Therefore, submaximal and field tests to estimate maximal values

Therefore, submaximal and field tests to estimate maximal values are invaluable in clinical practice, and may also be quite useful in some research settings. A second strength is the meta-analysis used to combine data from multiple studies, which provides a general estimate of expected values in this population. This review summarises

the values that have been reported in the literature to date for various components of physical function, namely aerobic capacity, upper and lower extremity strength and mobility in women diagnosed with breast cancer. Values for aerobic capacity and upper extremity strength are generally lower than published normative values in similar age groups. Lower extremity strength does not appear to follow this pattern, with values higher than population norms. This review Z-VAD-FMK manufacturer also highlights the variety of tests used in the literature

to assess physical function and the variations in testing protocols that may potentially contribute to the heterogeneity in values reported. Objective assessments of various aspects of physical function are important for documenting deficits in physical function and reporting change in response to specific interventions and monitoring individual progress in physiotherapy practice and research settings. As more research becomes available, expected values for sub-populations of different selleck screening library ages, stages of treatment and with various co-morbidities will be useful for both researchers and clinicians working with women after a breast cancer diagnosis. What is already known on this topic: Breast cancer and its treatment can cause impairment in physical function in women. What this study adds: Compared to normative data, women during and after treatment for breast cancer had reduced aerobic fitness. Upper and lower extremity strength was also reduced for women who were currently others receiving cancer treatment. Lower extremity strength was above population norms for women who had completed treatment. eAddenda: Tables 3, 4, 5 and 6, and Appendix 1 and 2 can be found online at doi:10.1016/j.jphys.2014.09.005 Ethics approval: N/A Competing interests: Nil. Source(s) of support: SENS and AAK are supported

by doctoral student awards from the Canadian Institute for Health Research. Acknowledgements: We wish to acknowledge Jonathan Chu, Jackson Lam, Kenneth Lo, and Vincent Sy, members of the 2012 MPT class at the University of British Columbia for their work on developing the search strategy for an earlier version of this review. Correspondence: Kristin L Campbell, Department of Physical Therapy, University of British Columbia, Vancouver, Canada. Email: [email protected]
“Contractures are a common secondary problem after acquired brain injury.1 and 2 Traditional treatment for contractures has primarily involved passive stretch. However, a systematic review found that commonly-used passive stretch interventions do not produce clinically worthwhile effects.3 Two reasons may explain this finding.

Dunlop et al (2005) demonstrated that lack of regular vigorous ph

Dunlop et al (2005) demonstrated that lack of regular vigorous physical activity almost doubled the odds of worsening of limitations and that regular vigorous physical activity reduced this

worseing by as much as 32%. The results of our study show that the level of physical activity was higher in the experimental group than in the control group. We found a 5.3 fold in the short term and 2.9 fold in the long term greater odds of people receiving behavioural graded activity meeting the recommendation for physical activity compared with those receiving usual care, mainly due to an increase in the amount of time spent walking in the behavioural graded activity. The difference in physical activity between the groups may be due to the fact that more of the experimental group were advised to perform home activities than the control group. In the experimental group, the most problematic activities were increased GSK126 gradually and previous research has shown that walking is the most prevalent limitation in activities in people with osteoarthritis (Ewert et al 2004). There are a few limitations to this study that need to be mentioned. First of all, the design of our study does not allow any conclusions to be drawn about which aspect of behavioural graded activity (eg, booster sessions) is most important

for improving exercise adherence and physical activity. Second, a gold standard in measuring exercise adherence does not exist

(Sluijs et al 2006). In our study, exercise adherence was measured using a self-report questionnaire. Although used selleck kinase inhibitor widely, the validity of using self-report questionnaires to measure exercise adherence is debatable. They are known to overestimate adherence and are susceptible to bias caused by memory, social desirability, and need for social approval (Sluijs et al 2006). However, a self-report questionnaire is a simple measurement to collect and is probably no more subject to bias than diaries and interviews. Although accelerometers/pedometers provide reasonably accurate measures of walking, they cannot evaluate other types of activities. Importantly, it is unlikely that potential sources of bias inherent in self-reports explain Sodium butyrate the between-group differences, because both groups had similar baseline adherence. In conclusion, behavioural graded activity with booster sessions results in better exercise adherence and a greater amount of physical activity than usual physiotherapy intervention, both in the short- and long-term. Integration of behavioural graded activity principles and adding booster sessions to exercise programs seems to be useful in enhancing exercise adherence and physical activity after discharge from physiotherapy intervention. eAddenda: Appendix 1 and Appendix 2 available at Ethics: The Medical Ethical Committee of the VU University Medical Center, Amsterdam, The Netherlands approved this study.

Primary antibodies against the following proteins were used: anti

Primary antibodies against the following proteins were used: anti-phospho GSK-3β (Ser9) (pGSK-3β, 1:1000), anti-GSK-3β (1:1000), and anti-β-actin (1:1000). The membranes were then incubated with horseradish peroxidase-conjugated anti-rabbit antibody (1:1000). The chemioluminescence (ECL) was detected using X-ray films (Kodak X-Omat). Films were scanned and the percentage of band intensity was analyzed using Optiquant software (Packard Instrument). For each experiment, the test

groups (treated with GM1, fibrillar Aβ25–35, or simultaneously treated with both GM1 and GSKJ4 fibrillar Aβ25–35), were compared to control cultures (exposed neither to Aβ25–35 nor to GM1), which were considered 100%, thus assuring the same signal intensity for control and test groups. Data are expressed as percentage of phosphorylated protein for GSK3β, which was obtained by the ratio of the phospho-protein (pGSK-3β) with its whole amount (GSK-3β) (Frozza et al., 2009). Protein contents were measured by the method of Peterson (1977). In order to normalize the value of protein, we detected β-actin in the same

analysis. Data are expressed as mean ± S.D. One-way or two-way analysis of variance (ANOVA) was applied to the means to determine statistical differences between experimental groups. Post hoc comparisons were performed using the Tukey test for multiple comparisons. Differences between mean values were considered significant when p < 0.05. Culture exposure to fibrillar Aβ25–35 Megestrol Acetate (25 μM) caused NVP-BKM120 order marked fluorescence in hippocampal slices after 48 h of treatment, indicating a high incorporation of PI, which in turn means peptide-induced cellular death. On the other hand, the non-fibrillar form of Aβ25–35 (25 μM) caused no significant cellular death to the hippocampal slices, as observed in Fig. 1A. The quantification of PI incorporation is shown in Fig. 1B. We did not observe any increase in fluorescence in hippocampal slices exposed to the reverse sequence of peptides (Aβ35–25) at

25 μM (data not shown). Although neither the fibrillar nor the non-fibrillar β-amyloid forms were able to cause any change to total radiolabeling (Fig. 2A), chromatographic and densitometric analysis revealed that they exerted distinct effects on the profile and distribution of expressed gangliosides. While non-fibrillar Aβ caused a significant increase in GM1 expression (p < 0.05), the fibrillar form induced an increase in GM3 (p < 0.05) and a decrease in GD1b (p < 0.05) metabolic labeling ( Fig. 2B and C). We did not observe any effect of the reverse sequence of peptides (Aβ35–25) upon ganglioside expression (data not shown). To test for a possible GM1 neuroprotective effect in organotypic hippocampal slice cultures, we challenged the fibrillar Aβ-induced toxicity above described (Fig. 1). As shown in Fig.

In other situations subjects may desire to reduce their natural s

In other situations subjects may desire to reduce their natural skin colour or the skin darkening caused by exposure to GDC-0973 mouse intense sun rays. The complexion of the skin is determined by the pigment melanin. Melanocytes are the pigment producing cells that provide photo protection to the skin by synthesizing and distributing the pigment melanin to keratinocytes. These melanocytes are located in the basal layer of

keratinocytes. Melanocytes and keratinocytes are resident population of epidermis and the color of skin is only because of the melanin in keratinocytes which is transferred from melanocytes. Melanin is synthesized and packed in cytoplasmic organelles of melanocytes, called melanosomes and are later transferred to keratinocytes through specialized structures in the melanocytes called dendrites. Since melanocytes are the minor population in the epidermis, the presence of the multiple dendrites facilitates transfer of melanosomes to keratinocytes that surround melanocytes. Movement of the melanosomes along melanocyte dendrites is also necessary for the transfer of melanin

pigment from melanocytes to basal and suprabasal keratinocytes to maintain the normal skin color.1 Melanocyte dendrite formation is regulated selleck by multiple signaling pathways stimulated by paracrine factors released by keratinocytes.2 The most effective mode of transfer of the melanin to the keratinocytes is governed by the dendritic phenomena of the melanocytes. Abroagating the dendricity of the melanocytes is of great importance for controlling skin colour.3 There are several dendrite inhibitors either crude extracts or pure compounds already reported in the literature. These compounds are benzoquinone group moiety that includes centaureidin,3 methyl-ophiopogonanone B from Ophiopogon japonicus ker-Gawler, 4 and 1, 3-dioxolane derivative of methyl-ophiopogonanone B, 5 berberine derivative, 6 and betuligenol. 7 In our continuous

interest on the isolation of biologically active molecules from medicinal plants for personal care applications,8, 9, 10, 11, 12, 13, 14 and 15 we have undertaken the chemical examination of the leaves of Artocarpus altilis Parkinson. The genus, Artocarpus is small to large evergreen trees, distributed from Sri Lanka, GBA3 India to south China and through Malaysia to the Solomon Islands. Nine species are recorded in India. The plant, A. altilis (syn. A. communis) is indigenous to Malaysia and commonly cultivated in South India. It is known as Breadfruit in English, Dephal in Bengali and Seema panasa in Telugu. The fruit is being used culinary preparations, as bread and pudding. The root is used as in controlling diarrhea and dysentery. The root bark is utilized in the treatment of fractures. The petiole is used for eye sores, irritation and itch. 16 The plant is rich source for pectin (5.7%) and also having good jelling properties.

Tr-1 conversion depends on TCR signaling and a direct T-/B-intera

Tr-1 conversion depends on TCR signaling and a direct T-/B-interaction through CD40/CD40L and B7-1/CD28. B cell-induced Tr-1 cells Selleckchem Buparlisib acquire suppressive activity in vitro and in vivo. In addition, systemic injection of Pam2 lipopeptides (a TLR-2 ligand) induced IL-10 in a TLR2-dependent manner [31]. The Pam2 lipopeptides increased the frequencies of Foxp3+CD4+ regulatory T (T reg) cells in a TLR2- and IL-10-dependent manner.

Then, the possibility that human OMV vaccination induced T regulatory cells which suppressed B cell activation cannot be ruled out and further investigation may be conducted in the future. Interesting enough, we have previously reported a negative dose-effect on booster bactericidal antibody response, in that mice immunised with four doses of VA-MENGOC-BC®, but not with two or three DAPT doses, responded less well to the booster dose compared with the primary series [14]. In conclusion, this study suggests that vaccination with the VA-MENGOC-BC® induced a robust immune response after three injections of vaccine. Vaccination induced the generation and activation of memory T-cells

after primary and booster schedules but failed to maintain a memory B-cell population at a stable size and/or functionality. The weak boosting antibody response reinforces suboptimal recall functions of the remaining memory B-cell population. More studies are needed in view of the scarce knowledge about cellular mechanisms of antibody response and development of immunological memory by meningococcal vaccines. We are thankful to Ricardo da Costa Cruz for proof-reading the manuscript. We acknowledge FAPERJ/SR2-UERJ/CAPES from and CNPq for financial support.

This study would not be possible without the consent of the volunteers. “
“The first barriers that microorganisms including viruses must breach for being successful pathogens are imposed by the innate immune system of which the complement system constitutes a major arm [1], [2], [3] and [4]. The complement system comprises of an intricate group of both soluble and cell-associated proteins activated through three major pathways, the classical, alternative and lectin pathways. Complement activation results in the generation of active components, including C3b and C4b, which aid in the assembly of enzymes called as C3/C5-convertases that facilitate downstream cleavage and formation of the membrane attack complex (MAC) capable of lysing pathogens. Additionally, the activation products C3a and C5a show anaphylatoxic and chemotactic properties [5] and also play a role in T cell activation [6], and surface bound complement components derived from C3 interact with specific immune receptors, thus acting as a connecting link with the adaptive immune system [7]. Hence, the complement system exerts assault on pathogens directly by lysis and indirectly by boosting the pathogen-specific immune responses [8].

8 ± 14 4 months) Among the rotavirus infected children, 58 5% we

8 ± 14.4 months). Among the rotavirus infected children, 58.5% were in the age group of 7–12 months, while 14.5% belonged to ≤6 months. Analysis of the clinical severity scores indicated very severe, severe,

moderate and mild disease in 2.8%, 56.5%, 38.7% and 2.3% of the patients suffering for rotavirus gastroenteritis. As against this, 5%, 47%, 38.3% and 7.7% of the patients tested negative for rotavirus experienced very severe, severe, moderate check details and mild disease, respectively. In general, children with rotavirus diarrhea had significantly less mild and more severe disease than those with rotavirus-negative diarrhea (P < 0.05). Rotavirus infected children had more episodes of vomiting than did uninfected children (P < 0.05). The multiplex PCR conducted for genotyping of rotavirus strains showed amplification of VP7 and VP4 genes in 197 (81.7%) and 190 (78.8%) strains respectively and identified genotypes of both genes in 178 (73.8%) strains (Table 2). 32 (13.2%) strains remained untypeable for both genes. We detected infections with mixed rotavirus strains in 18 (10.1%) of the 178 specimens. Among the strains typed for both VP7 and VP4 genes, G1P[8] strains attained the highest score (31.4%). This was followed by G2P[4] (20.2%); G9P[8] (11.8%); G9P[4]

(10.1%); G12P[6] (6.1%); G12P[8] (3.3%); G2P[8] (2.8%); G2P[6] (2.2%); G3P[8] (0.5%); G4P[4] (0.5%) and G1P[4] (0.5%) rotavirus strains. G1P[8] strains continued to remain prevalent in all the years of study except selleck the year 2009 in

which G9P[8] strains (15.2%) were predominant. G9P[8] strains remained second highest in the year 2010 and Histamine H2 receptor declined markedly in circulation in 2011–2012. We found higher circulation of G9P[4] strains, an unusual combination of G and P types in 2010–2012 as compared to 2009. Mixed infections were highest (27.1%) in the year 2009 and declined drastically in the following years (Table 3). Two rotavirus vaccines, Rotarix™ and RotaTeq® have been licensed in ∼90 to 100 countries to use against rotavirus diarrhea. Both vaccines are recommended by the World Health Organization (WHO) in childhood immunization programs conducted globally [9]. Studies report difference in the efficacies of these vaccines against severe rotavirus diarrhea in high and middle income (85–98%) and low income (39–72%) countries [10]. In countries like India, where the vaccine efficacy data is yet to be acquired, monitoring of rotavirus disease and strains is essential to assess the impact of rotavirus vaccines and circulating rotavirus strains on each other. The data obtained in this direction in the present study reaffirm earlier reports (2005–2009) of the characteristics of rotavirus infections, large rotavirus disease burden and strain diversity among children in Pune, western India [3] and [4]. Our data showed that rotavirus positivity continued to remain significant in each year of the study period (2009–2012) and concurred with recent study reports from India [11].

The statistical analyses were performed using STATISTICA 9 1 soft

The statistical analyses were performed using STATISTICA 9.1 software (Statsoft), using the normalized variables. The effect of each variable was estimated, as was standard error, and was assessed Capmatinib by the t-test, with all results giving p < 0.05 being considered statistically significant. Cell growth was measured by absorbance at 600 nm. This was converted to dry mass of cells using a standard calibration curve. Samples of cells from 1 mL culture were resuspended in a sample buffer (60 mM Tris–HCl, pH 6.8, 10% glycerol, 5% β-mercaptoethanol, 2% SDS, 0.5% Bromophenol Blue) to obtain the total protein extract, at a ratio of 25 μL buffer to each 0.1 Abs600 nm. These samples were added to

12.5% SDS-PAGE [17], stained with Coomassie Blue R-250. The same gel also had 2 μL low molecular weight marker (LMW, Amersham Bioscience) added, with 97 kDa, 66 kDa, 45 kDa, 30 kDa, 20.1 kDa and 14.4 kDa bands and 1340 ng, 1660 ng, 2940 ng, 1660 ng, 1600 ng and 2320 ng protein weight in each band, respectively, for the purpose of comparing with the bands corresponding to ClpP. The amount of protein expressed under each condition was analyzed

by densitometry using a Bio-Rad GS-800 calibrated densitometer and QuantityOne 4.4.1 software. The concentration of expressed protein was obtained using the ratio (mg/L) = (Abs600 nm × band in densitometry)/4, where 4 was the concentration factor used in the preparation selleck chemicals llc of the total protein extract samples. In order to analyze plasmid segregation, 100 μL samples were taken from each experiment at the end of the 4 h expression period, with analysis done on two aliquots from each experiment. Each aliquot was serially diluted in sterile PBS to 10−6 (Fig. 1). 10 μL samples of each dilution with at least three replications were added to LB Agar plates with kanamycin (50 μg/mL) and without it. Plasmid stability was measured as the fraction of plasmid-bearing cells (Φ) by

calculating the ratio between the number of colony forming units (CFU/mL) on the plate with the antibiotic and on the plate without the antibiotic. A statistical evaluation was made with the aim of checking the reproducibility and variability of the procedures not for assessing plasmid stability (serial dilution and colony count). Student’s t-test was used to find out whether the mean values from the colony count were equivalent, while the F-test (Fisher) was used to find out whether the errors made at each stage of the count were equivalent. These tests were done using the values obtained from CFU/mL in the experiments at the center point of the experimental design, comparing different aliquots diluted to the same degree from the same culture, and the same aliquots diluted to different degrees from the same culture, as shown in the diagram in Fig. 1. In order to do the F  -test, F   was calculated using Eq.

5 °C at 100 rpm At different time intervals, sample was withdraw

5 °C at 100 rpm. At different time intervals, sample was withdrawn, diluted and analyzed by UV-spectrophotometer at 335 nm and 210 nm for outer and core tablets respectively. After estimating different drugs contents and in-vitro study results, the optimized tab-in-tab formulation (T3) was retained for 3 months under accelerated stability conditions of temperature and relative humidity (40 ± 2 °C/75 ± 5% RH) in stability chamber (Thermolab, India). The samples were taken out at 30, 60 and 90 days and evaluated for appearance, weight, hardness, drugs content and dissolution study. Three male rabbits of weight 2–2.5 kg

were fasted overnight in each experiment, although free access to water was allowed. During the course of the experiment, water was not given until 2 h after administration of test preparation. The oral doses of the drugs were calculated on the basis of their CHIR-99021 cell line body weights and then accordingly formulated for animals. After oral administration of the test preparation, 3 ml blood samples were collected at predetermined time intervals. Plasma

was immediately separated by centrifugation of the blood samples at 10,000 rpm for 10 min. All plasma samples were immediately frozen at −20 °C until analysis. A sample was extracted with methylene chloride, NIF was separated on ODS column by isocratic elution with acetonitrile- 5 mmol/L ammonium acetate (52:48 v/v) at the flow rate of 1 ml/min, and detected by mass spectrometry Ku-0059436 supplier in the selected ion monitoring (SIM) mode.9 The solid-phase extraction technique was used for the extraction of RAM from the sample. Chromatography was performed on Aquasil column, with the simple reversed isocratic phase consisting of acetonitrile–water (65:35 ratio) and 1.0 ml/L ammonium trifluoroacetate solution (1.0 M) and followed by detection using mass spectrometry.10 Data was statistically evaluated using SPPS software. P value of <0.05 was considered to be significant. The SE micrograph of NIF-loaded gelatin microcapsule was spherical in shape

with smooth surface (Fig. 2). This might be due to proteinaceous nature too of gelatin and decrease surface indentation. The geometric mean diameter of microcapsules was 6.52 ± 0.26 μm. The % EE of NIF in the gelatin microcapsules was 98.01 ± 2.1. The gelatin microcapsules enhance its encapsulation due to increase solubility in ethanol. SLS was used to avoid attaching gelatin microcapsule to the inner wall of spray-drying chamber and to produce free-flowing powder.11 NIF solubility and the amount of encapsulated ethanol increased due to optimum amount of SLS. The amount of NIF dissolved from gelatin microcapsules for 30 min were much higher 85.31 ± 0.96% as shown in Fig. 3. This signifies its solubility increased in SGF. The bioavailability of poorly water-soluble NIF was improved in gelatin microcapsules due to amorphous form of drug and cosolvent effect of ethanol because the gelatin wall of microcapsule was very soluble.

Cost estimates were converted from Year 2005 international dollar

Cost estimates were converted from Year 2005 international dollars to 2010 US dollars using the Consumer Price Index [33] and official exchange rates [34]. Vaccination program costs include

those costs associated with storing, delivering and administering the vaccine once it arrives in the country. The vaccine program costs PS-341 chemical structure were estimated using the WHO Global Immunization Vision and Strategy (GIVS) costing tool [35]. A program cost per dose was estimated for each of the countries, and a regional, weighted average was calculated and used in the analysis. We used updated country estimates of childhood deaths due to diarrhea and rotavirus-specific illness, to revise the baseline disease burden figures for our analysis [1] and [36]. We estimated rotavirus-associated outpatient visits and hospitalizations by multiplying the total diarrhea-related outpatient visits and hospitalizations by the estimated proportion attributable to rotavirus [37]. Rotavirus medical visits and deaths were distributed into

the following age categories: 0–2 months, 3–5 months, 6–8 months, 9–11 months, 12–23 months, 24–35 months, 36–47 months, and 48–59 months [19]. Recent clinical trials of rotavirus vaccine in sub-Saharan Africa and Southeast Asia found lower levels of vaccine efficacy than observed in trials in Latin America that were used in the original model [21], [22] and [23]. As noted by the WHO Strategic Advisory Group of Experts (SAGE), this finding is not unexpected selleckchem [38] and is consistent with results from studies of other live, oral vaccines such as polio, typhoid and cholera that suggest lower efficacy or immunogenicity in developing country populations compared to industrialized countries [39], [40] and [41]. Efficacy estimates against severe rotavirus diarrhea, any rotavirus diarrhea,

and all-cause severe gastroenteritis for countries in the African and Asian regions were calculated and applied by child mortality strata (see Table 1). Pooled random effects mean estimates from the Adenylyl cyclase trials conducted in the high mortality countries of Ghana, Kenya, Bangladesh, South Africa, Malawi and Mali were applied to countries with under-5 mortality rates >30/1000. Estimates from the study in Vietnam were applied to countries with child mortality rates ≤30/1000. Previous estimates from trials in Latin America were still used for Latin American and Caribbean countries. Estimates of efficacy against severe rotavirus gastroenteritis are used as a proxy for efficacy against mortality and hospitalization, and efficacy against any rotavirus gastroenteritis corresponds to efficacy against outpatient visits. Atherly et al. [19] demonstrated that estimates of the impact and cost-effectiveness of vaccination over time depend heavily on assumptions about which countries introduce vaccine, the timing of their introduction and how price changes over time as a result of market factors such as increased demand and the entry of new manufacturers.

As an example,

we published a paper detailing a moderatel

As an example,

we published a paper detailing a moderately large randomised controlled trial (PEDro score 9/10) which tested the hypothesis that customised foot orthotics were no more effective than sham orthotics in people with painful pes cavus (Burns et al 2006). We found a positive effect in terms of pain reduction (the primary outcome) from the customised orthotics compared to the slightly smaller pain reduction found with the sham. We subsequently continued our analysis in an attempt to explain these findings and reported that, while the experimental group did demonstrate AUY 922 significantly greater pain relief, we could not attribute MEK inhibitor this to any change in the patterns or magnitudes of pressure distribution under the foot (Crosbie and Burns 2007). As the whole point of the orthotic was to redistribute pressure away from painful areas, this led us to conclude that the

findings of the original study were the result of something other than a mechanical change, possibly a simple placebo effect. Sadly, although our original paper has been cited 26 times, the important explanatory paper has attracted only four citations, two of which were by one of the original authors. Perhaps greater support for the proposal made by Herbert (2008) that researchers make their data more accessible for others to explore will help make explanatory analysis more widespread, but the evidence to date seems unconvincing. What message does a focus on randomised trials to the exclusion of other designs send to the next generation of physiotherapy researchers and those mentoring them? Research training, whether as part of a formal degree or an informal process, needs to offer as wide an experience

these as possible and to develop skills that are not confined to one specific research design. The Council of Australian Deans and Directors of Graduate Studies (2007) opined that ‘… a best practice doctoral program should include but not be limited by … development of new research methods and new data analysis …. and … research that makes a significant and original contribution to knowledge. It should therefore be necessary for original and significant research to be undertaken in order to earn a doctorate in an Australian university. The systematic review and randomised controlled trial have become, in effect, the sine qua non of many (but thankfully not all) contemporary physiotherapy PhD theses. One must question whether this is limiting the potential to produce original thinkers.