Joan Skurnick

Telomere Length as an Indicator of Biological Aging: The Gender Effect and Relation With Pulse Pressure and Pulse Wave Velocity

Chronological age is the primary determinant of stiffness of central arteries. Increased stiffness is an independent indicator of cardiovascular risk. The aim of this study was to determine whether telomere length, a possible index of biological aging, provides a better account than chronological age for variation in arterial stiffness, evaluated by measuring pulse pressure and aortic pulse wave velocity. The study population included 193 French subjects (120 men, 73 women), with a mean age of 56±11 years, who were not on any antihypertensive medications. Telomere length was evaluated in white blood cells by measuring the mean length of the terminal restriction fragments. Age-adjusted telomere length was longer in women than in men (8.67±0.09 versus 8.37±0.07 kb;P =0.016). In both genders, telomere length was inversely correlated with age (P <0.01). Multivariate analysis showed that in men, but not in women, telomere length significantly contributed to pulse pressure and pulse wave velocity variations. In conclusion, telomere length provides an additional account to chronological age of variations in both pulse pressure and pulse wave velocity among men, such that men with shorter telomere length are more likely to exhibit high pulse pressure and pulse wave velocity, which are indices of large artery stiffness. The longer telomere length in women suggests that for a given chronological age, biological aging of men is more advanced than that of women.

Telomere Length in the Newborn

Telomere length is similar in different organs of the human fetus but variable among fetuses. During extrauterine life telomere length is highly variable among individuals and longer in women than men. In the present work we addressed the following questions:1) Are there sex-related differences in telomere length at birth? 2) Is there synchrony (i.e. correlation in length) of telomeres in tissues within the newborn? 3) Is the variability in telomere length among newborns as large as that in adults? We studied normal male and female newborns who donated DNA samples from three sources: white blood cells, umbilical artery, and foreskin. Telomere length was measured by the mean length of the terminal restriction fragments (TRF). TRF length was not different between male and female newborns. It was highly synchronized among the DNA samples from white blood cells, umbilical artery and skin within individual donors but exhibited a high variability among donors. We conclude that there is no evidence for the effect of sex on telomere length at birth, suggesting that longer telomeres in women than men arise from a slower rate of telomeric attrition in women. The variability in telomere length among newborns and synchrony in telomere length within organs of the newborn are consistent with the concept that variations in telomere length among adults are in large part attributed to determinants (genetic and environmental) that start exerting their effect in utero.

Telomere Length Inversely Correlates With Pulse Pressure and Is Highly Familial

There is evidence that telomeres, the ends of chromosomes, serve as clocks that pace cellular aging in vitro and in vivo. In industrialized nations, pulse pressure rises with age, and it might serve as a phenotype of biological aging of the vasculature. We therefore conducted a twin study to investigate the relation between telomere length in white blood cells and pulse pressure while simultaneously assessing the role of genetic factors in determining telomere length. We measured by Southern blot analysis the mean length of the terminal restriction fragments (TRF) in white blood cells of 49 twin pairs from the Danish Twin Register and assessed the relations of blood pressure parameters with TRF. TRF length showed an inverse relation with pulse pressure. Both TRF length and pulse pressure were highly familial. We conclude that telomere length, which is under genetic control, might play a role in mechanisms that regulate pulse pressure, including vascular aging.

Urinary incontinence predictors and life impact in ethnically diverse perimenopausal women.

OBJECTIVE To document prevalence of mild, moderate, and severe urinary incontinence among ethnically diverse perimenopausal women, identify risk factors, and assess the effect of severity on womens daily lives using treatment seeking, bother, and nighttime voiding as indicators. METHODS Baseline data from the longitudinal cohort of the Study of Womens Health Across the Nation, a prospective, multiethnic, multisite study of the natural history of menopausal transition was used (n = 3302). Interview and self‐completed questionnaires assessed most variables of interest. Body mass index and diabetes mellitus were measured clinically. Incontinence severity was derived by multiplying frequency by volume leaked. Risk factors and effect on treatment seeking, bother, and nighttime voiding were assessed by the construction of multiple logistic regression models for each ethnic group and the total population. RESULTS Mean age was 46.4 years. Incontinence prevalence was 57%, with nearly 15% categorized as moderate and 10% as severe. Biologic factors constituted the most important risk for severity, specifically perimenopausal compared with premenepausal status (odds ratio [OR] 1.35), body mass index (OR 1.04), diabetes mellitus (OR 1.55), and current smoking (OR 1.38). Nonwhite groups had lower risk, but the relationship of ethnicity is complex. Severity was associated with likelihood of discussing with a health care provider, with bothersomeness, and with likelihood of nighttime voiding. CONCLUSION Large numbers of perimenopausal women experience urinary incontinence with 25% wearing protection or changing undergarments on several days per week. Mutable factors predicting severity included body mass index and current smoking.

Sexual functioning and practices in a multi‐ethnic study of midlife women: Baseline results from swan

This study examined the sexual practices and function of midlife women by ethnicity (African American, Caucasian, Chinese, Hispanic, Japanese) and menopausal status. Sexual behavior was compared in 3,262 women in the baseline cohort of SWAN. Participants were 42 to 52 years old, premenopausal or early perimenopausal, and not hysterectomized or using hormones. Analysis used multivariate proportional odds regression. In our sample, 79% had engaged in sex with a partner in the last 6 months, and a third considered sex to be very important. Common reasons for no sex (n = 676) were lack of partner (67%), lack of interest (33%), and fatigue (16%). Compared with Caucasians, Japanese and Chinese women were less likely, and African Americans more likely, to report sex as very important (p < 0.005). Significant ethnic differences were found for frequency of all practices. Perimenopause status was associated only with higher frequencies of masturbation and pain during intercourse.

Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths

In this protocol we describe a method to obtain telomere length parameters using Southern blots of terminal restriction fragments (TRFs). We use this approach primarily for epidemiological studies that examine leukocyte telomere length. However, the method can be adapted for telomere length measurements in other cells whose telomere lengths are within its detection boundaries. After extraction, DNA is inspected for integrity, digested, resolved by gel electrophoresis, transferred to a membrane, hybridized with labeled probes and exposed to X-ray film using chemiluminescence. Although precise and highly accurate, the method requires a considerable amount of DNA (3 μg per sample) and it measures both the canonical and noncanonical components of telomeres. The method also provides parameters of telomere length distribution in each DNA sample, which are useful in answering questions beyond those focusing on the mean length of telomeres in a given sample. A skilled technician can measure TRF length in ∼130 samples per week.

Admission or Observation Is Not Necessary after a Negative Abdominal Computed Tomographic Scan in Patients with Suspected Blunt Abdominal Trauma: Results of a Prospective, Multi-institutional Trial

OBJECTIVES Hospitalization for observation is the current standard of practice for patients who have sustained blunt abdominal trauma and who do not require emergent operation, despite having undergone diagnostic studies that exclude the presence of an intra-abdominal injury. The reasons for this practice are multifactorial and include the perceived false-negative rate of all standard diagnostic tests, the belief that hospitalization will allow for the prompt diagnosis of occult injuries, and medicolegal considerations about the risk of early discharge. The focus of this study was to determine whether hospitalization for observation is necessary after a negative diagnostic evaluation after blunt abdominal trauma, to determine the negative predictive value of abdominal computed tomographic (CT) scanning in a prospective series of patients, and to identify which patients can be safely released from the emergency department without observation or hospitalization after blunt abdominal trauma. METHODS In a prospective, multi-institutional study over 22 months at four Level I trauma centers, all patients with blunt abdominal trauma suspected by either physical examination or mechanism of injury were evaluated using the following protocol: physical examination in the emergency department, followed by abdominal CT scanning, followed by hospitalization for observation. The standardized physical examination was repeated between 4 and 8 hours. Outcomes were measured at 20 hours and at discharge and included clinical deterioration, the need for celiotomy, and mortality. Other data collected included demographics, mechanism of injury, and findings on physical examination and abdominal CT scanning. RESULTS Three thousand eight hundred twenty-two consecutive patients with suspected abdominal trauma presented to the four trauma centers. Two thousand seven hundred seventy-four of these met study eligibility criteria and were prospectively enrolled. Of these, 2299 fulfilled the entire study protocol. CT scan was negative in 1,809 patients, positive for organ injury or abdominal fluid in 389 patients, and nondiagnostic in 78 patients. Abdominal tenderness or bruising was present in 1,380 patients (61%), but only 22% had a positive CT scan. Nineteen percent of patients with a positive CT scan had no tenderness. Computed tomography detected 22 of the 25 blunt intestinal injuries in this series. Free intraperitoneal fluid without solid visceral injury was present in 90 patients, and but only 7 patients had intestinal injuries. There were nine celiotomies in patients whose CT scan was initially interpreted as negative: six were therapeutic (intestine in three, bladder in one, kidney in one, and diaphragm in one), two were nontherapeutic, and one was negative. The negative predictive power of an abdominal CT scan based on the preliminary reading and as defined by the subsequent need for a celiotomy in the population fully satisfying the protocol was 99.63% (lower 95 and 99% confidence bounds of 99.31 and 99.16%, respectively). CONCLUSION These data indicate that abdominal tenderness is not predictive of an abdominal injury and that patients with a negative CT scan after suspected blunt abdominal trauma do not benefit from hospital admission and prolonged observation.

Telomere attrition of the human abdominal aorta: relationships with age and atherosclerosis

Little is known about the turnover rate (i.e. the rate of replication and death) of cells in the intima and media of human arteries as a function of age and atherosclerosis. One indicator of the replicative history of cells is telomere length. In this work we explored the rate of telomere attrition as a function of age and atherosclerosis in cells of the human abdominal aorta. Telomere length, measured by the terminal restriction fragment using Southern analysis, was determined in the intima and media of the distal (infrarenal) versus proximal (suprarenal) segments of the abdominal aorta. Telomere length was then correlated with age and atherosclerotic grade. The rate of age-dependent telomere attrition was higher in both the intima and media of the distal versus proximal abdominal aorta. In addition, telomere length was negatively correlated with atherosclerotic grade. However, after adjustment for age, this relationship was not statistically significant. The high rate of age-dependent telomere attrition in the distal abdominal aorta probably reflects enhanced cellular turnover rate due to local factors such as an increase in shear wall stress in this vascular segment.

Efficacy of treatment of MS with IFNβ-1b or glatiramer acetate by monthly brain MRI in the BECOME study

Background: There are no published MRI studies comparing interferon beta 1b (IFNβ-1b) and glatiramer acetate (GA) for treatment of relapsing multiple sclerosis (MS). Objective: To compare the efficacy of IFNβ-1b and GA for suppression of MS disease activity as evidenced on frequent brain MRI. Methods: A total of 75 patients with relapsing-remitting MS or clinically isolated syndromes were randomized to standard doses of IFNβ-1b or GA and followed by monthly brain MRI for up to 2 years with a protocol optimized to detect enhancement. The primary outcome was the number of combined active lesions (CAL) per patient per scan during the first year, which included all enhancing lesions and nonenhancing new T2/fluid-attenuated inversion recovery (FLAIR) lesions. Secondary outcomes were the number of new lesions and clinical exacerbations over 2 years. Results: Baseline characteristics were similar between the groups. The primary outcome showed similar median (75th percentile) CAL per patient per scan for months 1–12, 0.63 (2.76) for IFNβ-1b, and 0.58 (2.45) for GA (p = 0.58). There were no differences in new lesion or clinical relapses for 2 years. Only 4.4% of CAL on monthly MRI scans were nonenhancing new T2/FLAIR lesions. Conclusion: Patients with relapsing multiple sclerosis randomized to interferon beta 1b or glatiramer acetate showed similar MRI and clinical activity.

Emergency Department Discharge of Patients With a Negative Cranial Computed Tomography Scan After Minimal Head Injury

OBJECTIVE To determine the negative predictive value of cranial computed tomography (CT) scanning in a prospective series of patients and whether hospital admission for observation is mandatory after a negative diagnostic evaluation after minimal head injury (MHI). SUMMARY BACKGROUND DATA Hospital admission for observation is a current standard of practice for patients who have sustained MHI, despite having undergone diagnostic studies that exclude the presence of an intracranial injury. The reasons for this practice are multifactorial and include the perceived false-negative rate of all standard diagnostic tests, the belief that admission will allow prompt diagnosis of occult injuries, and medicolegal considerations about the risk of early discharge. METHODS In a prospective, multiinstitutional study during a 22-month period at four level I trauma centers, all patients with MHI were evaluated using the following protocol: a standardized physical and neurologic examination in the emergency department, cranial CT scanning, and then admission for observation. MHI was defined as either a documented loss of consciousness or evidence of posttraumatic amnesia and an emergency department Glasgow Coma Scale score of 14 or 15. Outcomes were measured at 20 hours and at discharge and included clinical deterioration, need for craniotomy, and death. RESULTS Two thousand one hundred fifty-two consecutive patients fulfilled the study protocol. The CT was interpreted as negative for intracranial injury in 1,788, positive in 217, and equivocal in 119. Five patients with CT scans initially interpreted as negative required intervention. There was one craniotomy in a patient whose CT scan was initially interpreted as negative. This patient had facial fractures that required surgical intervention and elevation of depressed intracranial fracture fragments. The negative predictive power of a cranial CT scan based on the preliminary reading of the CT scan and defined by the subsequent need for neurosurgical intervention in the population fully satisfying the protocol was 99.70%. CONCLUSIONS Patients with a cranial CT scan, obtained on a helical CT scanner, that shows no intracerebral injury and who do not have other body system injuries or a persistence of any neurologic finding can be safely discharged from the emergency department without a period of either inpatient or outpatient observation. Implementation of this practice could result in a potential decrease of more than 500,000 hospital admissions annually.