Sarah J. Ratcliffe

Precision of the CASL-perfusion MRI technique for the measurement of cerebral blood flow in whole brain and vascular territories

To analyze the precision of cerebral blood flow (CBF) measurements made with continuous arterial spin labeling(CASL) perfusion magnetic resonance imaging (MRI) over experimentally relevant intervals.

Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization.

OBJECTIVE: Singleton neonates born after in vitro fertilization (IVF) are at increased risk for low birth weight, preterm delivery, or both. We sought to assess whether the alteration of the peri-implantation maternal environment resulting from ovarian stimulation may contribute to increased risk of low birth weight in IVF births. METHODS: The Society for Assisted Reproductive Technologies database was used to identify IVF-conceived neonates born in the United States between 2004 and 2006. Associations were assessed in neonates born after fresh compared with frozen and thawed embryo transfer in women of similar ovarian responsiveness, in paired analysis of neonates born to the same woman after both types of embryo transfer, and in neonates born after oocyte donation. RESULTS: Of 56,792 neonates identified, 38,626 and 18,166 were conceived after transfer of fresh and frozen embryos, respectively. In singletons, there was no difference in preterm delivery. However, the odds of overall low birth weight (10% compared with 7.2%; adjusted odds ratio [OR] 1.35; 95% confidence interval [CI] 1.20–1.51), low birth weight at term (2.5% compared with 1.2%, adjusted OR 1.73, 95% CI 1.31–2.29), and preterm low birth weight (34.1% compared with 23.8%, adjusted OR 1.49, 95% CI 1.24–1.78) were all significantly higher after fresh embryo transfer. In singletons, after either fresh or frozen embryo transfer in the same patient, this association was even stronger (low birth weight: 11.5% compared with 5.6%, adjusted OR 4.66, 95% CI 1.18–18.38). In oocyte donor recipients who do not undergo any ovarian hormonal stimulation for either a fresh or a frozen embryo transfer, no difference in low birth weight was demonstrated (11.5% compared with 11.3% adjusted OR 0.99, 95% CI 0.82–1.18). CONCLUSION: The ovarian stimulation-induced maternal environment appears to represent an independent mediator contributing to the risk of low birth weight, but not preterm delivery, in neonates conceived after IVF. LEVEL OF EVIDENCE: II

Heterosexual Transmission of Human Immunodeficiency Virus Type 1 Subtype C: Macrophage Tropism, Alternative Coreceptor Use, and the Molecular Anatomy of CCR5 Utilization

ABSTRACT Human immunodeficiency virus type 1 transmission selects for virus variants with genetic characteristics distinct from those of donor quasispecies, but the biological factors favoring their transmission or establishment in new hosts are poorly understood. We compared primary target cell tropisms and entry coreceptor utilizations of donor and recipient subtype C Envs obtained near the time of acute infection from Zambian heterosexual transmission pairs. Both donor and recipient Envs demonstrated only modest macrophage tropism, and there was no overall difference between groups in macrophage or CD4 T-cell infection efficiency. Several individual pairs showed donor/recipient differences in primary cell infection, but these were not consistent between pairs. Envs had surprisingly broad uses of GPR15, CXCR6, and APJ, but little or no use of CCR2b, CCR3, CCR8, GPR1, and CXCR4. Donors overall used GPR15 better than did recipients. However, while several individual pairs showed donor/recipient differences for GPR15 and/or other coreceptors, the direction of the differences was inconsistent, and several pairs had unique alternative coreceptor patterns that were conserved across the transmission barrier. CCR5/CCR2b chimeras revealed that recipients as a group were more sensitive than were donors to replacement of the CCR5 extracellular loops with corresponding regions of CCR2b, but significant differences in this direction were not consistent within pairs. These data show that sexual transmission does not select for enhanced macrophage tropism, nor for preferential use of any alternative coreceptor. Recipient Envs are somewhat more constrained than are donors in flexibility of CCR5 use, but this pattern is not universal for all pairs, indicating that it is not an absolute requirement.

Depletion of CD4+ T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques

CD4+ T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4+ T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SIV-infected rhesus macaques (RMs) that suggest that CD4+ T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4+ T cells during primary SIV infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4+ lymphocyte-depleted RMs showed a similar peak of viremia, but did not manifest any post-peak decline of virus replication despite CD8+ T cell- and B cell-mediated SIV-specific immune responses comparable to those observed in control animals. Interestingly, depleted animals displayed rapid disease progression, which was associated with increased virus replication in non-T cells as well as the emergence of CD4-independent SIV-envelopes. Our results suggest that the antiviral CD4+ T cell response may play an important role in limiting SIV replication, which has implications for the design of HIV vaccines.

Single procedure efficacy of isolating all versus arrhythmogenic pulmonary veins on long-term control of atrial fibrillation: A prospective randomized study

BACKGROUND Current atrial fibrillation (AF) ablation involves isolation of all pulmonary veins (PVs) with or without additional linear lesions. However, whether such extensive ablation is necessary is unclear. OBJECTIVE The purpose of this study was to assess the efficacy of different ablation strategies on long-term AF control. METHODS We prospectively randomized patients to undergo isolation of all versus arrhythmogenic PVs (identified by standardized stimulation protocol). PV isolation was guided by circular mapping catheter. The endpoint was entry/exit block persisting for > or = 20 minutes. Patients were evaluated at three clinic visits (at 6 weeks, 6 months, and 1 year) and multiple transtelephonic monitoring periods. Antiarrhythmic drugs were discontinued at 6 weeks. Primary study endpoint was long-term AF control (freedom or >90% reduction in AF burden off or on previously ineffective antiarrhythmic drugs at 1 year after a single ablation procedure). RESULTS Over a 20-month period, 105 patients (76 men and 29 women, age 57 +/- 9 years; paroxysmal AF = 77) were randomized, and 103 patients completed 1-year follow-up (51 patients in all-PV arm, 52 patients in arrhythmogenic PV arm). The primary endpoint was achieved in 75 (73%) patients and was similar in patients randomized to all-PV arm versus arrhythmogenic PV arm [38 (75%) patients vs 37 (71%) patients, respectively; odds ratio 1.18, 95% confidence interval 0.50, 2.83, P = .70]. Secondary study endpoints, including freedom from AF off antiarrhythmic drugs, total procedure/fluoroscopy times, and occurrence of serious adverse events, were not different between the two groups. CONCLUSION In a randomized comparison, isolation of arrhythmogenic veins was as efficacious as empiric isolation of all veins in achieving long-term AF control.

Baseline Ad5 serostatus does not predict Ad5 HIV vaccine-induced expansion of adenovirus-specific CD4+ T cells.

The mechanisms underlying possible increased HIV-1 acquisition in adenovirus 5 (Ad5)-seropositive subjects vaccinated with Ad5–HIV-1 vectors in the Merck STEP trial remain unclear. We find that Ad5 serostatus does not predict Ad5-specific CD4+ T cell frequency, and we did not observe durable significant differences in Ad5-specific CD4+ T cells between Ad5-seropositive and Ad5-seronegative subjects after vaccination. These findings indicate no causative role for Ad5-specific CD4+ T cells in increasing HIV-1 susceptibility in the STEP trial.

Higher Serum Testosterone Concentration in Older Women is Associated with Insulin Resistance, Metabolic Syndrome, and Cardiovascular Disease

CONTEXT Early postmenopausal women with higher testosterone (T) levels have increased insulin resistance (IR) and cardiovascular risk factors, but whether this translates into increased cardiovascular disease later in life is unknown. OBJECTIVE The objective of the study was to determine whether higher T levels are associated with IR, the metabolic syndrome (MetSyn), and coronary heart disease (CHD) in elderly women. DESIGN Total T and free T by equilibrium dialysis were measured using ultrasensitive assays in 344 women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to examine the associations between total and free T and IR, MetSyn, and CHD. RESULTS There was a stepwise increase in the homeostasis model assessment of insulin resistance with increasing total (P = 0.0.003) and free T (P = 0.02) level and a corresponding decrease in Quantitative Insulin Sensitivity Check Index (P < 0.001 and P = 0.002, respectively). In adjusted models, higher levels of both total and free T were strongly associated with abdominal obesity and high fasting glucose, the two MetSyn components most strongly linked to IR. After adjustment, women in the top quartile of total T levels had a 3-fold greater odds of MetSyn (odds ratio 3.15, 95% confidence interval 1.57-6.35) than those in the bottom quartile and a 3-fold greater odds of CHD (odds ratio 2.95, 95% confidence interval 1.2-7.3) than those in second quartile, whereas free T was not significantly associated with MetSyn or CHD. CONCLUSIONS Higher levels of T are associated with IR, MetSyn, and CHD in elderly women. Whether T is a marker or mediator of cardiovascular disease in this population merits further investigation.

Stroke After Aortic Valve Surgery Results From a Prospective Cohort

Background— The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized. Methods and Results— We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1–9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P=0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P=0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay. Conclusions— Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality.Background— The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized. Methods and Results— We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1–9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P =0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P =0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay. Conclusions— Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality. # CLINICAL PERSPECTIVE {#article-title-47}

Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys

Naturally SIV-infected sooty mangabeys (SMs) remain asymptomatic despite high virus replication. Elucidating the mechanisms underlying AIDS resistance of SIV-infected SMs may provide crucial information to better understand AIDS pathogenesis. In this study, we assessed the determinants of set-point viremia in naturally SIV-infected SMs, i.e., immune control of SIV replication versus target cell limitation. We depleted CD4+ T cells in 6 naturally SIV-infected SMs by treating with humanized anti-CD4 mAb (Cdr-OKT4A-huIgG1). CD4+ T cells were depleted almost completely in blood and BM and at variable levels in mucosal tissues and LNs. No marked depletion of CD14+ monocytes was observed. Importantly, CD4+ T cell depletion was associated with a rapid, significant decline in viral load, which returned to baseline level at day 30-45, coincident with an increased fraction of proliferating and activated CD4+ T cells. Throughout the study, virus replication correlated with the level of proliferating CD4+ T cells. CD4+ T cell depletion did not induce any changes in the fraction of Tregs or the level of SIV-specific CD8+ T cells. Our results suggest that the availability of activated CD4+ T cells, rather than immune control of SIV replication, is the main determinant of set-point viral load during natural SIV infection of SMs.

Shortened sleep duration does not predict obesity in adolescents

Obesity continues to be a major public health issue. In adolescents, there are limited studies on the relationship between obesity and sleep duration. We found hypothesized that an average sleep duration of <6 h in adolescents was associated with obesity. Data were from the National Longitudinal Study of Adolescent Health (ADD Health); a survey of 90 000 youths, aged 12–18 years; surveyed in several waves. The sample population for our study was 13 568. Weighted multiple logistic regression was used to identify the relationship between obesity at Wave II and sleep duration, having adjusted for skipping breakfast ≥ 2/week; race, gender, parental income, TV ≥ 2 h per day, depression, and obesity at Wave I. At Wave I, the mean age was 15.96 ± 0.11 years; mean sleep hours were 7.91 ± 0.04. At Waves I and II, respectively, 10.6 and 11.2% of adolescents were obese. Adjusted analyses suggest that the effect of shortened sleep duration in Wave I was not significantly predictive of obesity in Wave II (P < 0.218). Longitudinally, depression and TV ≥ 2  h per day at Wave I was associated with a higher risk of obesity at Wave II in adjusted analyses. Depressed adolescents were almost twice as likely to be obese (OR = 1.84, 95% CI = 1.25–2.72); adolescents who watched TV ≥ 2 h per day were 37% more likely to be obese (OR = 1.37, 95% CI = 1.09–1.72). Environmental factors including TV ≥ 2 h per day and depression were significantly associated with obesity; shortened sleep duration was not. Future longitudinal studies in adolescents are needed to determine whether timing of television watching directly influences sleep patterns and, ultimately, obesity.