Therapeutic effects of the MLs were inconsistent and not very impressive in the reviewed experiments. However, in other tumour types, MLs have also shown substantial growth-inhibiting effects (e.g. [154–157]). Interestingly, in two experiments, the application of VAE-activated macrophages in mice not directly treated with VAE also showed tumour-growth inhibiting effects, while the application of non-activated macrophages had no effects [121]. Similarly in melanoma, the application of VAE-activated splenocytes inhibited

metastasis [158, 159]. In general, the predictive reliability of the preclinical studies for clinical application is check details fairly limited in most instances. Clinical cancer disease is insufficiently mimicked by animal models, with major differences regarding age, general condition, co-morbidity, invasiveness, metastases, antigenicity, immune system etc. The results of preclinical screening, especially for treatment of solid tumours, have therefore been largely disappointing. The models currently regarded as best for cytotoxic substances use patient-derived tumours that grow subcutaneously or orthotopically in nude mice, as in several cases reviewed here. Immuno-active substances buy AZD3965 may however still be insufficiently assessed in immune-deficient animals, as the main components of the immune system

are missing (nude mice, for instance, cannot generate mature T-lymphocytes). Nevertheless, these preclinical experiments can provide important additional information for detecting the possible anti-cancer effects of medicinal

plants, their active compounds, their mode of action and potential risks [20, 160–162]. Safety aspects Mistletoe therapy was well tolerated in the reviewed studies. Mild flu-like symptoms and local reactions at the injections sites are frequent, dose-dependent and self-limited. Allergic reactions can occur, and a few case reports of anaphylactic reactions exist [163–166]. A phase I study, conducted at the NCCAM/NCI, investigated safety, toxicity and drug interactions between VAE and gemcitabine Florfenicol [73] and reported good tolerability, with neither dose-limiting toxicity of the VAE nor any effects on the plasma concentration of gemcitabine [44]. Combination of VAE with chemotherapy or radiotherapy did not negatively influence remission rate in clinical and in animal studies [56, 63, 118]. A higher prevalence of depression in VAE-treated patients in one study was observed in raw data of a self-selected population, without adjustment of baseline imbalances. This difference can be ascribed to variations in the patient population; for instance, they differed markedly in the prevalence of hormone treatment. No toxicity was observed in animal experiments.

Stat Med 26:2389–2430. doi:10.​1002/​sim.​2712 PubMedCrossRef Ruotsalainen JH, Verbeek JH, Salmi JA, Jauhiainen M, Laamanen I, Pasternack I et al (2006) Evidence on the effectiveness of occupational health interventions. Am J Ind Med 49:865–872. doi:10.​1002/​ajim.​20371 PubMedCrossRef Virtanen M, Kivimäki M, Vahtera J, Elovainio M, Sund R, Virtanen P et al (2006) Sickness absence as a risk factor for job termination, unemployment, and disability pension among temporary and permanent employees. Occup Environ Med 63:212–217. doi:10.​1136/​oem.​2005.​020297 PubMedCrossRef”
“Dear Sir, Regarding the

Akt inhibitor letter concerning our article, González-Yebra et al. (2008), we want to make some statements. First: We reported median instead of means because our data did not show a normal distribution. We acknowledge the accidental typing error made in the text of the discussion where we wrote a median of 0, the correct value is 0.1 as shown in Table 3. As for the alcohol

consumption and its possible relationship with the induction of micronuclei, we carried out two types of analysis as described in the materials and methods. The Kruskal–Wallis test to identify differences between the study groups. With this analysis we found a significant difference between the alcohol consuming exposed group and the non alcohol consuming exposed group. Afterwards we conducted a multiple regression analysis to identify the variables associated click here with the presence of micronuclei, with this analysis we found no association with the consumption very of alcohol. It is possible that the Kruskall–Wallis analysis shows a synergism between exposure to solvents and alcohol consumption. We agree with the author of the letter on the irrelevance of the reference Fenech et al. (1985). As for the commentary on the evaluation of only 1,000 exfoliated cells, we would like to emphasize that we scored at least one thousand cells (Material and methods right column last paragraph), according to Tolbert et al. (1992), Gonsebatt et al. (1997), Reis et al. (2002), Domínguez et al. (2005) and we can provide another reference, Wu et al. (2004). We thank the advice on the evaluation of cells by means

of oil immersion and magnification ×1,000 and may consider it for future studies. With are positive that Fig 1b, is a broken egg phenomenon, clearly showing a smaller fragment irregularly shaped. We apologize for the very few lapses in which we have incurred in our English writing on our paper, and most of all for not having erased the Spanish “nucleos rotos” for broken eggs. References Domínguez O, Rojas V, Romero G, Rodríguez T, Pérez A (2005) Lesiones citológicas bucoepiteliales en trabajadores expuestos a productos químicos. Rev Med IMSS 43(3):221–227 Gonsebatt ME, Vega L, Salazar AM, Montero R, Gusman P, Blas J, Del Razo LM, García-Vargas G, Albores A, Cebrián ME, Kelch M, Ostrosky-Wegman P (1997) Cytogenetic effects in human exposure to arsenic.

Preliminary safety evaluation of enterococci: presence of virulence factors, production of gelatinase and hemolysin and antibiotic susceptibility Concerning E. faecalis, most of the strains (20 strains, 95%) harboured, at least, INCB024360 cell line one relevant virulence factor: efaAfs (95%), gelE (71%), or agg (67%) genes (Table 2). A positive gelatinase reaction was found in 15 E. faecalis strains (71%) which harboured

gelE, from which 12 also harboured agg gene. Only one E. faecalis strain (E. faecalis SDP10) (5%), harbouring cylL L -cylL S -cylM, exerted hemolytic activity, while none of the strains amplified hyl or esp genes. With regard to E. faecium, 20 strains (53%) harboured, at least, one relevant virulence factor: efaAfs (45%), gelE (24%) or agg (8%), but only 4 strains (11%) exerted gelatinase activity. None of the E. faecium strains exerted hemolytic activity nor amplified hyl or esp genes. The results of the antibiotic susceptibility tests revealed that 39 enterococccal strains (66%) displayed acquired antibiotic resistance to antibiotics other than penicillin G, chloramphenicol and high-level gentamicin. In this respect, 13 E. faecalis strains (62%) showed acquired resistance to (i) second generation quinolones (ciprofloxacin and/or norfloxacin) (12 strains, 57%), (ii) rifampicin (5 strains, 24%), (iii) nitrofurantoin

(5 strains, 24%), (iv) glycopeptides (vancomycin and teicoplanin) (4 strains, 19%), and/or (v) erythromycin (1 strain, 5%). However, 26 E. Pexidartinib faecium strains (68%), including 17 strains that encode virulence factors and nine strains without these traits, displayed acquired resistance to (i) erythromycin (14 Inositol monophosphatase 1 strains, 37%), (ii) nitrofurantoin (11 strains, 29%), (iii) second generation quinolones (ciprofloxacin and/or norfloxacin) (10 strains, 26%), (iv) rifampicin (4 strains, 11%), (v) tetracycline (2 strains, 5%), and/or (vi) glycopeptides (vancomycin and teicoplanin) (1 strain, 3%). Moreover, multiple antibiotic resistance (two to six antibiotics)

was found in E. faecalis (10 strains, 48%) and, to a lesser extent, in E. faecium (12 strains, 32%) (Table 2). According to the results above, 21 E. faecalis strains were discarded for further studies based on the presence of virulence factors (8 strains, 38%), acquired antibiotic resistance (1 strain, 5%) or both (12 strains, 57%). Regarding E. faecium strains, 29 (76%) were dropped from further screening based on acquired antibiotic resistance (9 strains, 24%), the presence of virulence factors (3 strains, 8%) or both (17 strains, 45%). Table 2 Preliminary safety evaluation of enterococci Enterococcus spp. Strain Virulence Factors Antibiotic resistance phenotypec Genotypea Phenotypeb E. faecalis SMF10 efaAfs +, gelE +, agg + GelE+, Hly- CIP, NOR   SMF28 efaAfs +, gelE + GelE+, Hly- CIP, NOR   SMF37 efaAfs +, gelE +, agg + GelE+, Hly- –   SMF69 efaAfs +, gelE +, agg + GelE+, Hly- CIP, RIF   SMM67 n.d.

5 μl of 10 × buffer and 2 U of restriction enzyme (New England Biolabs). Restriction see more digests were analyzed by agarose gel electrophoresis (2.5% gel containing 0.5 μg ml-1 EtBr in 1 × TAE buffer). Gels were run at 60 V and photographed under UV transillumination. The 50 bp and 100 bp DNA ladders (New England Biolabs or MBI Fermentas) served as the molecular weight standards. The restriction patterns for all the isolates were analyzed using Diversity Database Software (version 2, Bio-Rad). Distinct restriction patterns for each locus were considered to represent separate alleles, and each allele was assigned a numeral. As with

MLEE, the combination of alleles at each of the six loci gave a restriction type (RT). Strains were considered different if the allele of any of the six loci differed. The genetic diversity h was calculated as described for MLEE. The restriction profile for each isolate was entered into a database and used to construct a phylogenetic tree based on unweighted-pair group method with average (UPGMA) linkage of distance, using the START (Sequence Type Analysis and Recombination Tests) software package http://​outbreak.​ceid.​ox.​ac.​uk/​software.​htm. In addition, clonal complexes within 81 biovar 1A strains were investigated using the BURST (Based Upon Related U0126 clinical trial Sequence Types) algorithm of START software

package. DNA sequencing and analysis For mafosfamide each allele identified for the six genes used in MLRT, one amplicon was sequenced to confirm its identity. PCR products were purified with the QIAquick gel extraction kit (Qiagen) and DNA sequencing was performed by the Big-Dye terminator kit using an automated DNA sequencer (ABI PRISM 3730 genetic analyzer). Linkage disequilibrium

analysis Linkage disequilibrium for MLEE and MLRT data was calculated on the basis of the distribution of allelic mismatches between pairs of bacterial isolates among all the loci examined. The ratio of the variance observed (V O) in mismatches to the variance expected (V E) at linkage equilibrium provides a measure of multilocus linkage disequilibrium and can be expressed as the index of association (I A) as: I A = V O/V E – 1 [34, 35]. For populations in linkage equilibrium, V O = V E and I A is not significantly different from zero, whereas values of I A significantly greater than zero indicate that recombination has been rare or absent. To determine whether V O was significantly different from V E in any sample, a Monte Carlo procedure was iterated, wherein alleles are repeatedly scrambled to eliminate any effect of linkage disequilibrium [36]. The LIAN version 3.5 software program [37] was used to calculate I A and standardized I A (I S A) values and perform Monte Carlo procedure.

All patients reached the scheduled cumulative epirubicin dose of 400 mg/m2. Chemotherapy associated with salidroside was well tolerated in all patients. Fifteen patients were randomly selected to undertake the intra- and interobserver reproducibility of the SR. Conventional Echocardiography,

SRI, and Laboratory Data No significant abnormalities of the LVEF were found in either of the two groups throughout the entire treatment period (table II). However, we observed a reduction in the SR peak at t2 (p < 0.05) at an epirubicin dose of 200 mg/m2, with no significant differences between the salidroside and placebo groups (1.35 ± 0.36 vs 1.42 ± 0.49/second, p > 0.05). With growing cumulative doses of epirubicin, the SR normalized only in the salidroside group, showing a significant

difference in comparison with the placebo group at epirubicin doses of 300 mg/m2 (1.67 ± 0.43 vs 1.32 ± 0.53/second, p < 0.05) and find more 400 mg/m2 (1.68 ± 0.29 vs 1.40 ± 0.23/second, p < 0.05) [table II]. Furthermore, Ibrutinib solubility dmso the ROS serum concentrations significantly increased at t2 in the placebo group (498 ± 41 vs 849 ± 15 FORT-U, p < 0.05), whereas they remained unchanged in the salidroside group (498 ± 30 vs 519 ± 12 FORT-U, p > 0.05) [table III]. We randomly selected 15 patients to undertake the intra- and interobserver reproducibility of the myocardial strain, and both intra- and interobserver variability were below 13% (table IV). Table II Conventional echocardiographic and strain rate imaging parameters in Idelalisib the two groupsa Table III Serum concentrations of reactive oxygen species in the two groupsa Table IV Intra- and interobserver variabilitya of the strain rate in 15 randomly selected patients Correlations between Echocardiographic and Laboratory Data We also correlated early impairment of significant echocardiographic parameters (calculated as a change in the SR [ΔSR] by subtracting the values from the baseline values) with an increase

in serum concentrations of ROS after 200 mg/m2 of epirubicin. We found modest correlations between the ΔSR and an increase in plasma concentrations of ROS (r =0.49, p < 0.05). Discussion Although epirubicin is one of the most powerful antineoplastic agents, its clinical use is limited by dose-related cardiotoxicity.[7] Epirubicin-induced myocardial dysfunction detected early by serial tissue Doppler echocardiography has been correlated with oxidative stress markers with an unchanged LVEF during epirubicin chemotherapy.[8] DTI associated with SRI has shown its value in early detection of epirubicin-induced cardiotoxicity, and a measurable SR peak depression has been regarded as the earliest sign of left ventricular regional systolic dysfunction in epirubicin-treated patients long before a clinical manifestation of heart failure.

The structure of the flagellar transition zone is variable among kinetoplastids and euglenids, particularly in regard INK 128 manufacturer to the presence/absence of peripheral elements and transitional plates. Kinetoplastids and diplonemids possess distal and proximal transitional plates and a hollow transition zone [30, 32, 42], while euglenids only possess the

proximal transitional plate. Although the transition zone of most euglenids is also hollow, the transition zone in some euglenids, such as Entosiphon applanatum and Notosolenus (Petalomonas)mediocanellata, has been shown to be electron dense. However, the detailed structure of these transition zones still remains to be characterized in detail [29, 43]. The central area of the transition zone in C. aureus is also electron dense and contains a complex system of elements that have never been observed in any other Euglenozoan so far (Figure 6). Characterization of the flagellar transition zone in Postgaardi might demonstrate several homologous elements that would help to further establish a close relationship between this lineage and C. aureus. Nonetheless, Diplonema ambulator, Rhynchopus euleeides, R. coscinodiscivorus and C. aureus all have fibers that extend from each microtubular doublet to the flagellar membrane; these fibers have

been called “”transitional fibers”" [30,

32, 44]. “”Transitional fibers”" Rebamipide has also been used PCI-32765 purchase to describe fibers that extended from each microtubular triplet of a basal body to the flagellar membrane, which is potentially confusing [45–47]. Nonetheless, the “”radial connectives”" extending from the doublets in the transition zone of C. aureus are nearly identical, and likely homologous, to the ‘transitional fibers’ extending from the doublets in diplonemids, such as D. ambulator. Feeding Apparatus Each of the euglenozoan subgroups contains members with an elaborate feeding apparatus [20, 26, 29, 39]. Most phagotrophic euglenids, for instance, have a distinctive feeding apparatus consisting of 4–5 central vanes and 2–3 supporting rods [28, 48, 49]. Some bacteriovorous euglenids (e.g. Petalomonas), however, possess a much simpler feeding apparatus that is very similar to the MTR feeding pockets found in many kinetoplastids (e.g. Bodo) [26]. The microtubules that support the rods in phagotrophic euglenids and the MTR pockets in bacteriovorous euglenozoans originate from the ventral root of the ventral basal body. Similarly, the feeding pocket in C. aureus was also supported by microtubules that originated from the ventral root and is almost certainly homologous to the MTR pockets or rods found in other euglenozoans, including Postgaardi [33].

The results from this study will, however, help guide future efforts. Future directions are to determine if the use of a telepresence system for mentoring and consultation purposes impacts the process and outcomes of care. Conclusion In conclusion, a robotic telepresence system that

is mobile and compact in size was readily accepted by the staff in the operating room and physicians. Physicians were able to use the ControlStation with little training or experience. We were able to test the system’s functionalities on a variety of trauma and surgical cases. The potential applications of this system for military and civilian purposes should be further evaluated. Acknowledgements This article has been published as part of World Journal of Emergency Surgery Volume 7 Supplement 1, 2012: Proceedings of the World Trauma Congress 2012. The full contents PS-341 purchase of the supplement are available online at http://​www.​wjes.​org/​supplements/​7/​S1. References 1. Williams TE, Ellison EC: Population analysis predicts a future critical shortage of general surgeons. Surgery 2008, 144:548–556.PubMedCrossRef 2. Harvard School of Public Health: More than 2 billion people worldwide lack access to surgical services. ScienceDaily 2010. 3. Ereso AQ, Garchia P, Tseng E, et al.: Live transference of surgical subspecialty

skills using telerobotic proctoring to remote general surgeons. J Am Coll Surg 2010,211(3):400–411.PubMedCrossRef 4. Jarvis-Selinger

S, et al.: Clinical telehealth across the disciplines: lessons learned. Telemed J E Health 2008, 14:720–725.PubMedCrossRef 5. Moore EE, Cogbill TH, Malangoni M, Crizotinib manufacturer Jurkovich GJ, Champion HR: Scaling System for organ specific injuries. Competing interests The authors declare that they have no competing interests. Authors’ contributions AM provided the direction and guidance to the research conception and design. FK was involved with the data management and analysis, and drafted the manuscript. EP and DR assisted with the data collection and entry. PA-R assisted with the data interpretation and draft of manuscript. CS assisted with study concept and design, and data interpretation. All authors read and approved the final manuscript.”
“Introduction Trauma injuries are becoming an increasing public health issue, especially in developing countries, whether due to Adenosine triphosphate their high mortality rates, or due to the high financial costs of treatment and recovery of these patients. Reicheneim et al [1, 2] classify violence in Brazil as the sixth highest cause of hospitalization, and the third highest cause of mortality. They found that young black men from poor communities are the principal victims, and also the principal offenders, in relation to community violence. In this country, the health authorities delegate responsibility for this service to the Fire Department, removing the health-related aspect of this attendance [3].

As discussed, OPN binds to several integrin receptors including α4β1, α9β1, and α9β4 expressed by leukocytes. These receptors have been well-established

to function in cell adhesion, migration, and survival in these cells. Therefore, recent research efforts have focused on the role of OPN in mediating such responses [14]. OPN gene transcription in bone tissue is regulated by the interaction between transactivating factors and vitamin D3 responsive elements [15]. Previous study has confirmed that OPN is overexpressed in the NSCLC tumor tissues compared to adjacent normal counterparts; and its overexpression is significantly correlated with TNM stages and lymph metastasis [16]. However

there are no relative reports about the relationship between OPN polymorphisms with survival of NSCLC and risk of bone metastasis currently. In the present study, we recruited selleck chemical 360 NSCLC patients and 360 cancer-free control, aim to investigate whether OPN-66 T/G, -156G/GG, and -443C/T genotypes affect the survival of patients; meanwhile to determine whether they have an association with incidence of bone metastasis development. Patients and methods Patients Three hundred sixty ambulatory patients with stage I to IV lung cancer patients who were admitted to the College of Medicine of Shan Dong LDK378 University, Qi Lu Hospital in Jinan, China between October 2003 and July 2007 were studied. 79 patients with bone metastasis Staurosporine price and

281 patients without bone metastasis were included in this study. The median age was 57.21 years (range, 24 to 81 years); 199 patients were male and 161 patients were female. The diagnosis of lung cancer was confirmed cytologically or histologically. All patients gave their informed consent to the diagnostic procedures. The TNM stage mentioned in the current study was diagnosed at first hospitalization. Healthy control group consisted of a random sample of 360 ethnic Han Chinese from Shan Dong province. Bone metastasis evaluation: All patients were evaluated for bone metastasis by bone scintigraphy. A total of 25 mCi 99mTechnetium methylene diphosphonates (MDP) was injected intravenously, and front and back images of the whole body were taken after 3 hours. The apparatus used was a double-detector gamma camera (VERTEX, ADAC Co., CA, USA). Bone scintigraphy was read by two radiologists and classified into either a bone metastasis-positive or a negative group. When the bone scintigraphic interpretation differed among radiologists, positive scans were further assessed by additional radiographs; computerized tomography, magnetic resonance imaging, positron emission tomography or bone biopsy, except when the increased uptake was recognized as being due to a benign condition [17, 18].

E.M. for the average fold changes. Statistical significance (p < 0.05) between expression following nanomaterial exposure and the controls is denoted by an asterisk (*). Western blot analysis Transgelin 2 protein was analyzed by Western blot in all treatment groups (nano-SiO2, nano-Fe3O4, SWCNTs) Pictilisib supplier (Figure  4B). Transgelin 2 protein expression was significantly

increased at all doses of nanomaterial exposure compared with the control group (p < 0.05), but there was almost no significant difference between high dose and low dose in nanomaterial exposure groups. Discussion A nanomaterial is a kind of ultrafine material composed of nanosized particles, between 0.01 and 100 nm in diameter. Recently, research and development of these particles have increased [11], and their potential adverse effects are being investigated by researchers around the world [12–14]. Some report that ultrafine particles may cause damage to the body due to their higher activity and selectivity [13]. The effects of ultrafine particles on the lungs have received much more attention. In spite of the lungs being the most direct target organ for such particles, the methods to study lung injury are limited except for histopathobiology, so we attempt to use biochemical analysis and

comparative proteome to detect lung damage in vivo after nanomaterial exposure to find the difference between the nanomaterials selleck chemicals llc and non-nanomaterials. We selected the three typical nanomaterials because of their different chemical compositions (nano-SiO2 is an inorganic oxide, nano-Fe3O4 is a metal oxide, and SWCNT is a carbon) and different shapes (nano-SiO2 second has a crystal structure, nano-Fe3O4 is a sphere, and SWCNT is rope-shaped). In our study, we found that the three nanomaterials induced oxidative damage and

inflammation in BALF. In addition, there are 17 different proteins regardless of the composition and shape of nanomaterials which expressed a similar nanosize. Epidemiologic and experimental animal studies have shown an increased risk of respiratory and cardiovascular morbidity and mortality associated with exposure to ultrafine particles [15, 16]. Nanoparticle exposure induced production of cytokines in lung epithelial cells and in lung tissue [17, 18]. The aim of this study was to characterize the biochemical changes in BALF and protein profiles in the lung tissue of rats following exposure to three nanomaterials using newly available technologies especially comparative proteomics. Higher protein concentrations in the nanomaterial-exposed BALF samples are likely a result of plasma extravasation. Consistent with this view, many of the plasma-derived proteins identified in both exposed and control samples do indeed change in abundance, for example, albumin [17], but additional work will be required to provide accurate quantification.

However, only 13 % of participants who completed the baseline survey and visited the study homepage actually took part in the genetic testing. Those individuals were characterized by a strong motivation to change their behavior, high genetic literacy (i.e., they understood genetic risks as probabilistic,

not deterministic) and they were internet-savvy (Kaphingst et al. 2012). Most of them shared their test results with family members, very few consulted or intended to consult their primary physician, and visits to specialist doctors did not increase significantly after testing (Reid PLX3397 et al. 2012). Overall, those who chose to be tested did tend to see physicians more often than non-tested persons. Dr. Baxevanis emphasized that no negative effects produced by knowledge of personalized genetic risk information were observed within this study, but he acknowledged that differences in perception between different groups and individuals might exist. To overcome problems in the way genetic risk information is conveyed to, and understood by the public, adequate information is needed and evidence-based communication strategies as well as in-person support are required. Following the speakers’ session, ABT-263 clinical trial the symposium ended with a plenary discussion, held in German, which

was chaired by Thomas Wienker from the Max Planck Institute for Molecular Genetics, Berlin. Peter Dabrock (Dep. Theology, Friedrich-Alexander University Erlangen-Nürnberg), Irmgard Nippert, Marcella Rietschel (Dep. Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim), Ralf Schwarzer (Dep. Health Psychology, Freie Universität Berlin), Ludwig Siep (Faculty of Philosophy, Westfälische Wilhelms-University Münster), and Malte Spielmann (Institute of Medical Genetics and Human Genetics, Charité, Berlin) were the podium guests. The full discussion was videotaped and a shortened version can be viewed on the following website: http://​www.​rki.​de/​DE/​Content/​Kommissionen/​GendiagnostikKom​mission/​Symposium/​symposium_​node.​html;jsessionid=​2CD43F6E8E545450​7C61822BAE13FA56​.​2_​cid390.

The conclusion reached at the discussion was that most tests offered directly to consumers solely Fludarabine purchase satisfy curiosity, but otherwise lack benefit (i.e., they either are of questionable or no demonstrable meaning). The preliminary evidence drawn from the results of the studies undertaken at Scripps Translational Institute and at the NIH and presented by Dr. Bloss and Dr. Baxevanis was that the potential benefit of recently available direct-to-consumer genetic tests lies in the provision of an alleged feeling of security or, as Peter Dabrock, Professor of Theology and Ethics expressed it, the tests “serve as a secular sacraments’ surrogate.” It still remains unclear whether the increasing amount of information (e.g.