Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

Reproducibility and diurnal variation in middle cerebral artery blood velocity in healthy humans.

NEW FINDINGS: What is the central question of this study? We sought to establish between-day reproducibility in estimates of middle cerebral artery blood velocity (MCAv) and cerebrovascular reactivity (CVR) in young, healthy male and female adults in tightly controlled experimental conditions. What is the main finding and its importance? Measures of MCAv assessed during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in CVR, with values being highest during the evening compared with the morning. Greater diurnal variation in CVR is associated with more efficient sleep and greater nocturnal blood pressure dipping. These data enhance our understanding of modulators of MCAv and CVR. ABSTRACT: Transcranial Doppler (TCD) is used to assess cerebral blood velocity (CBV) and cerebrovascular reactivity (CVR). Assessments of TCD reproducibility are limited, and few include multiple within-day measurements. We sought to establish reproducibility of CBV and CVR in healthy adults during three time periods (morning, afternoon and evening). We hypothesized that CBV and CVR measured at the same time of day are reproducible between days. We also hypothesized that CBV and CVR exhibit diurnal variation, with measurements being higher in the evening compared with morning/afternoon hours. Twelve adults [six male and six female, 27 years (95% CI, 22-31 years)] completed three measurements (morning, afternoon and evening) on two separate days in controlled conditions (e.g., meals, activity and sleep). Middle cerebral artery blood velocity (MCAv, TCD) was measured continuously at rest and during two CVR tests (end-expiratory apnoea and carbogen inhalation). Intraclass correlation coefficients for resting MCAv showed moderate to good reproducibility, which did not differ between morning, afternoon and evening (0.87, 0.56 and 0.67, respectively; P > 0.05). Intraclass correlation coefficients for peak MCAv during apnoea (0.80, 0.46 and 0.65, respectively; P > 0.05) and minute 2 of carbogen inhalation (0.81, 0.74 and 0.73, respectively; P > 0.05) were also not different from morning compared with afternoon/evening. Time of day had no effect on resting MCAv (F = 0.69, P = 0.51, ƞp 2  = 0.06) or the peak response to apnoea (F = 1.00, P = 0.39, ƞp 2  = 0.08); however, peak MCAv during carbogen breathing exhibited diurnal variation, with highest values in the evening (F = 3.41, P = 0.05, ƞp 2  = 0.24). Measures of CBV and CVR assessed via TCD during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in the MCAv response to carbogen exposure, with CVR being highest during evening compared with morning hours.

Naturally menstruating women exhibit lower cardiovagal baroreflex sensitivity than oral contraceptive users during the lower hormone phase.

The present study evaluated cardiovagal baroreflex sensitivity (BRS) across the menstrual/pill cycle in naturally menstruating women (NAT women) and women using oral hormonal contraceptives (OCP women). In 21 NAT women (23 ± 4 years old) and 22 OCP women (23 ± 3 years old), cardiovagal BRS and circulating concentrations of estradiol and progesterone were evaluated during the lower hormone (early follicular/placebo pill) and higher hormone (late follicular to early luteal/active pill) phases. During the lower hormone phase, cardiovagal BRS up, down and mean gain were lower in NAT women (15.6 ± 8.3, 15.2 ± 6.1 and 15.1 ± 7.1 ms/mmHg) compared with OCP women (24.7 ± 9.4, 22.9 ± 8.0 and 23.0 ± 8.0 ms/mmHg) (P = 0.003, P = 0.002 and P = 0.003, respectively), and higher oestrogen (R2  = 0.15, P = 0.024), but not progesterone (R2  = 0.06, P = 0.18), concentrations were predictive of lower BRS mean gain. During the higher hormone phase, higher progesterone concentrations were predictive of lower BRS mean gain (R2  = 0.12, P = 0.024). A multivariate regression model revealed group (NAT or OCP) to be a significant predictor of cardiovagal BRS mean gain in the lower hormone phase when hormone concentrations were adjusted for (R2  = 0.36, P = 0.0044). The multivariate regression model was not significant during the higher hormone phase (P > 0.05). In summary, cardiovagal BRS is lower in NAT compared with OCP women during the lower hormone phase of the menstrual/pill cycle and might be associated with higher oestrogen concentrations. In contrast, during the higher hormone phase of the menstrual/OCP cycle, higher progesterone concentrations were predictive of lower cardiovagal BRS. NEW FINDINGS: What is the central question of this study? Does cardiovagal baroreflex sensitivity (BRS) differ between naturally menstruating women (NAT women) and women using oral contraceptives (OCP women)? What is the main finding and its importance? The main findings are as follows: (1) NAT women exhibit lower cardiovagal BRS than OCP women during the lower hormone phase of the menstrual or pill cycle; and (2) circulating oestrogen concentrations are significant predictors of cardiovagal BRS during the lower hormone phase, with higher oestrogen concentrations predicting lower BRS. The present data advance our understanding of the effect of endogenous ovarian hormones and OCP use on cardiovascular control mechanisms.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

Effect of oral hormonal contraceptive pill use on the hemodynamic response to the cold pressor test.

Acute increases in sympathetic nervous system activity (SNA) often elicit peripheral vasoconstriction and increases in blood pressure (BP). Given sympathetic support of BP is modulated by ovarian sex hormones (e.g., estradiol), we sought to examine the effect of menstrual cycle and oral hormonal contraceptive pill (OC) phase on the hemodynamic response to acute increases in SNA. We hypothesized sympathoexcitation via cold pressor test (CPT) would elicit greater peripheral vasoconstriction and increases BP in females with natural menstrual cycles (NC) compared with females taking OC. We further hypothesized that SNA-mediated vasoconstriction would be attenuated during the high estradiol (HE) phase versus the low estradiol (LE) phase of the menstrual/pill cycle. Female NC (n = 11, 25 ± 1 yr) and OC (n = 10, 24 ± 1 yr) participants were studied during the LE (early follicular, placebo pill) and HE (late follicular, active pill) phase of the menstrual/pill cycle. BP (finger photoplethysmography), heart rate (HR, ECG), and forearm blood flow (FBF, venous occlusion plethysmography) were measured during a 5-min baseline and a 2-min CPT. CPT elicited an increase in BP in both groups (time, P < 0.01). During CPT, OC participants exhibited greater and sustained increases in HR compared with NC participants (group × time, P < 0.01). Higher HRs were met with increases in FBF in OC participants during the CPT, which was not observed in NC participants (group × time, P < 0.01). OC participants exhibit greater increases in HR, and paradoxical vasodilation during acute sympathetic activation compared with NC participants. Group differences are unaffected by menstrual/pill phase.NEW & NOTEWORTHY Acute increases in sympathetic nervous system activity often elicit peripheral vasoconstriction and increases in blood pressure (BP). Given sympathetic support of BP is modulated by ovarian sex hormones (e.g., estradiol), we sought to examine the effect of menstrual cycle and oral hormonal contraceptive pill (OC) phase on the hemodynamic response to acute increases in sympathetic nervous system activity via the cold pressor test. We show OC participants exhibit paradoxical vasodilation during acute sympathetic activation compared with participants with natural menstrual cycles; notably, group differences were unaffected by menstrual/pill phase.

Sex differences in the effect of acute intermittent hypoxia on respiratory modulation of sympathetic activity.

Sex-related differences in respiratory modulation of sympathetic activity have been observed in rodent models of sleep apnea [intermittent hypoxia (IH)]. In light of sex disparities in the respiratory response to acute IH in humans as well as changes in respiratory modulation of muscle sympathetic nerve activity (MSNA) in clinical sleep apnea, we examined sex-related differences in respiratory modulation of MSNA following acute IH. We hypothesized that respiratory modulation of MSNA would be altered in both male and female participants after IH; however, the respiratory patterning of MSNA following IH would be sex specific. Heart rate, MSNA, and respiration were evaluated in healthy male (n = 21, 30 ± 5 yr) and female (n = 10, 28 ± 5 yr) participants during normoxic rest before and after 30 min of IH. Respiratory modulation of MSNA was assessed by fitting polynomials to cross-correlation histograms constructed between sympathetic spikes and respiration. MSNA was elevated after IH in male (20 ± 6 to 24 ± 8 bursts/min) and female (19 ± 8 to 22 ± 10 bursts/min) participants (P < 0.01). Both male and female participants exhibited respiratory modulation of MSNA (P < 0.01); however, the pattern differed by sex. After IH, modulation of MSNA within the breath was reduced in male participants (P = 0.03) but increased in female participants (P = 0.02). Both male and female adults exhibit changes in respiratory patterning of MSNA after acute IH; however, this pattern differs by sex. These data support sex disparities in respiratory modulation of MSNA and may have implications for conditions such as sleep apnea.

Hyperinsulinemia blunts sympathetic vasoconstriction: a possible role of ß-adrenergic activation.

Herein we report in a sample of healthy young men (n = 14) and women (n = 12) that hyperinsulinemia induces time-dependent decreases in total peripheral resistance and its contribution to the maintenance of blood pressure. In the same participants, we observe profound vasodilatory effects of insulin in the lower limb despite concomitant activation of the sympathetic nervous system. We hypothesized that this prominent peripheral vasodilation is possibly due to the ability of the leg vasculature to escape sympathetic vasoconstriction during systemic insulin stimulation. Consistent with this notion, we demonstrate in a subset of healthy men (n = 9) and women (n = 7) that systemic infusion of insulin blunts sympathetically mediated leg vasoconstriction evoked by a cold pressor test, a well-established sympathoexcitatory stimulus. Further substantiating this observation, we show in mouse aortic rings that insulin exposure suppresses epinephrine and norepinephrine-induced vasoconstriction. Notably, we found that such insulin-suppressing effects on catecholamine-induced constriction are diminished following ß-adrenergic receptor blockade. In accordance, we also reveal that insulin augments ß-adrenergic-mediated vasorelaxation in isolated arteries. Collectively, these findings support the idea that sympathetic vasoconstriction can be attenuated during systemic hyperinsulinemia in the leg vasculature of both men and women and that this phenomenon may be in part mediated by potentiation of ß-adrenergic vasodilation neutralizing α-adrenergic vasoconstriction.

Sex differences in the vascular response to sympathetic activation during acute hypoxaemia.

NEW FINDINGS: What is the central question of this study? Sympathetically mediated vasoconstriction is preserved during hypoxaemia in humans, but our understanding of vascular control comes from predominantly male cohorts. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not? What is the main finding and its importance? Sympathetically mediated vasoconstriction is preserved or even enhanced during steady-state hypoxia in young men, and the peripheral vascular response to sympathetic activation during hypoxaemia is attenuated in young women. These data advance our understanding of sex-related differences in hypoxic vascular control. ABSTRACT: Activation of the sympathetic nervous system causes vasoconstriction and a reduction in peripheral blood flow. Sympathetically mediated vasoconstriction may be attenuated during systemic hypoxia to maintain oxygen delivery; however, in predominantly male participants sympathetically mediated vasoconstriction is preserved or even enhanced during hypoxaemia. Given the potential for sex-specific differences in hypoxic vascular control, prior results are limited in application. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not. Healthy young men (n = 13, 25 ± 4 years) and women (n = 11, 24 ± 4 years) completed two trials consisting of a 2-min cold pressor test (CPT, a well-established sympathoexcitatory stimulus) during baseline normoxia and steady-state hypoxaemia. Beat-to-beat blood pressure (finger photoplethysmography) and forearm blood flow (venous occlusion plethysmography) were measured continuously. Total and forearm vascular conductance (TVC and FVC, respectfully) were calculated. A change (Δ) in TVC and FVC from steady-state during the last 1 min of CPT was calculated and differences between normoxia and systemic hypoxia were assessed. In men, the reduction in TVC during CPT was greater during hypoxia compared to normoxia (ΔTVC, P = 0.02), whereas ΔTVC did not differ between conditions in women (P = 0.49). In men, ΔFVC did not differ between normoxia and hypoxia (P = 0.92). In women, the reduction in FVC during CPT was attenuated during hypoxia (ΔFVC, P < 0.01). We confirm sympathetically mediated vasoconstriction is preserved or enhanced during hypoxaemia in young men, whereas peripheral vascular responsiveness to sympathetic activation during hypoxaemia is attenuated in young women. The results advance our understanding of sex-related differences in hypoxic vascular control.

Sympathetically mediated increases in cardiac output, not restraint of peripheral vasodilation, contribute to blood pressure maintenance during hyperinsulinemia.

Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin.NEW & NOTEWORTHY We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.

Sex differences in integrated neurocardiovascular control of blood pressure following acute intermittent hypercapnic hypoxia.

Repetitive hypoxic apneas, similar to those observed in sleep apnea, result in resetting of the sympathetic baroreflex to higher blood pressures (BP). This baroreflex resetting is associated with hypertension in preclinical models of sleep apnea (intermittent hypoxia, IH); however, the majority of understanding comes from males. There are data to suggest that female rats exposed to IH do not develop high BP. Clinical data further support sex differences in the development of hypertension in sleep apnea, but mechanistic data are lacking. Here we examined sex-related differences in the effect of IH on sympathetic control of BP in humans. We hypothesized that after acute IH we would observe a rise in muscle sympathetic nerve activity (MSNA) and arterial BP in young men (n = 30) that would be absent in young women (n = 19). BP and MSNA were measured during normoxic rest before and after 30 min of IH. Baroreflex sensitivity (modified Oxford) was evaluated before and after IH. A rise in mean BP following IH was observed in men (+2.0 ± 0.7 mmHg, P = 0.03), whereas no change was observed in women (-2.7 ± 1.2 mmHg, P = 0.11). The elevation in MSNA following IH was not different between groups (4.7 ± 1.1 vs. 3.8 ± 1.2 bursts/min, P = 0.65). Sympathetic baroreflex sensitivity did not change after IH in either group (P > 0.05). Our results support sex-related differences in the effect of IH on neurovascular control of BP and show that any BP-raising effects of IH are absent in young women. These data enhance our understanding of sex-specific mechanisms that may contribute to BP changes in sleep apnea.

Placental changes caused by food restriction during early pregnancy in mice are reversible.

In a previous study, 50% calorie restriction in mice from d1.5 to 11.5 of pregnancy resulted in reduced placental weights and areas,relative sparing of labyrinth zone area compared to junctional zone area, and dramatic changes in global gene expression profiles.However, little lasting effect was seen on adult offspring of these pregnancies, with a slight reduction in adiposity in males and some changes in liver gene expression in both sexes. The goals of the present study were to determine whether the placental changes induced by caloric restriction in early pregnancy had permanent, irreversible effects on the placenta, and whether the changes in liver gene expression in adult offspring were present before birth. There were no differences in placental weights or areas, or the areas of individual placental zones near term in mice that had previously been food restricted. Global gene expression profiles at d18.5 were indistinguishable in placentas from control and previously food-restricted mothers. In fetuses from restricted dams at d18.5, liver expression of Gck, a key regulator of glycogen synthesis, was reduced, whereas its expression was increased in livers from adult offspring of restricted dams. Ppara expression was also reduced in fetal livers from restricted dams at d18.5, but not in adult offspring livers. We conclude that alterations in the placenta caused by nutrient restriction in early pregnancy are reversible, and that alterations in gene expression in livers of adult offspring are not a result of changes initiated during pregnancy and maintained through adulthood.

Incorporating Patient Satisfaction Metrics in Assessing Multidisciplinary Breast Cancer Care Quality.

OBJECTIVES: The Medical University of South Carolina implemented a patient-centered multidisciplinary breast clinic program (MDBC) in August 2012. In this study, patient satisfaction with the MDBC care delivery model and communication with healthcare providers was examined to inform the refinement of the MDBC program. METHODS: During the first 10 months of the MDBC, patients were asked to complete a 14-question postconsultation telephone survey. A statistical analysis was performed to explore potential associations between age, race, and stage with overall patient satisfaction scores. RESULTS: Overall, patients (N = 52, 56% white, 42% African American, 2% Hispanic; mean age 61 years) rated the quality of care highly (mean 4.7, range [1 = poor to 5 = excellent]) and felt comfortable with their plan of care (mean 1.63, range [1 = extremely comfortable to 5 = not at all comfortable]). No statistically significant differences in overall satisfaction were found by age, race, or stage; however, patient responses were commonly not optimal (ie, either "no" or "yes, but not as much as I would like") when asked if the care team addressed the impact of their diagnosis on personal relationships (40.4%) or emotional health (28.9%). CONCLUSIONS: Patients were highly satisfied with the care they received in the MDBC program. Findings suggest that this model is well suited to a diverse patient population and have highlighted quality improvement targets such as increased emphasis on providers' communication about psychosocial issues.

The forearm vascular response to sympathetic activation is attenuated in female, but not male, participants following acute intermittent hypoxia.

Acute exposure to hypoxia promotes both an increase in sympathetic nervous system activity (SNA) and local vasodilation. In rodents, intermittent hypoxia (IH)-mediated increases in SNA are associated with an increase in blood pressure in males but not females; notably, the protective effect of female sex is lost following ovariectomy. These data suggest the vascular response to hypoxia and/or SNA following IH may be sex- and/or hormone specific-although mechanisms are unclear. We hypothesized that hypoxia-mediated vasodilation and SNA-mediated vasoconstriction would be unchanged following acute IH in male adults. We further hypothesized that hypoxic vasodilation would be augmented and SNA-mediated vasoconstriction would be attenuated in female adults following acute IH, with the greatest effect when endogenous estradiol was high. Twelve male (25 ± 1 yr) and 10 female (25 ± 1 yr) participants underwent 30 min of IH. Females were studied in a low (early follicular) and high (late follicular) estradiol state. Preceding and following IH, participants completed two trials [steady-state hypoxia and cold pressor test (CPT)], where forearm blood flow and blood pressure were measured and used to determine forearm vascular conductance (FVC). The FVC response to hypoxia (P = 0.67) and sympathetic activation (P = 0.73) were unchanged following IH in males. There was no effect of IH on hypoxic vasodilation in females, regardless of estradiol state (P = 0.75). In contrast, the vascular response to sympathetic activation was attenuated in females following IH (P = 0.02), independent of estradiol state (P = 0.65). Present data highlight sex-related differences in neurovascular responsiveness following acute IH.NEW & NOTEWORTHY We examined the effects of acute intermittent hypoxia (AIH) on the vascular response to sympathetic activation and acute hypoxia. Present findings show, despite no effect of AIH on the vascular response to hypoxia, the forearm vasoconstrictor response to acute sympathetic activation is attenuated in females following AIH, independent of estradiol state. These data provide mechanistic understanding of potential benefits of AIH, as well as the impact of biological sex.

Endothelin-1 receptor blockade does not alter the sympathetic and hemodynamic response to acute intermittent hypoxia in men.

Repeat exposures to low oxygen (intermittent hypoxia, IH), like that observed in sleep apnea, elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans are unclear. We hypothesized that ET-receptor antagonism would ameliorate any rise in MSNA and BP following acute IH in humans. Twelve healthy men (31 ± 1 yr) completed two visits (control, bosentan) separated by at least 1 wk. MSNA, BP, and baroreflex sensitivity (modified Oxford) were assessed during normoxic rest before and following 30 min of IH. The midpoint (T50) for each individual's baroreflex curve was calculated. Acute IH increased plasma ET-1 (P < 0.01), MSNA burst frequency (P = 0.03), and mean BP (P < 0.01). There was no effect of IH on baroreflex sensitivity (P = 0.46), although an increase in T50 was observed (P < 0.01). MSNA burst frequency was higher (P = 0.04) and mean BP (P < 0.01) was lower following bosentan treatment compared with control. There was no effect of bosentan on baroreflex sensitivity (P = 0.53), although a lower T50 was observed on the bosentan visit (P < 0.01). There was no effect of bosentan on increases in MSNA (P = 0.81) or mean BP (P = 0.12) following acute IH. Acute IH results in an increase in ET-1, MSNA, and BP in healthy young men. The effect of IH on MSNA and BP is not attenuated following ET-receptor inhibition. Present data suggest that acute IH does not increase MSNA or BP through activation of ET-receptors in healthy young men.NEW & NOTEWORTHY Repeat exposures to low oxygen (intermittent hypoxia, IH) elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans were unclear. We show acute IH results in an increase in ET-1, MSNA, and BP in healthy young men; however, the effect of IH on MSNA and BP does not occur through activation of ET-receptors in healthy young men.

Toxicity, response rates and survival outcomes of induction cisplatin and irinotecan followed by concurrent cisplatin, irinotecan and radiotherapy for locally advanced esophageal cancer.

OBJECTIVE: Cisplatin-based chemoradiotherapy is standard treatment for locally advanced esophageal and gastroesophageal cancers; however, the optimal chemotherapy regimen remains to be defined. METHODS: Retrospective single institution analysis of toxicities, response rates and survival outcomes in patients with cT3-4 or N1/M1a esophageal squamous cell or adenocarcinoma treated with induction cisplatin and irinotecan followed by concurrent cisplatin, irinotecan and radiotherapy. Secondary analysis for association of disease control and outcomes with demographic, tumor and treatment factors (including histology). RESULTS: Fifty-three patients were eligible for the present analysis. All patients underwent endoscopic ultrasonography and were either cT3-4 and/or cN1 disease. Fifty patients completed radiotherapy as planned (median dose 50.4 Gy, range 0-61.2), and 35 patients completed four cycles of chemotherapy as planned (range 1-4). Severe acute toxicities included Grade ≥ 3 neutropenia and esophagitis in 13 and 12 patients, respectively. There were no Grade 5 (fatal) toxicities noted. At mean survivor follow-up of 24.5 months (range 2.7-63), 17 patients were alive (8 without disease) and 36 deceased. Forty patients experienced disease recurrence, with initial loco-regional, distant or both failures in 28, 9 and 3 patients, respectively. Estimated 2-year overall survival and freedom from failure were 42 and 9%, respectively, without significant difference by histology. CONCLUSIONS: Cisplatin/irinotecan chemoradiotherapy is tolerable, demonstrating similar efficacy for squamous cell and adenocarcinoma esophageal cancers.

Incidence and prognostic factors for seroma development after MammoSite breast brachytherapy.

PURPOSE: Describe the incidence and identify risk factors for seroma development after MammoSite breast brachytherapy (MBT). METHODS AND MATERIALS: MBT patient data were prospectively recorded into a quality assurance database. Departmental and electronic records were reviewed to extract patient-, treatment-, and outcome-specific data. Stepwise logistic regression analysis was performed to identify factors associated with development of any seroma including the subset of clinically significant seroma (CSS). CSS was defined as a symptomatic seroma requiring multiple aspirations, biopsy, and/or excision. Variables analyzed included age, weight, number of excisions, time from resection to catheter placement, placement technique, balloon volume, dosimetric factors, and postbrachytherapy infection. RESULTS: MBT was performed in 109 patients, of whom 97 had minimum 6 months (median, 36) post-MBT follow-up or earlier development of seroma. All patients received 34 Gy to 1cm depth from balloon surface, delivered twice daily in 10 fractions. Seroma developed in 41% of patients at a median of 3 months (range, 0.1-25) post-MBT. One-third of seromas (13% of all patients) were CSS. The only factor identified as statistically significant for development of any seroma was catheter placement on day of resection vs. > or =1 day later (59% vs. 33%; p = 0.0066). Post-MBT infection was highly statistically significant for development of CSS (64% vs. 7%; p<0.0001). Prophylactic antibiotics reduced the risk of post-MBT infection from 37.5% to 6% (p = 0.011). CONCLUSIONS: The incidence of CSS after MBT is low. Post-MBT infection is statistically significantly associated with CSS development, the incidence of which is reduced with prophylactic antibiotics.

Predictors of cosmetic outcome following MammoSite breast brachytherapy: a single-institution experience of 100 patients with two years of follow-up.

PURPOSE: To identify the factors that predict for excellent cosmesis in patients who receive MammoSite breast brachytherapy (MBT). METHODS AND MATERIALS: One hundred patients with Stage 0, I, or II adenocarcinoma of the breast underwent adjuvant therapy using MBT. A dose of 34 Gy, delivered in 10 fractions twice daily, was prescribed to 1-cm depth using (192)Ir high-dose-rate brachytherapy. Patients were assessed for acute toxicity on the day of therapy completion, 4 weeks after therapy, and at least every 3 months by radiation, surgical, and/or medical oncologists. All available data were reviewed for documentation of cosmesis and rated using the Harvard Scale. All patients had a minimum follow-up of 6 months (median = 24 months). RESULTS: Of 100 patients treated, 90 had adequate data and follow-up. Cosmesis was excellent in 62 (68.9%), good in 19 (21.1%), fair in 8 (8.9%), and poor in 1 (1.1%) patient. Using stepwise logistic regression, the factors that predicted for excellent cosmesis were as follows: the absence vs. presence of infection (p = 0.017), and the absence vs. presence of acute skin toxicity (p = 0.026). There was a statistically significant association between acute skin toxicity (present vs. absent) and balloon-to-skin distance (<8 vs. >8 mm, p = 0.001). Factors that did not predict for cosmesis were age, balloon placement technique, balloon volume, catheter days in situ, subcutaneous toxicity, and chemotherapy or hormonal therapy. CONCLUSIONS: The acute and late-term toxicity profiles of MBT have been acceptable. Cosmetic outcome is improved by proper patient selection and infection prevention.

Acute complications of MammoSite brachytherapy: a single institution's initial clinical experience.

PURPOSE: To report the acute complications incurred by the initial 37 patients who underwent accelerated partial breast irradiation with the MammoSite balloon breast brachytherapy applicator at the Medical University of South Carolina. METHODS AND MATERIALS: Between May 2002 and March 2003, 37 patients with ductal carcinoma in situ or invasive carcinoma had MammoSite brachytherapy catheters successfully place after lumpectomy by one of four surgeons and were deemed eligible for high-dose-rate brachytherapy. An open technique was used in 32 implants and the scar entry technique was used in 5 implants. Patients had Stage pTis-pT2N1 with negative margins. A dose of 34 Gy was prescribed to 1 cm from the balloon surface using (192)Ir high-dose-rate brachytherapy and was delivered in 10 fractions twice daily. CT was used to confirm that the balloon surface was adherent to the lumpectomy cavity and to measure the balloon surface to skin surface distance. CT images and daily fluoroscopic simulations were used for treatment planning. Patients were assessed for acute toxicity on the day of therapy completion and 4 weeks after therapy by the radiation oncologist. In addition, all available data from radiation, surgical, and medical oncology were retrospectively reviewed for documentation of complications. All patients in this series had a minimal follow-up of 3 months; the mean follow-up for all patients was 7 months. RESULTS: The acute complications were categorized as operative wound complications, infections, skin toxicity, seromas, or catheter failures. Operative wound complications occurred in 3 patients (8%). Radiation Therapy Oncology Group Grade 2 and Grade 3 toxicity occurred in 2 (5.4%) and 1 (2.7%) patient, respectively. Six (16.2%) developed wound infections and 12 (32.4%) seromas. Catheter failures due to leak occurred in 2 patients (5.4%) and rupture in 3 (8%). CONCLUSION: The types of complications in this experience were similar to those in the Phase I trial of the MammoSite brachytherapy applicator. However, catheter failure due to leak occurred in our experience and was not described in the Phase I trial. The incidence of complications was greater in our series than in the Phase I trial; however, differences in toxicity scoring and the length of follow-up between the two series impeded direct comparisons. The incidences of complications over time reflect the steep learning curve for accelerated partial breast irradiation using the MammoSite brachytherapy applicator. Finally, radiation recall dermatitis developed in 1 patient treated after this review was completed.

Chest wall dose in MammoSite breast brachytherapy: radiobiologic estimations of late complication risk based on dose-volume considerations.

PURPOSE: To estimate the risk of late effects in women treated with MammoSite brachytherapy (MBT), the balloon catheters of which were placed near the ribs. METHODS AND MATERIALS: Upon reviewing 93 plans, 16 patients (17%) treated with MBT were considered to have received a high chest wall dose (>or=120% isodose line in contact with a rib). A dose-volume histogram was generated for this rib, and its distance from the MBT balloon measured. Using the linear quadratic equation, the equivalent dose, delivered in 10 fractions, to the dose that causes a 5% and 50% risk of rib late effects at 5 years using 2Gy per fraction, was calculated to be 37 and 44Gy, respectively. The rib volume receiving greater than or equal to these doses (V37 and V44) was correlated to the balloon-to-rib distance. Chest wall signs, symptoms, and radiologic findings for all 16 patients were recorded. RESULTS: The median balloon-to-rib distance was 4.8mm. The median values of V37 and V44 were 13.5% and 3.3%, respectively. All patients with a V37>or=15% and V44>or=5% had a minimum balloon-to-rib distance of <5mm. Two patients reported treatment-related chest wall tenderness (both had balloons placed <5mm from the chest wall), but neither presented with radiologic complications. CONCLUSIONS: Sixteen patients considered to receive relatively high chest wall doses had less than one-third of their primary rib volume being exposed to the estimated TD 5/5 and TD 50/5 doses. Therefore, we estimate the risk of late effects in women treated with MBT, the balloon catheters of which placed near the ribs were negligible, and believe that MBT remains a safe and effective treatment for selected patients with early stage breast cancer.

Effect of food restriction and leptin supplementation on fetal programming in mice.

Metabolic disease is a significant global health and economic problem. In a phenomenon referred to as fetal programming, offspring of underweight or overweight mothers have an increased incidence of adulthood obesity and metabolic disease. Undernourished individuals have decreased levels of leptin, a regulator of energy balance, whereas obese people develop hyperleptinemia and leptin resistance. We hypothesize that alterations in circulating leptin during pregnancy contribute to programming events caused by maternal nutritional status. To test this hypothesis, pregnant mice were randomly placed in one of three treatment groups: ad libitum feed plus saline injection (control, n = 5), 50% food restriction plus saline injection (restricted, n = 4), or 50% food restriction plus 1 mg/kg · d leptin injection (restricted, leptin treated, n = 4). Mice were treated from 1.5 to 11.5 d after conception and then returned to ad libitum feeding until weaning. At 19 wk after weaning, offspring were placed on a 45% fat diet and then followed up until 26 wk after weaning, at which time they were killed, and samples were collected for further analysis. Our results demonstrate that males are more negatively impacted by high-fat diet than females, regardless of maternal treatment. We provide evidence that differential response to leptin may mediate the sexual dimorphism observed in fetal programming in which male offspring are more affected by maternal undernutrition and female offspring by maternal overnutrition. We show that female offspring born to food-restricted, leptin-supplemented mothers are obese and insulin resistant. This may mimic fetal programming events seen in offspring of overweight women.