimated 11.5 Gt during 1959–2007 (Chu et al., 2009). Terrestrial fluxes of N and P to coastal waters have been reduced following management of point sources, such as waste water treatment plants, phosphate mines and P-detergents (Boesch, 2002 and Cloern, 2001) (Tables 1c and 2). For example,

regulation has reduced the contributions from waste water treatment plants and industrial discharges to total annual average N and P loads to the Danish coast from ∼50% to <10%, and from 59% to ∼20%, respectively, over 14 years (Carstensen et al., 2006). The learn more nutrient regulation in Denmark followed lobster mortality in coastal waters in the 1980s which was attributed to algal blooms and hypoxia induced by agricultural nutrient run-off (Windolf et al., 2012). Similar declines in nutrient loads from point sources have resulted in reductions in coastal nutrient and chlorophyll a (chl a)

concentrations ( Greening and Janicki, 2006), enhanced benthic irradiance ( Greening and Janicki, 2006), seagrass recovery ( Tomasko et al., 2005), and concomitant decline in macroalgae ( Cardoso et al., 2010 and Vaudrey et al., 2010), including on coastal coral reefs ( Laws and Allen, 1996 and Smith et al., 1981). Further recovery, including to a coral-reef dominated state, may be partly constrained by nutrient sources other than point sources ( Hunter and Evans, 1995), as well as obscured by increases in human population, changes in diffuse sources and

variation in freshwater discharge ( Williams et al., 2010). Reducing diffuse source loads becomes increasingly important where point source discharges comprise only a small percentage of the total N and P loads, such as in the Great Barrier Reef (GBRMPA, 2009). Major recent reviews provide recommendations to reduce excessive or inappropriate input of N and P from diffuse sources such as agriculture, 3-oxoacyl-(acyl-carrier-protein) reductase fossil-fuel and animal husbandry (Canfield et al., 2010, Elser and Bennett, 2011, Galloway et al., 2008 and Vitousek et al., 2009). Deliberate management of agricultural diffuse pollution has contributed to reducing nutrient fluxes to coastal waters in Denmark (Windolf et al., 2012) and The Netherlands (Duarte et al., 2009) within decades (Tables 1c and 2). Moreover, decreasing nutrient fluxes have been measured in several Eastern European rivers, namely the Danube, Daugava, Elbe, Leilupe, Oder and Vistula rivers, in the years following economic decline and associated drop in agricultural subsidies in the early 1990s (Duarte et al., 2009, GEF-UNDP, 2006, Mee, 2001, Pastuszak et al.

The good correlations of some

The good correlations of some Akt inhibitor BAL markers for lung tissue damage, such as LDH release or total protein, with γ-H2AX as a marker for DSB might indicate a link between tissue damage and occurrence of profound DNA damage with mutagenic potential. If not adequately repaired, DSB may lead to genomic instability, cell death, or cancer (Jeggo and Lobrich, 2007). Comparing the mean group data on genotoxicity marker expression in alveolar lining cells with the group means of the histopathology data from the carcinogenicity study, there were comparable patterns for γ-H2AX and 8-OH-dG and thus induction of DSB and oxidative DNA damage and tumor incidences

Ponatinib purchase (based on

the standard analysis procedure with one section per lung lobe). There was also high correlation of the mean histopathologic inflammation score three months after the first particle instillation with tumor incidences in the carcinogenicity study part (see Kolling et al., 2008 and Kolling et al., 2011), irrespective of the differences in the administered particle mass doses, thus providing a link between particle exposure, particle-driven inflammation, induction of DNA damage, and lung tumor development. In conclusion, the present study has demonstrated that immunohistochemical detection and quantification of local genotoxicity in vivo in pulmonary alveolar lining cells by using appropriate genotoxicity markers is feasible, and identified γ-H2AX and 8-OH-dG as sensitive genotoxicity markers that are able to distinguish particles with different genotoxic

potencies. In addition, their expression three months after the first particle exposure corresponded well with the inflammatory and finally carcinogenic potential of the particles, and they might thus be sensitive predictors of tumor development. Furthermore, this study demonstrated that L-NAME HCl different genotoxic events, especially induction of DSB and oxidative DNA base lesions, seem to play an important role in particle-induced lung tumor development at high particle doses. As data were obtained from animals that had been treated intratracheally at high dose levels, with total lung loads amounting to >3 mg/lung, strong and persistent lung inflammation was induced. Therefore, these results cannot conclusively answer the question as to whether secondary inflammation-dependent mechanisms only or also particle-specific primary mechanisms of genotoxicity participate in lung tumor induction by MNP. At severe particle overload in the lung, secondary mechanisms may overwhelm and confuse potentially existing primary genotoxic events, thus preventing a clear distinction between the different primary and secondary genotoxic mechanisms.