Immediate transmucosal implant placement in molar extraction sites: a 12-month prospective multicenter cohort study

AIM: To assess the clinical and radiographic outcomes of immediate transmucosal placement of implants into molar extraction sockets. STUDY DESIGN: Twelve-month multicenter prospective cohort study. MATERIAL AND METHODS: Following molar extraction, tapered implants with an endosseous diameter of 4.8 mm and a shoulder diameter of 6.5 mm were immediately placed into the sockets. Molars with evidence of acute periapical pathology were excluded. After implant placement and achievement of primary stability, flaps were repositioned and sutured allowing a non-submerged, transmucosal healing. Peri-implant marginal defects were treated according to the principles of guided bone regeneration (GBR) by means of deproteinized bovine bone mineral particles in conjunction with a bioresrobable collagen membrane. Standardized radiographs were obtained at baseline and 12 months thereafter. Changes in depth and width of the distance from the implant shoulder (IS) and from the alveolar crest (AC) to the bottom of the defect (BD) were assessed. RESULTS: Eighty-two patients (42 males and 40 females) were enrolled and followed for 12 months. They contributed with 82 tapered implants. Extraction sites displayed sufficient residual bone volume to allow primary stability of all implants. Sixty-four percent of the implants were placed in the areas of 36 and 46. GBR was used in conjunction with the placement of all implants. No post-surgical complications were observed. All implants healed uneventfully yielding a survival rate of 100% and healthy soft tissue conditions after 12 months. Radiographically, statistically significant changes (P<0.0001) in mesial and distal crestal bone levels were observed from baseline to the 12-month follow-up. CONCLUSIONS: The findings of this 12-month prospective cohort study showed that immediate transmucosal implant placement represented a predictable treatment option for the replacement of mandibular and maxillary molars lost due to reasons other than periodontitis including vertical root fractures, endodontic failures and caries.

Biomechanical comparison of different surface modifications for dental implants

Purpose: A satisfactory clinical outcome in dental implant treatment relies on primary stability for immediate load bearing. While the geometric design of an implant contributes to mechanical stability, the nature of the implant surface itself is also critically important. Biomechanical and microcomputerized tomographic evaluation of implant osseointegration was performed to compare alternative structural, chemical and biochemical, and/or pharmaceutical surface treatments applied to an identical established implant design. Materials and Methods: Dental implants with the same geometry but with 6 different surface treatments were tested in vivo in a sheep model (pelvis). Peri-implant bone density and removal torque were compared at 2, 4, and 8 weeks after implantation. Implant surfaces tested were: sandblasted and acid-etched titanium (Ti), sandblasted and etched zirconia, Ti coated with calcium phosphate (CaP), Ti modified via anodic plasma-chemical treatment (APC), bisphosphonate-coated Ti (Ti + Bisphos), and Ti coated with collagen containing chondroitin sulfate (CS). Results: All dental implants were well integrated at the time of sacrifice. There were no significant differences observed in peri-implant bone density between implant groups. After 8 weeks of healing, removal torque values for Ti, Ti + CaP, Ti + Bisphos, and Ti + collagen + CS were significantly higher than those for zirconia and Ti + APC. Conclusions: Whereas the sandblasted/acid-etched Ti implant can still be considered the reference standard surface for dental implants, functional surface modifications such as bisphosphonate or collagen coating seem to enhance early peri-implant bone formation and should be studied further.

Quantifying the influence of bone density and thickness on resonance frequency analysis: an in vitro study of biomechanical test materials

PURPOSE: Resonance frequency analysis (RFA) offers the opportunity to monitor the osseointegration of an implant in a simple, noninvasive way. A better comprehension of the relationship between RFA and parameters related to bone quality would therefore help clinicians improve diagnoses. In this study, a bone analog made from polyurethane foam was used to isolate the influences of bone density and cortical thickness in RFA. MATERIALS AND METHODS: Straumann standard implants were inserted in polyurethane foam blocks, and primary implant stability was measured with RFA. The blocks were composed of two superimposed layers with different densities. The top layer was dense to mimic cortical bone, whereas the bottom layer had a lower density to represent trabecular bone. Different densities for both layers and different thicknesses for the simulated cortical layer were tested, resulting in eight different block combinations. RFA was compared with two other mechanical evaluations of primary stability: removal torque and axial loading response. RESULTS: The primary stability measured with RFA did not correlate with the two other methods, but there was a significant correlation between removal torque and the axial loading response (P < .005). Statistical analysis revealed that each method was sensitive to different aspects of bone quality. RFA was the only method able to detect changes in both bone density and cortical thickness. However, changes in trabecular bone density were easier to distinguish with removal torque and axial loading than with RFA. CONCLUSIONS: This study shows that RFA, removal torque, and axial loading are sensitive to different aspects of the bone-implant interface. This explains the absence of correlation among the methods and proves that no standard procedure exists for the evaluation of primary stability.

Sinus floor elevation: comparison of the presurgical ridge height of different techniques - a retrospective analysis.

Purpose: Radiographic evaluation of the vertical presurgical ridge height (PRH) of implants, placed using the transcrestal or lateral window sinus floor elevation (SFE) technique in edentulous and partially dentate patients. The 5-year implant survival rate and the prosthetic restoration following the SFE procedure were also evaluated. Methods: Radiographs of 83 tapered implants placed in 53 patients were available for analysis. 31 implants were placed by the transcrestal and 52 were placed by the lateral window technique. In the lateral window technique 21 implants were placed simultaneously, 31 in a staged approach. The PRH, the implant survival rate after five years and the prosthetic restoration were evaluated with respect to the chosen SFE procedure. Results: The PRH was significantly higher for the transcrestal than both lateral window techniques, mean values: 8.0 ± 2.7 mm (transcrestal); 4.2 ± 2.6 mm (lateral simultaneous); 4.5 ± 2.8 mm (lateral staged). There was no significant difference of PRH between the edentulous and partially dentate patients. All loaded implants were stable, resulting in a 100% implant survival rate after 5 years. There was a small overproportion of single crown restorations in the transcrestal SFE technique group. Conclusion: This study confirms that the transcrestal technique is chosen, when a higher PRH is available. The choice of a simultaneous or staged lateral window approach is mainly dependent on the expected primary stability of the implant and not only on the PRH. SFE procedures are a safe and predictable treatment option to place implants in the vertical atrophic maxilla.

Análisis de micromovilidad en vástagos femorales mediante ensayo dinámico de oscilaciones libres

La artroplastia de cadera se considera uno de los mayores avances quirúrgicos de la Medicina. La aplicación de esta técnica de Traumatología se ha incrementado notablemente en los últimos anos, a causa principalmente del progresivo incremento de la esperanza de vida. En efecto, con la edad aumentan los problemas de artrosis y osteoporosis, enfermedades típicas de las articulaciones y de los huesos que requieren en muchos casos la sustitución protésica total o parcial de la articulación. El buen comportamiento funcional de una prótesis depende en gran medida de la estabilidad primaria, es decir, el correcto anclaje de la prótesis en el momento de su implantación. Las prótesis no cementadas basan su éxito a largo plazo en la osteointegración que tiene lugar entre el material protésico y el tejido óseo, y para lograrla es imprescindible conseguir unas buenas condiciones de estabilidad primaria. El aflojamiento aséptico es la principal causa de fallo de artroplastia total de cadera. Este es un fenómeno en el que, debido a complejas interacciones de factores mecánicos y biológicos, se producen movimientos relativos que comprometen la funcionalidad del implante. La minimización de los correspondientes danos depende en gran medida de la detección precoz del aflojamiento. Para lograr la detección temprana del aflojamiento aséptico del vástago femoral se han ensayado diferentes técnicas, tanto in vivo como in vitro: análisis numéricos y técnicas experimentales basadas en sensores de movimientos provocados por cargas transmitidas natural o artificialmente, tales como impactos o vibraciones de distintas frecuencias. Los montajes y procedimientos aplicados son heterogéneos y, en muchas ocasiones, complejos y costosos, no existiendo acuerdo sobre una técnica simple y eficaz de aplicación general. Asimismo, en la normativa vigente que regula las condiciones que debe cumplir una prótesis previamente a su comercialización, no hay ningún apartado referido específicamente a la evaluación de la bondad del diseño del vástago femoral con respecto a la estabilidad primaria. El objetivo de esta tesis es desarrollar una metodología para el análisis, in vitro, de la estabilidad de un vástago femoral implantado, a fin de poder evaluar las técnicas de implantación y los diferentes diseños de prótesis previamente a su oferta en el mercado. Además se plantea como requisito fundamental que el método desarrollado sea sencillo, reversible, repetible, no destructivo, con control riguroso de parámetros (condiciones de contorno de cargas y desplazamientos) y con un sistema de registro e interpretación de resultados rápido, fiable y asequible. Como paso previo, se ha realizado un análisis cualitativo del problema de contacto en la interfaz hueso-vástago aplicando una técnica optomecánica del campo continuo (fotoelasticidad). Para ello se han fabricado tres modelos en 2D del conjunto hueso-vástago, simulando tres tipos de contactos en la interfaz: contacto sin adherencia y con holgura, contacto sin adherencia y sin holgura, y contacto con adherencia y homogéneo. Aplicando la misma carga a cada modelo, y empleando la técnica de congelación de tensiones, se han visualizado los correspondientes estados tensionales, siendo estos más severos en el modelo de unión sin adherencia, como cabía esperar. En todo caso, los resultados son ilustrativos de la complejidad del problema de contacto y confirman la conveniencia y necesidad de la vía experimental para el estudio del problema. Seguidamente se ha planteado un ensayo dinámico de oscilaciones libres con instrumentación de sensores resistivos tipo galga extensométrica. Las muestras de ensayo han sido huesos fémur en todas sus posibles variantes: modelos simplificados, hueso sintético normalizado y hueso de cadáver, seco y fresco. Se ha diseñado un sistema de empotramiento del extremo distal de la muestra (fémur) con control riguroso de las condiciones de anclaje. La oscilación libre de la muestra se ha obtenido mediante la liberación instantánea de una carga estética determinada y aplicada previamente, bien con una maquina de ensayo o bien por gravedad. Cada muestra se ha instrumentado con galgas extensométricas convencionales cuya señal se ha registrado con un equipo dinámico comercial. Se ha aplicado un procedimiento de tratamiento de señal para acotar, filtrar y presentar las respuestas de los sensores en el dominio del tiempo y de la frecuencia. La interpretación de resultados es de tipo comparativo: se aplica el ensayo a una muestra de fémur Intacto que se toma de referencia, y a continuación se repite el ensayo sobre la misma muestra con una prótesis implantada; la comparación de resultados permite establecer conclusiones inmediatas sobre los efectos de la implantación de la prótesis. La implantación ha sido realizada por un cirujano traumatólogo utilizando las mismas técnicas e instrumental empleadas en el quirófano durante la práctica clínica real, y se ha trabajado con tres vástagos femorales comerciales. Con los resultados en el dominio del tiempo y de la frecuencia de las distintas aplicaciones se han establecido conclusiones sobre los siguientes aspectos: Viabilidad de los distintos tipos de muestras sintéticas: modelos simplificados y fémur sintético normalizado. Repetibilidad, linealidad y reversibilidad del ensayo. Congruencia de resultados con los valores teóricos deducidos de la teoría de oscilaciones libres de barras. Efectos de la implantación de tallos femorales en la amplitud de las oscilaciones, amortiguamiento y frecuencias de oscilación. Detección de armónicos asociados a la micromovilidad. La metodología se ha demostrado apta para ser incorporada a la normativa de prótesis, es de aplicación universal y abre vías para el análisis de la detección y caracterización de la micromovilidad de una prótesis frente a las cargas de servicio. ABSTRACT Total hip arthroplasty is considered as one of the greatest surgical advances in medicine. The application of this technique on Traumatology has increased significantly in recent years, mainly due to the progressive increase in life expectancy. In fact, advanced age increases osteoarthritis and osteoporosis problems, which are typical diseases of joints and bones, and in many cases require full or partial prosthetic replacement on the joint. Right functional behavior of prosthesis is highly dependent on the primary stability; this means it depends on the correct anchoring of the prosthesis at the time of implantation. Uncemented prosthesis base their long-term success on the quality of osseointegration that takes place between the prosthetic material and bone tissue, and to achieve this good primary stability conditions is mandatory. Aseptic loosening is the main cause of failure in total hip arthroplasty. This is a phenomenon in which relative movements occur, due to complex interactions of mechanical and biological factors, and these micromovements put the implant functionality at risk. To minimize possible damage, it greatly depends on the early detection of loosening. For this purpose, various techniques have been tested both in vivo and in vitro: numerical analysis and experimental techniques based on sensors for movements caused by naturally or artificially transmitted loads, such as impacts or vibrations at different frequencies. The assemblies and methods applied are heterogeneous and, in many cases, they are complex and expensive, with no agreement on the use of a simple and effective technique for general purposes. Likewise, in current regulations for governing the conditions to be fulfilled by the prosthesis before going to market, there is no specific section related to the evaluation of the femoral stem design in relation to primary stability. The aim of this thesis is to develop a in vitro methodology for analyzing the stability of an implanted femoral stem, in order to assess the implantation techniques and the different prosthesis designs prior to its offer in the market. We also propose as a fundamental requirement that the developed testing method should be simple, reversible, repeatable, non-destructive, with close monitoring of parameters (boundary conditions of loads and displacements) and with the availability of a register system to record and interpret results in a fast, reliable and affordable manner. As a preliminary step, we have performed a qualitative analysis of the contact problems in the bone-stem interface, through the application of a continuous field optomechanical technique (photoelasticity). For this proposal three 2D models of bone–stem set, has been built simulating three interface contact types: loosened an unbounded contact, unbounded and fixed contact, and bounded homogeneous contact. By means of applying the same load to each model, and using the stress freezing technique, it has displayed the corresponding stress states, being more severe as expected, in the unbounded union model. In any case, the results clearly show the complexity of the interface contact problem, and they confirm the need for experimental studies about this problem. Afterward a free oscillation dynamic test has been done using resistive strain gauge sensors. Test samples have been femur bones in all possible variants: simplified models, standardized synthetic bone, and dry and cool cadaveric bones. An embedding system at the distal end of the sample with strong control of the anchoring conditions has been designed. The free oscillation of the sample has been obtained by the instantaneous release of a static load, which was previously determined and applied to the sample through a testing machine or using the gravity force. Each sample was equipped with conventional strain gauges whose signal is registered with a marketed dynamic equipment. Then, it has applied a signal processing procedure to delimit, filter and present the time and frequency response signals from the sensors. Results are interpreted by comparing different trials: the test is applied to an intact femur sample which is taken as a reference, and then this test is repeated over the same sample with an implanted prosthesis. From comparison between results, immediate conclusions about the effects of the implantation of the prosthesis can be obtained. It must be said that the implementation has been made by an expert orthopedic surgeon using the same techniques and instruments as those used in clinical surgery. He has worked with three commercial femoral stems. From the results obtained in the time and frequency domains for the different applications the following conclusions have been established: Feasibility of the different types of synthetic samples: simplified models and standardized synthetic femur. Repeatability, linearity and reversibility of the testing method. Consistency of results with theoretical values deduced from the bars free oscillations theory. Effects of introduction of femoral stems in the amplitude, damping and frequencies of oscillations Detection of micromobility associated harmonics. This methodology has been proved suitable to be included in the standardization process of arthroplasty prosthesis, it is universally applicable and it allows establishing new methods for the analysis, detection and characterization of prosthesis micromobility due to functional loads.

Análise da correlação entre índices radiomorfométricos de densidade óssea, perfil de qualidade óssea em software de implante, quociente de estabilidade e torque de inserção em implantes

A qualidade óssea, bem como a estabilidade inicial dos implantes, está diretamente relacionada com o sucesso das reabilitações na implantodontia. O presente estudo teve como objetivo analisar a correlação entre índices radiomorfométricos de densidade óssea por meio de radiografias panorâmicas, perfil de qualidade óssea com o auxílio de Tomografia Computadorizada de Feixe Cônico (TCFC) com o uso do software de imagens OsiriX, Análise da Frequência de Ressonância (RFA) e Torque de Inserção do implante. Foram avaliados 160 implantes de 72 indivíduos, com média etária de 55,5 (±10,5) anos. Nas radiografias panorâmicas foram obtidos os índices IM, IPM e ICM, e nas tomografias computadorizadas de feixe cônico, os valores de pixels e a espessura da cortical da crista óssea alveolar, além da estabilidade primária por meio do torque de inserção e análise da frequência de ressonância. Os resultados foram analisados pelo coeficiente de correlação de Spearman, para p<= 0,01 foi obtido entre o torque de inserção e valores de pixels (0.330), o torque de inserção e a espessura da cortical da crista alveolar (0.339), o torque de inserção e o ISQ vestibulo-lingual (0.193), os valores de pixels e espessura da cortical da crista alveolar (0.377), as duas direções vestíbulo-lingual e mesio-distal do ISQ (0.674), o ISQ vestíbulo-lingual e a espessura da cortical da crista alveolar (0.270); os índices radiomorfométricos foram correlacionados entre eles e para p<= 0,05 foi obtido entre torque de inserção e ISQ mesio-distal (0.131), entre o ISQ vestibulo-lingual e os valores de pixels (0.156) e ISQ mesio-distal e IPMI esquerdo (0.149) e ISQ mesio-distal e IPMS esquerdo (0.145). Existe correlação entre a TCFC, o torque de inserção e a RFA na avaliação da qualidade óssea. É possível utilizar, pré-cirurgicamente, os exames de TCFC para avaliar a qualidade e quantidade óssea, tendo em vista as correlações obtidas neste estudo.

Efeito da geometria do implante dentário e do protocolo de fresagem óssea na estabilidade primária e na osseointegração inicial: estudo experimental em cães

CHAPTER 1 - This study histologically evaluated two implant designs: a classic thread design versus another specifically designed for healing chamber formation placed with two drilling protocols. Forty dental implants (4.1 mm diameter) with two different macrogeometries were inserted in the tibia of 10 Beagle dogs, and maximum insertion torque was recorded. Drilling techniques were: until 3.75 mm (regular-group); and until 4.0 mm diameter (overdrillinggroup) for both implant designs. At 2 and 4 weeks, samples were retrieved and processed for histomorphometric analysis. For torque and BIC (bone-to-implant contact) and BAFO (bone area fraction occupied), a general-linear model was employed including instrumentation technique and time in vivo as independent. The insertion torque recorded for each implant design and drilling group significantly decreased as a function of increasing drilling diameter for both implant designs (p<0.001). No significant differences were detected between implant designs for each drilling technique (p>0.18). A significant increase in BIC was observed from 2 to 4 weeks for both implants placed with the overdrilling technique (p<0.03) only, but not for those placed in the 3.75 mm drilling sites (p>0.32). Despite the differences between implant designs and drilling technique an intramembranous-like healing mode with newly formed woven bone prevailed. CHAPTER 2 - The objective of this preliminary histologic study was to determine whether the alteration of drilling protocols (oversized, intermediate, undersized drilling) present different biologic responses at early healing periods of 2 weeks in vivo in a beagle dog model. Ten beagle dogs were acquired and subjected to surgeries in the tibia 2 weeks before euthanasia. During surgery, 3 implants, 4 mm in diameter by 10 mm in length, were placed in bone sites drilled to 3.5 mm, 3.75 mm, and 4.0 mm in final diameter. The insertion and removal torque was recorded for all samples. Statistical significance was set to 95% level of confidence and the number of dogs was considered as the statistical unit for all comparisons. For the torque and BIC and BAFO, a general linear model was employed including instrumentation technique and time in vivo as independent. Overall, the insertion torque increased as a function of drilling diameter from 4.0 mm, to 3.75 mm, to 3.5 mm, with a significant difference in torque levels between all groups (p<0.001). Statistical assessment of BIC and BAFO showed significantly higher values for the 3.75 mm (recommended) drilling group was observed relative to the other two groups (p<0.001). Different drilling dimensions resulted in variations in insertion torque values (primary stability) and different pattern of healing and interfacial remodeling was observed for the different groups. CHAPTER 3 - The present study evaluated the effect of different drilling dimensions (undersized, regular, and oversized) in the insertion and removal torques of dental implants in a beagle dog model. Six beagle dogs were acquired and subjected to bilateral surgeries in the radii 1 and 3 weeks before euthanasia. During surgery, 3 implants, 4 mm in diameter by 10 mm in length, were placed in bone sites drilled to 3.2 mm, 3.5 mm, and 3.8 mm in final diameter. The insertion and removal torque was recorded for all samples. Statistical analysis was performed by paired t tests for repeated measures and by t tests assuming unequal variances (all at the 95% level of significance). Overall, the insertion torque and removal torque levels obtained were inversely proportional to the drilling dimension, with a significant difference detected between the 3.2 mm and 3.5 mm relative to the 3.8 mm groups (P < 0.03). Although insertion torque–removal torque paired observations was statis- tically maintained for the 3.5 mm and 3.8 mm groups, a significant decrease in removal torque values relative to insertion torque levels was observed for the 3.2 mm group. A different pattern of healing and interfacial remodeling was observed for the different groups. Different drilling dimensions resulted in variations in insertion torque values (primary stability) and stability maintenance over the first weeks of bone healing.

Interaction Between Polar Components and the Degree of Unsaturation of Fatty Acids on the Oxidative Stability of Emulsions

Minor components (polar components) and the degree of unsaturation of the fatty acids are the main factors responsible for the oxidative stability of bulk oils and emulsions. The isolated effects of these two factors and their interaction were evaluated in oil-in-water emulsions stored at 32 A degrees C. Samples of coconut, olive, soybean, linseed and fish oils, both full and stripped of their polar components, were used to prepare the emulsions (1% w/w). The maximum concentration of hydroperoxide (LOOH(max)) and the rate of formation of hydroperoxides (mu mol L(-1) h(-1)) were used to measure the primary products. Hexanal, propanal and malondialdehyde were used to determine the secondary products of the oxidized emulsions containing polyunsaturated fatty acids. LOOH(max) varied from 0.16 to 12.75 mmol/kg among the samples. The interaction between the polar components and the degree of unsaturation of the fatty acids was significant (p < 0.001) when the hydroperoxides were evaluated. In general, the degree of unsaturation (beta(1)) and the absence of polar components (beta(2)), respectively, represented 30 and 20% of the contribution to increase the mean oxidation, with the interaction (beta(12)) contribution being more sensitive to the rate of formation of hydroperoxides (16%) than to the LOOH(max) (5%). The significance of this interaction suggests that both strategies present synergism and should be applied to improve the oxidative stability of food emulsions.

Influence of Phase Inversion on the Formation and Stability of One-Step Multiple Emulsions

A novel method of preparation of water-in-oil-in-micelle-containing water (W/O/W(m)) Multiple emulsions using the one-step emulsification method is reported. These multiple emulsions were normal (not temporary) and stable over a 60 day test period. Previously, reported multiple emulsion by the one-step method were abnormal systems that formed at the inversion point of simple emulsion (where there is an incompatibility in the Ostwald and Bancroft theories, and typically these are O/W/O systems). Pseudoternary phase diagrams and bidimensional process-composition (phase inversion) maps were constructed to assist in process and composition optimization. The surfactants used were PEG40 hydrogenated castor oil and sorbitan oleate, and mineral and vegetables oils were investigated. Physicochemical characterization studies showed experimentally, for the First time, the significance of the ultralow surface tension point oil multiple emulsion formation by one-step via phase inversion processes. Although the significance of ultralow surface tension has been speculated previously, to the best of our knowledge, this is the first experimental confirmation. The multiple emulsion system reported here was dependent not only upon the emulsification temperature, but also upon the component ratios, therefore both the emulsion phase inversion and the phase inversion temperature were considered to fully explain their formation. Accordingly, it is hypothesized that the formation of these normal multiple emulsions is not a result of a temporary incompatibility (at the inversion point) during simple emulsion preparation, as previously reported. Rather, these normal W/O/W(m) emulsions are a result of the simultaneous occurrence of catastrophic and transitional phase inversion processes. The formation of the primary emulsions (W/O) is in accordance with the Ostwald theory and the formation of the multiple emulsions (W/O/W(m)) is in agreement with the Bancroft theory.

Isoproterenol induces primary loss of dystrophin in rat hearts: correlation with myocardial injury

The mechanism of isoproterenol-induced myocardial damage is unknown, but a mismatch of oxygen supply vs. demand following coronary hypotension and myocardial hyperactivity is the best explanation for the complex morphological alterations observed. Severe alterations in the structural integrity of the sarcolemma of cardiomyocytes have been demonstrated to be caused by isoproterenol. Taking into account that the sarcolemmal integrity is stabilized by the dystrophin-glycoprotein complex (DGC) that connects actin and laminin in contractile machinery and extracellular matrix and by integrins, this study tests the hypothesis that isoproterenol affects sarcolemmal stability through changes in the DGC and integrins. We found different sensitivity of the DGC and integrin to isoproterenol subcutaneous administration. Immunofluorescent staining revealed that dystrophin is the most sensitive among the structures connecting the actin in the cardiomyocyte cytoskeleton and the extracellular matrix. The sarcomeric actin dissolution occurred after the reduction or loss of dystrophin. Subsequently, after lysis of myofilaments, gamma-sarcoglycan, beta-dystroglycan, beta 1-integrin, and laminin alpha-2 expressions were reduced followed by their breakdown, as epiphenomena of the myocytolytic process. In conclusion, administration of isoproterenol to rats results in primary loss of dystrophin, the most sensitive among the structural proteins that form the DGC that connects the extracellular matrix and the cytoskeleton in cardiomyocyte. These changes, related to ischaemic injury, explain the severe alterations in the structural integrity of the sarcolemma of cardiomyocytes and hence severe and irreversible injury induced by isoproterenol.

The Stability of the Blood Oxygenation Level-Dependent Functional MRI Response to Motor Tasks Is Altered in Patients With Chronic Ischemic Stroke

Background and Purpose-Functional MRI is a powerful tool to investigate recovery of brain function in patients with stroke. An inherent assumption in functional MRI data analysis is that the blood oxygenation level-dependent (BOLD) signal is stable over the course of the examination. In this study, we evaluated the validity of such assumption in patients with chronic stroke. Methods-Fifteen patients performed a simple motor task with repeated epochs using the paretic and the unaffected hand in separate runs. The corresponding BOLD signal time courses were extracted from the primary and supplementary motor areas of both hemispheres. Statistical maps were obtained by the conventional General Linear Model and by a parametric General Linear Model. Results-Stable BOLD amplitude was observed when the task was executed with the unaffected hand. Conversely, the BOLD signal amplitude in both primary and supplementary motor areas was progressively attenuated in every patient when the task was executed with the paretic hand. The conventional General Linear Model analysis failed to detect brain activation during movement of the paretic hand. However, the proposed parametric General Linear Model corrected the misdetection problem and showed robust activation in both primary and supplementary motor areas. Conclusions-The use of data analysis tools that are built on the premise of a stable BOLD signal may lead to misdetection of functional regions and underestimation of brain activity in patients with stroke. The present data urge the use of caution when relying on the BOLD response as a marker of brain reorganization in patients with stroke. (Stroke. 2010; 41:1921-1926.)

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-I, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 mu M. Their activities against HIV-1 protease (K-i 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Angstrom (1) and 1.85 Angstrom (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.