Cyclosporine population pharmacokinetics in pediatric renal transplant recipients

Cyclosporine is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. To improve cyclosporine dose individualization in children, we used population pharmacokinetic modeling to study the effects of developmental, clinical, and genetic factors on cyclosporine pharmacokinetics in altogether 176 subjects (age range: 0.36–20.2 years) before and up to 16 years after renal transplantation. Pre-transplantation test doses of cyclosporine were given intravenously (3 mg/kg) and orally (10 mg/kg), on separate occasions, followed by blood sampling for 24 hours (n=175). After transplantation, in a total of 137 patients, cyclosporine concentration was quantified at trough, two hours post-dose, or with dose-interval curves. One-hundred-four of the studied patients were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. Pharmacokinetic modeling was performed with the nonlinear mixed effects modeling computer program, NONMEM. A 3-compartment population pharmacokinetic model with first order absorption without lag-time was used to describe the data. The most important covariate affecting systemic clearance and distribution volume was allometrically scaled body weight i.e. body weight**3/4 for clearance and absolute body weight for volume of distribution. The clearance adjusted by absolute body weight declined with age and pre-pubertal children (< 8 years) had an approximately 25% higher clearance/body weight (L/h/kg) than did older children. Adjustment of clearance for allometric body weight removed its relationship to age after the first year of life. This finding is consistent with a gradual reduction in relative liver size towards adult values, and a relatively constant CYP3A content in the liver from about 6–12 months of age to adulthood. The other significant covariates affecting cyclosporine clearance and volume of distribution were hematocrit, plasma cholesterol, and serum creatinine, explaining up to 20%–30% of inter-individual differences before transplantation. After transplantation, their predictive role was smaller, as the variations in hematocrit, plasma cholesterol, and serum creatinine were also smaller. Before transplantation, no clinical or demographic covariates were found to affect oral bioavailability, and no systematic age-related changes in oral bioavailability were observed. After transplantation, older children receiving cyclosporine twice daily as the gelatine capsule microemulsion formulation had an about 1.25–1.3 times higher bioavailability than did the younger children receiving the liquid microemulsion formulation thrice daily. Moreover, cyclosporine oral bioavailability increased over 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1–1.5 years. The largest cyclosporine doses were administered in the first 3–6 months after transplantation, and thereafter the single doses of cyclosporine were often smaller than 3 mg/kg. Thus, the results suggest that cyclosporine displays dose-dependent, saturable pre-systemic metabolism even at low single doses, whereas complete saturation of CYP3A4 and MDR1 (P-glycoprotein) renders cyclosporine pharmacokinetics dose-linear at higher doses. No significant associations were found between genetic polymorphisms and cyclosporine pharmacokinetics before transplantation in the whole population for which genetic data was available (n=104). However, in children older than eight years (n=22), heterozygous and homozygous carriers of the ABCB1 c.2677T or c.1236T alleles had an about 1.3 times or 1.6 times higher oral bioavailability, respectively, than did non-carriers. After transplantation, none of the ABCB1 SNPs or any other SNPs were found to be associated with cyclosporine clearance or oral bioavailability in the whole population, in the patients older than eight years, or in the patients younger than eight years. In the whole population, in those patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055C haplotype, however, the bioavailability of cyclosporine was about one tenth lower, per allele, than in non-carriers. This effect was significant also in a subgroup of patients older than eight years. Furthermore, in patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055T haplotype, the bioavailability was almost one fifth higher, per allele, than in non-carriers. It may be possible to improve individualization of cyclosporine dosing in children by accounting for the effects of developmental factors (body weight, liver size), time after transplantation, and cyclosporine dosing frequency/formulation. Further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

Detection of recently discovered human polyomaviruses in a longitudinal kidney transplant cohort

A large number of human polyomaviruses have been discovered in the last 7 years. However, little is known about the clinical impact on vulnerable immunosuppressed patient populations. Blood, urine, and respiratory swabs collected from a prospective, longitudinal adult kidney transplant cohort (n = 167) generally pre-operatively, at day 4, months 1, 3, and 6 posttransplant, and at BK viremic episodes within the first year were screened for 12 human polyomaviruses using real-time polymerase chain reaction. Newly discovered polyomaviruses were most commonly detected in the respiratory tract, with persistent shedding seen for up to 6 months posttransplant. Merkel cell polyomavirus was the most common detection, but was not associated with clinical symptoms or subsequent development of skin cancer or other skin abnormalities. In contrast, KI polyomavirus was associated with respiratory disease in a subset of patients. Human polyomavirus 9, Malawi polyomavirus, and human polyomavirus 12 were not detected in any patient samples.

Memory Meanders : Place, Home and Commemoration in an Ex-Rhodesian Diaspora Community

Memory Meanders is an ethnographic analysis of a postcolonial migrant community, white former Rhodesians, who have emigrated from Zimbabwe to South Africa after Zimbabwe s independence in 1980. An estimated 100 000 whites left the country during the first years of independence. Majority of these emigrants settled in South Africa. In recent years President Mugabe s land redistribution program has inflicted forced expulsions and violence against white farmers and black farm workers, and instigated a new wave of emigration. Concerning the study of Southern Africa, my research is therefore very topical. In recent years there has been a growing concern to study postcolonialism as it unfolds in the lived realities of actual postcolonies. A rising interest has also been cast on colonial cultures and white colonials within complex power relationships. My research offers insight to these discussions by investigating the ways in which the colonial past affects and effects in the present activities and ideas of former colonials. The study also takes part in discussing fundamental questions concerning how diaspora communities socially construct their place in the world in relation to the place left behind, to their current places of dwelling and to the community in dispersal. In spite of Rhodesia s incontestable ending, it is held close by social practices; by thoughts and talks, by material displays, and by webs of meaningful relationships. Such social memory practices, I suggest, are fundamental to how the community understands itself. The vantage points from which I examine how the ex-Rhodesians reminisce about Rhodesia concern ideas and practices related to place, home and commemoration. I first focus on the processes of symbolic investment that go into understanding place and landscape in Rhodesia and ask how the once dwelled-in places, iconic landscapes and experiences within places are reminisced about in diaspora. Secondly, I examine how home both as a mundanely organized sphere of everyday lives and as an idea of belonging is culturally configured, and analyze how and if homes travel in diaspora. In the final ethnographic section I focus on commemorative practices. I first analyze how food and culturally specific festive occasions of commensality are connected to social and sensual memory, considering the unique ways in which food acts as a mnemonic trigger in a diaspora community. The second example concerns the celebration of a centenary of Rhodesia in 1990. Through this case I describe how the mnemonic power of commemoration rests on the fact that culturally meaningful experiences are bodily re-enacted. I show how habitual memory connected to performance is one example of how memory gets passed-on in non-textual ways.

Two ex situ fungal technologies to treat contaminated soil

Wood-degrading fungi are able to degrade a large range of recalcitrant pollutants which resemble the lignin biopolymer. This ability is attributed to the production of lignin-modifying enzymes, which are extracellular and non-specific. Despite the potential of fungi in bioremediation, there is still an understanding gap in terms of the technology. In this thesis, the feasibility of two ex situ fungal bioremediation methods to treat contaminated soil was evaluated. Treatment of polycyclic aromatic hydrocarbons (PAHs)-contaminated marsh soil was studied in a stirred slurry-phase reactor. Due to the salt content in marsh soil, fungi were screened for their halotolerance, and the white-rot fungi Lentinus tigrinus, Irpex lacteus and Bjerkandera adusta were selected for further studies. These fungi degraded 40 - 60% of a PAH mixture (phenanthrene, fluoranthene, pyrene and chrysene) in a slurry-phase reactor (100 ml) during 30 days of incubation. Thereafter, B. adusta was selected to scale-up and optimize the process in a 5 L reactor. Maximum degradation of dibenzothiophene (93%), fluoranthene (82%), pyrene (81%) and chrysene (83%) was achieved with the free mycelium inoculum of the highest initial biomass (2.2 g/l). In autoclaved soil, MnP was the most important enzyme involved in PAH degradation. In non-sterile soil, endogenous soil microbes together with B. adusta also degraded the PAHs extensively, suggesting a synergic action between soil microbes and the fungus. A fungal solid-phase cultivation method to pretreat contaminated sawmill soil with high organic matter content was developed to enhance the effectiveness of the subsequent soil combustion. In a preliminary screening of 146 fungal strains, 28 out of 52 fungi, which extensively colonized non-sterile contaminated soil, were litter-decomposing fungi. The 18 strains further selected were characterized by their production of lignin-modifying and hydrolytic enzymes, of which MnP and endo-1,4-β-glucanase were the main enzymes during cultivation on Scots pine (Pinus sylvestris) bark. Of the six fungi selected for further tests, Gymnopilus luteofolius, Phanerochaete velutina, and Stropharia rugosoannulata were the most active soil organic matter degraders. The results showed that a six-month pretreatment of sawmill soil would result in a 3.5 - 9.5% loss of organic matter, depending on the fungus applied. The pretreatment process was scaled-up for a 0.56 m3 reactor, in which perforated plastic tubes filled with S. rugosoannulata growing on pine bark were introduced into the soil. The fungal pretreatment resulted in a soil mass loss of 30.5 kg, which represents 10% of the original soil mass (308 kg). Despite the fact that Scots pine bark contains several antimicrobial compounds, it was a suitable substrate for fungal growth and promoter of the production of oxidative enzymes, as well as an excellent and cheap natural carrier of fungal mycelium. This thesis successfully developed two novel fungal ex situ bioremediation technologies and introduce new insights for their further full-scale application. Ex situ slurry-phase fungal reactors might be applied in cases when the soil has a high water content or when the contaminant bioavailability is low; for example, in wastewater treatment plants to remove pharmaceutical residues. Fungal solid-phase bioremediation is a promising remediation technology to ex situ or in situ treat contaminated soil.

Effect of Nanostructuring and Ex situ Amorphous Carbon Coverage on the Lithium Storage and Insertion Kinetics in Anatase Titania

Implications of nanostructuring and conductive carbon interface on lithium insertion/removal capacity and insertion kinetics innanoparticles of anatase polymorph of titania is discussed here.Sol-gel synthesized nanoparticles of titania (particle size similar to 6 nm) were hydrothermally coated ex situ with a thin layer of amorphous carbon (layer thickness: 2-5 nm) and calcined at a temperature much higher than the sol-gel synthesis temperature. The carbon-titania composite particles (resulting size similar to 10 nm) displayed immensely superior cyclability and rate capability (higher current rates similar to 4 g(-1)) compared to unmodified calcined anatase titania. The conductive carbon interface around titania nanocrystal enhances the electronic conductivity and inhibits crystallite growth during electrochemical insertion/removal thus preventing detrimental kinetic effects observed in case of unmodified anatase titania. The carbon coating of the nanoparticles also stabilized the titania crystallographic structure via reduction in the accessibility of lithium ions to the trapping sites. This resulted in a decrease in the irreversible capacity observed in the case of nanoparticles without any carbon coating.

Cox-2, tenascin, CRP, and ingraft chimerism in a model of post-transplant obliterative bronchiolitis

Chronic rejection in the form of obliterative bronchiolitis (OB) is the major cause of death 5 years after lung transplantation. The exact mechanism of OB remains unclear. This study focused on the role of cyclo-oxygenase (COX) -2, tenascin, and C-reactive protein (CRP) expression, and the occurrence of ingraft chimerism (= cells from two genetically distinct individuals in a same individual) in post-transplant OB development. In our porcine model, OB developed invariably in allografts, while autografts stayed patent. The histological changes were similar to those seen in human OB. In order to delay or prevent obliteration, animals were medicated according to certain protocol. In the beginning of the bronchial allograft reaction, COX-2 induction occurred in airway epithelial cells prior to luminal obliteration. COX-2 expression in macrophages and fibroblasts paralleled the onset of inflammation and fibroblast proliferation. This study demonstrated for the first time, that COX-2 expression is associated with the early stage of post- transplant obliterative airway disease. Tenascin expression in the respiratory epithelium appeared to be predictive of histologic features observed in human OB, and influx of immune cells. Expression in the bronchial wall and in the early obliterative lesions coincided with the onset of onset of fibroblast and inflammatory cell proliferation in the early stage of OB and was predictive of further influx of inflammatory and immune cells. CRP expression in the bronchial wall coincided with the remodelling process. High grade of bronchial wall CRP staining intensity predicted inflammation, accelerated fibroproliferation, and luminal obliteration, which are all features of OB. In the early obliterative plaque, majority of cells expressed CRP, but in mature, collagen-rich plaque, expression declined. Local CRP expression might be a response to inflammation and it might promote the development of OB. Early appearance of chimeric (= recipient-derived) cells in the graft airway epithelium predicted epithelial cell injury and obliteration of the bronchial lumen, which both are features of OB. Chimeric cells appeared in the airway epithelium after repair following transplantation-induced ischemic injury. Ingraft chimerism might be a mechanism to repair alloimmune-mediated tissue injury and to protect allografts from rejection after transplantation. The results of this study indicate, that COX-2, tenascin, CRP, and ingraft chimerism have a role in OB development. These findings increase the understanding of the mechanisms of OB, which may be beneficial in further development of diagnostic options.

Radical Annulation Strategy to Chiral Pupukeanones: Total Synthesis of (+)-10-ex&l(- Naphthyl)pupukean-9-onea nd (+)-lO-exo-l(- Naphthyl)-5-epipupukean-9-ones1

Intramolecular alkylation reaction of the bromoenone 12, obtained from S-carvone in three steps, furnished the bicyclo[2.2.2]octenone 13. Contrary to the anticipated radical annulation reaction, the bicyclic bromides 14 and 15, obtained from the enone 13, generated exclusively the cyclopropane product 18 via a 3-exo-trig radical cyclization on reaction with nBu3SnH and AIBN, even in the presence of a large excess of a radicophile. On the other hand, bromoenone 24, synthesized from R-carvone via S-naphthylcarvone 21, underwent radical annulation reaction in the presence of radicophiles to furnish the isotwistanes 25-28 in a regio- and stereospecific manner. Hydrogenation of the olefin 34, obtained from the diketone 27 via a regiospecific Wittig reaction, furnished the naphthyl-5-epipupukean-9-one 33, whereas stereoselective hydrogenation of the enone 36, prepared from the keto ester 25 via a Grignard reaction and dehydration sequence, generated the naphthylpupukeanone 32.

In vitro micropropagation of scented geranium (Pelargonium graveolens L. Her. ex Ait: syn P. roseum willd)

The objective of this study was to develop a rapid and efficient system for regenerating shoots from nodal explants of scented geranium (Pelargonium graveolens L. Her. ex Ait: syn. P. roseum willd). Single node stem explants were inoculated in MS media containing different combinations of 6-benzylaminopurine (BAP) with indole-3-acetic acid (IAA) or naphthalene acetic acid (NAA) (0, 0.5, 1.0, 2.0 mg/l) in a 4x4 factorial experiment. Multiple shoots were induced in media supplemented with BAP and IAA, Maximum number of shoots (56 per explant) were observed in the medium containing BAP and IAA at 1 mg/l each, 30 days after inoculation. Micro shoots were subcultured once in every four weeks. Adventitious shoots were induced from in vitro grown leaves and petioles. Several regenerated shoots were rooted on MS half-strength medium supplemented with 0.5 mg/l indole-3-butyric acid (IBA) and the plantlets were hardened in the growth chamber. This micropropagation system could be used for rapid and large-scale production of scented geranium.

Non-viral ex vivo hepatic gene transfer by in situ lipofection of liver and intraperitoneal transplantation of hepatocytes

Perfusion of liver with plasmid DNA-lipofectin complexes via the portal vein results in efficient accumulation of the vector in hepatocytes. Such hepatocytes, when administered intraperitoneally into a hepatectomized rat, repopulate the liver and express the transgene efficiently. This procedure obviates the need for large-scale hepatocyte culture for ex vivo gene transfer. Further, intraperitoneal transplantation is a simple and cost-effective strategy of introducing genetically modified hepatocytes into liver. Thus, in situ lipofection of liver and intraperitoneal transfer of hepatocytes can be developed into a novel method of non-viral ex vivo gene transfer technique that has applications in the treatment of metabolic disorders of liver and hepatic gene therapy.

Ex Situ X-ray Diffraction, X-ray Absorption Near Edge Structure, Electron Spin Resonance, and Transmission Electron Microscopy Study of the Hydrothermal Crystallization of Vanadium Oxide Nanotubes: An Insight into the Mechanism of Formation

The nucleation and growth of vanadium oxide nanotubes (VOx-NT) have been followed by a combination of numerous ex situ techniques. long the hydrothermal process. Intermediate solid phases extracted at different reaction times have been characterized by powder X-ray diffraction, scanning and transmission electron microscopy, electron spin resonance, and V-K edge :X-ray absorption near-edge structure spectroscopy. The supernatant vanadate solutions extracted during the hydrothermal treatment have been studied by liquid V-51 NMR and flame. spectroscopy. For short durations of the hydrothermal synthesis, the initial V2O5-surfactant intercalate. is progressively transformed into VOx-NT whose crystallization starts to be detected after a hydrothermal treatment of 24 h. Upon heating from 24 h to 7 days, VOx-NT are obtained in larger amount and with an improved crystallinity. The detection of soluble amines and cyclic metavanadate V4O12](4-) in the supernatant solution along the hydrothermal process suggests that VOx-NT result from a dissolution precipitation mechanism. Metavanadate species V4O12](4-) could behave as molecular precursors in the polymerization reactions leading to VOx-NT.

Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity

Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine.

Evaluación ex-ante del mejoramiento de los sistemas de producción ganadero de doble propósito a través de inversiones propuestas por los mismos ganaderos en la zona de Muy Muy, Matagalpa

El presente trabajo se realizó con el objetivo de evaluar exante la factibilidad técnica y financiera de inversiones propuestas por los mismos ganaderos en la zona de Muy muy, Matagalpa. El estudio se llevó a cabo en dos fases: Una fase preliminar de diagnóstico, en la que se determinó, la disponibilidad y uso actual de los recursos en las fincas, así como las propuestas planteadas por los productores, comprendiéndose en una sub-fase de ésta etapa preliminar un diagnóstico de las características generales de los canales de comercialización y precios de los productos agropecuarios generados por la actividad ganadera de la zona. La segunda fase comprendió el procesamiento y computación de la información. La información relativa a los recursos, se procesó para cada una de las fincas y en base a ello, se estimaron los diferentes parámetros técnicos y elementos fuentes de ingresos y egresos, elaborándose también las diferentes proyecciones de hato por finca, así mismo de disponibilidades de pastos, mano de obra e insumos. Para efectos de analizar tanto el uso eficiente de las pasturas como de los resultados financieros, las fincas se agruparon en cuatro dominios de recomendación en función de sus áreas. En los aspectos técnicos se determinó que la actividad de las fincas es la ganadería ya que en promedio, el 82.33% de las áreas totales por finca se destina a esta actividad, ocupando los pastos mejorados en promedio el 67.44% y un promedio de 32.56% los pastos naturales. Con el proyecto el área ganadera se incrementa en un promedio de 2.46%, pasando a representar los pastos mejorados un promedio de 92.65% y el natural el 7.35%, reduciéndose éste último en un promedio de 25.21%. Las cargas animales encontradas fluctuaron en un rango de 18.6 U.A./mz. a 268.3 U.A./mz. siendo éste en cinco de las nueve fincas superiores a las disponibilidades que resultan por tanto negativas en un rango de -36.3 a -3.8 U.A., con el proyecto las cargas animales se incrementan a valores comprendidos entre 54.2 y 456.5 U.A., resultando sin embargo las disponibilidades positivas en seis de las nueve fincas para el año décimo del proyecto en un rango comprendido entre +2.5 a +16.2 U.A., a excepción de tres fincas en las cuales los déficit reflejan valores entre -2.6 y -43.1 U.A. En lo que se refiere a los niveles de eficiencia en el aprovechamiento de las pasturas, las fincas La Palma y El Castaño resultaron ser las más eficientes, manteniendo sus niveles de aprovechamiento próximo al nivel óptimo de manera en periodo de años más prolongados. El número de cabezas de ganado encontrado por finca, fluctuó entre 20 y 290, como efecto de los proyectos el hato total tendría un incremento promedio anual de 7.5%, es decir 10.58 cabezas por año. La natalidad encontrada en promedio fue mortalidad de terneros 7.04%, descarte de vacas de 50.8%, 10.72% y relación vaca-toro 19:1. Para el año décimo de los los promedios de estos coeficientes alcanzan: 53.1%, mortalidad de terneros 4.46% y descarte de 19.55%. proyectos natalidad vientres. La edad de incorporación de vaquillas resultó entre 2.5 a 3 años. En la composición racial se encontró que predomina un alto encastamiento con razas europeas. La relación producción total por área en el año base resultó en promedio de 42.53 galones de leche/manzana y 52.68 kilogramos de carne manzana y para el ultimo año de los proyectos alcanzan en promedio los 67.56 galones de leche/manzana y 96.14 kilogramos de carne/manzana. La producción promedio de leche por época correspondió a 4 litros/vaca/día en el verano y 6 litros/vaca/día en invierno. Partiendo del promedio de éstos valores, el incremento anual de ésta producción con el proyecto alcanzarla en promedio el 7.3%. En el aspecto de ingresos en promedio la producción de leche aporta en el año base el 43.44%, la producción de carne 34.09%, la venta de otras categorías 12.5% y la agricultura el 9.95% de los ingresos totales. con el proyecto se presenta una recomposición en éstos, de manera que el aporte de la producción de leche alcanza el 46.99%, el de la carne 46.67% y la parte agrícola el 5.25%. En los gastos, en el año base en promedio, la mano de obra representa el mayor porcentaje con 54.63%, medios circulantes y servicios 37.94%, impuestos 7.4%, variando éstos para el año décimo a promedios de: 48.25%, 42.54% y 9.17% respectivamente, reflejándose un incremento en los gastos de medios circulantes y servicios en un promedio de 4.6% y 1.77% los gastos en impuestos. Los costos de producción por litro de leche en el año base, fluctuaron entre C$1.23 y C$1.61 y en el último año varian ligeramente a un rango entre C$0.87 y C$1.53. En el mercado de aspecto la leche de comercialización, el control del en el municipio está en posesión de los manteros, un segundo siendo la agente de Unión de Cooperativas de Boaco (UCASBO) importancia en la comercialización. En el caso de la carne, los mayores volúmenes de ganado comercializado es controlado por los comerciantes intermediarios, que en los años 1990 y 1992 extrajeron de la zona 6000 y 8000 cabezas respectivamente. En el fluctuaron aspecto de los precios, en el caso de la leche con la estacionalidad de la producción C$0.95 en invierno manteros) tipo A y UCASBO). el peso, con pesos y C$1.00 en el verano (al comercializar con y por calidad de la leche entregada C$1.375 leche tipo A y By C$1.12 para el tipo e (al comercializar con las El ganado en cambio, su precio está determinado por obteniéndose C$1,500.00 y C$1,600.00 por novillos de 380 y 420 kilogramos respectivamente. De las inversiones a realizarse, la adquisición de ganado representa el mayor porcentaje con un 49.67%, las instalaciones y equipos con un 29.02% y mejoramiento de pastizales con 21.31% del monto total propuesto equivalente a C$829,400.00, de los cuales el total solicitado representa el 76.68% equivalente a C$636,000.00. Para el análisis financiero, se utilizó el formato y metodología del Banco Mundial. Los resultados de rentabilidad de éste análisis al interés propuesto del 9% ocupan un rango entre 21.78 y 9.10%, relación inversión­ beneficio neto entre 2.2 y 1.07. Con el interés bancario del 12.5%, los resultados pasan a .ocupar valores de TIR entre 16.2% y 7.85% y la relación inversión-beneficio neto alcanza valores entre 1.93 y 0.98. Con la utilización de recursos propios los resultados son inferiores a los obtenidos con el 9% de interés en siete de las nueve fincas y superiores que los resultados logrados con el interés del 12.5%, siendo los valores extremos de las TIR encontradas de 18.42% y 10.19%. En el aspecto de sensibilidad, al incrementarse los gastos operativos en un 10%, el proyecto de la finca La Perla resulta ser el más sensible con el interés del 9%, alcanzando una TIR de 1.04% y un VAN negativo de C$-21,503.08. En la correlación inversión-rentabilidad, las inversiones en ganado ejercieron la mejor influencia, seguida de las inversiones en pastos, fundamentalmente cuando éstas van acompañadas de una alta tasa de parición. Los flujos de efectivos encontrados, resultaron con fuertes déficit a excepción de la finca San Felipe que presentó una situación menos desfavorable. Los déficit encontrado hacen que los proyectos de éstas fincas aún y cuando sean rentables, no sean factibles, al no tener disponibilidades de efectivo para el sostenimiento de las unidades familiares durante los primeros años de proyecto.