A novel treatment planning methodology for high dose 166Ho-DOTMP therapy in patients with multiple myeloma

Bone marrow ablation, i.e., the complete sterilization of the active bone marrow, followed by bone marrow transplantation (BMT) is a comment treatment of hematological malignancies. The use of targeted bone-seeking radiopharmaceuticals to selectively deliver radiation to the adjacent bone marrow cavities while sparing normal tissues is a promising technique. Current radiopharmaceutical treatment planning methods do not properly compensate for the patient-specific variable distribution of radioactive material within the skeleton. To improve the current method of internal dosimetry, novel methods for measuring the radiopharmaceutical distribution within the skeleton were developed. 99mTc-MDP was proven as an adequate surrogate for measuring 166Ho-DOTMP skeletal uptake and biodistribution, allowing these measures to be obtained faster, safer, and with higher spatial resolution. This translates directly into better measurements of the radiation dose distribution within the bone marrow. The resulting bone marrow dose-volume histograms allow prediction of the patient disease response where conventional organ scale dosimetry failed. They indicate that complete remission is only achieved when greater than 90% of the bone marrow receives at least 30 Gy. ^ Comprehensive treatment planning requires combining target and non-target organ dosimetry. Organs in the urinary tract were of special concern. The kidney dose is primarily dependent upon the mean transit time of 166 Ho-DOTMP through the kidney. Deconvolution analysis of renograms predicted a mean transit time of 2.6 minutes for 166Ho-DOTMP. The radiation dose to the urinary bladder wall is dependent upon numerous factors including patient hydration and void schedule. For beta-emitting isotopes such as 166Ho, reduction of the bladder wall dose is best accomplished through good patient hydration and ensuring a partially full bladder at the time of injection. Encouraging the patient to void frequently, or catheterizing the patient without irrigation, will not significantly reduce the bladder wall dose. ^ The results from this work will produce the most advanced treatment planning methodology for bone marrow ablation therapy using radioisotopes currently available. Treatments can be tailored specifically for each patient, including the addition of concomitant total body irradiation for patients with unfavorable dose distributions, to deliver a desired patient disease response, while minimizing the dose or toxicity to non-target organs. ^

The effect of thyroxine and triiodothyronine on fatigue, depression, and memory in a hypothyroid population

Background. This study was planned at a time when important questions were being raised about the adequacy of using one hormone to treat hypothyroidism instead of two. Specifically, this trial aimed to replicate prior findings which suggested that substituting 12.5 μg of liothyronine for 50 μg of levothyroxine might improve mood, cognition, and physical symptoms. Additionally, this trial aimed to extend findings to fatigue. ^ Methods. A randomized, double-blind, two-period, crossover design was used. Hypothyroid patients stabilized on levothyroxine were invited to participate. Thirty subjects were recruited and randomized. Sequence one received their standard levothyroxine dose in one capsule and placebo in another during the first six weeks. Sequence two received their usual levothyroxine dose minus 50 μg in one capsule and 10 μg of liothyronine in another. At the end of the first six week period, subjects were crossed over. T tests were used to assess carry-over and treatment effects. ^ Results. Twenty-seven subjects completed the trial. The majority of completers had an autoimmune etiology. Mean baseline levothyroxine dose was 121 μg/d (±26.0). Subjects reported small increases in fatigue as measured by the Piper Fatigue Scale (0.9, p = 0.09) and in symptoms of depression measured by the Beck Depression Inventory-II (2.3, p = 0.16) as well as the General Health Questionnaire-30 (4.7, p = 0.14) while treated with substitution treatment. However, none of these differences was statistically significant. Measures of working memory were essentially unchanged between treatments. Thyroid stimulating hormone was about twice as high during substitution treatment (p = 0.16). Free thyroxine index was reduced by 0.7 (p < 0.001), and total serum thyroxine was reduced by 3.0 (p < 0.001) while serum triiodothyronine was increased by 20.5 (p < 0.001) on substitution treatment. ^ Conclusions. Substituting an equivalent amount of liothyronine for a portion of levothyroxine in patients with hypothyroidism does not decrease fatigue, symptoms of depression, or improve working memory. However, due to changes in serum hormone levels and small increments in fatigue and depression symptoms on substitution treatment, a question was raised about the role of T3 in the serum. ^

Prevalence and risk factors for polyomavirus reactivation in solid-organ transplantation

Background. Polyomavirus reactivation is common in solid-organ transplant recipients who are given immunosuppressive medications as standard treatment of care. Previous studies have shown that polyomavirus infection can lead to allograft failure in as many as 45% of the affected patients. Hypothesis. Ubiquitous polyomaviruses when reactivated by post-transplant immunosuppressive medications may lead to impaired renal function and possibly lower survival prospects. Study Overview. Secondary analysis of data was conducted on a prospective longitudinal study of subjects who were at least 18 years of age and were recipients of liver and/or kidney transplant at Mayo Clinic Scottsdale, Arizona. Methods. DNA extractions of blinded urine and blood specimens of transplant patients collected at Mayo Clinic during routine transplant patient visits were performed at Baylor College of Medicine using Qiagen kits. Virologic assays included testing DNA samples for specific polyomavirus sequences using QPCR technology. De-identified demographic and clinical patient data were merged with laboratory data and statistical analysis was performed using Stata10. Results. 76 patients enrolled in the study were followed for 3.9 years post transplantation. The prevalence of BK virus and JC virus urinary excretion was 30% and 28%. Significant association was observed between JC virus excretion and kidney as the transplanted organ (P = 0.039, Pearson Chi-square test). The median urinary JCV viral loads were two logs higher than those of BKV. Patients that excreted both BKV and JCV appeared to have the worst renal function with a mean creatinine clearance value of 71.6 millimeters per minute. A survival disadvantage was observed for dual shedders of BKV and JCV, log-rank statistics, p = 0.09; 2/5 dual-shedders expired during the study period. Liver transplant and male sex were determined to be potential risk factors for JC virus activation in renal and liver transplant recipients. All patients tested negative for SV40 and no association was observed between polyomavirus excretion and type of immunosuppressive medication (tacrolimus, mycophenolate mofetil, cyclosporine and sirolimus). Conclusions. Polyomavirus reactivation was common after solid-organ transplantation and may be associated with impaired renal function. Male sex and JCV infection may be potential risk factors for viral reactivation; findings should be confirmed in larger studies.^

GENETIC ANALYSIS OF THE HIPPO PATHWAY IN MOUSE LIVER

Cancer therapy and tumor treatment remain unsolved puzzles. Genetic screening for tumor suppressor genes in Drosophila revealed the Hippo-signaling pathway as a kinase cascade consisting of five core components. Disrupting the pathway by deleting the main component genes breaks the balance of cell proliferation and apoptosis and results in epithelial tissue tumorigenesis. The pathway is therefore believed to be a tumor suppressor pathway. However, a corresponding role in mammals is yet to be determined. Our lab began to investigate the tumor suppression function of the potent mammalian Hippo pathway by putting floxed alleles into the mouse genome flanking the functional-domain-expressing exons in each component (Mst1, Mst2, Sav1, Lats1 and Lats2). These mice were then crossed with different cre-mouse lines to generate conditional knockout mice. Results indicate a ubiquitous tumor suppression function of these components, predominantly in the liver. A further liver specific analysis of the deletion mutation of these components, as well as the Yap/Taz double deletion mutation, reveals essential roles of the Hippo pathway in regulating hepatic quiescence and embryonic liver development. One of the key cellular mechanisms for the Hippo pathway’s involvement in these liver biological events is likely its cell cycle regulation function. Our work will help to develop potential therapeutic approaches for liver cancer.

Cellular Uptake of Neutrohpil Elastase Links Inflammation to Adaptive Immunity

Many tumors arise from sites of inflammation providing evidence that innate immunity is a critical component in the development and progression of cancer. Neutrophils are primary mediators of the innate immune response. Upon activation, an important function of neutrophils is release of an assortment of proteins from their granules including the serine protease neutrophil elastase (NE). The effect of NE on cancer has been attributed primarily to its ability to degrade the extracellular matrix thereby promoting invasion and metastasis. Recently, it was shown that NE could be taken up by lung cancer cells leading to degradation of insulin receptor substrate-1 thereby promoting hyperactivity of the phosphatidylinositol-3 kinase (PI3K) pathway and tumor cell proliferation. To our knowledge, nobody has investigated uptake of NE by other tumor types. In addition, NE has broad substrate specificity suggesting that uptake of NE by tumor cells could impact processes regulating tumorigenensis other than activation of the PI3K pathway. Neutrophil elastase has been identified in breast cancer specimens where high levels of NE have prognostic significance. These studies have assessed NE levels in whole tumor lysates. Because the major source of NE is from activated neutrophils, we hypothesized that breast cancer cells do not have endogenous NE but may take up NE released by tumor associated neutrophils in the tumor microenvironment and that this could provide a link between the innate immune response to tumors and specific adaptive immune responses. In this thesis, we show that breast cancer cells lack endogenous NE expression and that they are able to take up NE resulting in increased generation of low molecular weight cyclin E (CCNE) and enhanced susceptibility to lysis by CCNE-specific cytotoxic T lymphocytes. We also show that after taking up NE and proteinase 3 (PR3), a second primary granule protease with significant homology to NE, breast cancer cells cross-present the NE- and PR3-derived peptide PR1 rendering them susceptible to PR1-targeted therapies. Taken together, our data support a role for NE uptake in modulating adaptive immune responses against breast cancer.

Exploring the Impact of Decreased AMPK Pathway Activity on Brain Injury Outcome

Each year, 150 million people sustain a Traumatic Brain Injury (TBI). TBI results in life-long cognitive impairments for many survivors. One observed pathological alteration following TBI are changes in glucose metabolism. Altered glucose uptake occurs in the periphery as well as in the nervous system, with an acute increase in glucose uptake, followed by a prolonged metabolic suppression. Chronic, persistent suppression of brain glucose uptake occurs in TBI patients experiencing memory loss. Abberant post-injury activation of energy-sensing signaling cascades could result in perturbed cellular metabolism. AMP-activated kinase (AMPK) is a kinase that senses low ATP levels, and promotes efficient cell energy usage. AMPK promotes energy production through increasing glucose uptake via glucose transporter 4 (GLUT4). When AMPK is activated, it phosphorylates Akt Substrate of 160 kDa (AS160), a Rab GTPase activating protein that controls Glut4 translocation. Additionally, AMPK negatively regulates energy-consumption by inhibiting protein synthesis via the mechanistic Target of Rapamycin (mTOR) pathway. Given that metabolic suppression has been observed post-injury, we hypothesized that activity of the AMPK pathway is transiently decreased. As AMPK activation increases energy efficiency of the cell, we proposed that increasing AMPK activity to combat the post-injury energy crisis would improve cognitive outcome. Additionally, we expected that inhibiting AMPK targets would be detrimental. We first investigated the role of an existing state of hyperglycemia on TBI outcome, as hyperglycemia correlates with increased mortality and decreased cognitive outcome in clinical studies. Inducing hyperglycemia had no effect on outcome; however, we discovered that AMPK and AS160 phosphorylation were altered post-injury. We conducted vii work to characterize this period of AMPK suppression and found that AMPK phosphorylation was significantly decreased in the hippocampus and cortex between 24 hours and 3 days post-injury, and phosphorylation of its downstream targets was consistently altered. Based on this period of observed decreased AMPK activity, we administered an AMPK activator post-injury, and this improved cognitive outcome. Finally, to examine whether AMPK-regulated target Glut4 is involved in post-injury glucose metabolism, we applied an inhibitor and found this treatment impaired post-injury cognitive function. This work is significant, as AMPK activation may represent a new TBI therapeutic target.

Evaluation of memory B cells among perinatally HIV infected children from Houston Texas

Background: HIV associated B cell exhaustion is a notable characteristic of HIV viremic adults. However, it is not known if such alterations are present in perinatal HIV infected children, whose viral dynamics differs from those seen in adults. In the present study we perform an analysis of B cells subsets and measure antigen-specific memory B cells (MBC) in a pediatric HIV infected cohort. ^ Methods: Peripheral mononuclear cells (PBMC) of perinatal HIV infected individuals are characterized into naïve (CD21hi/CD27−), classic (CD27+), tissue like (CD21lo/CD27 −) and activated MBC (CD27+CD21− ) by FACS. A memory ELISPOT assay is used to detect antibody secreting cells. We measure total IgG and antibodies specific for influenza, HBV, mumps, measles, rubella and VZV. Memory was expressed as spot forming cells (SPC) /million of PBMC. Wilcoxon rank-sum was used to compare unpaired groups and linear regression analysis was used to determine predictors of B cell dysfunction ^ Results: 41 HIV perinatal infected children are included (51.2% females and 65.9% Black). Age at study is median (range) 8.78 years (4.39-11.57). At the time of testing they have a CD4% of 30.9 (23.2-39.4), a viral load (VL) of 1.95 log10 copies/ml (1.68-3.29) and a cumulative VL of 3.4 log10 copy × days (2.7-4.0). Ninety two percent of the children are on cARV for > 6 months. Overall, HIV+ children compared with controls have a significant lower number of IgG and antigen specific SFC. In addition, they have a lower proportion of classical MBC 12.9 (8.09-19.85) vs 29.4 (18.7-39.05); 0.01, but a significant higher proportion of tissue like memory MBC 6.01 (2.79-12.7) vs 0.99 (0.87-1.38); 0.003, compared with controls. Patients are parsed on VL (<400 and ≥ 400 copies/ml) with the objective to evaluate the effect of VL on B cell status. Patients with a VL ≥ 400 copies/ml have a significantly lower IgG, HBV, measles, rubella and VZV SPC compared with those with a VL < 400 copies/ml. There are no significant differences in B cell subpopulations between the groups. A moderate negative correlation was observed between the time of cARV initiation and the frequency of IgG memory B cells, suggesting that early initiation of cARV appears to lead to a better functionality of the IgG memory B cells (P=0.05). A statistically significant positive correlation was observed between the total number of IgG memory cells and the number of antigen-specific memory B cells/SPCs. Suggesting that the progressive recovery of the IgG memory B cell pull goes along with a progressive increase in the number of antigen-specific SPCs. ^ Conclusion: A pediatric cohort in overall good status with respect to HIV infection and on ART has defects in B cell function and numbers (reduced total and antigen specific MBC and increased tissue like and reduced classical MBC).^

Classification of cellular malignancy associated changes in cervical cancer

Cervical cancer is the leading cause of death and disease from malignant neoplasms among women in developing countries. Even though the Pap smear has significantly decreased the number of deaths from cervical cancer in the past years, it has its limitations. Researchers have developed an automated screening machine which can potentially detect abnormal cases that are overlooked by conventional screening. The goal of quantitative cytology is to classify the patient's tissue sample based on quantitative measurements of the individual cells. It is also much cheaper and potentially can take less time. One of the major challenges of collecting cells with a cytobrush is the possibility of not sampling any existing dysplastic cells on the cervix. Being able to correctly classify patients who have disease without the presence of dysplastic cells could improve the accuracy of quantitative cytology algorithms. Subtle morphologic changes in normal-appearing tissues adjacent to or distant from malignant tumors have been shown to exist, but a comparison of various statistical methods, including many recent advances in the statistical learning field, has not previously been done. The objective of this thesis is to use different classification methods applied to quantitative cytology data for the detection of malignancy associated changes (MACs). In this thesis, Elastic Net is the best algorithm. When we applied the Elastic Net algorithm to the test set, we combined the training set and validation set as "training" set and used 5-fold cross validation to choose the parameter for Elastic Net. It has a sensitivity of 47% at 80% specificity, an AUC 0.52, and a partial AUC 0.10 (95% CI 0.09-0.11).^

Dissection of antitumor activity by lymphokine -activated killer cells: Role of FcR+ precursors and obligatory role of tumor necrosis factor-$\alpha$ in antibody -dependent cellular cytotoxicity

Human peripheral blood lymphocytes (PBL) cultured for varying lengths of time in IL-2 are able to mediate antibody independent cellular cytotoxicity (AICC) as well as antibody dependent cellular cytotoxicity (ADCC) against a wide range of tumor targets. The objective of our study is to determine the cytotoxic potential of the subset of LAK cells involved in ADCC, the tumor recognition mechanism in ADCC, the kinetics of ADCC mediated by PBL cultured under various conditions and the role of TNF-$\alpha$ in the development and maturation of ADCC effectors in the LAK population.^ The model system in this study for ADCC used a monoclonal antibody 14G2a (IgG2a), that recognizes the GD2 epitope on human melanoma cell line, SK-Mel-1. The target recognition mechanism operative in AICC (traditionally known as lymphokine activated killing or LAK) is an acquired property of these IL-2 activated cells which confers on them the unique ability to distinguish between tumor and normal cells. This recognition probably involves the presence of a trypsin sensitive N-linked glycoprotein epitope on tumor cells. Proteolytic treatment of the tumor cells with trypsin renders them resistant to AICC by PBL cultured in IL-2. However, ADCC is unaffected. This ADCC, mediated by the relatively small population of cells that are positive for the Fc receptor for IgG (FcR), is an indication that this subset of "LAK" cells does not require the trypsin sensitive epitope on tumor cells to mediate killing. Enriching PBL for FcR+ cells markedly enhanced both AICC and ADCC and also reduced the IL-2 requirement of these cells.^ The stoichiometry of Fc receptor (FcR) expression on the cytotoxic effectors does not correlate with ADCC lytic activity. Although FcRs are necessary to mediate ADCC, other factors, appear to regulate the magnitude of cytolytic activity. In order to investigate these putative factors, the kinetics of ADCC development was studied under various conditions (in IL-2 (10u/ml) and 100u/ml), in IL-2(10u/ml) + TNF$\alpha$ (500u/ml) and in TNF-$\alpha$ (500u/ml) alone). Addition of exogenous TNF-$\alpha$ into the four hour cytotoxicity assay did not increase ADCC, nor did anti-TNF antibodies result in inhibition. On the other hand, addition of anti-TNF antibodies to PBL and IL-2 for 24 hours, resulted in a marked inhibition of the ADCC, suggesting that endogenous TNF-$\alpha$ is obligatory for the maturation and differentiation of ADCC effectors. ^

Fulminant hepatic and multiple organ failure following acute viral tonsillitis: a case report.

BACKGROUND Pyogenic tonsillitis may often be observed in the general Western population. In severe cases, it may require antibiotic treatment or even hospitalization and often a prompt clinical response will be noted. Here we present an unusual case of progressive multiple organ failure including fulminant liver failure following acute tonsillitis initially mistaken for "classic" pyogenic (that is bacterial) tonsillitis. CASE PRESENTATION A 68-year-old previously healthy white man was referred with suspicion of pyogenic angina. After tonsillectomy, he developed acute liver failure and consecutive multiple organ failure including acute hemodynamic, pulmonary and dialysis-dependent renal failure. Immunohistopathological analysis of his tonsils and liver as well as serum polymerase chain reaction analyses revealed herpes simplex virus-2 to be the causative pathogen. Treatment included high-dose acyclovir and multiorgan supportive intensive care therapy. His final outcome was favorable. CONCLUSIONS Fulminant herpes simplex virus-2-induced multiple organ failure is rarely observed in the Western hemisphere and should be considered a potential diagnosis in patients with tonsillitis and multiple organ failure including acute liver failure. From a clinical perspective, it seems important to note that fulminant herpes simplex virus-2 infection may masquerade as "routine" bacterial severe sepsis/septic shock. This persevering condition should be diagnosed early and treated goal-oriented in order to gain control of this life-threatening condition.

Proyectando entre ruinas : lógicas de intervención continua en la arquitectura contemporánea

Los cambios percibidos hacia finales del siglo XX y a principios del nuevo milenio, nos ha mostrado que la crisis cultural de la que somos participes refleja también una crisis de los modelos universales. Nuestra situación contemporánea, parece indicar que ya no es posible formular un sistema estético para atribuirle una vigencia universal e intemporal más allá de su estricta eficacia puntual. La referencia organizada, delimitada, invariable y específica que ofrecía cualquier emplazamiento, en tanto preexistencia, reflejaba una jerarquía del sistema formal basado en lo extensivo: la medida, las normas, el movimiento, el tiempo, la modulación, los códigos y las reglas. Sin embargo, actualmente, algunos aspectos que permanecían latentes sobre lo construido, emergen bajo connotaciones intensivas, transgrediendo la simple manifestación visual y expresiva, para centrase en las propiedades del comportamiento de la materia y la energía como determinantes de un proceso de adaptación en el entorno. A lo largo del todo el siglo XX, el desarrollo de la relación del proyecto sobre lo construido ha sido abordado, casi en exclusiva, entre acciones de preservación o intervención. Ambas perspectivas, manifestaban esfuerzos por articular un pensamiento que diera una consistencia teórica, como soporte para la producción de la acción aditiva. No obstante, en las últimas décadas de finales de siglo, la teoría arquitectónica terminó por incluir pensamientos de otros campos que parecen contaminar la visión sesgada que nos refería lo construido. Todo este entramado conceptual previo, aglomeraba valiosos intentos por dar contenido a una teoría que pudiese ser entendida desde una sola posición argumental. Es así, que en 1979 Ignasi Solá-Morales integró todas las imprecisiones que referían una actuación sobre una arquitectura existente, bajo el termino de “intervención”, el cual fue argumentado en dos sentidos: El primero referido a cualquier tipo de actuación que se puede hacer en un edificio, desde la defensa, preservación, conservación, reutilización, y demás acciones. Se trata de un ámbito donde permanece latente el sentido de intensidad, como factor común de entendimiento de una misma acción. En segundo lugar, más restringido, la idea de intervención se erige como el acto crítico a las ideas anteriores. Ambos representan en definitiva, formas de interpretación de un nuevo discurso. “Una intervención, es tanto como intentar que el edificio vuelva a decir algo o lo diga en una determinada dirección”. A mediados de 1985, motivado por la corriente de revisión historiográfica y la preocupación del deterioro de los centros históricos que recorría toda Europa, Solá-Morales se propone reflexionar sobre “la relación” entre una intervención de nueva arquitectura y la arquitectura previamente existente. Relación condicionada estrictamente bajo consideraciones lingüísticas, a su entender, en sintonía con toda la producción arquitectónica de todo el siglo XX. Del Contraste a la Analogía, resumirá las transformaciones en la concepción discursiva de la intervención arquitectónica, como un fenómeno cambiante en función de los valores culturales, pero a su vez, mostrando una clara tendencia dialógica entres dos categorías formales: El Contraste, enfatizando las posibilidades de la novedad y la diferencia; y por otro lado la emergente Analogía, como una nueva sensibilidad de interpretación del edificio antiguo, donde la semejanza y la diversidad se manifiestan simultáneamente. El aporte reflexivo de los escritos de Solá-Morales podría ser definitivo, si en las últimas décadas antes del fin de siglo, no se hubiesen percibido ciertos cambios sobre la continuidad de la expresión lingüística que fomentaba la arquitectura, hacia una especie de hipertrofia figurativa. Entre muchos argumentos: La disolución de la consistencia compositiva y el estilo unitario, la incorporación volumétrica del proyecto como dispositivo reactivo, y el cambio de visión desde lo retrospectivo hacia lo prospectivo que sugiere la nueva conservación. En este contexto de desintegración, el proyecto, en tanto incorporación o añadido sobre un edificio construido, deja de ser considerado como un apéndice volumétrico subordinado por la reglas compositivas y formales de lo antiguo, para ser considerado como un organismo de orden reactivo, que produce en el soporte existente una alteración en su conformación estructural y sistémica. La extensión, antes espacial, se considera ahora una extensión sensorial y morfológica con la implementación de la tecnología y la hiper-información, pero a su vez, marcados por una fuerte tendencia de optimización energética en su rol operativo, ante el surgimiento del factor ecológico en la producción contemporánea. En una sociedad, como la nuestra, que se está modernizando intensamente, es difícil compartir una adecuada sintonía con las formas del pasado. Desde 1790, fecha de la primera convención francesa para la conservación de monumentos, la escala de lo que se pretende preservar es cada vez más ambiciosa, tanto es así, que al día de hoy el repertorio de lo que se conserva incluye prácticamente todas las tipologías del entorno construido. Para Koolhaas, el intervalo entre el objeto y el momento en el cual se decide su conservación se ha reducido, desde dos milenios en 1882 a unas décadas hoy en día. En breve este lapso desaparecerá, demostrando un cambio radical desde lo retrospectivo hacia lo prospectivo, es decir, que dentro de poco habrá que decidir que es lo que se conserva antes de construir. Solá-Morales, en su momento, distinguió la relación entre lo nuevo y lo antiguo, entre el contraste y la analogía. Hoy casi tres décadas después, el objetivo consiste en evaluar si el modelo de intervención arquitectónica sobre lo construido se ha mantenido desde entonces o si han aparecido nuevas formas de posicionamiento del proyecto sobre lo construido. Nuestro trabajo pretende demostrar el cambio de enfoque proyectual con la preexistencia y que éste tiene estrecha relación con la incorporación de nuevos conceptos, técnicas, herramientas y necesidades que imprimen el contexto cultural, producido por el cambio de siglo. Esta suposición nos orienta a establecer un paralelismo arquitectónico entre los modos de relación en que se manifiesta lo nuevo, entre una posición comúnmente asumida (Tópica), genérica y ortodoxa, fundamentada en lo visual y expresivo de las últimas décadas del siglo XX, y una realidad emergente (Heterotópica), extraordinaria y heterodoxa que estimula lo inmaterial y que parece emerger con creciente intensidad en el siglo XXI. Si a lo largo de todo el siglo XX, el proyecto de intervención arquitectónico, se debatía entre la continuidad y discontinuidad de las categorías formales marcadas por la expresión del edificio preexistente, la nueva intervención contemporánea, como dispositivo reactivo en el paisaje y en el territorio, demanda una absoluta continuidad, ya no visual, expresiva, ni funcional, sino una continuidad fisiológica de adaptación y cambio con la propia dinámica del territorio, bajo nuevas reglas de juego y desplegando planes y estrategias operativas (proyectivas) desde su propia lógica y contingencia. El objeto de esta investigación es determinar los nuevos modos de continuidad y las posibles lógicas de producción que se manifiestan dentro de la Intervención Arquitectónica, intentando superar lo aparente de su relación física y visual, como resultado de la incorporación del factor operativo desplegado por el nuevo dispositivo contemporáneo. Creemos que es acertado mantener la senda connotativa que marca la denominación intervención arquitectónica, por aglutinar conceptos y acercamientos teóricos previos que han ido evolucionando en el tiempo. Si bien el término adolece de mayor alcance operativo desde su formulación, una cualidad que infieren nuestras lógicas contemporáneas, podría ser la reformulación y consolidación de un concepto de intervención más idóneo con nuestros tiempos, anteponiendo un procedimiento lógico desde su propia necesidad y contingencia. Finalmente, nuestro planteamiento inicial aspira a constituir un nueva forma de reflexión que nos permita comprender las complejas implicaciones que infiere la nueva arquitectura sobre la preexistencia, motivada por las incorporación de factores externos al simple juicio formal y expresivo preponderante a finales del siglo XX. Del mismo modo, nuestro camino propuesto, como alternativa, permite proyectar posibles sendas de prospección, al considerar lo preexistente como un ámbito que abarca la totalidad del territorio con dinámicas emergentes de cambio, y con ellas, sus lógicas de intervención.Abstract The perceived changes towards the end of the XXth century and at the beginning of the new milennium have shown us that the cultural crisis in which we participate also reflects a crisis of the universal models. The difference between our contemporary situation and the typical situations of modern orthodoxy and post-modernistic fragmentation, seems to indicate that it is no longer possible to formulate a valid esthetic system, to assign a universal and eternal validity to it beyond its strictly punctual effectiveness; which is even subject to questioning because of the continuous transformations that take place in time and in the sensibility of the subject itself every time it takes over the place. The organised reference that any location offered, limited, invariable and specific, while pre-existing, reflected a hierarchy of the formal system based on the applicable: measure, standards, movement, time, modulation, codes and rules. Authors like Marshall Mc Luhan, Paul Virilio, or Marc Augé anticipated a reality where the conventional system already did not seem to respond to the new architectural requests in which information, speed, disappearance and the virtual had blurred the traditional limits of place; pre-existence did no longer possess a specific delimitation and, on the contrary, they expect to reach a global scale. Currently, some aspects that stayed latent relating to the constructed, surface from intensive connotations, transgressing the simple visual and expressive manifestation in order to focus on the traits of the behaviour of material and energy as determinants of a process of adaptation to the surroundings. Throughout the entire Century, the development of the relation of the project relating to the constructed has been addressed, almost exclusively, in preservational or interventianal actions. Both perspectives showed efforts in order to express a thought that would give a theoretical consistency as a base for the production of the additive action. Nevertheless, the last decades of the Century, architectural theory ended up including thoughts from other fields that seem to contaminate the biased vision 15 which the constructed related us. Ecology, planning, philosophy, global economy, etc, suggest new approaches to the construction of the contemporary city; but this time with a determined idea of change and continuous transformation, that enriches the panorama of thought and architectural practice, at the same time, according to some, it puts disciplinary specification at risk, given that there is no architecture without destruction, the constructed organism requires mutation in order to adjust to the change of shape. All of this previous conceptual framework gathered valuable intents to give importance to a theory that could be understood solely from an argumental position. Thusly, in 1979 Ignasi Solá-Morales integrated all of the imprecisions that referred to an action in existing architecture under the term of “Intervention���, which was explained in two ways: The first referring to any type of intervention that can be carried out in a building, regarding protection, conservation, reuse, etc. It is about a scope where the meaning of intensity stays latent as a common factor of the understanding of a single action. Secondly, more limitedly, the idea of intervention is established as the critical act to the other previous ideas such as restauration, conservation, reuse, etc. Both ultimately represent ways of interpretation of a new speech. “An intervention, is as much as trying to make the building say something again or that it be said in a certain direction���. Mid 1985, motivated by the current of historiographical revision and the concerns regarding the deterioration of historical centres that traversed Europe, Solá-Morales decides to reflect on “the relationship” between an intervention of the new architecture and the previously existing architecture. A relationship determined strictly by linguistic considerations, to his understanding, in harmony with all of the architectural production of the XXth century. From Contrast to Analogy would summarise transformations in the discursive perception of architectural intervention, as a changing phenomenon depending on cultural values, but at the same time, showing a clear dialogical tendency between two formal categories: Contrast, emphasising the possibilities of novelty and difference; and on the other hand the emerging Analogy, as a new awareness of interpretation of the ancient building, where the similarity and diversity are manifested simultaneously. For Solá-Morales the analogical procedure is not based on the visible simultaneity of formal orders, but on associations that the subject establishes throughout time. Through analogy it is tried to overcome the simple visual relationship with the antique, to focus on its spacial, physical and geographical nature. If the analogical attempt guides an opening towards a new continuity; it still persists in the connection of dimensional, typological and figurative factors, subordinate to the formal hierarchy of the preexisting subjects. 16 The reflexive contribution of Solá-Morales’ works could be final, if in the last decades before the end of the century there had not been certain changes regarding linguistic expression, encouraged by architecture, towards a kind of figurative hypertrophy, amongst many arguments we are in this case interested in three moments: The dissolution of the compositional consistency and the united style, the volumetric incorporation of the project as a reactive mechanism, and the change of the vision from retrospective towards prospective that the new conservation suggests. The recurrence to the history of architecture and its recognisable forms, as a way of perpetuating memory and establishing a reference, dissolved any instinct of compositive unity and style, provoking permanent relationships to tend to disappear. The composition and coherence lead to suppose a type of discontinuity of isolated objects in which only possible relationships could appear; no longer as an order of certain formal and compositive rules, but as a special way of setting elements in a specific work. The new globalised field required new forms of consistency between the project and the pre-existent subject, motivated amongst others by the higher pace of market evolution, increase of consumer tax and the level of information and competence between different locations; aspects which finally made stylistic consistence inefficient. In this context of disintegration, the project, in incorporation as well as added to a constructed building, stops being considered as a volumetric appendix subordinate to compositive and formal rules of old, to be considered as an organism of reactive order, that causes a change in the structural and systematic configuration of the existing foundation. The extension, previsouly spatial, is now considered a sensorial and morphological extension, with the implementation of technology and hyper-information, but at the same time, marked by a strong tendency of energetic optimization in its operational role, facing the emergence of the ecological factor in contemporary production. The technological world turns into a new nature, a nature that should be analysed from ecological terms; in other words, as an event of transition in the continuous redistribution of energy. In this area, effectiveness is not only determined by the capacity of adaptation to changing conditions, but also by its transforming capacity “expressly” in order to change an environment. In a society, like ours, that is modernising intensively, it is difficult to share an adecuate agreement with the forms of the past. From 1790, the date of the first French convention for the conservation of monuments, the scale of what is expexted to be preserved is more and more ambitious, so much so that nowadays the repertoire of that what is conserved includes practically all typologies of the constructed surroundings. For Koolhaas, the ínterval between the object and the moment when its conservation is decided has been reduced, from two 17 milennia in 1882 to a few decades nowadays. Shortly this lapse will disappear, showing a radical change of retrospective towards prospective, that is to say, that soon it will be necessary to decide what to conserve before constructing. The shapes of cities are the result of the continuous incorporation of architecture, and perhaps that only through architecture the response to the universe can be understood, the continuity of what has already been constructed. Our work is understood also within that system, modifying the field of action and leaving the road ready for the next movement of those that will follow after us. Continuity does not mean conservatism, continuity means being conscient of the transitory value of our answers to specific needs, accepting the change that we have received. That what has been constructed to remain and last, should cause future interventions to be integrated in it. It is necessary to accept continuity as a rule. Solá-Morales, in his time, distinguished between the relationship with new and old, between contrast and analogy. Today, almost three decades later, the objective consists of evaluating whether the model of architectural intervention in the constructed has been maintained since then or if new ways of positioning the project regarding the constructed have appeared. Our work claims to show the change of the approach of projects with pre-existing subjects and that this has got a close relation to the incorporation of new concepts, techniques, tools and necessities that impress the cultural context, caused by the change of centuries. This assumption guides us to establish a parallelism between the forms of connection where that what is new is manifested between a commonly assumed (topical), generic and orthodox position, based on that what is visual and expressive in the last decades of the XXth century, and an emerging (heterotopical), extraordinary and heterodox reality that stimulates the immaterial and that seems to emerge with growing intensity in the XXIst century. If throughout the XXth century the project of architectural intervention was considered from the continuity and discontinuity of formal categories, marked by the expression of the pre-existing building, the new contemporary intervention, as a reactive device in the landscape and territory, demands an absolute continuity. No longer a visual, expressive or functional one but a morphological continuity of adaptation and change with its own territorial dynamics, under new game rules and unfolding new operative (projective) strategies from its own logic and contingency. 18 The aim of this research is to determine new forms of continuity and the possible logic of production that are expressed in the Architectural Intervention, trying to overcome the obviousness of its physical and visual relationship, at the beginning of this new century, as a result of the incorporation of the operative factor that the new architectural device unfolds. We think it is correct to maintain the connotative path that marks the name architectural intervention by bringing previous concepts and theorical approaches that have been evolving through time together. If the name suffers from a wider operational range because of its formulation, a quality that our contemporary logic provokes, the reformulation and consolidation of an interventional concept could be more suitable for our times, giving preference to a logical method from its own necessity and contingency. It seems that now time shapes the topics, it is no longer about materialising a certain time but about expressing the changes that its new temporality generates. Finally, our initial approach aspires to form a new way of reflection that permits us to understand the complex implications that the new architecture submits the pre-existing subject to, motivated by the incorporation of factors external to simple formal and expressive judgement, prevailing at the end of the XXth century. In the same way, our set road, as an alternative, permits the contemplation of possible research paths, considering that what is pre-existing as an area that spans the whole territory with emerging changing dynamics and, with them, their interventional logics.