Usefulness of heart rate as an independent predictor for survival after heart transplantation.
It was unclear whether increased heart rate (HR) increased long-term mortality after heart transplantation (HT). The aim of this study was to evaluate whether HR predicted survival after HT. A retrospective analysis of patients who underwent HT at our institution was performed. Ethnicity, gender, date of birth, age at transplantation, length of follow-up after transplantation, cardiac rhythm within 3 months after transplantation, age at death, reason for transplantation, cause of death, and baseline medications after transplantation were recorded. Continuous variables, such as HR, blood pressure, cardiac ejection fraction, presence of allograft vasculopathy, and serum creatinine, were recorded at <3 months, 6 months, and 1 year after HT, then annually to 10 years after HT. Seventy-eight patients with a mean age of 50 +/- 13 years were identified. Mean survival was 8.5 +/- 6.5 years. Of 78 patients, 32 patients had an HR 90 beats/min within 3 months after HT. There was a mean decrease in HR of 6 beats/min during 10 years (p <0.03). Multivariate survival analysis showed that HR >90 beats/min was a significant predictor of early mortality (hazard ratio 2.8, 95% confidence interval 1.5 to 5.1, p <0.0013). Patients with a net increase in HR during 10 years had an increased risk of death compared with patients with no change or a net decrease in HR (hazard ratio 4.7, 95% confidence interval 1.9 to 12.0, p <0.002). No significant differences in cause of death between patients with an HR 90 beats/min existed. In conclusion, HT patients with an HR >90 beats/min within the first 3 months after HT were 2.8 times more likely to die than patients with an HR
Association of healthy aging with parental longevity.
Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI34 scores were computed from 34 common health variables and compared between the two groups. The FI34 was better correlated than chronological age with mortality. The mean FI34 value of the OSLP was 31 % higher than that of the OLLP (P = 0.0034). The FI34 increased exponentially, at an instantaneous rate that accelerated 2.0 % annually in the OLLP (P = 0.024) and 2.7 % in the OSLP (P < < 0.0001) consequently yielding a 63 % larger accumulation in the latter group (P = 0.0002). The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, sib pairs were significantly correlated regarding FI34 scores, and heritability of the FI34 was estimated to be 0.39. Finally, hierarchical clustering suggests that the OLLP and OSLP differ in their aging patterns. Variation in the FI34 is, in part, due to genetic variation; thus, the FI34 can be a phenotypic measure suitable for genetic analyses of healthy aging.
High-throughput screening of stem cell therapy for globoid cell leukodystrophy using automated neurophenotyping of twitcher mice.
Globoid cell leukodystrophy (Krabbes disease) is an autosomal recessive neurodegenerative disorder that results from the deficiency of galactosylceramidase, a lysosomal enzyme involved in active myelination. Due to the progressive, lethal nature of this disease and the limited treatment options available, multiple laboratories are currently exploring novel therapies using the mouse model of globoid cell leukodystrophy. In order to establish a protocol for motor function assessment of the twitcher mouse, this study tested the capability of an automated system to detect phenotypic differences across mouse genotypes and/or treatment groups. The sensitivity of this system as a screening tool for the assessment of therapeutic interventions was determined by the administration of murine bone marrow-derived stem cells into twitcher mice via intraperitoneal injection. Animal behavior was analyzed using the Noldus EthoVision XT7 software. Novel biomarkers, including abnormal locomotion (e.g., velocity, moving duration, distance traveled, turn angle) and observed behaviors (e.g., rearing activity, number of defecation boli), were established for the twitcher mouse. These parameters were monitored across all mouse groups, and the automated system detected improved locomotion in the treated twitcher mice based on the correction of angular velocity, turn angle, moving duration, and exploratory behavior, such as thigmotaxis. Further supporting these findings, the treated mice showed improved lifespan, gait, wire hang ability, twitching severity and frequency, and sciatic nerve histopathology. Taken together, these data demonstrate the utility of computer-based neurophenotyping for motor function assessment of twitcher mice and support its utility for detecting the efficacy of stem cell-based therapy for neurodegenerative disorders.
Diagnosing PTSD in early childhood: an empirical assessment of four approaches.
Prior studies have argued that the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria were insensitive for diagnosing posttraumatic stress disorder (PTSD) in young children. Four diagnostic criteria sets were examined in 284 3- to 6-year-old trauma-exposed children. The DSM-IV criteria resulted in significantly fewer cases (13%) compared to an alternative algorithm for young children (PTSD-AA, 45%), the proposed DSM-5 posttraumatic stress in preschool children (44%), and the DSM-5 criteria with 2 symptoms that are under consideration by the committee (DSM-5-UC, 49%). Using DSM-IV as the standard, the misclassification rate was 32% for PTSD-AA, 32% for DSM-5, and 37% for DSM-5-UC. The proposed criteria sets showed high agreement on the presence (100%), but low agreement on the absence (58-64%) of diagnoses. The misclassified cases were highly symptomatic, M = 7 or more symptoms, and functionally impaired, median = 2 domains impaired. The additional symptoms had little impact. Evidence for convergent validation for the proposed diagnoses was shown with elevations on comorbid disorders and Child Behavior Checklist Total scores compared to a control group (n = 46). When stratified by age (3-4 years and 5-6 years), diagnoses were still significantly elevated compared to controls. These findings lend support to a developmental subtype for PTSD.
Interleukin-17 promotes formation and growth of prostate adenocarcinoma in mouse models.
The contributions of interleukin (IL)-17 to cancer remain unclear and somewhat controversial. We took a genetic approach to explore its role in prostate cancers by interbreeding IL-17 receptor C (IL-17RC)-deficient mice with mice that are conditionally mutant for PTEN, one established preclinical model for prostate cancer. Mice that were IL-17RC-deficient (IL-17RC(-)) displayed prostates that were smaller than mice that maintained IL-17RC expression (IL-17RC(+)). In addition, IL-17RC(-) mice developed a reduced number of invasive prostate adenocarcinomas with lower rates of cellular proliferation and higher apoptosis than IL-17RC(+) mice. Moreover, the fibromuscular stroma surrounding prostatic glands was relatively thicker in IL-17RC(-) mice and was associated with decreased matrix metalloproteinase (Mmp)7 expression and increased Timp1, 2, and 4 expression, whereas administration of recombinant mouse IL-17 induced prostatic expression of Mmp7. Taken together, our results suggested that IL-17 promotes the formation and growth of prostate adenocarcinoma, and that an IL-17-MMP7 signaling axis is required for the transition of prostatic intraepithelial neoplasia to frank adenocarcinoma.