Allergic reactions to small-molecule drugs: Will we move from reaction to prediction?

PURPOSE: This primer provides background and an update on immune mechanisms which allow small-molecule drugs to trigger drug allergy. SUMMARY: For many years, understanding of drug allergy was limited. The hapten model of drug allergy applies only to a subset of drugs known to cause allergic reactions. More recently, the understanding of immune reactions has expanded to include pharmacologic interactions with the molecules involved in immune identity and surveillance. These insights are presented and discussed here. CONCLUSION: Greater understanding of allergic reactions to drugs offers the promise to move from a position of reacting to immune reactions to a more proactive model. This may translate to new opportunities to characterize risk in drug development, confirm the nature of reactions in clinical settings, enhance the targeting of alerts, and ultimately to allow patient-specific prediction.

Recommendations for selecting drug-drug interactions for clinical decision support.

PURPOSE: Recommendations for including drug-drug interactions (DDIs) in clinical decision support (CDS) are presented. SUMMARY: A conference series was conducted to improve CDS for DDIs. A work group consisting of 20 experts in pharmacology, drug information, and CDS from academia, government agencies, health information vendors, and healthcare organizations was convened to address (1) the process to use for developing and maintaining a standard set of DDIs, (2) the information that should be included in a knowledge base of standard DDIs, (3) whether a list of contraindicated drug pairs can or should be established, and (4) how to more intelligently filter DDI alerts. We recommend a transparent, systematic, and evidence-driven process with graded recommendations by a consensus panel of experts and oversight by a national organization. We outline key DDI information needed to help guide clinician decision-making. We recommend judicious classification of DDIs as contraindicated and more research to identify methods to safely reduce repetitive and less-relevant alerts. CONCLUSION: An expert panel with a centralized organizer or convener should be established to develop and maintain a standard set of DDIs for CDS in the United States. The process should be evidence driven, transparent, and systematic, with feedback from multiple stakeholders for continuous improvement. The scope of the expert panel's work should be carefully managed to ensure that the process is sustainable. Support for research to improve DDI alerting in the future is also needed. Adoption of these steps may lead to consistent and clinically relevant content for interruptive DDIs, thus reducing alert fatigue and improving patient safety.

Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure.

Compared with conventional diuretic (CD) therapy, ultrafiltration (UF) is associated with greater weight loss and fewer re-hospitalizations in patients admitted with decompensated heart failure (HF). Concerns have been raised regarding its safety and efficacy in patients with more advanced heart failure. The authors conducted a single-center, prospective, randomized controlled trial in patients with advanced HF admitted to an intensive care unit for hemodynamically guided therapy, comparing UF (n=17) with CD (n=19) at admission. The primary end point was the time required for pulmonary capillary wedge pressure (PCWP) to be maintained at a value of ≤18 mm Hg for at least 4 consecutive hours. Secondary end points included levels of cytokines and neurohormones, as well as several clinical outcomes. In our study cohort, the time to achieve the primary end point was lower in the UF group but did not reach statistical significance (P = .08). UF resulted in greater weight reduction, higher total volume removed, and shorter hospital length of stay. There were no differences in kidney function, biomarkers, or adverse events. In patients with advanced HF under hemodynamically tailored therapy, UF can be safely performed to achieve higher average volume removed than CD therapy without leading to adverse outcomes.

Optimization of microCT imaging and blood vessel diameter quantitation of preclinical specimen vasculature with radiopaque polymer injection medium.

Vascular networks within a living organism are complex, multi-dimensional, and challenging to image capture. Radio-angiographic studies in live animals require a high level of infrastructure and technical investment in order to administer costly perfusion mediums whose signals metabolize and degrade relatively rapidly, diminishing within a few hours or days. Additionally, live animal specimens must not be subject to long duration scans, which can cause high levels of radiation exposure to the specimen, limiting the quality of images that can be captured. Lastly, despite technological advances in live-animal specimen imaging, it is quite difficult to minimize or prevent movement of a live animal, which can cause motion artifacts in the final data output. It is demonstrated here that through the use of postmortem perfusion protocols of radiopaque silicone polymer mediums and ex-vivo organ harvest, it is possible to acquire a high level of vascular signal in preclinical specimens through the use of micro-computed tomographic (microCT) imaging. Additionally, utilizing high-order rendering algorithms, it is possible to further derive vessel morphometrics for qualitative and quantitative analysis.

Optimization of volumetric computed tomography for skeletal analysis of model genetic organisms.

Forward and reverse genetics now allow researchers to understand embryonic and postnatal gene function in a broad range of species. Although some genetic mutations cause obvious morphological change, other mutations can be more subtle and, without adequate observation and quantification, might be overlooked. For the increasing number of genetic model organisms examined by the growing field of phenomics, standardized but sensitive methods for quantitative analysis need to be incorporated into routine practice to effectively acquire and analyze ever-increasing quantities of phenotypic data. In this study, we present platform-independent parameters for the use of microscopic x-ray computed tomography (microCT) for phenotyping species-specific skeletal morphology of a variety of different genetic model organisms. We show that microCT is suitable for phenotypic characterization for prenatal and postnatal specimens across multiple species.

Assessment of pain relief provided by interscalene regional block and infusion pump after arthroscopic shoulder surgery.

PURPOSE: This study was performed to evaluate the efficacy of interscalene regional blocks and infusion pumps for postoperative pain control after arthroscopic subacromial decompression with or without arthroscopic rotator cuff repair. METHODS: Seventy-six patients were included in the prospective study. Participants were randomized into 4 treatment groups: (1) interscalene regional block, (2) infusion pump with 0.5% bupivacaine, (3) interscalene block combined with an infusion pump containing 0.5% bupivacaine, and (4) interscalene block combined with an infusion pump containing 0.9% saline solution. The interscalene regional block was performed with a nerve stimulator. Infusion pump catheters were positioned in the subacromial space. Visual analog scale (VAS) data were collected preoperatively, at 1 and 2 hours postoperatively, and daily for an additional 6 days postoperatively. An analysis of variance with a Student-Newman-Keuls post hoc test was used to identify statistically significant (P < .05) differences in VAS scores between the groups at each time point. Percentages of patients who took medication for pain management in the recovery room were compared between the 4 groups by use of chi(2) analysis. RESULTS: Significant differences were noted in VAS scores postoperatively. Group 2 (pump only) had significantly higher scores than all other groups for the first 2 hours. Furthermore, group 4 (block and pump filled with saline solution) had significantly lower VAS scores than group 1 (block only) at 1 hour. This difference was no longer significant by the second hour. The percentage of patients who required oral narcotics or intravenous pain medication was significantly larger for group 2 than for the other groups. CONCLUSIONS: The interscalene regional block provided more pain relief than infusion pumps immediately after arthroscopic shoulder surgery. Infusion pumps did not significantly reduce pain levels after the blocks wore off. LEVEL OF EVIDENCE: Level II, prospective comparative therapeutic study.

Elbow function after repair of the distal biceps brachii tendon with a two-incision approach.

A modified Boyd-Anderson 2-incision approach is commonly used to repair the distal biceps tendon after avulsion from the radial tuberosity. Using suture anchors for fixation instead of a bone trough simplifies the procedure. This retrospective study enrolled 32 patients who underwent surgical repair of the distal biceps tendon with a 2-incision approach and 2 suture anchors. The mean postoperative follow-up was 42 months. Elbow strength, endurance, and range of motion for flexion, pronation, and supination were measured for each arm. For each strength and endurance measurement, the mean for the involved arm was at least 95% of that for the uninvolved arms. The largest flexion, pronation, and supination deficits for an injured arm, as compared with the uninjured arm, were 9 degrees, 15 degrees, and 16 degrees, respectively. A 2-incision approach for distal biceps tendon repair with suture anchor fixation can restore elbow function and satisfy patients.

Multimodality Chamber for coregistered anatomical and molecular imaging of small animals.

Modern imaging methods are applied extensively in translational animal research, and combined analysis of anatomical and functional imaging results is of increasing importance. Many imaging centers handle multiple independent animal colonies and use several imaging modalities, often in combination. The authors have developed and successfully tested a two-piece acrylic Multimodality Chamber that enables investigators to coregister images from two or more modalities, including microMR, microCT, microPET and optical imaging.

Viscoelasticity and temperature variations decrease tension and stiffness of hamstring tendon grafts following anterior cruciate ligament reconstruction.

BACKGROUND: Hamstring tendon grafts used for anterior cruciate ligament reconstruction are typically harvested early in the surgical procedure and are preconditioned prior to reimplantation. Postoperatively, the grafts undergo stress relaxation and warm from the temperature of the operating room to body temperature. The hypothesis of this study was that the tension within semitendinosus and gracilis tendon grafts and the stiffness of the grafts significantly decrease postoperatively because of both stress relaxation and an increase in temperature. METHODS: Double-strand grafts were created from six semitendinosus tendons and six gracilis tendons harvested from cadaver specimens. The grafts were loaded to 65 N while at operating-room temperature (20 degrees C). After fifteen minutes of stress relaxation, graft tension was measured and the grafts were stretched by 0.1 mm to determine stiffness. The tension and stiffness measurements represented graft properties immediately following reconstruction. Additional tension and stiffness measurements were made following three hours of stress relaxation and after increasing the temperature to the body temperature at the knee (34 degrees C). Both types of graft were examined for differences in stiffness and tension due to stress relaxation and the temperature increase. RESULTS: For both types of graft, the tension and stiffness decreased following stress relaxation to approximately 50% and 80%, respectively, of the value immediately after reconstruction. Increasing the temperature decreased the tension and stiffness further to approximately 40% and 70%, respectively, of the value after reconstruction for both types of graft. All changes in tension and stiffness were significant (p < 0.01). CONCLUSIONS: Graft tension and stiffness achieved immediately following reconstruction are not maintained postoperatively because of stress relaxation and a temperature increase. This could lead to increased knee laxity.

Locking plates improve torsional resistance in the stabilization of three-part proximal humeral fractures.

This study quantified the torsional resistance provided by locking plates and angled blade plates used to stabilize proximal humeral fractures. Three-part proximal humeral fractures were created in 6 pairs of cadaveric humeri. One specimen of each pair was reconstructed with a proximal humeral locking plate, whereas the other specimen was reconstructed with an angled blade plate. An external rotation torque, varying from 0 to 5 N-m, was applied to the humeral head until the head rotated 30 degrees or 10,000 loading cycles were applied. The mean initial torsional stiffness was significantly larger for the locking plates (0.99 N-m/degree) than for the blade plates (0.59 N-m/degree). For each pair, the maximum rotation was larger for the blade plate than for the locking plate. For this in vitro model of a reconstructed 3-part proximal humeral fracture, the locking plate provided better torsional fatigue resistance and stiffness than the blade plate.

Comparing two estimations of the quadriceps force distribution for use during patellofemoral simulation.

EMG analysis has indicated that the vastus lateralis and vastus medialis contribute less to the quadriceps moment during knee extension than the physiological cross-sectional areas (PCSA's) of the muscles indicate. Both PCSA- and EMG-based quadriceps force distributions were utilized while computationally simulating knee extension. For both distributions, a 10 degrees increase in the Q-angle and a 50% decrease in the force applied by the vastus medialis were simulated, and the influence of these changes on the resultant force and moment applied by the quadriceps muscles and the patella tendon was quantified. For both quadriceps force distributions, increasing the Q-angle increased the lateral force and the moment acting to rotate the distal patella laterally. Due to the relatively large forces initially attributed to the vastus medialis and vastus lateralis for the PCSA-based quadriceps force distribution, decreasing the vastus medialis force created a large force imbalance between these two muscles. For the PCSA-based quadriceps force distribution, decreasing the vastus medialis force increased the lateral rotation moment and the moment acting to tilt the patella laterally. For the EMG-based quadriceps force distribution, decreasing the vastus medialis force produced relatively little change in the tilt and rotation moments. For both quadriceps force distributions, increasing the Q-angle increased the maximum and mean cartilage pressure during flexion, but decreasing the vastus medialis force only increased the cartilage pressures for the PCSA-based quadriceps distribution. The choice of the initial quadriceps distribution can influence the outcome of patellofemoral simulation when manipulating quadriceps muscle forces.

Structural properties of lateral collateral ligament reconstruction at the fibular head.

BACKGROUND: Anatomical reconstruction of a ruptured lateral collateral ligament using allograft tissue secured within the fibular head with an interference screw has been described. HYPOTHESIS: Interference fixation at the fibular head does not reproduce the strength of the intact ligament. STUDY DESIGN: Controlled laboratory study. METHODS: Ten intact lateral collateral ligaments were tested to failure. The distal fixation of 11 ligaments reconstructed with a graft including a bone plug and 11 ligaments reconstructed with a graft without a bone plug were also tested. RESULTS: The reconstructed ligaments consistently failed at the fibular head. The intact specimens predominately failed through ligament rupture. The mean strength and stiffness values were 460 +/- 163 N and 82 +/- 25 N/mm, respectively, for the intact ligaments, 113 +/- 40 N and 36 +/- 10 N/mm, respectively, for reconstruction with a bone plug, and 135 +/- 81 N and 34 +/- 14 N/mm, respectively, for reconstruction without a bone plug. The strength and stiffness were significantly (P < .05) greater for the intact ligaments than for either reconstruction group. The variation in strength was significantly larger for reconstruction without a bone plug than for reconstruction with a bone plug. CONCLUSION: Tension applied to lateral collateral ligaments reconstructed using fibular interference fixation should be limited immediately after surgery. Soft tissue fixation should be employed with care because of the inconsistency in the failure strength. CLINICAL RELEVANCE: Although fibular interference fixation is increasingly being described in the literature, the properties of reconstructed lateral collateral ligaments have not previously been quantified.

Image based modeling of defibrillation in children.

Volume imaging, defibrillation electrode models, and finite element modeling are employed in patient-specific procedural modeling in pediatric patients with cardiac arrhythmias. Due to variable size and anatomy, these patients may not be well-served by devices designed for adult defibrillation. A pipeline for rapid creation of image based models that can be interactively interrogated to determine optimal defibrillation scenarios and preliminary proof-of-concept work are presented. This approach has potential clinical applications for therapy planning and broad applications for finite element modeling in anatomical models. Clinical studies investigating the effects of body size, habitus, and anatomical variation on myocardial voltage gradients are planned.

Practical vessel imaging by computed tomography in live transgenic mouse models for human tumors.

Contrast-enhanced small-animal computed tomography is an economical and highly quantitative tool for serially examining tumor development in situ, for analyzing the network of blood vessels that nourish them, and for following the response of tumors to preclinical therapeutic intervention(s). We present practical considerations for visualizing the vascular network of transgenic mouse tumors. Using a long-acting iodinated triglyceride blood-pool contrast agent, we present optimized scanner acquisition parameters and volume-rendering techniques for examining the intermediate and large vessels of complex spontaneous tumors (e.g., alveolar rhabdomyosarcomas) in transgenic mice. Our findings indicate that multiple-frame, 360-720 view acquisitions were mandatory for clarifying bone and soft tissue from vessel contrast. This finding was consistent in visualizations using a one-dimensional transfer function where voxel color and opacity was assigned in proportion to CT value and a two-dimensional transfer function where voxel color and opacity was assigned in proportion to CT value and gradient magnitude. This study lays a groundwork for the qualitative and quantitative assessment of anti-angiogenesis preclinical studies using transgenic mice.

Reducing the lateral force acting on the patella does not consistently decrease patellofemoral pressures.

BACKGROUND: Extensor mechanism procedures that decrease the lateral component of the patellar tendon or quadriceps force acting on the patella do not consistently reduce pain. HYPOTHESIS: Patellofemoral treatments do not consistently decrease patellofemoral pressures because of variations in the moments acting on the patella. STUDY DESIGN: Computer simulation study. METHODS: Computational models of 4 knees were constructed to characterize the patellofemoral pressure distribution during simulated squatting from 40 degrees to 90 degrees. The knees were given an initial Q angle of 25 degrees. Patellofemoral treatments were simulated by increasing the percentage of the quadriceps force applied by the vastus medialis by 50% and by medializing the tibial tuberosity to decrease the Q angle to 15 degrees. RESULTS: Decreasing the Q angle caused a larger decrease in the lateral component of the force applied by the quadriceps and patellar tendon than did increasing the force applied by the vastus medialis and, therefore, was more effective at decreasing patellofemoral pressures and the force needed to resist lateral subluxation. Both treatments also decreased the moments acting to rotate the distal patella laterally and tilt the patella laterally during flexion. Variations in these moments increased patellofemoral pressures for some knees. CONCLUSIONS: Treatments that reduce patellofemoral subluxation can have an unexpected influence on patellofemoral pressures because of the moments acting on the patella. CLINICAL RELEVANCE: Extensor mechanism procedures that restore patellofemoral stability may not provide pain relief.

White matter tractography using diffusion tensor deflection.

Diffusion tensor MRI provides unique directional diffusion information that can be used to estimate the patterns of white matter connectivity in the human brain. In this study, the behavior of an algorithm for white matter tractography is examined. The algorithm, called TEND, uses the entire diffusion tensor to deflect the estimated fiber trajectory. Simulations and imaging experiments on in vivo human brains were performed to investigate the behavior of the tractography algorithm. The simulations show that the deflection term is less sensitive than the major eigenvector to image noise. In the human brain imaging experiments, estimated tracts were generated in corpus callosum, corticospinal tract, internal capsule, corona radiata, superior longitudinal fasciculus, inferior longitudinal fasciculus, fronto-occipital fasciculus, and uncinate fasciculus. This approach is promising for mapping the organizational patterns of white matter in the human brain as well as mapping the relationship between major fiber trajectories and the location and extent of brain lesions.

Intracellular distribution of peroxynitrite during doxorubicin cardiomyopathy: evidence for selective impairment of myofibrillar creatine kinase.

Cardiac peroxynitrite and protein nitration are increased during doxorubicin cardiotoxicity, but the intracellular targets and functional consequences have not been defined. We investigated the intracellular distribution of protein nitration during doxorubicin cardiotoxicity in mice. Following in vivo cardiac function assessments by echocardiography, cardiac tissues were prepared for immunohistochemistry and electron microscopy 5 days after doxorubicin (20 mg kg(-1)) or vehicle control. Increased cardiac 3-nitrotyrosine was observed using light microscopy in doxorubicin treated animals. Immunogold electron microscopy (55,000x) revealed increased myofibrillar and mitochondrial 3-nitrotyrosine levels following doxorubicin, but cellular 3-nitrotyrosine density was 2 fold higher in myofibrils. We therefore investigated the actions of peroxynitrite on intact cardiac contractile apparatus. Skinned ventricular trabeculae were exposed to physiologically relevant peroxynitrite concentrations (50 or 300 nM) for 1 h, then Ca(2+) induced contractile responses were measured in the presence of ATP (4 mM) or phosphocreatine (12 mM) as high energy phosphate supplier. ATP maximal force generation was unaltered after 50 nM peroxynitrite, but phosphocreatine/ATP response was reduced (0.99+/-0.63 vs 1.59+/-0.11), suggesting selective inactivation of myofibrillar creatine kinase (MM-CK). Reduction of ATP maximal force was observed at 300 nM peroxynitrite and phosphocreatine/ATP response was further reduced (0.64+/-0.30). Western blotting showed concentration dependent nitration of MM-CK in treated trabeculae. Similarly, cardiac tissues from doxorubicin treated mice demonstrated increased nitration and inactivation of MM-CK compared to controls. These results demonstrate that peroxynitrite-related protein nitration are mechanistic events in doxorubicin cardiomyopathy and that the cardiac myofibril is an important oxidative target in this setting. Furthermore, MM-CK may be a uniquely vulnerable target to peroxynitrite in vivo.