MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction

Pathological remodeling of the left ventricle (LV) after myocardial infarction (MI) is a major cause of heart failure. Although cardiac hypertrophy after increased loading conditions has been recognized as a clinical risk factor for human heart failure, it is unknown whether post-MI hypertrophic remodeling of the myocardium is beneficial for cardiac function over time, nor which regulatory pathways play a crucial role in this process. To address these questions, transgenic (TG) mice engineered to overexpress modulatory calcineurin-interacting protein-1 (MCIP1) in the myocardium were used to achieve cardiac-specific inhibition of calcineurin activation. MCIP1-TG mice and their wild-type (WT) littermates, were subjected to MI and analyzed 4 weeks later. At 4 weeks after MI, calcineurin was activated in the LV of WT mice, which was significantly reduced in MCIP1-TG mice. WT mice displayed a 78% increase in LV mass after MI, which was reduced by 38% in MCIP1-TG mice. Echocardiography indicated marked LV dilation and loss of systolic function in WT-MI mice, whereas TG-MI mice displayed a remarkable preservation of LV geometry and contractility, a pronounced reduction in myofiber hypertrophy, collagen deposition, and beta-MHC expression compared with WT-MI mice. Together, these results reveal a protective role for MCIP1 in the post-MI heart and suggest that calcineurin is a crucial regulator of postinfarction-induced pathological LV remodeling. The improvement in functional, structural, and molecular abnormalities in MCIP1-TG mice challenges the adaptive value of post-MI hypertrophy of the remote myocardium. The full text of this article is available online at http://circres.ahajournals.org.     

Failure of adult marrow-derived stem cells to generate marrow stroma after successful hematopoietic stem cell transplantation

OBJECTIVE: The existence of adult, marrow-derived stem cells that retain the ability to generate various tissues is an appealing concept that has considerable therapeutic potential. The aim of this study was to test the extent of this proposed plasticity by defining the ability of adult marrow and peripheral blood stem cells to generate stromal cells of the marrow microenvironment. PATIENTS AND METHODS: We examined expanded populations of stromal cells from four patients 1 to 27 years after allogeneic, sex-mismatched marrow, or peripheral blood stem cell transplantation. The cultured stromal cells were stained by immunofluorescence and with nonspecific esterase (NSE) to detect macrophages, which can constitute a significant component of a primary long-term marrow culture. Fluorescence in situ hybridization (FISH) probes for chromosomes X and Y were applied to distinguish donor from host cells. RESULTS: FISH analysis of replicate slides indicated a good correlation between the number of NSE(+) cells and the number of donor-derived cells. By applying NSE and FISH to the same cells and capturing both bright-field and epifluorescence images, we confirmed that all donor signals were derived from NSE(+) macrophages. CONCLUSION: After successful allogeneic stem cell transplantation, the marrow stroma remains host in origin, even after 27 years of 100% donor hematopoiesis.     

Associations of Uncertainty With Psychological Health and Quality of Life in Older Adults With Advanced Cancer

ContextOlder adults with advanced cancer face uncertainty related to their disease and treatment.ObjectivesTo evaluate the associations of uncertainty with psychological health and quality of life (QoL) in older adults with advanced cancer.MethodsSecondary cross-sectional analysis of baseline data from a national clustered geriatric assessment trial. Patients 70 years and older with advanced cancer considering a new line of chemotherapy were recruited. We measured uncertainty using the modified nine-item Mishel Uncertainty in Illness Scale. Dependent variables included anxiety (Generalized Anxiety Disorder-7), depression (Generalized Depression Scale-15), distress (distress thermometer), QoL (Functional Assessment of Cancer Therapy—General), and emotional well-being (Functional Assessment of Cancer Therapy—General subscale). We used multivariate linear regression analyses to evaluate the association of uncertainty with each dependent variable. We conducted a partial least squares analysis with a variable importance in projection (VIP) plot to assess the contribution of individual variables to the model. Variables with a VIP <0.8 were considered less influential.ResultsWe included 527 patients (median age 76 years; range 70–96). In multivariate analyses, higher levels of uncertainty were significantly associated with greater anxiety (β = 0.11; SE = 0.04), depression (β = 0.09; SE = 0.02), distress (β = 0.12; SE = 0.02), as well as lower QoL (β = ?1.08; SE = 0.11) and emotional well-being (β = ?0.29; SE = 0.03); the effect sizes were considered small. Uncertainty items related to disease and treatment were most strongly associated with psychological health and QoL scores (all VIP >0.8).ConclusionUncertainty among older patients with advanced cancer is associated with worse psychological health and QoL. Tailored uncertainty management strategies are warranted.     

Critical Re-examination of the Specificity of Auto-anti-Rh Antibodies in Patients with a Positive Direct Antiglobulin Test

Forty-eight autoantibodies with apparent 'simple' anti-Rh specificity (anti-e, -E, -c, -D, -C, -Ce, -G), have been studied by means of multiple absorption tests. The finding that 34 (70.8%) of these antibodies could bind to red blood cells lacking the antigens that the antibodies appeared to define, indicated that the antibodies had different specificities than seemed to be the case in initial antibody identification tests. Those autoantibodies that at first appeared to be directed against the Rh antigens e, E or c, most often had anti-Hr or anti-Hro specificity. These data explain why some apparent anti-Rh autoantibodies can be eluted from the red blood cells of patients negative for the antigens that the antibodi:s appear to define. However, they also illustrate that the phenomenon of autoantibodies mimicking specificities that they do not possess is common in patients positive for the antigens against which their autoantibodies appear to be directed. An explanation for the mode of action of these autoantibodies in complexing with the Rh agglutinogen is proposed, and the significance of the antibodies in transfusion therapy is considered.     

Effects of bacterial vaginosis and other genital infections on the natural history of human papillomavirus infection in HIV-1-infected and high-risk HIV-1-uninfected women

BACKGROUND: Whether the natural history of human papillomavirus (HPV) infection is affected by bacterial vaginosis (BV) or Trichomonas vaginalis (TV) infection has not been adequately investigated in prospective studies. METHODS: Human immunodeficiency virus 1 (HIV-1)-infected (n=1763) and high-risk HIV-1-uninfected (n=493) women were assessed semiannually for BV (by Nugent's criteria), TV infection (by wet mount), type-specific HPV (by polymerase chain reaction with MY09/MY11/HMB01 HPV primers), and squamous intraepithelial lesions (SIL) (by cytological examination). Sexual history was obtained from patient report at each visit. Risk factors for prevalent and incident HPV infection and SIL were evaluated by use of multivariate models. RESULTS: BV was associated with both prevalent and incident HPV infection but not with duration of HPV infection or incidence of SIL. TV infection was associated with incident HPV infection and with decreased duration and lower prevalence of HPV infection. TV infection had no association with development of SIL. Effects of BV and TV infection were similar in HIV-1-infected and high-risk HIV-1-uninfected women. HIV-1 infection and low CD4(+) lymphocyte count were strongly associated with HPV infection and development of SIL. CONCLUSIONS: BV and TV infection may increase the risk of acquisition (or reactivation) of HPV infection, as is consistent with hypotheses that the local cervicovaginal milieu plays a role in susceptibility to HPV infection. The finding that BV did not affect persistence of HPV infection and that TV infection may shorten the duration of HPV infection helps explain the lack of effect that BV and TV infection have on development of SIL.     

Incidence and prevalence of dementia in the Cardiovascular Health Study

OBJECTIVES: To estimate the incidence and prevalence of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in the Cardiovascular Health Study (CHS) cohort. DESIGN: Longitudinal cohort study using prospectively and retrospectively collected data to evaluate dementia. SETTING: Four U.S. communities. PARTICIPANTS: There were 3,602 CHS participants, including 2,865 white and 492 African-American participants free of dementia, who completed a cranial magnetic resonance image between 1992 and 1994 and were followed for an average of 5.4 years. MEASUREMENTS: Dementia was classified by neurologist/psychiatrist committee review using neuropsychological tests, neurological examinations, medical records, physician questionnaires, and proxy/informant interviews. Demographics and apolipoprotein E (APOE) genotype were collected at baseline. Incidence by type of dementia was determined using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD and Alzheimer's Disease Diagnostic and Treatment Center's State of California criteria for VaD. RESULTS: Classification resulted in 227 persons with prevalent dementia at entry into the study and 480 incident cases during follow-up. Incidence rates of dementia scaled to age 80 were 34.7 per 1,000 person-years for white women, 35.3 for white men, 58.8 for African-American women, and 53.0 for African-American men. Sex differences were not significant within race. Adjusted for age and education, racial differences were only of borderline significance and may have been influenced by ascertainment methodology. Rates differed substantially by educational attainment but were only significant for whites. Those with the APOE epsilon4 allele had an incidence rate at age 80 of 56.4, compared with 29.6 for those without this allele (P<.001). In whites, type-specific incidence at age 80 was 19.2 for AD versus 14.6 for VaD. These rates were 34.7 and 27.2 for African Americans. At termination of observation, women had only a slightly higher prevalence of dementia (16.0%) than men (14.7%). CONCLUSION: Sex and racial differences were not found, and VaD was higher than reported in other studies. These data provide new estimates of dementia incidence in a community sample for projection of future burden.     

Effect of limb movements on orienting of attention in right-hemisphere stroke

A deficit disengaging attention from the ipsilesional space in order to re-orient toward the contralesional space has been reported after right-hemisphere stroke (disengage deficit) and has been related to the severity of visuospatial neglect. Neglect rehabilitation studies have shown that left limb movements improve leftward orienting; the effect, however, is variable, and the mechanism of improvement is uncertain. Thus, this study examined whether limb movements specifically reduce the underlying disengage deficit of attention after right-hemisphere stroke. The effects of active and passive limb movements (vs. no limb movement) on orienting were examined using a covert exogenously cued orienting task in groups of right-hemisphere stroke patients with and without a significant disengage deficit (DD+, DD?) and healthy older adults. As previously seen, disengage deficit scores of stroke patients were positively correlated with the severity of neglect. The leftward disengage deficit was not affected by either active or passive limb movements, however, although movements did have both alerting and distracting effects on other aspects of orienting. Thus, our results suggest that the benefits of limb movements may not be related to changes in the underlying disengage deficit, but may impact other processes that underlie left-sided orienting (e.g., arousal and voluntary strategies).