Accordingly acne extraction buy aldara 5percent on-line, the Commission felt that it had a special obligation to take all possible steps to ensure the reliability of the evidence used to arrive at a finding acne out biotrade buy aldara 5percent low price. In cases where it had to identify specific individuals as having committed acne soap buy aldara 5percent, ordered or tolerated specific acts of violence acneorg discount 5percent aldara, it applied a stricter test of reliability. The Commission decided that, in each of the cases described in this report, it would specify the degree of certainty on which its ultimate finding was based. The Commission decided not to arrive at any specific finding on cases or situations, or any aspect thereof, in which there was less than "sufficient" evidence to support such a finding. In order to guarantee the reliability of the evidence it gathered, the Commission insisted on verifying, substantiating and reviewing all statements as to facts, checking them against a large number of sources whose veracity had already been established. It was decided that no single source or witness would be considered sufficiently reliable to establish the truth on any issue of fact needed for the Commission to arrive at a finding. It was also decided that secondary sources, for instance, reports from national or international governmental or private bodies and assertions by people without first-hand knowledge of the facts they reported, did not on their own constitute a sufficient basis for arriving at findings. However, these secondary sources were used, along with circumstantial evidence, to verify findings based on primary sources. In the peace agreements, the Parties made it quite clear that it was necessary that the "complete truth be made known", and that was why the Commission was established. After all, the Commission was not asked to write an academic report on El Salvador, it was asked to investigate and describe exceptionally important acts of violence and to recommend measures to prevent the repetition of such acts. This task cannot be performed in the abstract, suppressing information (for instance, the names of persons responsible for such acts) where there is reliable testimony available, especially when the persons identified occupy senior positions and perform official functions directly related to violations or the cover-up of violations. Not to name names would be to reinforce the very impunity to which the Parties instructed the Commission to put an end. In weighing aspects related to the need to protect the lives of witnesses against the interests of people who might be adversely affected in some way by the publication of their names in the report, the Commission also took into consideration the fact that the report is not a judicial or quasijudicial determination as to the rights or obligations of certain individuals under the law. As a result, the Commission is not, in theory, subject to the requirements of due process which normally apply, in proceedings which produce these consequences. As a result, the Commission is satisfied that the criteria of impartiality and reliability which it applied throughout the process were fully compatible with the functions entrusted to it and with the interests it had to balance. The considerations which prompted the Commission to receive confidential information without revealing the source also forced it to omit references from both the body and the footnotes of the reports on individual cases, with the exception of references to certain public, official sources. As a result, reference is made to official trial proceedings and other similar sources, but not to testimony or other information gathered by the Commission. The Commission took this approach in order to reduce the likelihood that those responsible for the acts of violence described herein, or their defenders, would be able to identify the confidential sources of information used by the Commission. In some of the reports on individual cases, the Commission also omitted details that might reveal the identity of certain witnesses. Chronology of Violence Introduction the Commission on the Truth had the task of investigating and analysing serious acts of violence that had occurred in El Salvador between January 1980 and July 1991. In taking into account "the exceptional importance that may be attached to the acts to be investigated, their characteristics and impact, and the social unrest to which they gave rise", 8 the Commission, for methodological reasons, divided the years 19801991 into four periods, namely: 1980-1983, 1983-1987, 1987-1989 and 1989-1991. Each of these periods corresponds to political changes in the country, developments in the war and the systematic nature or frequency of certain practices that violated human rights and international humanitarian law. Frequency of reports in the Salvadorian press concerning acts of violence (For more information, see annex 3) A Peasant massacres* B Murder of individuals* C Disappearances* D Abductions* * Average percentage of reports. The fragmentation of any opposition or dissident movement by means of arbitrary arrests, murders and selective and indiscriminate disappearances of leaders became common practice. Starting in 1980, there was a succession of indiscriminate attacks on the non-combatant civilian population and also collective summary executions, particularly against the rural population. Organized terrorism, in the form of the so-called "death squads", became the most aberrant manifestation of the escalation of violence. Civilian and military groups engaged in a systematic murder campaign with total impunity, while State institutions turned a blind eye. Measures were enacted restricting landholdings to a maximum of 100 hectares (Decree No. On 3 January 1980, the three civilian members of the Junta resigned, along with 10 of the 11 cabinet ministers. The process of political polarization triggered an unprecedented increase in death squad activities. On 6 February, United States Ambassador Frank Devine informed the State Department that mutilated bodies were appearing on roadsides as they had done in the worst days of the Romero regime and that the extreme right was arming itself and preparing for a confrontation in which it clearly expected to ally itself with the military. On 24 March, Monsignor Oscar Arnulfo Romero was shot dead by a sniper as he celebrated mass in the Chapel of the Hospital de la Divina Providencia 21 (see the case in chap. This crime further polarized Salvadorian society and became a milestone, symbolizing the point at which human rights violations reached their peak and presaging the all out war between the Government and the guerrillas that was to come. The panic-stricken crowd, estimated at 50,000 people, was machine-gunned, leaving an estimated 27 to 40 people dead and more than 200 wounded. This strengthened the most conservative sector in the Government 24 and was a clear example of the passivity and inertia of the judiciary during this period. In late 1980, as a change of Administration was taking place in the United States, the violence in El Salvador reached United States citizens. On 2 December, four churchwomen were arrested, raped and murdered by members of the National Guard (see the case in chap. On 3 January, the President of the Salvadorian Institute for Agrarian Reform and two United States advisers were murdered in the Sheraton Hotel 31 (see the case in chap. This incident was part of a campaign of murders of cooperative leaders and beneficiaries of the agrarian reform. Government sources reported that "at least 500 extremists" had died in the final offensive. The violence in El Salvador began to attract international attention and to have international repercussions. External political forces began to claim that the Salvadorian conflict was part of the East-West confrontation. On 14 January, the United States Administration restored military aid, which had been suspended after the murder of the United States churchwomen. The increasing flow of resources was intended to train, modernize and expand the structure of a number of elements of the armed forces. Counter-insurgency military operations affected the non-combatant civilian population, causing a high death toll and the emergence of a new phenomenon - displaced persons. On 17 March, as they tried to cross the Lempa river to Honduras, a group of thousands of peasants was attacked from the air and from land. Between 20 and 30 people were reported killed and a further 189 reported missing as a result of the attack. Something similar happened in October on the banks of the same river, on which occasion 147 peasants were killed, including 44 minors. The Apaneca Pact was signed on 3 August 1982, establishing a Government of National Unity, whose objectives were peace, democratization, human rights, economic recovery, security and a strengthened international position. An attempt was made to form a transitional Government which would establish a democratic system. Between February and April, a total of 439 acts of sabotage were reported42 and the number of acts of sabotage involving explosives or arson rose to 782 between January and September. According to some reports, the number of rebels ranged between 4,000 and 5,000; other sources put the number at between 6,000 and 9,000. In one of these operations (31 January), 150 civilians were reported killed by military forces in Nueva Trinidad and Chalatenango. On 10 March, some 5,000 peasants were fired at from helicopters and shelled as they fled the combat zone in San Esteban Catarina. In August, a military campaign of "pacification" in San Vicente reported 300 to 400 peasants killed.
This is the first alternative route of administration since the discovery of insulin in the 1920s skin care md order 5percent aldara otc. Depending on the materials employed and the preparation method skin care 911 purchase 5percent aldara mastercard, distinct particles can be used: nanoparticles acne jeans mens cheap 5percent aldara overnight delivery, liposomes za skincare buy generic aldara 5percent on line, polymeric micelles, ceramic nanoparticles, and dendrimers. Nanocrystals can increase in vitro stability by transforming soluble molecules into non-soluble forms. In this way, only the nanocrystal surface is accessible to degrading factors, such as water and oxygen. This means that an external monolayer of degraded molecules is formed to protect the inner part of the nanocrystal. Soluble molecules, such as peptides, nucleotides, and proteins can be transformed into particles by dispersing them into oil. After oral administration, the oil is degraded by lipases in vivo, releasing the drug. Another challenge is the delivery of a biopharmaceutical to its site of action, as the injection of molecules in solution leads to a partitioning of the molecules according to their physicochemical properties. One approach to deliver particles injected intravenously is based on the concept of ``differential protein adsorption. The adsorbed proteins determine the cells to which the particles will be directed (Muller and Keck, 2004). A popular approach to confer enhanced stability and improve the pharmacokinetics of therapeutic proteins is to conjugate them to different polymers. This technique, known as pegylation, is able to increase protein stability, improve pharmacokinetics, and potentially decrease immunogenicity (Chirino and Mire-Sluis, 2004). These products have enhanced stability, thus reducing the number of injections patients need to receive. However, the companies owning the patents commercialize pegylated biopharmaceuticals at prices much higher than the corresponding nonpegylated ones, preventing a broader use of the pegylated version, mainly in developing countries. The prices charged certainly do not represent the additional cost of polymer conjugation, but rather a market value that reflects a monopoly. This particularly affects product characterization, due to the complex production processes and protein structures. Thus, successful production of biopharmaceuticals relies mainly on strict protocols, clinical expertise, and follow-up during clinical application (Crommelin et al. For these reasons, the ability to compare products originating from different processes is more important than characterizing a biopharmaceutical product from a well established process. Modifications in the production process can result in changes in physicochemical properties and post-translational modifications. These modifications can influence biological activity, bioavailability, and immunogenicity of the product (Chirino and Mire-Sluis, 2004). Therefore, as discussed in Chapter 14, the regulatory agencies worldwide are discussing criteria to be applied to evaluate comparability of biological products (Food and Drug Administration, 2005; European Medicines Agency, 2005). Among the many tests available for characterizing biopharmaceuticals, assessment of protein structure, particularly quaternary structure, including aggregate formation, seems to be particularly important, since it can strongly influence immunogenicity. This remains a concern for the characterization of biological products, since preclinical studies, carried out in animals, are not able to predict the immunogenicity of a biological drug in the target population (Chirino and Mire-Sluis, 2004). In this context, product labelling becomes an important issue, since aggregate formation and continuous administration of a protein drug can lead to antibody production (Ryff and Schellekens, 2002). Biopharmaceutical labelling could thus provide information in such a way that the physician would understand the clinical and biological consequences of antibody production and, therefore, could make a decision that could lead to the suspension of a treatment. When glycosylation is not present or is not essential for biological activity, therapeutic proteins can be produced in bacteria. However, some studies propose the use of these systems for glycosylated proteins as well. Gerngross (2004) argues for the use of filamentous fungi and yeast for the production of therapeutic proteins by the expression of human glycosylation enzymes. Plant cells are another expression system, which is being evaluated for the production of recombinant therapeutic proteins. However, there are some limitations, such as the instability of recombinant proteins in plant cell culture media and the low protein yields reported so far for plant cells in culture (Hellwig et al. A concrete example of the application of plant cells is the first market license issued in January 2006 to a veterinary vaccine produced in plant cells (Katsnelson et al. This subunit vaccine consists of a protein expressed in recombinant tobacco cells and represents the first vaccine obtained from plant cells to be approved worldwide. Another possible system for the production of therapeutic proteins consists of transgenic animals. Although there is controversy regarding safety and reproducibility, many reports on this subject have been published and some proteins derived from these systems are currently under clinical trials. This protein, used in the treatment of autoimmune diseases, proved to be identical to the native form by mass spectrometry, circular dichroism, and pharmacokinetic tests. Using a different approach, some authors propose post-translational modification in vitro. Glycosylated proteins could be obtained by in vitro glycosylation after their production in non-mammalian expression systems. Synthetic strategies for preparing glycoproteins can be classified into two main categories: convergent and sequential. In the convergent strategy, the glycan is assembled separately by enzymatic or chemical methods, or obtained from natural sources, and is then attached to the polypeptide chain. In the sequential strategy, a mono- or disaccharide unit is introduced into the polypeptide, and then the complete glycan is synthesized by the sequential attachment of sugars by the action of glycosyltransferases. However, the development of simple and reliable methods for obtaining selectively and uniformly glycosylated proteins is still a challenge and will probably remain a focus of future research (Khmelnitsky, 2004). Finally, some authors propose the use of enzyme mixtures for the biosynthesis of complex molecules. However, even if the technical potential of this method is proved, its economical feasibility has still to be proven. Second-generation biopharmaceuticals are engineered molecules resulting from modifications 406 Animal Cell Technology of glycans or of amino acid composition, or from conjugation to other molecules, such as in the case of pegylated proteins. These alterations in the protein are carried out with different goals: (i) to improve the pharmacokinetic profile of the protein; (ii) to increase protein half-life; and/or (iii) to alter its immunogenic profile. Second-generation insulins are also available and consist of molecules with changes in one to two amino acids, aimed at accelerating the onset of activity (Lispro and Aspart insulin products) or increasing the half-life (Glargine insulin product). Humanized antibodies, discussed in more detail in Chapter 17, are also considered second-generation molecules. By humanization, the high immunogenicity of a murine antibody is eliminated, enabling improved therapeutic use. Protein engineering can also be used for creating fusion proteins or 1 hybrid biopharmaceuticals. The antibody portion of the fusion protein increases the half-life in blood (Walsh, 2004). Another approach relies on modifying the glycan of glycoproteins to improve pharmacokinetics of biopharmaceuticals. These will have significant advantages for patients, including lower immunogenicity, lower frequency of injections, and enhanced stability in serum. Recombinant therapeutic proteins 407 Baneyx F, Mujacic M (2004), Recombinant protein folding and misfolding in Escherichia coli, Nat. In: Walsh G, Murphy B (Eds), Biopharmaceuticals: An Industrial Perspective, Springer Verlag, Berlin, pp. Food and Drug Administration (2005), Scientific considerations related to developing follow-on protein products. Research and Markets (2005d), Monoclonal antibody therapeutics: current market dynamics & future outlook.
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