Citations

Background and Purpose —The National Institutes of Health Stroke Scale (NIHSS) is accepted widely for measuring acute stroke deficits in clinical trials, but it contains items that exhibit poor reliability or do not contribute meaningful information. To improve the scale for use in clinical research, we used formal clinimetric analyses to derive a modified version, the mNIHSS. We then sought to demonstrate the validity and reliability of the new mNIHSS. Methods —The mNIHSS was derived from our prior clinimetric studies of the NIHSS by deleting poorly reproducible or redundant items (level of consciousness, face weakness, ataxia, dysarthria) and collapsing the sensory item into 2 responses. Reliability of the mNIHSS was assessed with the certification data originally collected to assess the reliability of investigators in the National Institute of Neurological Disorders and Stroke (NINDS) rtPA (recombinant tissue plasminogen activator) Stroke Trial. Validity of the mNIHSS was assessed with the outcome results of the NINDS rtPA Stroke Trial. Results —Reliability was improved with the mNIHSS: the number of scale items with poor κ coefficients on either of the certification tapes decreased from 8 (20%) to 3 (14%) with the mNIHSS. With the use of factor analysis, the structure underlying the mNIHSS was found identical to the original scale. On serial use of the scale, goodness of fit coefficients were higher with the mNIHSS. With data from part I of the trial data, the proportion of patients who improved ≥4 points within 24 hours after treatment was statistically significantly increased by tPA (odds ratio, 1.3; 95% confidence limits, 1.0, 1.8; P =0.05). Likewise, the odds ratio for complete/nearly complete resolution of stroke symptoms 3 months after treatment was 1.7 (95% confidence limits, 1.2, 2.6) with the mNIHSS. Other outcomes showed the same agreement when the mNIHSS was compared with the original scale. The mNIHSS showed good responsiveness, ie, was useful in differentiating patients likely to hemorrhage or have a good outcome after stroke. Conclusions —The mNIHSS appears to be identical clinimetrically to the original NIHSS when the same data are used for validation and reliability. Power appears to be greater with the mNIHSS with the use of 24-hour end points, suggesting the need for fewer patients in trials designed to detect treatment effects comparable to rtPA. The mNIHSS contains fewer items and might be simpler to use in clinical research trials. Prospective analysis of reliability and validity, with the use of an independently collected cohort, must be obtained before the mNIHSS is used in a research setting.

Background and Purpose —The National Institutes of Health Stroke Scale (NIHSS) is a valid, reproducible scale that measures neurological deficit. Of 42 possible points, 7 points are directly related to measurement of language compared with only 2 points related to neglect. Methods —We examined the placebo arm of the NINDS t-PA stroke trial to test the hypothesis that the total volume of cerebral infarction in patients with right hemisphere strokes would be greater than the volume of cerebral infarction in patients with left hemisphere strokes who have similar NIHSS scores. The volume of stroke was determined by computerized image analysis of CT films and CT images stored on computer tape and optical disks. Cube-root transformation of lesion volume was performed for each CT. Transformed lesion volume was analyzed in a logistic regression model to predict volume of stroke by NIHSS score for each hemisphere. Spearman rank correlation was used to determine the relation between the NIHSS score and lesion volume. Results —The volume for right hemisphere stroke was statistically greater than the volume for left hemisphere strokes, adjusting for the baseline NIHSS ( P <0.001). For each 5-point category of the NIHSS score <20, the median volume of right hemisphere strokes was approximately double the median volume of left hemisphere strokes. For example, for patients with a left hemisphere stroke and a 24-hour NIHSS score of 16 to 20, the median volume of cerebral infarction was 48 mL (interquartile range 14 to 111 mL) as compared with 133 mL (interquartile range 81 to 208 mL) for patients with a right hemisphere stroke ( P <0.001). The median volume of a right hemisphere stroke was roughly equal to the median volume of a left hemisphere stroke in the next highest 5-point category of the NIHSS. The Spearman rank correlation between the 24-hour NIHSS score and 3-month lesion volume was 0.72 for patients with left hemisphere stroke and 0.71 for patients with right hemisphere stroke. Conclusions —For a given NIHSS score, the median volume of right hemisphere strokes is consistently larger than the median volume of left hemisphere strokes. The clinical implications of our finding need further exploration.

Background— The objective of the present study was to investigate the effect of cardiac resynchronization therapy (CRT) on cardiac autonomic function. Methods and Results— This prospective study included 45 consecutive patients with heart failure who received CRT devices with defibrillator and 20 age-matched, healthy control subjects. At baseline and 3 months and 6 months after CRT, we assessed New York Heart Association (NYHA) class, 6-minute walk distance, plasma sympathetic biomarker nerve growth factor, echocardiography, heart rate variability and cardiac presynaptic sympathetic function determined by iodine 123 metaiodobenzylguanidine scintigraphy. After CRT, NYHA class improved by 1 class ( P <0.001), and left ventricular ejection fraction increased by 8% ( P <0.001). Along with improvement in the standard deviation of all normal-to-normal R-R intervals (85.63±31.66 ms versus 114.79±38.99 ms; P =0.004) and the standard deviation of the averaged normal-to-normal R-R intervals (82.62±23.03 ms versus 100.50±34.87 ms; P =0.004), the delayed heart/mediastinum (H/M) ratio increased (1.82 [0.58] versus 1.97 [0.59]; P =0.03), whereas the mean (SD) H/M washout rate was reduced (48% [19%] versus 37% [22%]; P =0.01). Twenty-two of 45 study patients responded to CRT, with a reduction of left ventricular end-systolic volume index >15%. Compared with nonresponders, responders had a higher delayed H/M ratio (2.11 versus 1.48; P =0.003) and lower H/M washout rate (37% versus 62%; P =0.003) at baseline. Conclusions— CRT improved sympathetic function. Cardiac sympathetic reserve may be a marker for the reversibility of failing myocardial function.

Abstract DNA topoisomerase IIα (Topo IIα) is a critical target for cancer therapy and its protein expression, however, is frequently depleted by its inhibitors and strategies to maintain Topo IIα expression and thereby to sustain the Topo II drug sensitivity are still lacking. Here we show that p38γ MAPK is specifically activated by Topo II inhibitors and activated p38γ in turn phosphorylates Topo IIα, leading to increased Topo IIα protein expression through attenuating its proteasome-dependent degradation. The sensitivity of a panel of human breast cancer cell lines to Topo II inhibitors was found not to correlate with the intrinsic but with inducible Topo IIα protein expression and with endogenous protein expression of p38γ MAPK that is specifically phosphorylated in response to Topo II toxins. p38γ activation and inhibition alone were shown to increase and decrease Topo IIα expression and Topo drug toxicities. Mechanistically, p38γ MAPK phosphorylates Topo IIα at Ser 1524, leading to a decreased proteasome-dependent Topo IIα degradation. These results reveal a novel mechanism by which p38γ MAPK specifically confers Topo II drug toxicity in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 317.

Background— Right ventricular pacing increases the risk of heart failure in adults with structural heart disease. The impact of prolonged right ventricular pacing in adults without structural heart disease is not fully characterized and may depend on interactions of pacing with abnormal substrate predisposing to ventricular dysfunction. Methods and Results— We assessed the effect of right ventricular pacing in patients who underwent pacemaker implantation for isolated congenital atrioventricular block between 1964 and 2005. To assess for immunologic contribution to cardiac dysfunction, outcomes were compared between patients with (Ab + ) and without (Ab − ) antinuclear antibody during adulthood and an age- and sex-matched Olmsted County, Minnesota, population. Of 103 patients (mean±SD age, 32±19 years), 18 were Ab + . Long-term survival free of new heart failure after pacemaker implantation in isolated congenital atrioventricular block patients was worse than in the matched population ( P <0.001). This difference was attributable to the development of heart failure in 12 Ab + patients (67%; P <0.001), without differences between Ab − patients (2%) and the matched population (2%; P =0.7). Compared with baseline, at last follow-up, left ventricular ejection fraction did not decline in Ab − (53±9% to 57±12%) but decreased in Ab + (52±10% to 38±12%; P =0.03) patients. Survival was similar in Ab − patients and the Minnesota population (98%; P =0.7) but worse in Ab + patients (79%; P <0.01). Conclusions— The natural history of patients with isolated congenital atrioventricular block who require pacing depends upon their antibody status. Antinuclear antibody status was a predictor for the development of heart failure and death. Long-term right ventricular pacing alone does not appear to be associated with development of heart failure, deterioration in ventricular function, or reduced survival in Ab − isolated congenital atrioventricular block patients.

Abstract We describe a young woman who acquired a painful, diffuse osteosclerosis of the cervical, thoracic, and lumbar spine, pelvis, and long bones of the legs as an adult. Bone densitometry showed a large increase in apparent bone density. Skeletal radiographs demonstrated progressive endosteal and periosteal thickening of the cortices. A bone scan showed increased uptake of radiolabel. The serum total alkaline phosphatase and 1,25-(OH)2D3 levels were substantially elevated and the immunoreactive PTH was mildly elevated. Bone biopsy showed increased bone turnover, especially on endocortical and intracortical surfaces, but the structural indices were normal. By 4 years after presentation the bone pain had remitted and the serum alkaline phosphatase, 1,25-(OH)2D3, and PTH were normal. No cause for the occurrence of osteosclerosis in this patient could be found.

Purpose Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved. Patients and Methods Acute GVHD risk factors were analyzed in 1,960 adults after HLA-identical sibling myeloablative transplant for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML) reported by 226 centers worldwide to the Center for International Blood and Marrow Transplant Research from 1995 to 2002. Outcome was measured as time from transplant to onset of grade 2 to 4 acute GVHD, with death without acute GVHD as a competing risk. Results Cumulative incidence of grade 2 to 4 acute GVHD was 35% (95% CI, 33% to 37%). In multivariable analyses, factors significantly associated with grade 2 to 4 acute GVHD were cyclophosphamide + total-body irradiation versus busulfan + cyclophosphamide (relative risk [RR] = 1.4; P < .0001), blood cell versus bone marrow grafts in patients age 18 to 39 years (RR = 1.43; P = .0023), recipient age 40 and older versus age 18 to 39 years receiving bone marrow grafts (RR = 1.44; P = .0005), CML versus AML/ALL (RR = 1.35; P = .0003), white/Black versus Asian/Hispanic race (RR = 1.54; P = .0003), Karnofsky performance score less than 90 versus 90 to 100 (RR = 1.27; P = .014), and recipient/donor cytomegalovirus-seronegative versus either positive (RR = 1.20; P = .04). Stratification by disease showed the same significant predictors of grade 2 to 4 acute GVHD for CML; however, KPS and cytomegalovirus serostatus were not significant predictors for AML/ALL. Conclusion This analysis confirmed several previously reported risk factors for grade 2 to 4 acute GVHD. However, several new factors were identified whereas others are no longer significant. These new data may facilitate individualized risk estimates and raise several interesting biologic questions.