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New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi.
Methods and Findings
We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses.
Author Summary
This study describes the in vivo activity of fexinidazole against Trypanosoma cruzi, the protozoan parasite causing Chagas disease, using mice infected with parasite strains with varying susceptibility to benznidazole, the standard treatment for Chagas. Fexinidazole and benznidazole were shown to have similar activity against benznidazolesusceptible and partially resistant T. cruzi strains (CL and Y), but fexinidazole had potent activity against benznidazole-resistant strains (VL-10 and Colombian). Fexinidazole treatment resulted in parasitological cure during acute disease phase in 88.9% of mice infected with the VL-10 strain and 78% with Colombian strain; benznidazole treatment did not result in cure in animals infected with these strains. Fexinidazole treatment was also shown to reduce myocarditis in all VL-10- and Colombian-infected animals, although parasite eradication was not achieved in all treated animals. These data demonstrate that it is possible to achieved better cure rates with fexinidazole in these experimental infection models than what is achieved with the standard benznidazole at the doses tested in this animal study benznidazole treatment regimen.
Citation: Bahia MT, Andrade IMd, Martins TAF, Nascimento ÁFdSd, Diniz LdF, Caldas IS, et al. (2012) Fexinidazole: A Potential New Drug Candidate for Chagas Disease. PLoS Negl Trop Dis 6(11): e1870. https://doi.org/10.1371/journal.pntd.0001870
Editor: Michael P. Pollastri, Northeastern University, United States of America
Received: March 22, 2012; Accepted: September 5, 2012; Published: November 1, 2012
Copyright: © 2012 Bahia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work received financial support from the Drugs for Neglected Diseases initiative (DNDi; Geneva, Switzerland); Rede Mineira de Bioterismo (FAPEMIG); Universidade Federal de Ouro Preto; and research fellowships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (MTB and AT). DNDi would also like to thank the following donors for their support: Department for International Development (DFID), UK; Médecins Sans Frontières/Doctors without Borders (MSF), International; Spanish Agency for International Development Cooperation (AECID), Spain; Swiss Agency for Development and Cooperation (SDC), Switzerland; and private foundations and individual donors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
One century after its discovery, American trypanosomiasis, or Chagas disease, remains a serious health problem in Latin America, where it affects 8–10 million people with 100 million at risk of acquiring the disease [1]. Chemotherapy, together with vector and transfusion control, is one of the most important elements in the control of Chagas disease, since no vaccine is yet available to prevent infection. Treatment is dependent solely on two drugs, benznidazole and nifurtimox, which have a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against chronic disease. Nevertheless, as of today, these drugs are the only available therapeutic options in endemic and non-endemic areas.
New potential treatment options include inhibitors of the sterol biosynthesis pathway, in particular C14-α-demethylase inhibitors such as posaconazole and ravuconazole, which represent promising new drugs candidates [2], [3]. Despite the superior in vitro potency and in vivo efficacy of these novel azole derivatives against T. cruzi, and the absence of cross-resistance with currently available drugs, response to drug treatment varies among the different strains of the parasite [3]–[6]. Also, key disadvantages of currently marketed novel azole derivatives, such as posaconazole, are the complexity and cost of manufacturing these compounds, which will need to be addressed to facilitate access to resource-limited populations that constitute the vast majority of patients with Chagas disease [7].
Therefore, the continued search for new trypanocidal treatments that could be effective for Chagas disease remains a priority for Chagas disease control. Nitroimidazoles are a well-known class of pharmacologically active compounds, among which several have shown good activity against trypanosomes [8]. While concerns over mutagenicity have mitigated their potential as drug candidates, several members of this family including metronidazole [9] are widely used as antibiotics, indicating that it is possible to select compounds with acceptable activity/toxicity profile in this class. Today, two non-mutagenic novel nitroimidazole-oxazine compounds (PA-824 and OPC-67683) are in clinical development for tuberculosis [10], while the 2-substituded 5-nitroimidazole fexinidazole is in clinical development for human African trypanosomiasis (also known as sleeping sickness) [11].
Fexinidazole (previously known as Hoe 239) had been in preclinical development as a broad-spectrum antiprotozoal drug by Hoechst in the 1970s–1980s, but its clinical development was not pursued at the time. The molecule was "rediscovered" and selected for development by the Drugs for Neglected Diseases initiative (DNDi) as a new drug candidate for sleeping sickness [11], following a systematic review and profiling of more than 700 nitroheterocyclic compounds (mostly nitroimidazoles) from diverse sources, which included assessments of antiparasitic activity and mutagenic potential. Fexinidazole underwent extensive regulatory toxicology studies, including safety pharmacology (respiratory, cardiovascular, and general behavior) and 4 weeks of repeated-dose toxicokinetics studies in rat and dogs. Overall, fexinidazole was found to be well tolerated, with no specific toxicity or other concerns [11]. During 2010–2011, DNDi carried out two Phase I clinical trials assessing the safety and pharmacokinetics of fexinidazole in human volunteers given in single and multiple doses. A phase II/III clinical safety and efficacy study in sleeping sickness patients is slated to begin in mid-2012.
Fexinidazole has previously been described as effective and superior to benznidazole or nifurtimox in one acute murine infection model with the T. cruzi Brazil 32 strain [12], but the methodologies used to establish cure are no longer considered the most accurate. Here were evaluated the in vivo activity of fexinidazole in mice infected with a panel of T. cruzi strains with differing levels of benznidazole susceptibility and looking at both acute and chronic infection, and using state of the art methods to establish cure.
Materials and Methods
Parasite Strains
The Trypanosoma (Schizotrypanum) cruzi strains Y (DTU II), CL (DTU VI), VL-10 (DTU II), and Colombian (DTU I) [13] were used in this study. Y strain, partially resistant to benznidazole, was used as the standard strain because it induces high parasitemia and 100% mortality, which is generally observed at days 10 to 19 post-infection. CL strain is highly sensitive to benznidazole, and VL-10 and Colombian strains are highly resistant to benznidazole.
Study Drugs
Fexinidazole (1H-imidazole, 1-methyl-2-((4-(methylthio)phenoxy)methyl)-5-nitroimidazole) (Figure 1) was administrated orally in suspension containing methyl cellulose 0.5% w/v, with 5% v/v of polysorbate 80 (Tween 80). Benznidazole (2-nitroimidazole-(N-benzil-2-nitzo-1-imidazoleacetamide; Rochagan, Roche) (Figure 1) was used as the reference treatment in this study and was administered orally in a water suspension with 4% methyl cellulose. Cyclophosphamide (N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide; Genuxal, Asta Medica Oncologica) was diluted in ultrapure water and administered intraperitoneally. The treatment consisted of three cycles of 50 mg of cyclophosphamide/kg of body weight for four consecutive days with intervals of three days between each cycle.
Animal Model
Female Swiss mice from the Animal Facility at Ouro Preto Federal University (UFOP), Minas Gerais State, Brazil were used in this study. Animals were fed with commercial food and water was available ad libitum. Swiss mice (18–20 g) were inoculated intraperitoneally with 5.0×103 bloodstream trypomastigotes of the Y, CL, VL-10, and Colombian T. cruzi strains.
Dose Response
Mice infected with T. cruzi Y strain (6 animals/group) were treated with doses of 100, 200, and 300 mg/kg of body weight (mpk) of fexinidazole per day. The drugs were administered orally on day 4 post-infection for 7 consecutive days. Drug efficacy was assessed based on three parameters: parasite clearance, time of absence of parasitemia, and mortality. All parameters were compared to those observed in benznidazole treatment using a standardized therapeutic scheme of 100 mpk per day [14].
Determination of Efficacy by Parasitological Cure
The first set of experiments was designed to determine the efficacy of fexinidazole to induce parasitological cure in mice infected with Y strain (partially resistant to benznidazole). Groups of 10 mice infected with Y strain were treated with 4 different doses of fexinidazole (50, 100, 200, and 300 mpk of drug per day). The drug was administered at the time of parasitemia detection, which occurred at day 4 post-inoculation for 20 consecutive days. Parasitological cure was determined as described below, and the results were compared to those achieved with treatment with benznidazole [14]. A group of 10 animals infected with the parasite but receiving no treatment was used as control.
The second set of experiment was designed to determine the efficacy of fexinidazole to induce parasitological cure in mice infected with strains of different level of resistance to benznidazole: CL, VL-10, and Colombian. Because of the high benznidazole resistance of VL-10 and Colombian strains, the dose of fexinidazole used was the dose inducing the highest level of parasitological cure in animals infected with Y strain. The drug was administered at the time of parasitemia detection which occurred at day's 7–8 post-inoculation for 20 consecutive days. Parasitological cure was determinate as described below, and results were compared to those treated with benznidazole and with untreated control groups, infected or uninfected with parasites.
Additional experiments were performed in a murine model of chronic phase of the disease to confirm the therapeutic efficacy of fexinidazole as observed in the first and second screenings. In this model, animals (10 per group) were infected with the VL-10 strain, and fexinidazole was administered on day 120 post-infection for 20 consecutive days. According to Coura et al. [15], two to three months after Chagas infection, the acute phase of the disease is followed by a long chronic period that is initially asymptomatic. This concept was validated by a group of experts during the Applied Research Meeting on Chagas disease, held in Araxá (Minas Gerais), Brazil [16]. Based on this understanding, we chose to start the chronic-phase treatment 120 days after infection. Before treatment, parasitic infection was confirmed by fresh blood examination (FBE) during the acute phase and by detection of anti-T. cruzi IgG antibodies in blood. Mice that were uninfected and infected but untreated acted as controls.
Parasitological cure was determined following the methodology standardized by Caldas et al. [17] based on a battery of three independent tests: FBE before and after cyclophosphamide immunosuppression (CyI), blood culture, and PCR assays performed on blood samples from mice with negative parasitemia. Animals showing negative results in the three tests were considered as cured (Figure 2).
Animals were inoculated with 5000 trypomastigotes of Y, CL, VL-10, or Colombian Trypanosoma cruzi strains, and treatment was started on the first day of detected parasitemia. During all treatments and up to 30 days post-treatment, parasitemia was evaluated by fresh blood examination (FBE) to determine the potential for natural reactivation of infection. Animals that did not present reactivation of parasitemia after treatment were submitted to immunosuppression consisting of three cycles of 50 mg of cyclophosphamide/kg (CY-I) of body weight for four consecutive days with intervals of three days between each cycle. Parasitemia was evaluated during the CY-I, as well as for the following 10 days after immunosuppression. Blood culture and PCR assays were performed 30 and 180 days post-treatment in mice with negative results in FBE before and after CY-I.
For blood culture, animals that remained negative by FBE 30 and 180 days after treatment were bled from the orbital venous sinus and 400 µL of blood added in tubes containing 3 mL of LIT medium. The tubes were incubated at 28°C for 120 days and examined monthly for parasite detection.
For PCR assay, following the same procedure as for blood culture, 200 µL of collected blood was used for DNA extraction. DNA extraction and PCR were performed according to Gomes et al. [18] with some modifications. The primers used for the parasite minicircle amplification were: S35 5′- AAATAATGTACGGG(T/G)GAGATGCATGA-3′ and S36 5′-GGGTTCGATTGGGGTTGGTGT-3′ [19]. Thirty-five cycles of amplifications were carried out in a Research Programmable Thermal Controller (MiniCycler). The cycles consisted of a hold of 5 min at 95°C followed by 35 cycles of 1 min at 95°C for denaturation, 1 min at 65°C for primer annealing, and 1 min at 72°C for primer extension. Five microliters of the PCR product were analyzed by electrophoresis on a 6% polyacrylamide gel and visualized by silver staining.
Positive and negative blood samples and reagent controls were processed in parallel in each assay, and all experiments were conducted under controlled conditions. To avoid contamination, DNA extraction, mixing, and electrophoresis were performed in separate, delineated areas. To confirm the absence of inhibition factors, an internal control corresponding to a segment of the murine TNF-α gene was amplified [20].
IgG Levels
Blood from treated mice was collected from the orbital venous sinus (500 µL) at 180 days after treatment. T. cruzi specific antibodies were detected by the technique described by Voller et al. [21]. Enzyme-linked immunosorbent assay plates were coated with T. cruzi antigen prepared from alkaline extraction from Y strain at exponential growth in LIT medium. Anti-mouse IgG-peroxidase conjugated antibody (Sigma Chemical Co.) was used. The mean absorbance for 10 negative control samples plus two standard deviations were used as the cut-off to discriminate positive and negative results.
Myocardial Tissue Assessment
For histopathological analysis of myocardial tissues, mice were grouped into four categories – infected-treated-cured, infected-treated-not cured, infected-untreated (control), and uninfected (control) – and analyzed according to T. cruzi strain. Animals were sacrificed 180 days after treatment and heart tissues fixed with 10% formalin and embedded in paraffin. Blocks were cut into 4-µm sections and stained by hematoxylin–eosin (H&E) for inflammation assessment. Twenty fields from H&E slides were randomly chosen at 40× magnification for a total of 1.49×106 µm2 analyzed myocardium area. Images were captured using a Leica DM 5000 B microcamera (Leica Application Suite, model 2.4.0R1) and processed with Leica Qwin V3 image analyzer software. The inflammatory process was evaluated by the correlation index among the number of cells observed in myocardium muscle from infected-treated-cured, infected-treated-not cured, infected-untreated, and uninfected animals [22].
All procedures and experimental protocols were conducted in accordance with COBEA (Brazilian School of Animal Experimentation) guidelines for the use of animals in research and approved by the Ethics Committee in Animal Research at UFOP (Protocol number 2009/17).
To assess which dose-range of fexinidazole is able to suppress parasitaemia, animals infected with Y strain were treated with 100, 200, and 300 mpk of fexinidazole per day for 7 days. All doses tested resulted in a rapid suppression of the parasitaemia, similar to the standard benznidazole (Table 1, Figure 3). The 7-days treatment time however did not completely eliminate the parasites, and recrudescence of the parasitaemia occurred in all animals, yet slower in fexinidazole treated animals compared to benznidazole. While untreated animal all succumbed to the infection, all treatments were effective in preventing death (one animal died in the lowest fexinidazole dose).
Parasitemia curve obtained from 6 mice infected with 5000 trypomastigotes of T. cruzi Y strain and treated daily with doses of fexinidazole 100, 200, and 300 mg/kg of body weight (mpk) or benznidazole 100 mpk for 7 consecutive days. Arrows indicate the first and the last day of treatment. IC: infected and untreated control.
Based on these results, we evaluated the capacity of fexinidazole to induce parasitological cure in animals infected with Y strain over longer-term treatment. Infected animals were treated daily for 20 consecutive days using 50, 100, 200, and 300 mpk of fexinidazole, compared with 100 mpk of benznidazole. The time required to achieve parasite suppression by fexinidazole was dose-dependent, with the highest dose comparable to the standard benznidazole treatment (Table 2). When looking at the definitive clearance of parasitaemia through the combination of different methods, 80% of mice treated with fexinidazole 300 mpk were cured at the end of a 6-months follow up period versus 50% for benznidazole 100 mpk, fexinidazole 100 mpk and 200 mpk. These data suggest that a higher cure rate can be achieved in animals infected with T. cruzi Y strain with fexinidazole treatment, be it at a higher dose, than with the standard benznidazole dose of 100 mpk. All treatment regimens were effective in preventing death.
We also assessed whether the highest dose of fexinidazole would also be more effective than standard benznidazole in treating mice infected with the benznidazole-susceptible CL strain, and the benznidazole-resistant VL-10 and Colombian strains of T. cruzi (Table 3). For the CL-strain, both the time to achieve parasitaemia suppression and the final cure rate were similar. While benznidazole could not suppress parasitaemia fully for the VL-10 strain, and cured none of the VL-10-infected animals, fexinidazole induced a rapid suppression of parasitaemia (Figure 3A), and cured 88.9% of the mice (Table 3). And while both benznidazole and fexinidazole rapidly suppressed parasitaemia in all animals infected with the Colombian strain, only fexinidazole could clear the parasitaemia resulting in a cure rate of 78% (Table 3). In the benznidazole-treated group, parasitaemia reappeared after the end of treatment starting on day 8 and persisted in all animals up to day 30 post-treatment (data not shown).
Comparative analysis of specific T. cruzi antibodies detected in blood samples collected from mice inoculated with CL, VL-10, or Colombian T. cruzi strains, after 6 months post-treatment were performed. For these analyses, animals were classified based on results of parasitological and PCR evaluations: +fexinidazole or +benznidazole (mice treated with fexinidazole or benznidazole with positive parasitological and PCR results [parasitaemia present]); −fexinidazole or −benznidazole (mice treated with fexinidazole or benznidazole with negative parasitological and PCR results [no parasitaemia]); IC (infected and untreated controls); NIC (uninfected control mice). The −fexinidazole and −benznidazole animals had IgG antibody levels significantly lower than that of IC animals, and similar to healthy mice. In contrast, +fexinidazole or +benznidazole animals had antibody levels similar to that of IC mice (Figure 4B).
Mice were inoculated with 5000 trypomastigotes of T. cruzi CL, VL-10, or Colombian strains by intraperitoneal route and treated with fexinidazole 300 mg/kg of body weight (mpk) or benznidazole 100 mpk for 20 consecutive days. A. Parasitemia curve from mice infected with VL-10 T. cruzi strain. Arrows indicate first and last days of treatment. B. IgG antibodies in mice inoculated with CL, VL-10, or Colombian T. cruzi strains, 6 months post-treatment. C. Myocardial inflammatory cell count in mice infected with VL-10 T. cruzi strain, 6 months post-treatment. D. Myocardial inflammatory cell count in mice infected with Colombian T. cruzi strain, 6 months post-treatment. −Fex = mice with parasite negativity in fresh blood examination, blood culture, and PCR assay; +Fex or +Bz = mice positive of parasites in fresh blood examination, blood culture, and PCR assay: NIC = non-infected control; IC = infected and untreated control. * Significant difference compared to NIC; # significant difference compared to IC.
In order to evaluate the efficacy of early fexinidazole treatment in preventing the development of subsequent chronic myocardial lesions in mice infected with VL-10 and Colombian T. cruzi strain, quantitative analysis of inflammation of heart tissue in fexinidazole and benznidazole-treated mice was performed at 6 months post-treatment, and compared to heart tissue from untreated infected mice and health mice.
In mice infected with VL-10 strain, early fexinidazole treatment was shown to prevent or lessen the typical inflammation of heart tissue associated with the chronic phase of experimental Chagas disease, as illustrated by similar levels of inflammatory cells observed in the heart tissue of fexinidazole-treated and healthy animals (Figure 4C). In contrast, untreated mice and benznidazole-treated mice presented a higher number of inflammatory cells in their heart tissue (Figure 4C).
In mice infected with Colombian strain, treatment with either fexinidazole or benznidazole was shown to reduce the number of inflammatory cells in chronic phase of experimental Chagas disease, as illustrated by the significantly higher number of inflammatory cells in the hearts of untreated infected animals compared with fexinidazole- or benznidazole-treated animals (Figure 4D). Additionally, parasite detection was associated with inflammation intensity. Animals negative for T. cruzi (−fexinidazole) showed lower inflammation intensity in heart tissue than those positive of T. cruzi in parasitological or/and molecular tests. Also, no differences were observed in number of inflammatory cells between healthy and −fexinidazole treated mice (Figure 4D).
Based on the findings from treatment during acute-phase experimental Chagas disease, animals infected with VL-10 were treated during the chronic phase (120 days after inoculation) using the same treatment scheme. CyI treatment induced parasitemia reactivation in 20% (2/10) of animals treated with fexinidazole or benznidazole, and 60% (6/10) of untreated infected mice (Table 4). However, considering the results of blood culture and PCR assays performed at 30 and 180 days after treatment, therapeutic failure was detected in 30% (3/10) and 70% (7/10) of mice treated with fexinidazole and benznidazole, respectively (Table 4). The parasite or its kDNA was detected in 90% (9/10) of IC mice (Table 4).
Six months after treatment of the chronic infection, animals that had been successfully treated with either benznidazole or fexinidazole (i.e. no more parasites detected) had reduced levels of specific anti-T.cruzi IgG antibody levels, comparable to healthy animals. In contrast, the antibody levels remained high and comparable to untreated controls in animals that were treated with either benznidazole or fexinidazole, but without clearing the parasitaemia (Figure 5A). Interestingly, fexinidazole treatment performed during the chronic phase of the infection significantly reduced the cardiac inflammation (Figures 5B and C), both in cured animals and in animals that hadn't fully cleared their parasitemia. In contrast, among the benznidazole-treated animals, a reduction of cardiac inflammation was detected only in those mice that cleared the parasitemia. Benznidazole-treated animals that did not clear their infection had similar levels of inflammation as untreated animals (Figure 5B and C).
Mice were inoculated with 5000 trypomastigotes of VL-10 strain by intraperitoneal route and treated with fexinidazole 300 mg/kg of body weight (mpk), or benznidazole 100 mpk for 20 days. For controls, infected and untreated (IC) and uninfected (NIC) groups were also evaluated. A. IgG antibodies in mice treated with fexinidazole or benznidazole, compared with IC control group, 6 months post-treatment. B. Myocardial inflammatory cell count in cardiac tissue of mice infected with VL-10 T. cruzi strain, 6 months post-treatment. C. Hematoxilin-eosin stained slides. −Fex = mice with parasite negativity in fresh blood examination, blood culture, and PCR assay; +Fex or +Bz = mice positive of parasites in fresh blood examination, blood culture, and PCR assay: NIC = non-infected control; IC = infected and untreated control. * Significant difference compared to NIC; # significant difference compared to IC.
This study confirms that fexinidazole is effective in curing experimental Chagas infection models, both in the acute and chronic stage, and including infections with benznidazole-resistant T.cruzi strains. At higher but well-tolerated doses, fexinidazole treatment achieves better cure rates and prevention of cardiac inflammation than the current standard treatment of benznidazole.
Current specific chemotherapy options for Chagas disease – benznidazole and nifurtimox – have limitations such as lack of effectiveness in achieving parasitological cure or in preventing the chronic phase of the disease. Fexinidazole, 5-nitroimidazole compound, was originally selected as a broad-spectrum antiprotozoal agent and has recently been rediscovered as a potential drug candidate for treatment of human African trypanosomiasis [11], [12], [23].
Previous studies had shown that fexinidazole has curative activity superior to benznidazole and nifurtimox during acute T. cruzi infection with the Brazil 32 strain in a murine model [12]. However, the methodologies used in this 1983 study for detecting parasites in the blood, including subinoculation in healthy mice, are no longer considered adequate to establish cure. We therefore re-evaluated the efficacy of fexinidazole in experimental Chagas disease using more sensitive state of the art methodologies (including blood culture, PCR and immunosuppression to reactivate lingering parasites), as well as using a range of T. cruzi strains with variable levels of resistance to benznidazole.
The rapid in vivo activity of fexinidazole conferring complete protection against death to infected mice when it is used in a short-term (7 days) treatment is in line with the activity originally reported by Raether et al. [12]. In our study, we additionally demonstrate that the anti-T. cruzi activity of fexinidazole was dose-dependent, and that a 20 days treatment with 100 or 200 mpk fexinidazole generated 50% definitive cure in mice infected with the benznidazole-susceptible Y strain, comparable to treatment with the standard dose of 100 mpk benznidazole. Moreover, a cure rate of 80% could be achieved when using 300 mpk of fexinidazole. Additionally, fexinidazole (300 mpk) and benznidazole (100 mpk) have similar activity against the susceptible benznidazole T. cruzi CL strain, but fexinidazole was highly effective in curing mice infected with the benznidazole-resistant VL-10 and Colombian strains.
Early fexinidazole treatment effectively prevented or reduced the development of myocarditis associated with chronic Chagas disease in mice infected with the benznidazole-resistant VL-10 and Colombian T. cruzi strains. Notably, when treated during the chronic phase of a T.cruzi VL-10 infection, fexinidazole but not benznidazole was also able to reduce myocarditis in all treated animals. This remarkable in vivo anti-T. cruzi activity of fexinidazole may be result of a combination of potent antiparasitic activity and advantageous pharmacokinetics properties. According Torreele et al. [11], fexinidazole is well absorbed after oral administration and broadly distributed to all organs and tissues in animals. This has implications for in vivo efficacy, considering that after parasitemia control, parasites may slowly replicate in various tissues.
Differing patterns of heart lesions were detected in benznidazole-treated animals inoculated with VL-10 and Colombian T. cruzi strains. A reduction in myocarditis in Colombian infected animals was observed, but this was not seen in those infected with VL-10 strain. During benznidazole treatment, animals infected with Colombian strain had negative fresh blood examination (data not shown), while those infected with VL-10 strain had positive parasitemia results. These results suggest that parasite load plays an important role in the pathogenesis of the chronic chagasic cardiomyopathy. This idea is corroborated by observations of Bustamante et al. [24] that re-exposure to the parasite through repeated infections aggravates heart dysfunction. Additionally, Caldas et al. [25] suggested that the efficacy of treatment in preventing chronic cardiac lesions is T. cruzi strain-dependent and probably related to the level of drug resistance to the parasite stock.
Specific anti-T.cruzi IgG levels detected 6 months after fexinidazole treatment were similar in non-infected control animals and definitively cured animals, and significantly lower than in non-treated infected mice or treated mice that remained parasitemic. The correlation between parasite detection and increased IgG levels is corroborated by a study by Garcia et al. [26], which demonstrated that in sera of benznidazole-treated mice, lower levels of antibodies specific to T. cruzi antigens are observed. According to the authors, reduction of antibody levels is possibly correlated with reduction of tissue damage, since antibodies against T. cruzi antigen may exert effects on cross-reactive epitopes on cardiac receptors, modulating the intensity of the heart tissue lesions. This study confirms a strong correlation between specific anti-T.cruzi IgG levels and intensity or cardiac inflammation, along with the capacity of fexinidazole treatment to reduce both.
It is important to note that fexinidazole was well tolerated by the T. cruzi-infected animals, and no adverse events were observed during the treatment period. These results are in agreement with others [11], [12] who demonstrated that fexinidazole was generally well tolerated after a single oral dose or repeated dosing, even at relatively high doses. Our safety findings agree with previous toxicologic studies that showed no effects on blood pressure, heart rate, and electrocardiogram intervals in dogs after single oral dose up to 1000 mg/kg. At the same dose in rats, no effects were observed on behavior characteristics or on respiratory parameters [11]. The No Observed Adverse Event Level (NOAEL) in 4-weeks repeated dose toxicokinetics studies in dogs and rats was set at 200 mg/kg/day [11].
In our study, fexinidazole blood levels were not measured, but others have shown that fexinidazole acts as a prodrug, which is oxidized in vivo to the more therapeutically relevant sulfoxide and sulfone metabolites [11], [27]. The sulfoxide metabolite reaches considerably higher levels in mouse blood than the parent compound, up to 40,000 ng/mL at 2 hours following oral dosing. Fexinidazole sulfone, the final metabolite to appear in the blood, continues to accumulate over 8 hours, reaching a concentration of 55,000 ng/mL. In mice, rats, and dogs, the half-life of fexinidazole after oral treatment ranges from 1 to 3 hours, while the half-life of the sulfoxide ranges from 2 to 7 hours and sulfone up to 24 h after dosing [11].
As earlier studies had shown mutagenic activity in the Ames test [12], the genotoxic profile of fexinidazole and its active metabolites was recently re-assessed in detail [28]. Fexinidazole is mutagenic in the classic Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s) [28]. It is known that these enzymes can nitroreduce compounds with low redox potentials such as fexinidazole, whereas their mammalian cell counterparts cannot. In order to specifically detect mammalian genetic toxicity, fexinidazole was tested in a panel of complementary assays, including an in vitro micronucleus test in human lymphocytes, an in vivo bone marrow micronucleus test in mice and an ex vivo unscheduled DNA synthesis in rats, and all were negative. Thus, it can be concluded that fexinidazole does not pose a genotoxic hazard to patients [10], [28].
Taken together, these results show that treatment with 300 mpk fexinidazole was able to produce high levels of parasitological cure in mice infected with benznidazole-susceptible, partially resistant, and resistant T. cruzi strains in acute and chronic phases of the experimental Chagas disease, and this is an improvement compared to the current standard treatment with benznidazole. This potent intrinsic and broad anti-T. cruzi activity, taken together with the fact that it is already in clinical development for another parasitic disease, suggests that fexinidazole is a promising drug candidate for human Chagas disease chemotherapy. Safety profile will need to be confirmed on further preclinical testing adapted to the longer treatment duration and Chagas disease presentation.
We are grateful to Oliver Yun DNDi's Communications Manager and Eric Chatelain, DNDi's Head of Drug Discovery, for encouragement and excellent review of this manuscript.
Author Contributions
Conceived and designed the experiments: MTB AT BBT ET IR. Performed the experiments: IMA TAFM AFSN LFD ISC. Analyzed the data: MTB AT. Contributed reagents/materials/analysis tools: MTB AT. Wrote the paper: MTB IR ET.
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- 5. Toledo MJ, Bahia MT, Carneiro CM, Martins-Filho OA, Tibayrenc M, et al. (2003) Chemotherapy with Benznidazole and Itraconazole for mice infected with different Trypanosoma cruzi clonal genotypes. Antimicrob Agents Chemother 47: 223–230.
- 6. Molina J, Martins-Filho O, Brener Z, Romanha AJ, Loebenberg D, et al. (2000) Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts. Antimicrob Agents Chemother 44: 150–155.
- 7. Urbina JA (2009) Ergosterol biosynthesis and drug development for Chagas disease. Mem Inst Oswaldo Cruz 1: 311–8.
- 8. Winkelmann E, Raether W, Hartung H, Wagner WH (1977) Chemotherapeutically effective nitro compounds. 3rd communication: nitropyridines, nitroimidazopyridines and related compounds. Arzneimittelforschung 27: 82–9.
- 9. Freeman CD, Klutman NE, Lamp KC (1997) Metranidazole. A therapeutic review and update. Drugs 54: 679–708.
- 10. Van den Boogaard J, Kibiki GS, Kisanga ER, Boeree MJ, Aarnoutse RE (2009) New drugs against tuberculosis: problems, progress, and evaluation of agents in clinical development. Antimicrob Agents Chemother 53: 849–62.
- 11. Torreele E, Trunz BB, Tweats D, Kaiser M, Brun R, et al. (2010) Fexinidazole – A new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl Trop Dis 4: e923.
- 12. Raether W, Seidenath H (1983) The activity of Fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica. Ann Trop Med Parasitol 77: 13–26.
- 13. Moreno M, D'Avila DA, Silva MN, Galvão LMC, Macedo AM, et al. (2010) Trypanosoma cruzi Benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease. Mem Inst Oswaldo Cruz 105: 918–924.
- 14. Filardi LS, Brener Z (1987) Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Trans R Soc Trop Med Hyg 81: 755–759.
- 15. Coura JR, Borges-Pereira J (2011) Chronic Phase of Chagas Disease: Why should it be treated? A comprehensive review. Mem. Inst. Oswaldo Cruz 106: 641–645.
- 16. Anonymous (1985) Reunião de Pesquisa Aplicada em Doença de Chagas: Validade do conceito de Forma Indeterminada. Ver Bras Med Trop 18: 46–49.
- 17. Caldas S, Santos FM, Lana M, Diniz LF, Machado-Coelho GL, et al. (2008) Trypanosoma cruzi: acute and long-term infection in the vertebrate host can modify the response to Benznidazole. Exp Parasitol 118: 315–323.
- 18. Gomes ML, Macedo AM, Vago AR, Pena SD, Galvão LM, et al. (1998) Trypanosoma cruzi: optimization of polymerase chain reaction for detection in human blood. Exp Parasitol 88: 28–33.
- 19. Avila H, Gonçalves AM, Nehme NS, Morel CM, Simpson L (1990) Schizodeme analysis of Trypanosoma cruzi stocks from South and Central America by analysis of PCR-amplified minicircle variable region sequences. Mol Biochem Parasitol 42: 175–187.
- 20. Cummings KL, Tarleton RL (2003) Rapid quantitation of Trypanosoma cruzi in host tissue by real-time PCR. Mol Biochem Parasitol 129: 53–59.
- 21. Voller A, Bidwell DE, Bartlett A (1976) Enzyme immunoassays in diagnostic medicine. Theory and practice. Bull World Health Organ 53: 55–65.
- 22. Maltos KL, Menezes GB, Caliari MV, Rocha OA, Santos JM, et al. (2004) Vascular and cellular responses to pro-inflammatory stimuli in rat dental pulp. Arch Oral Biol 49: 443–450.
- 23. Barrett MP (2010) Potential new drugs for human African trypanosomiasis: some progress at last. Curr Opin Infect Dis 23: 603–608.
- 24. Bustamante JM, Rivarola HW, Fernandez AR, Enders JE, Fretes R, et al. (2002) Trypanosoma cruzi reinfections in mice determine the severity of cardiac damage. Int J Parasitol 32: 889–896.
- 25. Caldas IS, Talvani A, Caldas S, Carneiro CM, Lana M, et al. (2008) Benznidazole therapy during acute phase of Chagas disease reduces parasite load but does not prevent chronic cardiac lesions. Parasitol Res 103: 413–421.
- 26. Garcia S, Ramos CO, Senra JF, Vilas-Boas F, Rodrigues MM, et al. (2005) Treatment with Benznidazole during the chronic phase of experimental Chagas' disease decreases cardiac alterations. Antimicrob Agents Chemother 49: 1521–1528.
- 27. Sokolova AY, Wyllie S, Patterson S, Oza SL, Read KD, et al. (2010) Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis. Antimicrob Agents Chemother 54: 2893–2900.
- 28. Tweats D, Trunz BB, Torreele E (2012) Genotoxicity profile of fexinidazole—a drug candidate in clinical development for human African trypanomiasis (sleeping sickness). Mutagenesis 2012 [Epud ahead print].


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subset: commoncrawl


text:
Lawrence "Buck" Braswell says the worst thing that a farmer can do is get in a rut. "I was taught to be competitive and to learn all I can," said the farmer from Raymondville, Texas, and one of the winners of the 2006 High Cotton Awards. "My daddy instilled it in me, and I've tried to pass it on.
"I've tried to never get in a rut, and I challenge all of you here today, whatever you do in the farm industry, to never get in a rut. Always be looking forward to something better, always."
That kind of spirit has come to typify the winners of the High Cotton Awards. This year's winners were honored at a breakfast at the Beltwide Cotton Conferences in San Antonio. Braswell represented the Southwest; Cliff Fox, the Southeast; Joe Bostick; the Delta states; and Wally Shropshire, Far West.
The awards are sponsored by Farm Press Publications through a grant to The Cotton Foundation. Cosponsors of the 2006 awards include Beltwide Cotton Cooperative, Beltwide Cotton Genetics, Croplan Genetics Brand Cotton Seed, Delta and Pine Land Company, John Deere, Helena Chemical Company, Monsanto, Syngenta, The Seam, and U.S. Borax.
"The High Cotton awards were conceived with the idea of recognizing what farmers are doing to achieve the goals of consistently high yields of top quality cotton while carrying out practices that protect natural resources and enhance the environment — demonstrating that these practices aren't just another expense, but they pay tangible, worthwhile dividends," said Hembree Brandon, editorial director of the Farm Press Publications.
"This marks the 12th year of this program, and we're pleased to have been able to recognize dozens of outstanding growers for their contributions not only to the cotton industry but to environmental preservation and conservation."
"We are very proud of this year's winners and the conservation ideals they represent," said Greg Frey, publisher of the Farm Presses. "Each of them is dedicated to taking care of their land and the environment and leaving it better than they found it."
Braswell said the annual High Cotton video depicting the winners and their operations brought back memories of more than just the past year.
"Looking at those pictures you were showing, I thought back about my 41 years of farming. I honestly can't remember not being on the turn-row. I've dedicated my life to farming, and it's really hard to think about it without getting emotional."
Braswell said those 41 years have stretched from farming with mules and picking cotton with a sack to today's highly mechanized and technologically advanced cotton production systems. But he and the other winners are not ones to dwell in the past.
"There's so much in our hands today," he said. "We have things that are phenomenal, things that we need to use because we all have competition from other countries, from our neighbors or other regions of the Cotton Belt."
Ron Smith, editor of Southwest Farm Press, who presented the High Cotton Award to Braswell, said he first met the farmer at a Conservation Tillage Conference in Houston.
"Buck was a speaker at the conference and was sharing his knowledge about conservation tillage with other farmers, something I've learned he does regularly," said Smith, who interviewed Braswell for an article in the High Cotton issues of the Farm Presses, Southeast, Delta, Southwest and Western Farm Press.
In accepting the award, Braswell said he believes U.S. agriculture is on the threshold of even greater breakthroughs that will help farmers survive the increasing competition it faces around the world.
"We have to be more competitive in America, and it's up to everyone in this room to start," he said. "I've seen some things for the next three or four years that I can't believe, some that with the drought on our farm will be phenomenal and will help the whole country be more competitive. I hope I'm around for a lot of years because I want to see what happens."
Joe Bostick, who farms around Golden in northeast Mississippi, said the bronze Cotton Boll award that he received as a High Cotton winner "is one boll that won't be shipped out of the country."
He said he was proud that the award was produced in the USA and urged the audience of 150 to work to help make U.S. cotton more competitive and to make U.S. industry more competitive in world markets.
"I have faced a lot of challenges this year," said Bostick, who has produced up to 1,200 pounds of lint cotton per acre on thin soils without irrigation. "And I've learned three new words: Don't give up. Those words have come to mean a lot to me this year."
Cliff Fox, the Southeast winner from Capron, Va., thanked Extension agents and specialists Johnny Parker, Pat Phipps and Joe Faircloth, who helped him and his brother, Clark, get back into cotton in 1994 after the crop had all but disappeared from the Tidewater area of Virginia.
"I've learned that the cell phone can be a two-edged sword," he said. "I spend a lot of time on it, pacing on the turnrow asking Joel Faircloth and other experts a lot of questions."
Harry Cline, editor of Western Farm Press, noted that Far West High Cotton winner Wally Shropshire had once called the governor of California a thief for transferring funds from the California Cotton Pest Control Board's pink bollworm program.
"The governor tried to get even by not re-appointing Wally to the Fair Board, but Wally did call the governor of California a thief and he got the pink bollworm program's money back with interest."
Shropshire, who has chaired the California Cotton Pest Control Board for 38 years, said he was accepting the High Cotton award on behalf of the board as a whole and for the cotton producers of California who fund the board's programs with a $2 per bale assessment.
"We formed this board back in 1967, and Jack Stone, who many of you in this room know, and I were original members of that board," said Shropshire, who farms out of Blythe, Calif. "We got together last fall, and said we felt our appointment was kind of like a marriage license; that is, until death do us part."
Shropshire said he wanted to thank Harry Cline for the 30-plus years that Cline has attended the Cotton Pest Control Board meetings and kept the cotton growers and the agricultural community informed about the board's programs and facilities like the pink bollworm rearing facility in Phoenix, Ariz.
He also thanked the Farm Presses for making the High Cotton Awards possible. "In my many years as a cotton ginner, cotton grower, active in the pink bollworm program and a few other things that I've done a long the way, this has been a highlight of my career, accepting this most prestigious award.
e-mail: email@example.com


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UPDATE: Full story.
ROME — From the truly horrible 1970s building housing an insurance company upstairs, you'd never know that the oldest paintings of the Apostles Peter, Paul, John and Andrew are in the basement.
Going down a few steps from the street, visitors see the remains of a pagan necropolis.
The Italian government controls that part of the underground complex and has restored some of the mosaic floors of the burial chambers.
A few yards further into the basement, down a dirt slope, visitors enter the mini Basilica of St. Thecla where Christians would celebrate Mass when visiting the tombs of their loved ones or when they came on pilgrimage to Rome.
The Catacombs of St. Thecla are filled with corridors lined with niches for simple burials and cubicles where the families of the wealthy were interred. There also are several large burial chambers with niches scaling the walls.
After a press conference presenting the restoration of a frescoed cubicle, now known as the Cubicle of the Apostles, the Pontifical Commission for Sacred Archaeology allowed several dozen reporters and photographers to visit the catacombs, which are not open to the public.


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What is the Children's Program?
The Children's Program is a team of experienced clinicians who provide diagnostic, therapeutic and educational services to children, adolescents, and families. Our clinician directory provides a brief biography and areas of interest for each of our clinicians.
The Children's Program has helped more than 100,000 families since 1987. Recommendations from these families, as well as schools and physicians, are our most frequent source of referrals. Read about our clients and their stories.
Call us. We will help you determine which Children's Program clinician can best address your concerns. We will estimate the cost of your first appointment and talk with you about possible health insurance coverage for your visit. If we are not the right place for your needs we will try to direct you to a better fit.
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U.S. Senator Kay Hagan (NC) today announced her 2013 nominees to the U.S. Service Academies. As some of the most selective institutions of higher education in the country, the U.S. Service Academies require applicants to receive a nomination from a member of Congress in addition to meeting eligibility and entrance requirements.
�Congratulations to this year�s nominees, who are truly among the best of the best,� said Hagan. �These young men and women have distinguished themselves in the classroom, on the athletic field and within their communities. I wish them the best of luck as they continue the application process and I commend them for seeking a world-class education while serving our country.�
Among Hagan�s 2013 nominees to the U.S. Service Academies are:
Tyler Albright, Lincolnton - United States Air Force Academy
Dillon Lewis , Mount Holly - United States Naval Academy
Cole Matolka , Gastonia - United States Naval Academy
Each year, Hagan hosts Academy Day for middle and high school students interested in applying to a U.S. Service Academy. The event provides an opportunity for students to meet with cadets and midshipmen from the service academies and learn more about the nomination process through Hagan�s office. Representatives from all five academies � the U.S. Air Force Academy, U.S. Coast Guard Academy, U.S. Merchant Marine Academy, U.S. Military Academy, and U.S. Naval Academy � are on hand to speak with students, parents and guidance counselors. This year, over 400 students attended Academy Day in Winston-Salem.
Hagan, who serves on the Senate Armed Services Committee, comes from a military family. Her father-in-law was a two-star Marine General and her husband, father and brother all served in the Navy. Two of her nephews served in Iraq and Afghanistan.


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After the Draft, a New World for Rookies by Yeshayah Goldfarb
Yeshayah Goldfarb is the San Francisco Giants' director of minor league operations and quantitative analysis.
You might be wondering what happens to our draft picks once the draft is over. How do we begin developing them into players who might help us win another World Series?
It starts when a draft pick agrees to financial terms and we send him to our baseball complex in Scottsdale, Arizona, for a physical and a series of orientation sessions. There's a lot to absorb. Professional baseball is a sub-culture with its own customs, expectations, responsibilities and rules. We give all new players a handbook that covers everything from where each of our minor league teams is located to curfew regulations to how to wear the uniform and how much facial hair is acceptable.
Soon after they clear the team physical, they are assigned to either the Arizona League Giants in Scottsdale or the Salem-Keizer Volcanoes in Oregon. That's when the real work starts – for them and for us.
We need to learn the players' strengths, sharpen those strengths, teach new skills, build confidence, eliminate distractions, develop individual conditioning plans, evaluate performance, analyze results/statistics and shape character.
For position players, one of the first challenges is to adjust to wood bats. But that's just the beginning. They now play every day with very few days off usually far away from home — with unfamiliar teammates and coaches, new signs, new bunt plays, more fans, autograph seekers, community outreach events, and the constant fear that they will be released.
Our manager in Salem-Keizer, Tom Trebelhorn, is the perfect manager for rookies. He's a former big-league manager (with the Cubs and Brewers) who has a wealth of baseball knowledge but is still a kid at heart. Derin McMains is our rookie ball manager in Arizona and learned the job from Treb. They're both really encouraging and inspirational, which helps build the players' confidence and camaraderie right from the start.
We also begin right away developing their leadership skills. Every two weeks throughout the summer (and every regular season) the minor league coaching staff leads a discussion (guided by a DVD presentation and accompanying book) about a particular value or principle, such as humility, discipline, responsibility and character. We want Giants players to be good men and good teammates as well as good athletes.
While the players are in Arizona and Oregon, the front office here in San Francisco keeps close tabs on all of them. Everyone from general manager Brian Sabean on down receives a detailed, daily report about every player in every game. We capture statistics in deep detail to use as tools for both teaching and evaluation.
We know it's a big leap from amateur baseball to the professional level. Some will experience failure for the first time. We assure them that our coaches and support staff — with many years of major league and minor league experience – are 100 percent committed to helping them become the best players they can be.
Still, there will be times when they doubt themselves. I hope when that happens they'll remember the words at the end of Brian's letter to them after the draft.
"We look forward to watching your ascent to the Major Leagues as a San Francisco Giant,'' he wrote, "possibly even as a member of our next World Series Championship team.''
We're really proud of our selections in the 2012 draft. They're already off to a great start.
Thanks for reading. And try to get out to one of our minor-league parks and watch these guys. You'll have bragging rights later on: You always knew that raw outfielder with the loopy swing would be a star.
Anatomy of a Draft by John Barr
John Barr is the Giants' Director of Scouting. He shares a glimpse inside the draft room.
Late Monday afternoon, a voice from New York came through the speakerphone in a third-floor conference room at AT&T Park.
"This is Chuck. We are now eight minutes out.''
"Sounds like Mission Control before liftoff,'' one of our scouts cracked.
I laughed because that's kind of how draft day feels: Your entire staff has worked all year for this one moment.
We were sitting at two long tables in the so-called "war room'' facing a large video screen where the broadcast of the first round was about to begin on MLB network. I scanned the room at the people who had worked so hard all year. Every one of them had a key part in what would happen today and for the next two days of the draft.
There was Yeshayah Goldfarb, director of quantitative analysis; Jeremy Shelley, senior director of pro scouting; Dick Tidrow, director of player personnel; Bobby Evans, vice president of baseball operations; scouting coordinator Adam Nieting; minor-league operations coordinator Eric Flemming; information technology coordinator Dan Quill; our two national scouts – Ed Creech and Doug Mapson; our three regional scouting supervisors – Joe Strain, John Castleberry and Arnold Brathwaite; coordinator of minor league trainers Jay Williams; and, of course, general manager Brian Sabean and support staff.
"Who's going to carry the flag for our draft class?'' I said, studying yet again our "Top Players'' list on a white board in the front of the room.
We had begun seven days ago with 823 names on magnetized nameplates. From a database compiled and distilled by Adam and Eric, Yeshayah punched up video clips, projecting them onto the front screen. Simultaneously on a side screen he projected a spreadsheet showing the player's statistics, the scouts' "grades'' and evaluations plus notes about intangibles like character, competitiveness and maturity.
From morning til night, we dissected each player's mechanics and debated his potential. In the amateur draft, you're not choosing players because of who they are now; you're choosing the ones you project will have value for your organization after three or four or five years of development in the minor leagues. Jay advised us on possible health issues. Our quantitative analysts provided statistical insights and comparisons. Our scouting supervisors presented problems we might have in signing a particular player – for example, unrealistic money demands or a strong commitment to go to college.
Then we ranked the players one by one. Medical or "signability'' concerns were noted on the nameplates with different-color stickers.
Now the 823 names were in neat rows on huge white boards around the room, arranged in order of preference. For the first time in a week, our laptops were quiet. There was nothing to do but wait and see how the board would shake out.
We had the 20th pick in the first round.
As teams ahead of us made their choices, we removed nameplates from the board. We loved right-hander Chris Stratton, a big kid who had progressed from not being drafted out of high school to pitching out of the bullpen at Mississippi State to becoming the SEC pitcher of the year. I had watched him strike out 17 batters in a game against LSU this season. This kid was athletic and competitive on the mound. He had size and strength. He had four good pitches.
As the 10th, 11th, and 12th teams made their picks, Stratton was still there.
Bobby Evans sat at the back table working the phones. He was in constant touch with the agents, gathering information about which teams might take which players and what kind of money might be on the table.
The 13th, 14th, 15th picks – and still Stratton was on the board. So were a few other players we liked a lot.
"Can you get up Stratton's last outing?' I asked Yeshayah.
Stratton's video appeared an instant later on the side screen. We watched again his clean, athletic delivery that suggested he could pitch for a long time — was only going to get better.
"So everybody good with Stratton?'' I asked. "We like him better than the other guys up there?''
"No question.''
It was our turn. Adam Nieting leaned toward the speaker phone: "The Giants select Chris Stratton from Mississippi State.''
"Congratulations, everybody!'' I said, excited and relieved. I thought about all the work, all the travel, all the games, all the reading and all the time everyone in this room – particularly our scouts – had put into this selection and the selections that would come over the next two days.
Within seconds, Bobby was on the phone with Stratton.
"Well, congratulations. Long road, I'm sure, huh?'' Bobby said. "Are you at home? Is your family there with you? Is that right? That's great. Well, we're looking forward to working with you.''
Bobby brought the phone to me then Brian and Dick Tidrow so we could pass on congratulations and welcome him to the organization.
Around the tables, the laptops were firing up again. Who did we want next? Were we still OK with this guy instead that guy? We were looking again at the video and scouting reports, double-checking and triple-checking our rankings.
One round down.
Thirty-nine to go.


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The Design Experience
Design is an essential element of engineering. Project management is what makes a good design become a prototype and ultimately a tool that works.
Toward the end of their degree, B.E. students enroll in a two-term capstone design sequence. These projects focus on engineering design, project management, and project completion. Working in teams of 3 or 4, they choose projects that industries have submitted to Thayer School's Cook Engineering Design Center (CEDC).
Engineering Design Methodology
In the design sequence (ENGS 89/90), students select a problem and collaborate with their industry sponsor to solve it. The entire process, which covers two 10-week terms, involves all the elements of the design process from problem definition to the industry application and includes feasibility studies, decision making, economic analysis, prototyping, and often final implementation.
Lectures by experts on entrepreneurship, ethics, and legal issues are part of each course. At several points in each term, students practice their presentation skills before a review board of engineering professionals.
The final product—a hardware prototype or a software program or a manufacturing process—is delivered to the industry partner at the end of the second term.
Recent projects demonstrate the range of possibilities for student work.


text:
skullman80 wrote:Bryan is saddled with a bad comic gimmick with Kane that has run it's course. He's one of if not the best wrestlers that WWE has from an in ring standpoint. He's pretty good on the mic, but they don't ever let him talk other than comic bits. He's plenty big, and plenty good enough to be one of the top guys in WWE.
I still hate that the WWE killed the Yes Yes Yes almost immediately by muddling it with No No No. Bryan could have and should have slowly turned back into a mega-over face with the Yes Yes Yes goodwill he received from the B.S. mania match he had. Then when he started getting stale they could have dropped the No No No heel turn in... but he doesn't have the look Vince wants so whatevs.


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Visit SSU
Welcome to Sonoma State University
Sonoma State University occupies 269 acres in the beautiful wine county of Sonoma County, in Northern California. Located at the foot of the Sonoma hills, the campus is an hour's drive north of San Francisco and 40 minutes from the Pacific Ocean. Often complimented for its lush and beautiful grounds, the campus is used for weekend activities by many.
The University is mid-sized with 9,300 students and is dedicated to the liberal arts and sciences with selected professional programs. With 46 bachelor's degree programs, 15 master's degree programs, 9 credential programs; 8 graduate and undergraduate certificate programs, a joint master's degree in mathematics with San Francisco State University and a joint doctorate in educational leadership with the University of California, Davis— students enjoy a diverse and high quality education. Collaborative educational interactions between students and faculty lead to research and internship opportunities. Sonoma serves as the sole California university in the Council of Public Liberal Arts Colleges (COPLAC).
Approximately 80 percent of freshmen and 55 percent of transfer students come from outside the North Bay region. With 34 percent of its student body living on campus in residential apartments Sonoma is one of the most residential campuses within the system.
Sonoma State University is a member of the National Collegiate Athletic Association (NCAA) Division II and is part of the California Collegiate Athletic Association (CCAA) and the Western Water Polo Association (WWPA) and includes five men's sports and eight women's. The Seawolves have had much success including national championships in 1990 (women's soccer), 2002 (men's soccer) and 2009 (men's golf).


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Northeast Kingdom Community Action Tests Child Care Centers for Radon
BARTON – The Vermont Department of Health is testing child care facilities in Newport, Lyndonville, St. Johnsbury and Derby for radon gas at the request of Northeast Kingdom Community Action (NEKCA). Eventually, NEKCA hopes to test all 14 of their early childhood education centers. Nearly 200 children are educated and cared for by NEKCA Head Start.
"By testing for radon and switching to 'greener' cleaning products, we can create a better environment for the children," said Linda Michniewicz, program director for NEKCA Head Start. "We want to reduce the risk of radon, and work to improve the overall air quality as well."
The testing is mandated nationally by Head Start and included in the U.S. Environmental Protection Agency Action Plan to reduce the risk of radon in schools and childcare facilities. Prolonged exposure to radon, a colorless, ordorless gas, is the second leading cause of lung cancer in the United States.
"I was under the impression that you only had to test for radon in buildings with basements, but that's not true," Michniewicz said. "We're hoping that by telling parents about the testing in our childcare centers it will educate parents about the possible health risk and lead them to test their homes as well."
The Health Department sent 1,726 free test kits to homeowners and businesses upon request in 2011, and 2,034 kits in 2012. Test kits are still available.
Radon gas can get into your home from the soil and the water supply. A house can act like a large chimney, with warm air rising and escaping out upper floor windows and through cracks in the attic. This creates a vacuum at the lowest level of the house, which can pull the radon from the soil into the house.
The cost of having a certified professional properly ventilate a home can range from $800 to $2,500, depending on the home's size and shape.
For a free test kit, email your request to firstname.lastname@example.com. Put the words "radon test kit" in the subject line and be sure to include your name, phone number, and both your mailing and physical address, or call 1-800-439-8550.
For more information visit the Health Department at www.healthvermont.gov. Follow us on Twitter and join us on Facebook for up-to-date news, alerts and health information.
Read more: http://vtdigger.org/2013/03/04/northeast-kingdom-community-action-tests-child-care-centers-for-radon/


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Tuesday, July 24, 2012
Batman movie massacre a reflection of violent video games, TSA violence against citizens and psychiatric drugging of young white men
Medical student James Holmes of Aurora, Colorado reportedly opened fire on moviegoers who had filled a theater late last night to watch the newly-released "Batman" movie -- an orgy of violence and Big Brother propaganda. Dressed in riot gear and wearing a gas mask that resembled the fictional evil character "Bane" depicted in the movie itself, Holmes burst into the theater and began shooting moviegoers, injuring 50 and killing 12. ABC News reports that James Holmes was a medical student at the University of Colorado, pursuing a PhD. He attended the University of Colorado Denver Medical Campus. (http://abcnews.go.com/US/mass-shooting-colorado-movie-theater-14-peop...) What is truly extraordinary about this horrifying scene is that nobody shot back. Given the large number of lawful citizens in Colorado who carry concealed weapons -- off-duty police and Sheriffs, armed citizens and former military -- it seems likely that at least one person in the theater would have been carrying a concealed weapon which could have been deployed to help stop further bloodshed. Perhaps the confusion of the event prevented this from happening. Many moviegoers reported thinking it was some sort of "promotional special effects" event rather than a real massacre, according to news reports. The psychiatric drug connection and Columbine 2012 As most NaturalNews readers well know, it is highly likely that James Holmes has been on psychiatric drugs. Not only does he fit the classic definition of a person typically put on psych drugs -- young white disturbed male -- his actions in the movie theater almost perfectly resemble those of the psyched-out shooters in the 1999 Columbine High School massacre: Eric Harris and Dylan Klebold. (http://en.wikipedia.org/wiki/Columbine_High_School_massacre) Just like Homes today, the Columbine shooters rampaged through a crowd of people, opening fire randomly, in a "detached" mode of mental insanity that is not normal or healthy. This is what many people forget to ask when they learn of such massacres: No gun pulls its own trigger. There is a mind behind the act, and when that mind is bathed in mind-altering psychotropic drugs with a known side effects profile of violence and suicidal behavior (http://www.naturalnews.com/027425_drugs_drugs_violence.html), then worsened yet more with violent video games and movies like Batman, a violent outcome is almost a certainty. Mainstream media routines fails to mention psychiatric drugs As you might suspect, the mainstream media systematically refuses to investigate the psychiatric drug link to violent criminals. The vast majority of shootings witnessed over the last two decades have involved psychiatric drugs (http://www.naturalnews.com/025826_Antidepressants_school_shootings.ht...), which are known to cause people to feel "detached from reality." As Wikipedia reports about the Columbine shooter Eric Harris: In one of his scheduled meetings with his psychiatrist, Eric Harris complained of depression, anger and to possessing suicidal thoughts. As a result of this, he was prescribed the anti-depressant Zoloft. He subsequently complained to feeling restless and to experiencing a lack of concentration to his doctor, and in April, he was switched to a similar anti-depressant drug -- Luvox. At the time of his death, Harris had therapeutic Luvox levels in his system. Some analysts, such as psychiatrist Peter Breggin, have argued that one or both of these medications may have contributed to Harris's actions. Breggin claimed that side-effects of these drugs include increased aggression, loss of remorse, depersonalization, and mania. A subsequent study conducted by the Institute for Safe Medication Practices identified Luvox as being 8.4 times more likely than other medications to be associated with violence. (http://en.wikipedia.org/wiki/Columbine_High_School_massacre#Medicatio...) Federal government directly promotes culture of violence In the years since the 1999 shooting, the U.S. government has, itself, rolled out the TSA and subjected American citizens to sexual molestation, strip-searches, public humiliation, verbal assaults and physical harassment by the TSA workers. Those workers -- who ridiculously call themselves "officers" -- turn out to be pedophiles, drug dealers, child porn distributors and thieves -- this is now a matter of public record, of course. (http://www.naturalnews.com/036346_TSA_pedophiles_whistleblower.html) As a result, the U.S. government has escalated violence against innocent people and helped spread a "culture of violence and abuse" across America. Ultra-violent movies like Batman only add to the culture of violence, depicting emotionally intense scenes of runaway violence, only to be resolved by a masked vigilante character who colludes with government to "kill bad guys" outside the law, with no due process. The Pentagon also directly contributes to runaway violence of today's youth by dosing active-duty soldiers with record levels of mind-altering psychiatric drugs. Today, more than 110,000 soldiers are on mind-altering drugs (http://www.naturalnews.com/036001_soldiers_psychiatric_drugs_veterans...), and that number is rising by the week. Also today, more U.S. soldiers die from suicide than from combat -- a first in the history of the world. Psychiatric drugging of soldiers is at obscene levels (http://www.naturalnews.com/035232_US_troops_psychiatric_drugs_Afghani...), and it is conducted in part because it "detaches" soldiers from the reality of what they're doing, allowing them to more easily pull the trigger when their rifles are pointed at other human beings. See the NaturalNews Infographic on the psychiatric drugging of children: http://www.naturalnews.com/Infographic-Epidemic-Psychiatric-Drugging-... This practice is openly encouraged by the government itself, which wants soldiers to think of war as a type of video game with no real consequences. It is that type of warped, detached reality that was present in both the Columbine shootings as well as today's Batman movie shooting. Remember: The U.S. government teaches violence and engages in violence at every level. Virtually everything the government demands of its citizens is done under the threat of violence. Don't want to have your child subjected to chemotherapy? You'll be arrested at gunpoint. (http://www.naturalnews.com/026305.html) Don't want to vaccinate your children? You'll be rounded up like cattle and forced to vaccinate at gunpoint. (http://www.naturalnews.com/022267.html) For the government to say that "We are the peacekeepers and CITIZENS are the ones causing violence" is absurd and factually untrue. Virtually all the real violence carried out against innocent people over the last 100 years has been conducted by governments, including the U.S. government which dropped nuclear weapons on civilian populations in Japan. And that doesn't even mention the Dresden firebombing massacre in Germany, also carried out by the U.S. government. (http://en.wikipedia.org/wiki/Dresden_firebombing) The No. 1 cause of death of innocent people is, throughout the history of the world, democide -- death by government. (http://en.wikipedia.org/wiki/Democide) The deadly combination: Violent movies, video games, military training and psychiatric drugs Here's the bottom line in all this: America is a nation with a long history of private gun ownership, and for most of its years that was never a problem. So what changed? What changed is the mental state of Americans. Today, young males are absolutely inundated with violent video games, violent movies, sexual molestation by TSA goons and often firsthand military training. The military training is not, by itself, a negative thing, but when combined with psychiatric drugs, it can become a deadly combination. (http://www.naturalnews.com/027425_drugs_drugs_violence.html) America has become a cesspool of violent culture, and the minds of today's youth are further assaulted by processed food chemicals, fluoride and vaccines, all of which compromise healthy brain function. We are a culture gone mad from bad programming, bad food, bad chemicals and bad government. And the worst part is that the Obama administration is no doubt gleeful that people died in a shooting because this was part of Eric Holder's plan to begin with. Operation Fast & Furious, carried out by the U.S. government itself, sold thousands of guns into the hands of Mexican drug gangs for the purpose of seeing those guns spill back over into the USA and cause outbreaks of so-called "gun violence." (http://www.naturalnews.com/032934_ATF_illegal_firearms.html) Alex Jones said today there is a, "100 percent chance this shooting is a false flag event," meaning it was planned in advance and carried out for the purpose of furthering a political agenda to ban civilian ownership of firearms. Thus, today's shooting in Aurora, Colorado is no doubt putting a smile on the faces of people in the Obama administration who will try to seize upon this shooting as justification for taking lawful firearms away from ALL citizens, including off-duty peace officers. It fits right into their Fast and Furious plan, after all. Here's yet another example of the government actually promoting violence in order to achieve a political agenda. That agenda, of course, is the desire to disarm the entire civilian population. Such a move would obviously unleash even more violence among armed criminals who, by definition, do not turn in guns when ordered to do so by the state. This massacre could have been halted -- and lives saved -- if just one concealed carry holder in that movie theater had pulled out their gun and shot Holmes for the sole purpose of immediately stopping his actions and protecting innocent life. Had I personally been in that theater and not been one of the first victims shot by surprise, I would have taken decisive action to end that violence by engaging Holmes with my own firearm. Whether I lived or died, Holmes would have at least hesitated under a barrage of return fire, and that would have saved lives and helped protect innocents. Yes, I am a concealed carry permit holder. And if you ever see me die in the act of protecting innocents, rest assured my magazines will have been emptied in the direction of the threat. It's not heroism, it's just basic human decency to want to protect innocent lives against violent criminals, whether they be mentally impaired individuals or rogue governments. My heart and prayers go out to the families who lost their loves ones in Aurora, Colorado. I pray for an end to violence, an end to government violence against the people, and an end of the psychiatric drugging of children everywhere. Source - www.naturalnews.com
Posted by Anonymous at 11:50 PM
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As Al Jazeera demands the release of its four journalists detained in Egypt, the Committee to Protect Journalists has released a grim accounting of the year, declaring Egypt, Syria, and Iraq the most deadly nations in the world for the press. According to the report, seventy journalists have been killed for their work in 2013. Twenty-five more deaths are still under investigation.
"The Great American Novel—always capitalized, like the United States of America itself—has to be a book that contains and explains the whole country," writes Adam Kirsch in a review of Lawrence Buell's The Dream of the Great American Novel. Surely, books such as Herman Melville's Moby-Dick and William Faulkner's Absalom, Absalom fit the script. But what about Margaret Mitchell's Gone with the Wind, which covers many of the same themes as Faulker's masterpiece, outsold it by a factor of fifty to one, but hardly qualifies as an uncontested classic of American letters?
In the meantime, the Millions estimates that there are currently some 250,000 novelists at work in America.
The man behind the New York Times Magazine's most striking cover designs is leaving, and moving to Apple.
Soon to be spun off of Time Warner, Time Inc. is planning to strike out on its own.
According to a federal judge in Chicago, Sherlock Holmes has tumbled out of copyright protection and into the public domain.


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By creating a Microsoft account for each person in your family, you can personalize each family member's online experience based on age-appropriate limits that you set. Those settings will apply to any Xbox One or Windows 10 device they sign in to.
Family-friendly Microsoft Store
Family settings for all Xbox One and Windows 10 devices
Personalized play
For more information about Family membership and Family settings, go to the Family page.
Thanks for your feedback!
Provide feedback for this topic
Would you like to contact Support regarding the "Benefits of creating a family on Xbox One" issue you were reading about or a different issue?


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DEAR DR. FOX: Recently, I adopted a stray dog from the Humane Society. He is 8 years old, and part Lhasa apso, part poodle. He's a very sweet and bright animal.
DEAR DR. FOX: Recently, I adopted a stray dog from the Humane Society. He is 8 years old, and part Lhasa apso, part poodle. He's a very sweet and bright animal.
He has the strange habit of licking the sofa cushion and barking constantly. I am sure this is not healthy, but according to the veterinarian, it's just a habit. I don't agree. Is there something that can be done to cure him? D.M.W., Naples, Fla.
DEAR DR. FOX: Two months ago, I took in a 12-year-old female shih tzu. She had a yeast infection. I changed her dog food, and she seems to be over the infection. But she is constantly licking her face, her dog bed and the rugs.
Can you tell me why she is doing this? G.S., Mt. Airy, N.C.
DEAR D.M.W. and G.S.: This excessive licking is an obsessive-compulsive behavior, and it is quite common in toy and miniature breeds. As one of the founding fathers of applied animal ethology/veterinary behavioral therapy, I caution against immediately jumping to a psychological diagnosis before ruling out possible physical causes.
A thorough veterinary evaluation is called for to check for a possible source of chronic inflammation: conjunctivitis, gingivitis, pharyngitis, tonsillitis, contact dermatitis, possible food allergy/hypersensitivity and even impacted anal glands.
You should also consider boredom, lack of physical and mental activities and anxiety as a cause for this behavior.
When physical and rectifiable psychological causes are ruled out, a trial with a psychotropic medication such as Prozac may prove beneficial. But the best cure may lie in adopting another dog of similar size and friendly temperament.
DEAR DR. FOX: Some time ago, I lost my diabetic cat. He had a stroke and became blind and confused. I took him to the vet, and the vet had to put my cat down. I was in such a state that I failed to ask what caused the stroke.
For more than 12 years, I kept my cat alive by giving him his insulin shots and taking him to the vet for blood tests. Is there something I didn't do right, or did I do something to cause the stroke? I have not gotten over this feeling that maybe I did something that caused the stroke. I still miss him very much. P.D., Washington, Mo.
DEAR P.D.: I sympathize with you over the loss of your poor cat who was afflicted by diabetes.
Many diabetic cats develop various complications, just as human sufferers of this disease do. These complications are often compounded by liver and kidney problems.
Blood clots and burst blood vessels from high blood pressure can cause strokes, partial paralysis and blindness. These complications are no fault of yours, and you could have done nothing to prevent them — it's just the luck of the draw.
The only consolation is that your cat did not suffer long, and he enjoyed the security and pleasure of your loving care.
DEAR DR. FOX: One of my dogs had chronically loose stools. I have made one simple change that has completely resolved the issue.
We adopted the dog as a 1-year-old and have had him for three years. He is a labradoodle and is lean and otherwise healthy. I feed all three of my dogs a mixture of wet and dry Wellness food and some fish oil.
My dogs had free access to a large backyard where they could romp around at will, though most of the activity involved charging out to bark at a squirrel or a neighboring dog. They also got 30 minutes off-leash every day at a dog park. I thought things were going well.
We recently moved to a house in the hills with no yard at all. This requires me to give the dogs regular scheduled walks on a variety of routes around the neighborhood. It's not even for very long, sometimes just a brisk 20 minutes twice a day if that's all I can fit in. And every few days we have a two-hour off-leash hike where they can go full speed up and down the trails. That is the only change.
With this routine, the labradoodle's stools are now healthy, and the other male dog has stopped marking inside.
I just want to reinforce to your readers the importance of brisk and perhaps routinely scheduled walks. G.W., Topanga, Calif.
DEAR G.W.: Brisk, routinely scheduled walks and off-leash romps in safe and dog-sanctioned open space are all part of holistic canine health care.
Experienced veterinarians always determine such lifestyle factors in making a diagnosis and in recommending appropriate treatment for a variety of health problems.
A strict activity routine before meals helps prime the dog's appetite and digestive system before coming home and anticipating food. This mimics the dog's natural hunting/gathering/scavenging behavior — physical activity to various degrees of strenuousness before eating two or three small meals daily. One big meal can mean bloating, vomiting, indigestion and loose stools.
Send mail to email@example.com or to Dr. Michael Fox in care of Universal Uclick, 1130 Walnut St., Kansas City, MO 64106. Visit DrFoxVet.com.


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Mars Express orbiting precisely and safely
ESA's Mars Express orbiter, mothership of Europe's first mission to the Red Planet, is in a stable and precise orbit around Mars.
Thus, the most essential part of the European Mars mission is performing very well and we are expecting exciting science from January 2004 onwards.
The Mars Orbit Insertion (MOI) manoeuvre of Mars Express had been completed on 25 December at 3:47 CET. This brought the spacecraft as close as 400 kilometres to the surface of Mars. Afterwards, the spacecraft went into a highly elliptical orbit, going as far as 188 000 kilometres away from the planet.
Today, 27 December, the mission control team at ESOC prepared the next steps to turn Mars Express from a near-equatorial orbit into a polar orbit. Michael McKay, Mars Express Flight Director explained, "Our flight dynamics and flight operations teams thoroughly discuss, evaluate and prepare the commands to perform a series of manoeuvres starting with a major move on 30 December – where we will fire the main engine again for three minutes.
"These key manoeuvres will allow us to get even closer to Mars. They will not only allow us more frequent 'overflights' of the Beagle 2 landing area, but also ensure the beginning of the orbiter's science mission. As Mars Express is the planned main communication partner of the Beagle 2, the chances of obtaining a signal strongly increase with these manoeuvres after 4 January 2004."
Close European and international co-operation
The ESA control team at ESOC are in regular contact with their colleagues of the Beagle 2 team and the Jodrell Bank telescope in the UK, with NASA ground stations and with several other European partners (UK, Germany, Netherlands, etc.). Many international offers have been forthcoming to support the search for the Beagle 2 lander.
Status reports on Mars Express and Beagle 2
The ESA operations centre at ESOC keeps the press informed via the detailed ESA Mars Express web site http://mars.esa.int or via the info box 0049 6151 90 2609.
The latest on Beagle 2: http://www.beagle2.com
Infoline: +44- 1908- 332 017


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Catcher in the Rye dropped from US school curriculum
Schools in America are to drop classic books such as Harper Lee's To Kill a Mockingbird and JD Salinger's Catcher in the Rye from their curriculum in favour of 'informational texts'.
American literature classics are to be replaced by insulation manuals and plant inventories in US classrooms by 2014.
A new school curriculum which will affect 46 out of 50 states will make it compulsory for at least 70 per cent of books studied to be non-fiction, in an effort to ready pupils for the workplace.
Books such as JD Salinger's Catcher in the Rye and Harper Lee's To Kill a Mockingbird will be replaced by "informational texts" approved by the Common Core State Standards.
Suggested non-fiction texts include Recommended Levels of Insulation by the the US Environmental Protection Agency, and the Invasive Plant Inventory, by California's Invasive Plant Council.
The new educational standards have the backing of the influential National Governors' Association and the Council of Chief State School Officers, and are being part-funded by a grant from the Bill & Melinda Gates Foundation.
Jamie Highfill, a teacher at Woodland Junior High School in Arkansas, told the Times that the directive was bad for a well-rounded education.
"I'm afraid we are taking out all imaginative reading and creativity in our English classes.
"In the end, education has to be about more than simply ensuring that kids can get a job. Isn't it supposed to be about making well-rounded citizens?"
Supporters of the directive argue that it will help pupils to develop the ability to write concisely and factually, which will be more useful in the workplace than a knowledge of Shakespeare.
I know a lot of people hate Catcher in the Rye, but it's one of my favourite novels. And I think this is such bs because both of these novels are cornerstones of American literature.
And if you're so dense that you don't know how to write appropriately in the workplace by the time that you're an employed adult, then maybe you shouldn't be writing in the workplace at all.
What are your favourite books from school, ONTD?
UPDATE: Apparently this article mistakenly sourced a satirical artical originally published in the Washington Post. There has been no official change made to the US school curriculum, but if you'd like to read more about the Common Core English Language Arts standards that are mentioned here, click here. Thanks to nicholasdee for the update!


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Let's go through this trove of secrets. Three of the documents that could land Mr Drake in jail were copies of material he had submitted to the inspector-general in a complaint about a surveillance programme described by others as a "wasteful failure". The programme in question was abandoned in 2006 after eating up $1.2 billion. (Ms Mayer helpfully notes that the inspector general's website tells complainants to keep copies of their documents.) One of the other documents under scrutiny is a schedule of meetings marked "unclassified/for official use only". Prosecutors say the paper should've been secret and that Mr Drake should've known it should've been secret. The final document was declassified three months after Mr Drake's indictment.And that's it. At worst, he mishandled some documents, but even that's in question. It seems abundantly clear that the prosecution of Drake is because he annoyed his bosses at the NSA and embarrassed them by getting press coverage for the fact that they became enamored with the spin from some defense contractors, leading them to waste taxpayer money. And for that he gets charged with espionage, even as President Obama continues to insist that he values whistleblowers within the government. The Thomas Drake affair is shaping up to be yet another example of an executive branch out of control when it comes to abusing the power of its position. This is a problem that all Americans should be worried about, as both major parties seem more than happy to abuse power while in office.
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