Cleveland Foundation

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities. This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far. This study of 131 high-grade muscle-invasive urothelial bladder carcinomas, part of The Cancer Genome Atlas (TCGA) project, reports recurrent mutations in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date. Recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of viruses associated with gene inactivation are also identified. Importantly, potential therapeutic targets are identified in 69% of the tumours.

We compared patients who received an internal-mammary-artery graft to the anterior descending coronary artery alone or combined with one or more saphenous-vein grafts (n = 2306) with patients who had only saphenous-vein bypass grafts (n = 3625). The 10-year actuarial survival rate among the group receiving the internal-mammary-artery graft, as compared with the group who received the vein grafts (exclusive of hospital deaths), was 93.4 percent versus 88.0 percent (P = 0.05) for those with one-vessel disease; 90.0 percent versus 79.5 percent (P less than 0.0001) for those with two-vessel disease; and 82.6 percent versus 71.0 percent (P less than 0.0001) for those with three-vessel disease. After an adjustment for demographic and clinical differences by Cox multivariate analysis, we found that patients who had only vein grafts had a 1.61 times greater risk of death throughout the 10 years, as compared with those who received an internal-mammary-artery graft. In addition, patients who received only vein grafts had 1.41 times the risk of late myocardial infarction (P less than 0.0001), 1.25 times the risk of hospitalization for cardiac events (P less than 0.0001), 2.00 times the risk of cardiac reoperation (P less than 0.0001), and 1.27 times the risk of all late cardiac events (P less than 0.0001), as compared with patients who received internal-mammary-artery grafts. Internal-mammary-artery grafting for lesions of the anterior descending coronary artery is preferable whenever indicated and technically feasible.

To date, no instruments exist to quantify the psychosocial consequences of voice disorders. The aim of the present investigation was the development of a statistically robust Voice Handicap Index (VHI). An 85-item version of this instrument was administered to 65 consecutive patients seen in the Voice Clinic at Henry Ford Hospital. The data were subjected to measures of internal consistency reliability and the initial 85-item version was reduced to a 30-item final version. This final version was administered to 63 consecutive patients on two occasions in an attempt to assess test-retest stability, which proved to be strong. The findings of the latter analysis demonstrated that a change between two administrations of 18 points represents a significant shift in psychosocial function.

Coronary artery anomalies were found in 1,686 patients (1.3% incidence) undergoing coronary arteriography at the Cleveland Clinic Foundation from 1960 to 1988. Of the 1,686 patients, 1,461 (87%) had anomalies of origin and distribution, and 225 (13%) had coronary artery fistulae. Most coronary anomalies did not result in signs, symptoms, or complications, and usually were discovered as incidental findings at the time of catheterization. Eighty-one percent were "benign" anomalies: 1) separate origin of the left anterior descending and circumflex from the left sinus of Valsalva; 2) ectopic origin of the circumflex from the right sinus of Valsalva; 3) ectopic coronary origin from the posterior sinus of Valsalva; 4) anomalous coronary origin from the ascending aorta; 5) absent circumflex; 6) intercoronary communications; and 7) small coronary artery fistulae. Other anomalies may be associated with potentially serious sequelae such as angina pectoris, myocardial infarction, syncope, cardiac arrhythmias, congestive heart failure, or sudden death. Potentially serious anomalies include: 1) ectopic coronary origin from the pulmonary artery; 2) ectopic coronary origin from the opposite aortic sinus; 3) single coronary artery; and 4) large coronary fistulae. Coronary artery anomalies require accurate recognition, and at times, surgical correction.

BACKGROUND: The increase in heart rate that accompanies exercise is due in part to a reduction in vagal tone. Recovery of the heart rate immediately after exercise is a function of vagal reactivation. Because a generalized decrease in vagal activity is known to be a risk factor for death, we hypothesized that a delayed fall in the heart rate after exercise might be an important prognostic marker. METHODS: For six years we followed 2428 consecutive adults (mean [+/-SD] age, 57+/-12 years; 63 percent men) without a history of heart failure or coronary revascularization and without pacemakers. The patients were undergoing symptom-limited exercise testing and single-photon-emission computed tomography with thallium scintigraphy for diagnostic purposes. The value for the recovery of heart rate was defined as the decrease in the heart rate from peak exercise to one minute after the cessation of exercise. An abnormal value for the recovery of heart rate was defined as a reduction of 12 beats per minute or less from the heart rate at peak exercise. RESULTS: There were 213 deaths from all causes. A total of 639 patients (26 percent) had abnormal values for heart-rate recovery. In univariate analyses, a low value for the recovery of heart rate was strongly predictive of death (relative risk, 4.0; 95 percent confidence interval, 3.0 to 5.2; P<0.001). After adjustments were made for age, sex, the use or nonuse of medications, the presence or absence of myocardial perfusion defects on thallium scintigraphy, standard cardiac risk factors, the resting heart rate, the change in heart rate during exercise, and workload achieved, a low value for heart-rate recovery remained predictive of death (adjusted relative risk, 2.0; 95 percent confidence interval, 1.5 to 2.7; P<0.001). CONCLUSIONS: A delayed decrease in the heart rate during the first minute after graded exercise, which may be a reflection of decreased vagal activity, is a powerful predictor of overall mortality, independent of workload, the presence or absence of myocardial perfusion defects, and changes in heart rate during exercise.

The pleiotropic activities of interferons (IFNs) are mediated primarily through the transcriptional regulation of many downstream effector genes. The mRNA profiles from IFN-alpha, -beta, or -gamma treatments of the human fibrosarcoma cell line, HT1080, were determined by using oligonucleotide arrays with probe sets corresponding to more than 6,800 human genes. Among these were transcripts for known IFN-stimulated genes (ISGs), the expression of which were consistent with previous studies in which the particular ISG was characterized as responsive to either Type I (alpha, beta) or Type II (gamma) IFNs, or both. Importantly, many novel IFN-stimulated genes were identified that were diverse in their known biological functions. For instance, several novel ISGs were identified that are implicated in apoptosis (including RAP46/Bag-1, phospholipid scramblase, and hypoxia inducible factor-1alpha). Furthermore, several IFN-repressed genes also were identified. These results demonstrate the usefulness of oligonucleotide arrays in monitoring mammalian gene expression on a broad and unprecedented scale. In particular, these findings provide insights into the basic mechanisms of IFN actions and ultimately may contribute to better therapeutic uses for IFNs.

Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies. Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P =.002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P =.04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P =.02 compared with the placebo group of the meta-analysis). The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.

BACKGROUND: Atrial fibrillation (AF) may persist due to structural changes in the atria that are promoted by inflammation. C-reactive protein (CRP), a marker of systemic inflammation, predicts cardiovascular events and stroke, a common sequela of AF. We hypothesized that CRP is elevated in patients with atrial arrhythmias. METHODS AND RESULTS: Using a case-control study design, CRP in 131 patients with atrial arrhythmias was compared with CRP in 71 control patients. Among arrhythmia patients, 6 had frequent atrial ectopy or tachycardia, 86 had paroxysmal AF, 39 had persistent AF lasting >30 days, and 70 had lone arrhythmias. CRP was higher in arrhythmia than in control patients (median, 0.21 versus 0.096 mg/dL; P<0.001). Arrhythmia patients in AF within 24 hours before sampling had higher CRP than those in sinus rhythm (0.30 versus 0.15 mg/dL; P<0.001). CRP in controls was not different than in patients with atrial ectopy or tachycardia. Lone arrhythmia patients had a CRP of 0.21 mg/dL, which was not significantly lower than arrhythmia patients with structural heart disease (CRP, 0.23 mg/dL) but higher than controls (P=0.002). Persistent AF patients had a higher CRP (0.34 mg/dL) than paroxysmal AF patients (0.18 mg/dL; P=0.008); both groups had higher CRP levels than controls (P</=0.005). CONCLUSIONS: CRP is elevated in AF patients. This study is the first to document elevated CRP in non-postoperative arrhythmia patients. These findings are reinforced by stepwise CRP elevation with higher AF burden. Although the cause of elevated CRP levels in AF patients remains unknown, elevated CRP may reflect an inflammatory state that promotes the persistence of AF.

BACKGROUND: Stored red cells undergo progressive structural and functional changes over time. We tested the hypothesis that serious complications and mortality after cardiac surgery are increased when transfused red cells are stored for more than 2 weeks. METHODS: We examined data from patients given red-cell transfusions during coronary-artery bypass grafting, heart-valve surgery, or both between June 30, 1998, and January 30, 2006. A total of 2872 patients received 8802 units of blood that had been stored for 14 days or less ("newer blood"), and 3130 patients received 10,782 units of blood that had been stored for more than 14 days ("older blood"). Multivariable logistic regression with propensity-score methods was used to examine the effect of the duration of storage on outcomes. Survival was estimated by the Kaplan-Meier method and Blackstone's decomposition method. RESULTS: The median duration of storage was 11 days for newer blood and 20 days for older blood. Patients who were given older units had higher rates of in-hospital mortality (2.8% vs. 1.7%, P=0.004), intubation beyond 72 hours (9.7% vs. 5.6%, P<0.001), renal failure (2.7% vs. 1.6%, P=0.003), and sepsis or septicemia (4.0% vs. 2.8%, P=0.01). A composite of complications was more common in patients given older blood (25.9% vs. 22.4%, P=0.001). Similarly, older blood was associated with an increase in the risk-adjusted rate of the composite outcome (P=0.03). At 1 year, mortality was significantly less in patients given newer blood (7.4% vs. 11.0%, P<0.001). CONCLUSIONS: In patients undergoing cardiac surgery, transfusion of red cells that had been stored for more than 2 weeks was associated with a significantly increased risk of postoperative complications as well as reduced short-term and long-term survival.

At the Cleveland Clinic the diagnosis of carpal-tunnel syndrome has been made in 654 hands of 439 patients during the last seventeen years. The typical patient with this syndrome is a middle-aged housewife with numbness and tingling in the thumb and index, long, and ring fingers, which is worse at night and worse after excessive activity of the hands. The sensory disturbances, both objective and subjective, must be directly related to the sensory distribution of the median nerve distal to the wrist; but pain may be referred proximal to the wrist as high as the shoulder. There is usually a positive Tinel sign over the median nerve at the wrist, and the wrist-flexion test I described is also usually positive. About half of the patients also have some degree of thenar atrophy. If steroid injections into the carpal tunnel give only transient relief, treatment should be by complete section of the transverse carpal ligament. This procedure will almost always relieve the patient's pain and numbness in the hand, and in many cases will also cure the paralysis of the thenar muscles, which may be present.

BACKGROUND: The prognosis of patients hospitalized with acute myocardial ischemia is quite variable. We examined the value of serum levels of cardiac troponin T, serum creatine kinase MB (CK-MB) levels, and electrocardiographic abnormalities for risk stratification in patients with acute myocardial ischemia. METHODS: We studied 855 patients within 12 hours of the onset of symptoms. Cardiac troponin T levels, CK-MB levels, and electrocardiograms were analyzed in a blinded fashion at the core laboratory. We used logistic regression to assess the usefulness of baseline levels of cardiac troponin T and CK-MB and the electrocardiographic category assigned at admission-ST-segment elevation, ST-segment depression, T-wave inversion, or the presence of confounding factors that impair the detection of ischemia (bundle-branch block and paced rhythms)-in predicting outcome. RESULTS: On admission, 289 of 801 patients with base-line serum samples had elevated troponin T levels (> 0.1 ng per milliliter). Mortality within 30 days was significantly higher in these patients than in patients with lower levels of troponin T (11.8 percent vs. 3.9 percent, P < 0.001). The troponin T level was the variable most strongly related to 30-day mortality (chi-square = 21, P < 0.001), followed by the electrocardiographic category (chi-square = 14, P = 0.003) and the CK-MB level (chi-square = 11, P = 0.004). Troponin T levels remained significantly predictive of 30-day mortality in a model that contained the electrocardiographic categories and CK-MB levels (chi-square = 9.2, P = 0.027). CONCLUSIONS: The cardiac troponin T level is a powerful, independent risk marker in patients who present with acute myocardial ischemia. It allows further stratification of risk when combined with standard measures such as electrocardiography and the CK-MB level.

BACKGROUND: Atherosclerotic plaque stability is related to histological composition. However, current diagnostic tools do not allow adequate in vivo identification and characterization of plaques. Spectral analysis of backscattered intravascular ultrasound (IVUS) data has potential for real-time in vivo plaque classification. METHODS AND RESULTS: Eighty-eight plaques from 51 left anterior descending coronary arteries were imaged ex vivo at physiological pressure with the use of 30-MHz IVUS transducers. After IVUS imaging, the arteries were pressure-fixed and corresponding histology was collected in matched images. Regions of interest, selected from histology, were 101 fibrous, 56 fibrolipidic, 50 calcified, and 70 calcified-necrotic regions. Classification schemes for model building were computed for autoregressive and classic Fourier spectra by using 75% of the data. The remaining data were used for validation. Autoregressive classification schemes performed better than those from classic Fourier spectra with accuracies of 90.4% for fibrous, 92.8% for fibrolipidic, 90.9% for calcified, and 89.5% for calcified-necrotic regions in the training data set and 79.7%, 81.2%, 92.8%, and 85.5% in the test data, respectively. Tissue maps were reconstructed with the use of accurate predictions of plaque composition from the autoregressive classification scheme. CONCLUSIONS: Coronary plaque composition can be predicted through the use of IVUS radiofrequency data analysis. Autoregressive classification schemes performed better than classic Fourier methods. These techniques allow real-time analysis of IVUS data, enabling in vivo plaque characterization.

Nearly 40 years after its invention, the angiogram is still considered by most physicians to be the "gold standard" for defining coronary anatomy. Careful investigations have revealed many deficiencies inherent in this approach. The purpose of this article is to outline the evidence that our current preoccupation with coronary "luminology" may be misguided and to propose a rational paradigm for future practice and investigation. Angiography depicts coronary anatomy from a planar two-dimensional silhouette of the lumen. Angiography is limited in resolution to four or five line pairs per millimeter. Confounding factors include vessel tortuosity, overlap of structures, and the effects of lumen shape. After intervention, a hazy, broadened silhouette may overestimate the actual gain in lumen size. Studies show marked disparity between the apparent severity of lesions and their physiological effects. After myocardial infarction, cardiologists too often do not make an attempt to demonstrate the physiological significance of the stenosis before performing percutaneous coronary revascularization. Similarly, the allure of a better, more gratifying angiogram with new interventional devices appears to be a dominant factor in their popularity. Interventional cardiologists should be aware that techniques yielding marked angiographic benefit may also generate important but unrecognized hazards. The dissociation between the angiogram and clinical outcome should influence future research efforts. Our review of the literature indicates that we may benefit from shifting the current focus and preoccupation with coronary luminology to achieving the desired clinical end point: promoting survival and long-term freedom from myocardial infarction and the disabling symptoms of coronary heart disease.

BACKGROUND: Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between myeloperoxidase and both inflammation and cardiovascular disease. METHODS: We assessed the value of plasma levels of myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain. RESULTS: Initial plasma myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (<0.1 ng per milliliter) at base line (P<0.001). Myeloperoxidase levels at presentation also predicted the risk of major adverse cardiac events (myocardial infarction, the need for revascularization, or death) within 30 days and 6 months after presentation (P<0.001). In patients without evidence of myocardial necrosis (defined as those who were negative for troponin T), the base-line myeloperoxidase levels independently predicted the risk of major adverse coronary events at 30 days (unadjusted 2nd, 3rd, and 4th quartile odds ratios, 2.2 [95 percent confidence interval, 1.1 to 4.6], 4.2 [95 percent confidence interval, 2.1 to 8.4], and 4.1 [95 percent confidence interval, 2.0 to 8.4], respectively) and at 6 months. CONCLUSIONS: A single initial measurement of plasma myeloperoxidase independently predicts the early risk of myocardial infarction, as well as the risk of major adverse cardiac events in the ensuing 30-day and 6-month periods. Myeloperoxidase levels, in contrast to troponin T, creatine kinase MB isoform, and C-reactive protein levels, identified patients at risk for cardiac events in the absence of myocardial necrosis, highlighting its potential usefulness for risk stratification among patients who present with chest pain.

Detached osteochondral fragments from the dome of the talus have been described in orthopaedic publications by a variety of confusing terms. A clarification of this conflicting terminology is suggested. We believe that the traumatic etiology of the lesion has been confirmed both clinically and experimentally. The problems of clinical and roentgenographic diagnosis are discussed and illustrated by case histories. Various forms of treatment are evaluated, and the prognosis appraised.

BACKGROUND: Previous reports have shown that elevated circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure. However, these studies were limited by small numbers of patients and/or they were performed in a single center. In addition, these studies did not have sufficient size to address the influence of age, race, sex, and cause of heart failure on the circulating levels of these inflammatory mediators in patients with heart failure. METHODS AND RESULTS: We analyzed circulating levels of cytokines (tumor necrosis factor [TNF] and interleukin-6) and their cognate receptors in 1200 consecutive patients who were enrolled in a multicenter clinical trial of patients with advanced heart failure. This analysis constitutes the largest analysis of cytokines and cytokine receptors to date. Analysis of the patients receiving placebo showed that increasing circulating levels of TNF, interleukin-6, and the soluble TNF receptors were associated with increased mortality. In men, there was a linear increase in circulating levels of TNF with advancing age. Women < or = 50 years of age had relatively low levels of TNF, but TNF levels were disproportionately higher in women >50 years of age. No differences existed in cytokines and/or cytokine receptors in whites versus nonwhites, and circulating levels of cytokines and cytokine receptors were significantly greater in patients with ischemic heart disease. CONCLUSIONS: Cytokines and cytokine receptors are independent predictors of mortality in patients with advanced heart failure. Moreover, circulating levels of cytokines are modified by age, sex, and cause of heart failure.

An open angiography-based, dose rate escalation study on the effect of intravenous infusion of recombinant tissue plasminogen activator (rt-PA) on cerebral arterial recanalization in patients with acute focal cerebral ischemia was performed at 16 centers. Arterial occlusions consistent with acute ischemia in the carotid or vertebrobasilar territory in the absence of detectable intracerebral hemorrhage were prerequisites for treatment. After the 60-minute rt-PA infusion, arterial perfusion was assessed by repeat angiography and computed tomography scans were performed at 24 hours to assess hemorrhagic transformation. Of 139 patients with symptoms of focal ischemia, 80.6% (112) had complete occlusion of the primary vessel at a mean of 5.4 +/- 1.7 hours after symptom onset. No dose rate response of cerebral arterial recanalization was observed in 93 patients who completed the rt-PA infusion. Middle cerebral artery division (M2) and branch (M3) occlusions were more likely to undergo recanalization by 60 minutes than were internal carotid artery occlusions. Hemorrhagic infarction occurred in 20.2% and parenchymatous hematoma in 10.6% of patients over all dose rates, while neurological worsening accompanied hemorrhagic transformation (hemorrhagic infarction and parenchymatous hematoma) in 9.6% of patients. All findings were within prospective safety guidelines. No dose rate correlation with hemorrhagic infarction, parenchymatous hematoma, or both was seen. Hemorrhagic transformation occurred significantly more frequently in patients receiving treatment at least 6 hours after symptom onset. No relationship between hemorrhagic transformation and recanalization was observed. This study indicates that site of occlusion, time to recanalization, and time to treatment are important variables in acute stroke intervention with this agent.

STUDY DESIGN: An Institutional Review Board-approved Phase I efficacy study of inflatable bone tamp usage in the treatment of symptomatic osteoporotic compression fractures. OBJECTIVES: To evaluate the safety and efficacy of inflatable bone tamp reduction and cement augmentation, "kyphoplasty," in the treatment of painful osteoporotic vertebral compression fractures. SUMMARY OF BACKGROUND DATA: Osteoporotic compression fractures can result in progressive kyphosis and chronic pain. Traditional treatment for these patients includes bed rest, analgesics, and bracing. Augmentation of vertebral compression fractures with polymethylmethacrylate, "vertebroplasty," has been used to treat pain. This technique, however, makes no attempt to restore the height of the collapsed vertebral body. Kyphoplasty is a new technique that involves the introduction of inflatable bone tamps into the vertebral body. Once inflated, the bone tamps restore the vertebral body back toward its original height while creating a cavity that can be filled with bone cement. PATIENTS AND METHODS: Seventy consecutive kyphoplasty procedures were performed in 30 patients. The indications included painful primary or secondary osteoporotic vertebral compression fractures. Mean duration of symptoms was 5.9 months. Symptomatic levels were identified by correlating the clinical data with MRI findings. Perioperative variables and bone tamp complications or issues were recorded and analyzed. Preoperative and postoperative radiographs were compared to calculate the percentage height restored. Outcome data were obtained by comparing preoperative and latest postoperative SF-36 data. RESULTS: At the completion of the Phase I study there were no major complications related directly to use of this technique or use of the inflatable bone tamp. In 70% of the vertebral bodies kyphoplasty restored 47% of the lost height. Cement leakage occurred at six levels (8.6%).SF-36 scores for Bodily Pain 11.6-58.7, (P = 0.0001) and Physical Function 11.7-47.4, (P = 0.002) were among those that showed significant improvement. CONCLUSIONS: The inflatable bone tamp was efficacious in the treatment of osteoporotic vertebral compression fractures. Kyphoplasty is associated with early clinical improvement of pain and function as well as restoration of vertebral body height in the treatment of painful osteoporotic compression fractures.

The guanosine triphosphate (GTP)-binding protein Ras functions in regulating growth and differentiation; however, little is known about the protein interactions that bring about its biological activity. Wild-type Ras or mutant forms of Ras were covalently attached to an insoluble matrix and then used to examine the interaction of signaling proteins with Ras. Forms of Ras activated either by mutation (Gly12Val) or by binding of the GTP analog, guanylyl-imidodiphosphate (GMP-PNP) interacted specifically with Raf-1 whereas an effector domain mutant, Ile36Ala, failed to interact with Raf-1. Mitogen-activated protein kinase (MAP kinase) activity was only associated with activated forms of Ras. The specific interaction of activated Ras with active MAP kinase kinase (MAPKK) was confirmed by direct assays. Thus the forming of complexes containing MAPKK activity and Raf-1 protein are dependent upon the activity of Ras.