Citations

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow for detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state‐of‐the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory, and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real‐world situations so as to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally, and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

Metabolic syndrome (MetS) is associated with glomerular hyperfiltration and is a risk factor for chronic kidney disease, but the underlying mechanisms are poorly defined. This study tested the hypothesis that increased glomerular filtration rate (GFR) in early MetS is associated with renal adiposity and microvascular proliferation. Twelve MetS-prone Ossabaw pigs were randomized to 10 wk of a standard (lean, n = 6) or atherogenic (MetS, n = 6) diet. Kidney hemodynamics and function, perirenal fat volume, and tubular dynamics were assessed in vivo by multidetector computed tomography (CT) and blood oxygen level-dependent (BOLD)-MRI. Microvascular architecture was assessed ex vivo with micro-CT. Candidate injury mechanisms were evaluated in kidney tissue by Western blotting and histology. Basal GFR, renal blood flow, and renal cortical perfusion and volume were elevated in the MetS group. Perirenal and kidney tissue fat, proximal-nephron intratubular fluid concentration, and endothelial nitric oxide synthase expression were increased in MetS. GFR levels correlated with tissue triglyceride levels. Elevated spatial density of 20- to 40-μm cortical microvessels was accompanied by mild oxidative stress, inflammation, and with proximal tubular vacuolization. Medullary size and perfusion were relatively preserved, and BOLD-MRI showed intact medullary tubular response to furosemide. Increased GFR in early MetS is associated with renal adiposity and microvascular proliferation, which involve mainly the renal cortex and precede significant activation of oxidative stress and inflammation. Renal adiposity and proliferative microvessels may represent novel therapeutic targets for preserving renal function in early MetS.

Rationale: Although a cardioprotective function of target of rapamycin (TOR) signaling inhibition has been suggested by pharmacological studies using rapamycin, genetic evidences are still lacking. We explored adult zebrafish as a novel vertebrate model for dissecting signaling pathways in cardiomyopathy. Objective: We generated the second adult zebrafish cardiomyopathy model induced by doxorubicin. By genetically analyzing both the doxorubicin and our previous established anemia-induced cardiomyopathy models, we decipher the functions of TOR signaling in cardiomyopathies of different etiology. Methods and Results: Along the progression of both cardiomyopathy models, we detected dynamic TOR activity at different stages of pathogenesis as well as distinct effects of TOR signaling inhibition. Nevertheless, cardiac enlargement in both models can be effectively attenuated by inhibition of TOR signaling through short-term rapamycin treatment. To assess the long-term effects of TOR reduction, we used a zebrafish target of rapamycin ( ztor ) mutant identified from an insertional mutagenesis screen. We show that TOR haploinsufficiency in the ztor heterozygous fish improved cardiac function, prevented pathological remodeling events, and ultimately reduced mortality in both adult fish models of cardiomyopathy. Mechanistically, these cardioprotective effects are conveyed by the antihypertrophy, antiapoptosis, and proautophagy function of TOR signaling inhibition. Conclusions: Our results prove adult zebrafish as a conserved novel vertebrate model for human cardiomyopathies. Moreover, we provide the first genetic evidence to demonstrate a long-term cardioprotective effect of TOR signaling inhibition on at least 2 cardiomyopathies of distinct etiology, despite dynamic TOR activities during their pathogenesis.

Background— The efficacy of radiofrequency ablation for atrial fibrillation (AF) in patients with left ventricular (LV) systolic dysfunction and isolated diastolic dysfunction is uncertain. Methods and Results— A prospective cohort of patients with normal and abnormal LV function underwent ablation for antiarrhythmic drug (AAD)-refractory AF. Three groups were compared: 111 patients with systolic dysfunction, defined as LV ejection fraction (LVEF) ≤40%; 157 patients with isolated diastolic dysfunction but preserved LVEF ≥50%; and 100 patients with normal LV function. The primary end point was AAD-free AF elimination at 1 year after ablation. This end point was achieved in 62% of patients with systolic dysfunction, 75% of those with diastolic dysfunction, and 84% of controls ( P =0.007). AF control on or off AADs was achieved in 76% of patients with systolic dysfunction, 85% of those with diastolic dysfunction, and 89% of controls ( P =0.08). In the systolic dysfunction group, 49% experienced an increase in LVEF by ≥5% after ablation, of which 64% achieved normal LVEF. In the diastolic dysfunction group, 30% of patients demonstrated at least 1 grade improvement in diastolic dysfunction. Multivariable analysis demonstrated an increased relative risk of arrhythmia recurrence of 1.8 (95% CI, 1.1 to 3.1; P =0.02) in systolic dysfunction and 1.7 (1.0 to 2.7; P =0.04) in isolated diastolic dysfunction compared with normal function. Conclusions— Although an ablative approach for AF in patients with systolic or diastolic dysfunction is associated with an increased long-term recurrence risk, there is potential for substantial quality-of-life improvement and LV functional benefit.

AbstractA phase 2 study of the oral farnesyltransferase inhibitor tipifarnib was conducted in 93 adult patients with relapsed or refractory lymphoma. Patients received tipifarnib 300 mg twice daily on days 1-21 of each 28-day cycle. The median number of prior therapies was 5 (range, 1-17). For the aggressive B-cell, indolent B-cell, and T-cell and Hodgkin lymphoma (HL/T) groups, the response rates were 17% (7/42), 7% (1/15), and 31% (11/36), respectively. Of the 19 responders, 7 were diffuse large B-cell non-Hodgkin lymphoma (NHL), 7 T-cell NHL, 1 follicular grade 2, and 4 HL. The median response duration for the 19 responders was 7.2 months (mean, 15.8 months; range, 1.8-62), and 5 patients in the HL/T group are still receiving treatment at 29-64+ months. The grade 3/4 toxicities observed were fatigue and reversible myelosuppression. Correlative studies suggest that Bim and Bcl-2 should be examined as potential predictors of response in future studies. These results indicate that tipifarnib has activity in lymphoma, particularly in heavily pretreated HL/T types, with little activity in follicular NHL. In view of its excellent toxicity profile and novel mechanism of action, further studies in combination with other agents appear warranted. This trial is registered at www.clinicaltrials.gov as #NCT00082888.

AbstractElevated serum levels of the soluble form of IL-2 receptor α (sIL-2Rα) have been correlated with a poor prognosis in a variety of different types of cancers. However, its biologic relevance remains unclear and controversial. In patients with follicular B-cell non-Hodgkin lymphoma (FL), we observed that serum sIL-2Rα levels were elevated compared with controls and that elevated sIL-2Rα levels before treatment were associated with a poor outcome. To explore the mechanism by which sIL-2Rα may contribute to a poor prognosis in FL, we determined the effects of sIL-2Rα on IL-2 signaling and found that the sIL-2Rα–IL-2 complex promoted T-cell differentiation toward to inhibitory Treg cells rather than TH1 or TH17 cells. Shed by activated T cells that express membrane-bound IL-2Rα, sIL-2Rα further enhanced IL-2–mediated phosphorylation of Stat5 thereby significantly up-regulating Foxp3 expression in CD4+ T cells. We found that CD4+ T cells treated with either IL-2 or sIL-2Rα–IL-2 complex, but not with sIL-2Rα alone, inhibited the function of CD8+ T cells. Taken together, these results indicate that sIL-2Rα actually plays an active biologic role in FL by binding IL-2 and promoting IL-2 signaling rather than depleting IL-2 and blocking its function.

Abstract Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with multiple myeloma (MM). We opened 2 sequential phase 2 trials using the pomalidomide with weekly dexamethasone (Pom/dex) regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Pomalidomide was given orally 2 or 4 mg daily with dexamethasone 40 mg weekly. Thirty-five patients were enrolled in each cohort. Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%. Overall survival at 6 months is 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity. This nonrandomized data suggests no advantage for 4 mg over the 2 mg daily. Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896.

To improve the predictive accuracy of the signal-averaged electrocardiogram, we created a linear logistic model for predicting ventricular tachycardia during electrophysiologic testing. This signal-averaged electrocardiographic model was created from data obtained from 214 patients undergoing electrophysiologic testing (70 had ventricular tachycardia during electrophysiologic testing) by using stepwise logistic regression to rank eight clinical and nine signal-averaged electrocardiographic variables. The best predictors were ejection fraction, history of infarction, ventricular ectopic pairs or nonsustained ventricular tachycardia on Holter monitoring, QRS duration after 25-Hz filtering, and root mean square voltage of the terminal 40 msec of the QRS complex after 40- and 80-Hz filtering. Cross validation (a statistical technique that can be used to accurately evaluate how a predictive model will perform on a prospective patient population) was used to validate the model. After cross validation, the model's sensitivity was 91% and specificity was 59% for predicting ventricular tachycardia during electrophysiologic testing. This model compared favorably with established 25-Hz late-potential criteria (QRS duration of more than 110 msec and root mean square voltage of less than 25 microV of the terminal 40 msec of the QRS complex; sensitivity, 64%; specificity, 85%) and with established 40-Hz late-potential criteria (QRS duration of more than 114 msec or root mean square voltage of less than 20 microV of the terminal 40 msec of the QRS complex or duration of the low-amplitude signal less than 40 microV at the terminal QRS complex that is greater than 38 msec; sensitivity, 84%; specificity, 54%).(ABSTRACT TRUNCATED AT 250 WORDS)

Studies of the population of Rochester, Minnesota, have provided the only data on temporal trends for the incidence of stroke in North America. Among the residents of Rochester, the average annual incidence rate of stroke declined by 46%, from 213 to 115 per 100,000 population, between 1950-1954 and 1975-1979. The decline occurred in all age and sex groups, but it occurred earlier in women than in men. The rates stabilized in the 1970s, and did so earlier in women. For 1980-1984, the incidence rate of stroke was 17% higher than that for 1975-1979. The onset of the decline in incidence rates coincided with the introduction of effective antihypertensive therapy, but stabilized and increased rates were associated with continuing improvement in the control of hypertension. The increase in the incidence rates of stroke coincided with the introduction of computed tomography, which appeared to increase the detection of less severe strokes.