Citations

The propagation speed of shear waves is related to frequency and the complex stiffness (shear elasticity and viscosity) of the medium. A method is presented to solve for shear elasticity and viscosity of a homogeneous medium by measuring shear wave speed dispersion. Harmonic radiation force, introduced by modulating the energy density of incident ultrasound, is used to generate cylindrical shear waves of various frequencies in a homogeneous medium. The speed of shear waves is measured from phase shift detected over the distance propagated. Measurements of shear wave speed at multiple frequencies are fit with the theoretical model to solve for the complex stiffness of the medium. Experiments in gelatin phantoms show promising results validated by an independent method. Practical considerations and challenges in possible medical applications are discussed.

53BP1 participates early in the DNA damage response and is involved in cell cycle checkpoint control. Moreover, the phenotype of mice and cells deficient in 53BP1 suggests a defect in DNA repair (Ward et al., 2003b). Therefore, we asked whether or not 53BP1 would be required for the efficient repair of DNA double strand breaks. Our data indicate that homologous recombination by gene conversion does not depend on 53BP1. Moreover, 53BP1-deficient mice support normal V(D)J recombination, indicating that 53BP1 is not required for “classic” nonhomologous end joining. However, class switch recombination is severely impaired in the absence of 53BP1, suggesting that 53BP1 facilitates DNA end joining in a way that is not required or redundant for the efficient closing of RAG-induced strand breaks. These findings are similar to those observed in mice or cells deficient in the tumor suppressors ATM and H2AX, further suggesting that the functions of ATM, H2AX, and 53BP1 are closely linked.

Purpose To determine the effectiveness of an infusional chemotherapy regimen in patients with HIV-associated lymphoma treated before and after the use of highly active antiretroviral therapy (HAART) in routine clinical practice. Patients and Methods Ninety-eight assessable patients with HIV-associated intermediate- or high-grade non-Hodgkin’s lymphoma received cyclophosphamide 200 mg/m2/d, doxorubicin 12.5 mg/m2/d, and etoposide 60 mg/m2/d (CDE) given by continuous intravenous infusion for 4 days (96 hours) every 4 weeks plus filgrastim. Concurrent antiretroviral treatment consisted of the nucleoside analog didanosine in the first 43 patients enrolled before December 1996 (pre-HAART group), or HAART in the remaining 55 patients enrolled after that time (HAART group). Results Complete response occurred in 44 patients (45%; 95% CI, 35% to 55%). Failure-free survival and overall survival (OS) at 2 years was 36% (95% CI, 26% to 46%) and 43% (95% CI, 33% to 53%), respectively. At the time of the analysis, 30% in the pre-HAART group were alive compared with 47% in the HAART group; when adjusted for varying length of follow-up, patients in the HAART group had improved OS (P = .039). Patients in the HAART group experienced less grade 4 nonhematologic toxicity (22% v 42%; P = .037), thrombocytopenia (31% v 52%; P = .033), and anemia (9% v 27%; P = .021), and had fewer treatment-associated deaths (0% v 10%; P = .013). Conclusion Infusional CDE is an effective and potentially curative regimen for patients with HIV-associated lymphoma. Patients treated in the HAART era have less chemotherapy-associated toxicity and improved survival.

The specific aim of this study was to develop a quantitative method and a kinematic method to evaluate the maximal workspace of the trapeziometacarpal (TM) joint. Six fresh-frozen human cadaver hands were disarticulated 4 cm proximal to the wrist joint and used in this experiment. The three-dimensional motion data of the TM joint was collected by an electromagnetic tracking device at 30 Hz. The workspace was reconstructed according to a complete set of motion data included circumduction, flexion-extension and abduction-adduction. A spherical fitting technique was used to obtain a sphere encompassing all the motion trajectories and estimating the centre of the sphere. The surface area of the maximal TM workspace, located on the one part of the sphere surface, was calculated by surface integration. The interclass correlation coefficient values for the reliability estimation of the repeated measurements of the radius and surface area of all specimens were 0.91 and 0.98 respectively. The mean coefficients of variance of the measured radius and the surface area were 2.04 per cent and 3.65 per cent respectively. The results also showed that using a spherical model to calculate the maximal workspace as an index for assessing TM joint impairment is practical.

Purpose Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain. Patients and Methods Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets. Results Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. Conclusion Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs . This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.

Background— The renal actions of brain natriuretic peptide (BNP) in congestive heart failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF. Methods and Results— CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg · kg −1 · h −1 ). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg · kg −1 · h −1 ) and low-dose (2 pmol · kg −1 · min −1 ) BNP followed by 45-minute coinfusion of Fs (1 mg · kg −1 · h −1 ) and high-dose (10 pmol · kg −1 · min −1 ) BNP. Fs increased urinary flow, but the effect of Fs+BNP was greater. Similarly, urinary sodium excretion was higher in the Fs+BNP group. Although GFR tended to decrease in the Fs group, it increased in the Fs+BNP group (35±3 to 56±4*) (* indicates P <0.05 versus baseline) ( P <0.0001 between groups). Plasma aldosterone increased with Fs (41±10 to 100±11* ng/dL) but was attenuated in the Fs+BNP group (44±11 to 54±9 ng/dL low-dose and to 47±7 ng/dL high-dose) ( P =0.0007 between groups). Conclusions— Fs+BNP has more profound diuretic and natriuretic responses than Fs alone and also increases GFR without activation of aldosterone. Coadministration of BNP and loop diuretic is effective in maximizing natriuresis and diuresis while preserving renal function and inhibiting activation of aldosterone.

Mechanical unloading of the heart with a left ventricular assist device (LVAD) significantly decreases mortality in patients with heart failure. Moreover, it provides a human model to define the critical regulatory genes governing myocardial remodeling in response to significant reductions in wall stress. Statistical analysis of a gene expression library of 19 paired human heart samples harvested at the time of LVAD implant and again at explant revealed a set of 22 genes that were downregulated and 85 genes that were upregulated in response to mechanical unloading with a false discovery rate of less than 1%. The analysis revealed a high percentage of genes involved in the regulation of vascular networks including neuropilin-1 (a VEGF receptor), FGF9, Sprouty1, stromal-derived factor 1, and endomucin. Taken together these findings suggest that mechanical unloading alters the regulation of vascular organization and migration in the heart. In addition to vascular signaling networks, GATA-4 binding protein, a critical mediator of myocyte hypertrophy, was significantly downregulated following mechanical unloading. In summary, these findings may have important implications for defining the role of mechanical stretch and load on autocrine/paracrine signals directing vascular organization in the failing human heart and the role of GATA-4 in orchestrating reverse myocardial remodeling. This unbiased gene discovery approach in paired human heart samples has the potential to provide critical clues to the next generation of therapeutic treatments aimed at heart failure.

Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex. We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E ε4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether ε4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20–39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 ε4 heterozygotes, all with the ε3/ε4 genotype, and 15 noncarriers of the ε4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult ε4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middle-aged ε4 carriers, the young ε4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.

Background— While both the endothelin-1 (ET-1) and renin-angiotensin systems (RAS) are activated in congestive heart failure (CHF), the temporal sequence of this activation remains unclear. Understanding this pattern of neurohumoral activation may aid in understanding the significance of ET-1 in CHF and provide strategies for ET-1 antagonism. Although acute endothelin (ET) receptor antagonism improves systemic hemodynamics in CHF, clinical trials with chronic ET receptor antagonism report worsening CHF symptoms. Methods and Results— In a canine model of progressive left ventricular dysfunction, we demonstrated activation of myocardial and plasma ET-1 without activation of the RAS during transition to overt CHF, suggesting that ET-1 contributes to this transition. We next evaluated the effects of chronic oral ET-A receptor antagonism on neurohumoral function, renal hemodynamics, and sodium excretion in pacing-induced CHF. After 7 days of treatment (n=7) with ET-A receptor antagonism (with LU135252), sodium excretion did not improve in treated versus untreated CHF (n=6). Furthermore, both plasma renin activity and plasma ET-1 increased with ET-A receptor blockade. Conclusions— Activation of the myocardial and plasma ET-1 systems precedes activation of the myocardial and plasma RAS in CHF. ET-A receptor antagonism in experimental CHF further activates the RAS without improving sodium excretion. These findings suggest an important role for ET-1 in the progression of CHF and a potential mechanism for the exacerbation of CHF symptoms observed in clinical trials with chronic ET receptor antagonism. Further studies with combined modulation of the ET and other neurohumoral systems in CHF are required.