Analysis of a sub-optimal scheme of drug dosage in the AIDS treatment

Here the results for CD4+T cells count and the viral load obtained from HIV sero-positive patients are compared with results from numerical simulations by computer. Also, the standard scheme of administration of drugs anti HIV (HAART schemes) which uses constant doses is compared with an alternative sub-optimal teatment scheme which uses variable drug dosage according to the evolution of a quantitative measure of the side effects. The quantitative analysis done here shows that it is possible to obtain, using the alternative scheme, the same performance of actual data but using variable dosage and having fewer side effects. Optimal control theory is used to solve and also to provide a prognosis related to the strategies for control of viraemia.

Gobierno y gobernancia de los territorios, sectorialidad y territorialidad de las políticas públicas

El hecho de que, desde la Constitución de 1991, normas y sentencias tiendan en considerar que los ejecutivos locales (alcaldes, gobernadores) deben ser unos agentes regidores que practican el gobierno del territorio y la “descentralización controlada” más que unos actores gobernantes, defensores de la gobernancia de sus territorios, plantea la cuestión de saber por qué y cómo aquéllos pueden combinar este doble rol. La mayor parte de la respuesta se encuentra en el examen simultáneo de la lógica de regulación de las políticas pública (Muller, 1997 y 2002) y de las condiciones de su implementación en el territorio o “despliegue territorial” (Medellín, 2003).La territorialidad de una política pública se refiere, según Muller, a una situación en la cual la lógica dominante de una política pública es una lógica territorial u horizontal (regulación de un territorio geográfico en una dialéctica centro-periferia), mientras la sectorialidad se refiere a una situación en la cual la lógica dominante de una política pública es una lógica sectorial o vertical (regulación de la reproducción de un sector determinado verticalmente en una dialéctica global-sectorial). A cada lógica de regulación de las políticas públicas le corresponde una manera de gobernar un territorio: el gobierno del territorio para la sectorialidad y la gobernancia de los territorios para la territorialidad.Al contrario del caso francés en el cual la construcción del Estado marca el fin de una lógica de territorialidad (la “territorialidad tradicional”), el Estado colombiano es un Estado endémico, un Estado fragmentado confrontado a la lucha por el control territorial y el temor a la fractura de la unidad territorial (Navas, 2003). Su capacidad parcial por cubrir todo el territorio y actuar sobre él (su “territorialidad parcial” según Medellín) afecta su gobernabilidad y el despliegue territorial de las políticas públicas, sometido a negociaciones inciertas, cercanas a la temática de la gobernancia.Por ello, la gobernabilidad en Colombia sólo es posible mediante políticas públicas híbridas, hijas del “matrimonio indisoluble de la sectorialidad y de la territorialidad”, de la “secterritorialidad”, que combina en proporción variable lógica sectorial (o sectorialidad, que implica centralización) y lógica territorial (o territorialidad, que implica descentralización), gracias a un modo de gobierno híbrido, la “gobiernancia” del territorio, ésta es una “dosificación” compleja entre gobier-no y gobernancia. Es, entonces, posible determinar el grado de territorialidad y de sectorialidad de una política pública en un momento dado y clasificar las políticas públicas según su grado de territorialidad y de sectorialidad, es decir, según la importancia relativa de sus lógicas de regulación.Si el periodo que empieza al iniciar los años setenta, y que termina al iniciar los años ochenta es un periodo en el cual domina primordialmente la sectorialidad y se asegura la gobernabilidad recurriendo casi exclusivamente al gobierno del territorio a través del despliegue territorial separado de cada sector, el periodo que va de 1984 a la época actual, caracterizado por la “descentralización controlada”, señala un cambio parcial de lógica de regulación de las políticas públicas a través del recurrir parcial a la lógica de territorialidad como respuesta a alguna crisis de sectorialidad.Como bien lo muestra el análisis y la evaluación de las políticas públicas de vivienda de interés social, ordenamiento y desarrollo del territorio municipal, educación y acueducto y alcantarillado, la gobernabilidad en este secundo periodo está asegurada, entonces, sólo gracias a la gobiernancia en los territorios o combinación entre el gobierno del territorio y la gobernancia de los territorios, es decir, gracias a un modo de gobierno híbrido que les permite a los ejecutivos locales conciliar su inclinación por la gobernancia de sus territorios y sus obligaciones en cuanto al gobierno del territorio y ser, al mismo tiempo, actores gobernantes y agentes regidores.-----Since the 1991 Constitution, most rulings and sentences tend to consider that individuals in charge of the local executive power (mayors, governors) should be some sort of tuling aldermen responsible for their particular territories and their “controlled decentralization” instead of actual governing actors, advocates and defenders of the governance of their territories. This fact raises the questions of why and how they can possibly play this double role. The bulk of the answer to this question can be found by examining both the logic behind public policies (Muller) and the conditions in whixh these are implemented in each territory, or “territorial deployment” (Medellìn).According to Muller, the territoriality of a particular public policy refers to a situation whereby the prevailing logic is territorial or horizontal (regulation of a geographical territory follows a center-periphery scheme), whereas its sectoriality refers to a situation whereby the prevailing logic is sectorial or vertical (regulation of a sector’s reproduction is vertically determined by a global-sectorial scheme). For each regulation logic behind public policies there is a corresponding way of governing a particular territory: governing the territory for the sake of sectoriality, and governing it for the sake of territoriality.As opposed to the French case, whereby the construction of the State signals the purposes of a territorial logic (“traditional territoriality”), the Colombian State is na endemic one, a fragmented State struggling for territorial control and in fear of the fragmentation of territorial unity (Navas). Its limited capacity to cover the whole territory and to act on it (its “limited or partial territoriality”, according to Medellín) affects governability as well as the deployment of public policies, which is frequently subject to uncertain negotiations related to the problem of governance.That es why governability in Colombia is only possible through hybrid public policies, which are in turn the result of the “indissoluble marriage between sectoriality and territoriality”, the result of a sort of “secterritoriality” which combines in various proportions a sectorial logic (or sectoriallity, which implies centralization) and a territorial logic (or territoriallity, which implies decentralization), all due to a hybrid form of governmen, or “governance” of the territory, a complex and variable dosage of both government and governance. Keeping this in mind, it is possible to establish the degree of territoriality and sectoriality of a public policy at a particular time, and to classify public policies according to their degree of territoriality and/or sectoriality, that is, according to the relative importance of the logics behind their regulation.From the early 70s to the early 80s, sectoriality prevailed and governability was guaranteed almost exclusively through the separate territorial deployment of each sector, then, from 1984 to the present, “controlled decentralization” has shown partial changes in the regulation logic behind public policies by resorting, at least in part, to a logic of territoriality in response to some sort of sectorriality crisis.As can be clearly seen after analyzing and evaluatin public policies in matters such as statesubsidized housing, municipal land development and legislation, education, water and sewage services, governability during this second period can only be guaranteed by governance in the territories or by a combination of both, government in the territory and governance in the territories. In other words, governability is possible thanks to a type of hybrid government that allows those in charge of exercising local executive power to reconcile their bias towards the governance of their teritories and their duties vis-àvis the government of the territory, but capable of being, at the same time, governing actors and ruling agents, active modern-day aldermen.

Desenvolvimento e análise de um protótipo automatizado para dosagem pontual de fertilizantes sólidos em taxas variáveis

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Effects of Triclopyr on Variable-Leaf Watermilfoil

The objective of the study described here was to determine the effect on variable-leaf watermilfoil of various combinations of triclopyr concentrations and exposure times using dosage rates that controlled Eurasian watermilfoil under laboratory and field conditions (Netherland and Getsinger 1992, Getsinger et al. 1997, Petty et al. 1998).

Molecular investigations into vaginal immunization with HIV gp41 antigenic construct H4A in a quick release solid dosage form

A robust vaginal immune response is considered essential for an effective prophylactic vaccine that prevents transmission of HIV and other sexually acquired diseases. Considerable attention has recently focused on the potential of vaginally administered vaccines as a means to induce such local immunity. However, the potential for vaccination at this site remains in doubt as the vaginal mucosa is generally considered to have low immune inductive potential. In the current study, we explored for the first time the use of a quick release, freeze-dried, solid dosage system for practical vaginal administration of a protein antigen. These solid dosage forms overcome the common problem associated with leakage and poor retention of vaginally administered antigen solutions. Mice were immunized vaginally with H4A, an HIV gp41 envelope based recombinant protein, using quick release, freeze-dried solid rods, and the immune responses compared to a control group immunized via subcutaneous H4A injection. Vaginally immunized mice failed to elicit robust immune responses. Our detailed investigations, involving cytokine analysis, the stability of H4A in mouse cervicovaginal lavage, and elucidation of the state of H4A protein in the immediate-release dosage form, revealed that antigen instability in vaginal fluid, the state of the antigen in the dosage form, and the cytokine profile induced are all likely to have contributed to the observed lack of immunogenicity. These are important factors affecting vaginal immunization and provide a rational basis for explaining the typically poor and variable elicitation of immunity at this site, despite the presence of immune responsive cells within the vaginal mucosae. In future mucosal vaccine studies, a more explicit focus on antigen stability in the dosage form and the immune potential of available antigen-responsive cells is recommended. © 2012 Elsevier Ltd. All rights reserved.

Hydrodynamics and solid dosage form disintegration/dissolution : immediate release tablets and novel in situ polyelectrolyte gastroretentive drug delivery systems

Solid oral dosage form disintegration in the human stomach is a highly complex process dependent on physicochemical properties of the stomach contents as well as on physical variables such as hydrodynamics and mechanical stress. Understanding the role of hydrodynamics and forces in disintegration of oral solid dosage forms can help to improve in vitro disintegration testing and the predictive power of the in vitro test. The aim of this work was to obtain a deep understanding of the influence of changing hydrodynamic conditions on solid oral dosage form performance. Therefore, the hydrodynamic conditions and forces present in the compendial PhEur/USP disintegration test device were characterized using a computational fluid dynamics (CFD) approach. Furthermore, a modified device was developed and the hydrodynamic conditions present were simulated using CFD. This modified device was applied in two case studies comprising immediate release (IR) tablets and gastroretentive drug delivery systems (GRDDS). Due to the description of movement provided in the PhEur, the movement velocity of the basket-rack assembly follows a sinusoidal profile. Therefore, hydrodynamic conditions are changing continually throughout the movement cycle. CFD simulations revealed that the dosage form is exposed to a wide range of fluid velocities and shear forces during the test. The hydrodynamic conditions in the compendial device are highly variable and cannot be controlled. A new, modified disintegration test device based on computerized numerical control (CNC) technique was developed. The modified device can be moved in all three dimensions and radial movement is also possible. Simple and complex moving profiles can be developed and the influence of the hydrodynamic conditions on oral solid dosage form performance can be evaluated. Furthermore, a modified basket was designed that allows two-sided fluid flow. CFD simulations of the hydrodynamics and forces in the modified device revealed significant differences in the fluid flow field and forces when compared to the compendial device. Due to the CNC technique moving velocity and direction are arbitrary and hydrodynamics become controllable. The modified disintegration test device was utilized to examine the influence of moving velocity on disintegration times of IR tablets. Insights into the influence of moving speed, medium viscosity and basket design on disintegration times were obtained. An exponential relationship between moving velocity of the modified basket and disintegration times was established in simulated gastric fluid. The same relationship was found between the disintegration times and the CFD predicted average shear stress on the tablet surface. Furthermore, a GRDDS was developed based on the approach of an in situ polyelectrolyte complex (PEC). Different complexes composed of different grades of chitosan and carrageenan and different ratios of those were investigated for their swelling behavior, mechanical stability, and in vitro drug release. With an optimized formulation the influence of changing hydrodynamic conditions on the swelling behavior and the drug release profile was demonstrated using the modified disintegration test device. Both, swelling behavior and drug release, were largely dependent on the hydrodynamic conditions. Concluding, it has been shown within this thesis that the application of the modified disintegration test device allows for detailed insights into the influence of hydrodynamic conditions on solid oral dosage form disintegration and dissolution. By the application of appropriate test conditions, the predictive power of in vitro disintegration testing can be improved using the modified disintegration test device. Furthermore, CFD has proven a powerful tool to examine the hydrodynamics and forces in the compendial as well as in the modified disintegration test device. rn

Gene dosage and stochastic effects determine the severity and direction of uniparental ribosomal RNA gene silencing (nucleolar dominance) in Arabidopsis allopolyploids

Nucleolar dominance is an epigenetic phenomenon in which one parental set of ribosomal RNA (rRNA) genes is silenced in an interspecific hybrid. In natural Arabidopsis suecica, an allotetraploid (amphidiploid) hybrid of Arabidopsis thaliana and Cardaminopsis arenosa, the A. thaliana rRNA genes are repressed. Interestingly, A. thaliana rRNA gene silencing is variable in synthetic Arabidopsis suecica F1 hybrids. Two generations are needed for A. thaliana rRNA genes to be silenced in all lines, revealing a species-biased direction but stochastic onset to nucleolar dominance. Backcrossing synthetic A. suecica to tetraploid A. thaliana yielded progeny with active A. thaliana rRNA genes and, in some cases, silenced C. arenosa rRNA genes, showing that the direction of dominance can be switched. The hypothesis that naturally dominant rRNA genes have a superior binding affinity for a limiting transcription factor is inconsistent with dominance switching. Inactivation of a species-specific transcription factor is argued against by showing that A. thaliana and C. arenosa rRNA genes can be expressed transiently in the other species. Transfected A. thaliana genes are also active in A. suecica protoplasts in which chromosomal A. thaliana genes are repressed. Collectively, these data suggest that nucleolar dominance is a chromosomal phenomenon that results in coordinate or cooperative silencing of rRNA genes.

Molecular investigations into vaginal immunization with HIV gp41 antigenic construct H4A in a quick release solid dosage form

A robust vaginal immune response is considered essential for an effective prophylactic vaccine that prevents transmission of HIV and other sexually acquired diseases. Considerable attention has recently focused on the potential of vaginally administered vaccines as a means to induce such local immunity. However, the potential for vaccination at this site remains in doubt as the vaginal mucosa is generally considered to have low immune inductive potential. In the current study, we explored for the first time the use of a quick release, freeze-dried, solid dosage system for practical vaginal administration of a protein antigen. These solid dosage forms overcome the common problem associated with leakage and poor retention of vaginally administered antigen solutions. Mice were immunized vaginally with H4A, an HIV gp41 envelope based recombinant protein, using quick release, freeze-dried solid rods, and the immune responses compared to a control group immunized via subcutaneous H4A injection. Vaginally immunized mice failed to elicit robust immune responses. Our detailed investigations, involving cytokine analysis, the stability of H4A in mouse cervicovaginal lavage, and elucidation of the state of H4A protein in the immediate-release dosage form, revealed that antigen instability in vaginal fluid, the state of the antigen in the dosage form, and the cytokine profile induced are all likely to have contributed to the observed lack of immunogenicity. These are important factors affecting vaginal immunization and provide a rational basis for explaining the typically poor and variable elicitation of immunity at this site, despite the presence of immune responsive cells within the vaginal mucosae. In future mucosal vaccine studies, a more explicit focus on antigen stability in the dosage form and the immune potential of available antigen-responsive cells is recommended.

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Currently tacrolimus is the mainstay of immunosuppression for most children undergoing liver transplantation (LT). • The clinical use of this agent, however, is complicated by its various adverse effects (mainly nephrotoxicity), its narrow therapeutic-index and considerable pharmacokinetic variability. • The low and variable oral bioavailability of tacrolimus is thought to result from the action of the multidrug efflux-pump P-glycoprotein, encoded by the ABCB1 gene. WHAT THIS STUDY ADDS • A significant association between ABCB1 genetic polymorphisms and tacrolimus-associated nephrotoxicity in paediatric patients following LT is reported for the first time. Genotyping such polymorphisms may have the potential to individualize better initial tacrolimus therapy and enhance drug safety. • The long-term effect of ABCB1 polymorphisms on tacrolimus trough concentrations were investigated up to 5 years post-transplantation. A significant effect of intestinal P-glycoprotein genotypes on tacrolimus pharmacokinetics was found at 3 and 4 years post-transplantation suggesting that the effect is maintained long term. AIMS - The aim of this study was to investigate the influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation. METHODS - Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular filtration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes. RESULTS - The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (≥30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls, P= 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%, P= 0.057). Carriers of the G2677->T variant allele also had a significant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P= 0.031). Haplotype analysis showed a significant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P= 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were significantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation. CONCLUSIONS - These findings suggest that ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the first year post-transplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety.

Effect of Combination between CaCl2 Dosage and Electric Stimulation Period on Meat Quality Duck Adult

Research entitled “The effect of combination between CaCl2 dosage and length of electric stimulation on adult meat quality duck quality”. The aim was to know the effect of combination between CaCl2 and length of electric stimulation on quality. It was conducted at Technology of Animal Production Laboratory in Animal Science Faculty, Jenderal Soedirman University on June 2nd up to August 30rd 2002. Materials used in this research were 27 Tegal duck adult. Experimental design with Completely Randomized Design (CRD) with factorial 3 x 3 was performed in this research. The first factor was CaCl2 was dosage (a1=50cc; a2=100cc; and a3=150cc) and the second factor was length of electric stimulation period (b1=10 sec; b2=20 sec; and b3=30 sec). Each experiment was repeated three times, and variable of this research were pH, tenderness, WHC and CL. The result of research shows that CaCl2 dosage (50, 100, and 150 cc); length of electric stimulation and their interaction were gave no significant effect (P>0,05) on pH, tenderness, WHC and CL in adult duck meat. Conclusion of this research was CaCl2 dosage, electric stimulation period and their interaction gave the same effect on pH, tenderness, WHC and CL adult duck meat. (Animal Production 5(1): 25-34 (2003) Key word: Tenderness, WHC and CL, Duck, Meat, Electrical, Calsium Chlorida