The impact of histologic grade on the outcome of high-dose therapy and autologous stem cell transplantation for follicular lymphoma

The impact of the follicular lymphoma (FL) histologic grade on outcomes after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is unknown. We evaluated 219 consecutive patients with grades 1-3 FL who underwent HDT and ASCT at our center. Overall survival (OS), progression-free survival (PFS), relapse and non-relapse mortality (NRM) was estimated for each grade after controlling for other predictive factors. The number of patients with grades 1, 2 and 3 FL was 106 (48%), 75 (34%) and 38 (17%), respectively. Five-year outcome estimates for the entire cohort included 60% OS, 39% PFS and 46% relapse (median follow-up=7.8 years). PFS and relapse were nearly identical among patients with grade 3 FL versus grades 1-2 FL after adjusting for other contributing factors (hazard ratio (HR)=0.90, P=0.68; HR=1.07, P=0.80, respectively). The hazard for mortality (HR=0.70, P=0.23) and NRM (HR=0.33, P=0.07) was non-significantly lower among patients with grade 3 FL compared to patients with grades 1-2 disease. Factors associated with inferior PFS included elevated lactate dehydrogenase (HR=1.52, P=0.03), chemoresistance (HR=1.82, P=0.02), > or =2 prior therapies (HR=1.8, P=0.03) and prior radiation (HR=1.99, P=0.003). These data suggest that the histologic grade of FL does not impact PFS or relapse following HDT and ASCT.     

Volumetric neuroimage analysis extensions for the MIPAV software package

We describe a new collection of publicly available software tools for performing quantitative neuroimage analysis. The tools perform semi-automatic brain extraction, tissue classification, Talairach alignment, and atlas-based measurements within a user-friendly graphical environment. They are implemented as plug-ins for MIPAV, a freely available medical image processing software package from the National Institutes of Health. Because the plug-ins and MIPAV are implemented in Java, both can be utilized on nearly any operating system platform. In addition to the software plug-ins, we have also released a digital version of the Talairach atlas that can be used to perform regional volumetric analyses. Several studies are conducted applying the new tools to simulated and real neuroimaging data sets.     

Comparison of lesion-to-cerebellum uptake ratios and standardized uptake values in the evaluation of lung nodules with 18F-FDG PET

OBJECTIVE: To evaluate the clinical performance of the lesion-to-cerebellum uptake ratio (LCR), a semiquantitative index for differentiating malignant from benign lung nodules with [F]fluorodeoxyglucose positron emission tomography (F-FDG PET). METHODS: Thirty-six patients (16 females, 20 males; median age, 73 years; range, 41-87 years) with 42 known or suspected malignant lung nodules underwent whole-body PET imaging after an intravenous injection of a mean dose of 543+/-69 MBq (14.7+/-1.9 mCi) of F-FDG. The standardized uptake value (SUV) and the LCR were calculated for each nodule and receiver operating characteristic (ROC) curves were analysed using the ROCKIT 0.9B software package. RESULTS: Surgical pathology and follow-up with serial computed tomography scans for at least 24 months revealed 18 malignant lung lesions and 24 benign lesions less than 3.0 cm in size. The mean LCR was 0.70+/-0.40 for malignant nodules and 0.23+/-0.12 for benign nodules (P<0.001, two-tailed test). The area under the estimated ROC curve was 0.8660 for SUV data and 0.9197 for LCR data (P=0.2408, two-tailed test). CONCLUSIONS: The LCR method appears to be a valuable semiquantitative index for the evaluation of malignancy in pulmonary nodules with F-FDG PET, which is simple to perform clinically and does not require accurate measurements of body weight or the residual activity in the syringe utilized for F-FDG injection.     

Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans

Mutation in the prion gene PRNP accounts for 10-15% of human prion diseases. However, little is known about the mechanisms by which mutant prion proteins (PrPs) cause disease. Here we investigated the effects of 10 different pathogenic mutations on the conformation and ligand-binding activity of recombinant human PrP (rPrP). We found that mutant rPrPs react more strongly with N terminus-specific antibodies, indicative of a more exposed N terminus. The N terminus of PrP contains a glycosaminoglycan (GAG)-binding motif. Binding of GAG is important in prion disease. Accordingly, all mutant rPrPs bind more GAG, and GAG promotes the aggregation of mutant rPrPs more efficiently than wild-type recombinant normal cellular PrP (rPrP(C)). Furthermore, point mutations in PRNP also cause conformational changes in the region between residues 109 and 136, resulting in the exposure of a second, normally buried, GAG-binding motif. Importantly, brain-derived PrP from transgenic mice, which express a pathogenic mutant with nine extra octapeptide repeats, also binds more strongly to GAG than wild-type PrP(C). Thus, several rPrPs with distinct pathogenic mutations have common conformational changes, which enhance binding to GAG. These changes may contribute to the pathogenesis of inherited prion diseases.     

The formation of trajectories during goal-oriented locomotion in humans. II. A maximum smoothness model

Despite the theoretically infinite number of possible trajectories a human may take to reach a distant doorway, we observed that locomotor trajectories corresponding to this task were actually stereotyped, both at the geometric and the kinematic levels. In this paper, we propose a computational model for the formation of human locomotor trajectories. Our model is adapted from smoothness maximization models that have been studied in the context of hand trajectory generation. The trajectories predicted by our model are very similar to the experimentally recorded ones. We discuss the theoretical implications of this result in the context of movement planning and control in humans. In particular, this result supports the hypothesis that common principles, such as smoothness maximization, may govern the generation of very different types of movements (in this case, hand movements and whole-body movements).     

Exertional leg pain: Teasing out arterial entrapments

Vascular causes of exertional lower extremity pain are relatively rare, but may be the answer in athletes refractory to treatment for the more common overuse syndromes of the lower extremities. It is important to differentiate these vascular causes from chronic exertional compartment syndrome (CECS), medial tibial stress syndrome (MTSS), and stress fractures in order to develop appropriate treatment plans, avoid complications, and return athletes to play expeditiously. Important vascular etiologies to be considered are popliteal artery entrapment syndrome (PAES), endofibrotic disease, popliteal artery aneurysm, cystic adventitial disease, and peripheral arterial dissections. The diagnostic workup involves angiography or noninvasive vascular studies such as Doppler ultrasound or magnetic resonance angiography in both the neutral and provocative positions. Treatment of these vascular abnormalities typically involves surgical correction of the vascular anomaly.     

Roles for negative cell regulator 14-3-3sigma in control of MDM2 activities

The 14-3-3sigma, upregulated by p53 in response to DNA damage, can have a positive-feedback impact driving p53 activities and is a human cancer epithelial marker downregulated in various tumors. However, the precise roles of 14-3-3sigma during tumorigenesis are not well characterized. Here, we show that 14-3-3sigma is a critical regulator of murine double minute oncogene (MDM2). 14-3-3sigma interacts with MDM2 at the RING domain. The C-terminal region of 14-3-3sigma binds to MDM2 very efficiently. Importantly, 14-3-3sigma overexpression leads to destabilization of MDM2 through enhancing MDM2 self-ubiquitination and accelerating turnover rate. Conversely, loss of 14-3-3sigma results in a significant increase in MDM2 protein. Moreover, live-cell images indicated that 14-3-3sigma can affect the location of MDM2 from the nucleus to the cytoplasm, and that MDM2-mediated cytoplasmic localization of p53 can be reversed by the presence of 14-3-3sigma. Significantly, we further showed that 14-3-3sigma causes MDM2 downregulation, thereby stabilizing p53 and inhibiting tumor growth in animal tumors. Also, 14-3-3sigma blocks MDM2-mediated retinoblastoma degradation and p53 NEDDylation. Our results provide evidence that 14-3-3sigma is a pivotal MDM2 regulator involved in blocking a variety of activities of MDM2.     

Case of the month: Right coronary artery dissection following sports-related blunt trauma

Coronary artery dissection is a rare life-threatening complication resulting from blunt traumatic injury. Most cases of coronary artery injury, including dissection, involve the left anterior descending artery given its anatomical location relative to the impact. Right coronary artery (RCA) dissection secondary to blunt trauma is a particularly unusual occurrence, and has not previously been reported in the emergency medicine literature. We present a case of RCA dissection following low impact sport-related blunt chest trauma and discuss the pathophysiology, risk factors, diagnosis and current treatment options.