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In pregnancy, idiopathic oligohydramnios is an obstetrical complication that compromises maternal health with poor perinatal outcome. Effective therapeutic treatment of this condition has been hampered by the unknown etiology and lack of understanding of cellular and molecular mechanisms that underlie idiopathic oligohydramnios. Amniotic fluid volume (AFV) is determined by intramembranous (IM) transport of amniotic fluid across the amnion and this pathway is regulated to maintain AFV within the normal range. To gain understanding of the causes of idiopathic oligohydramnios, we performed proteomics analysis of the human amnion to investigate the changes in protein expression profiles of cellular transport pathways and regulators in patients with oligohydramnios. Placental amnions from five patients with normal pregnancies and five patients with oligohydramnios were subjected to proteomics experiments followed by bioinformatics analysis. Using Ingenuity Pathway Analysis (IPA) software, five categories of biological functions and multiple canonical pathways within each category were revealed. The top differentially expressed proteins that participate in mediating these pathways were identified. The functional pathways activated include: (a) cellular assembly and organization, (b) cell signaling and energy metabolism, and (c) immunological, infectious, and inflammatory functions. Furthermore, the analysis identified the category of pathways that facilitate molecular endocytosis and vesicular uptake. Under oligohydramniotic conditions, the mediators of clathrin vesicle‐mediated uptake and transport as well as intracellular trafficking mediators were up‐regulated. These findings suggest that idiopathic oligohydramnios may be associated with alternations in cellular organization and immunological functions as well as increases in activity of vesicular transport pathways across the amnion., The proteomics profile in placental amnion of normal and oligohydramniotic patients revealed changes in activity of several categories of cellular pathways and modulators associated with low amniotic fluid volume. Alterations in expression of the key regulators of vesicular endocytosis and intracellular trafficking pathways may affect amniotic fluid transport across the amnion leading to amniotic fluid volume disorders including oligohydramnios.

Women with ovulatory menstrual cycles show an increase in body temperature in the luteal phase, compared with follicular phase, particularly during the night. Several, albeit not all, studies reported higher energy expenditure in the luteal phase compared with follicular phase. Q10 of biological reactions lies between 2.0 and 3.0, predicting a 7‐12% increase in energy expenditure when body temperature rises by 1°C. In this study, temperature dependence of energy expenditure was assessed by comparing changes in sleeping energy expenditure and thermoregulation with menstrual cycle in 9 young females. Energy expenditure was measured using a metabolic chamber, in which sleep was recorded polysomnographically, and core body temperature and skin temperature were continuously monitored. Distal‐to‐proximal skin temperature gradient was assessed as an index of heat dissipation. In the luteal phase, a significant increase in average core body temperature (+0.27°C) and energy expenditure (+6.9%) were observed. Heat dissipation was suppressed during the first 2 hr of sleep in the luteal phase, compared with follicular phase. Rise in basal body temperature in the luteal phase was accompanied by increased energy expenditure and suppressed heat dissipation. The 6.9% increase in metabolic rate would require a Q10 of 12.4 to be attributable solely to temperature (+0.27°C), suggesting that energy expenditure in the luteal phase is enhanced through the mechanism, dependent and independent of luteal‐phase rise in body temperature presumably reflects other effects of the sex hormones., Body temperature, heat production and heat dissipation during sleep was compared between follicular and luteal phase. During the luteal phase, significant increase in average core body temperature (+0.27°C) and energy expenditure (+6.9%) was observed, and temperature dependence of energy expenditure assessed as Q10 was 12.4. Heat dissipation was suppressed during the first 2 hr of sleep in the luteal phase, compared with follicular phase

Muscle loss is a debilitating side effect to prostate cancer (PCa) experienced by nearly 60% of men. The purpose of this study was to test the hypothesis that Nexrutine®, a bark extract from the Phellodendrum amurense, can protect against prostate cancer induced muscle loss in a similar manner as exercise, using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Forty‐five, 8‐ to 10‐week old TRAMP mice were randomized to either control, Nexrutine® (600 mg/kg pelleted in chow) or exercise (voluntary wheel running). Mice were serially sacrificed at weeks 4, 8, 12, and 20, at which time either the left or right gastrocnemius muscle was harvested, weighted, and frozen. Proteolysis inducing factor (PIF), ubiquitin, and NF‐κB concentrations were quantified using ELISA kits. Nexrutine® and exercise were equally able to protect TRAMP mice against PCa‐induced muscle loss (P = 0.04). Both interventions decreased intramuscular PIF concentrations at 20 weeks compared to control (P

Bariatric surgery is now the most widely used intervention for the treatment of human obesity. A large body of literature has demonstrated its efficacy in sustained weight loss and improvement in its associated comorbidities. Here, we review the effect of bariatric surgery in gut hormone physiology, bone remodeling and the reproductive axis. Rapid improvements in insulin release and sensitivity appear to be weight loss independent and occur immediately after surgery. These effects on pancreatic beta cells are mostly due to increased gut hormone secretion due to augmented nutrient delivery to the small intestine. Bone remodeling is also affected by gut hormones. Phenotypic skeletal changes observed in mice deficient in GLP‐1 or GIP suggest that increased incretins may improve bone density. However, these positive effects may be counterbalanced by the association between weight loss and a reduction in bone density. Finally, studies have shown a marked improvement following bariatric surgery in infertility and PCOS in women and hypogonadism in men. Thus, the net effect on endocrine systems after bariatric surgery will likely vary on an individual basis and depend on factors such as comorbidities, peri‐menopausal state, amount of weight loss, and likelihood to adhere to vitamin supplementation after surgery.

In vivo metabolic studies typically concern complex open systems. However, a closed system allows better assessment of the metabolic limits. Ischemic priapism (IP) constitutes a special model of the compartment syndrome that allows direct sampling from a relatively large blood compartment formed by the corpora cavernosa (CC). The purpose of our study was to measure metabolic changes and the accumulation of end products within the CC during IP. Blood gas and biochemical analyses of aspirates of the CC were analyzed over an 8-year period. Mean +/- SD pH, pCO(2), pO(2), O-2-saturation, lactate, and glucose of the aspirated blood were determined with a point-of-care analyzer. Forty-seven initial samples from 21 patients had a pH of 6.91 +/- 0.16, pCO(2) of 15.3 +/- 4.4 kPa, pO(2) of 2.4 +/- 2.0 kPa, and an O-2-saturation of 19 +/- 24% indicating severe hypoxia with severe combined respiratory and metabolic acidosis. Glucose and lactate levels were 1.1 +/- 1.5 and 14.6 +/- 4.8 mmol/L, respectively. pH and pCO(2) were inversely correlated (R-2 = 0.86; P

Endometriosis is one of the most common reproductive diseases of women, with some important biochemical changes in the serum. Curcumin was reported to have anti‐endometriosis, anti‐inflammatory and antioxidant activity. This study explores the changes of serum levels of Cancer Antigen 125 (CA125), leptin, resistin, homocysteine, and total antioxidant capacity (TAC) in a rat model of endometriosis and the effect of curcumin treatment on these factors. Fifty female Sprague‐Dawley rats (220–250 gr body weight) were randomly divided into control (received 0.3 mL of the vehicle), sham(stress of surgery + 0.3 mL of the vehicle) and three endometriosis groups as danazol treatment (7.2 mg/kg BW, IP), curcumin treatment (48 mg/kg BW, IP) and test (received 0.3 mL of the vehicle). Endometriosis was induced by surgically auto‐transplantation of uterine tissue to the abdominal wall and intestinal mesentery. The animals were treated for 4 weeks. On the last day, the blood sample was collected by heart puncture, and the above‐mentioned factors were measured in the sera. Leptin in the curcumin treatment group was markedly higher than all of the studied groups, except the danazol group, while there were no significant differences between other groups (P 0.05). The serum levels of TAC in the control group were significantly higher than all of the studied groups (P

Preeclampsia (PE), a disorder of new‐onset maternal hypertension and vascular dysfunction during pregnancy, is thought to be linked to placental ischemia‐induced release of prohypertensive factors and reductions of vasoprotective factors in the maternal circulation. Although markers of sympathetic nervous activity are elevated in experimental models of placental ischemia‐induced hypertension and women with PE compared with their normal pregnant counterparts, the importance of adrenergic receptor signaling in the development of hypertension in PE is unknown. Therefore, we tested the hypothesis that adrenergic receptor blockade attenuates the development of placental ischemia‐induced hypertension in rats. Wistar Hannover rats underwent reduced uterine perfusion pressure (RUPP) or Sham surgeries on gestational day 14. By day 19, mean arterial blood pressure (MAP) was increased in RUPP over Sham rats. Groups of RUPP and Sham pregnant rats received terazosin and propranolol (3 mg/kg per day of each via subcutaneous osmotic minipump) to block α 1‐ and β‐adrenergic receptors, respectively, beginning on gestational day 14. Adrenergic blockade significantly attenuated the development of hypertension in the RUPP rats with a slight blood pressure‐lowering response in the Sham, normal pregnant rats by day 19. In conclusion, these data implicate that placental ischemia‐induced hypertension involves adrenergic receptor signaling to promote increases in blood pressure during PE.

An abnormal uterine environment can influence maternal–fetal communication, conception rate and disrupt normal embryo development, thereby affecting fertility and the reproductive performance of dairy cows. Animal variability means that development of endometrial cell lines with appropriate characteristic are required. We evaluated the effect of an infectious agent (i.e., bacterial lipopolysaccharide; LPS) and proinflammatory mediators (i.e., Interleukin 1 beta; IL‐1β, and tumor necrosis factor alpha; TNFα) on inflammatory mediator gene expression and production by bovine endometrial epithelial (bEEL) and stromal (bCSC) cell lines. Expression of CXCL8/IL8, IL1A, IL1B, and IL6 cytokine genes was significantly upregulated in both epithelial and stromal cells when treated with LPS and IL‐1β. LPS treatment of epithelial cells (compared with treatment by IL‐1β and TNFα) exhibited greater CXCL8/IL8, IL1A, IL1B, and IL6 cytokine gene expression. Whereas, in stromal cells, IL‐1β treatment (compared with LPS and TNFα) exhibited greater CXCL8/IL8, IL1A, IL1B, and IL6 cytokine gene expression. Interestingly, bEEL and bCSC cells treated with IL‐1β increased IL1B gene expression, suggesting that IL‐1β may act unusually in an autocrine‐positive feedback loop. Cytokine production was stimulated by these agents in both cell types. We suggest that the characteristics of these two cell lines make them excellent tools for the study of intrauterine environment.

It remains unclear how rapidly progesterone suppresses luteinizing hormone (LH) pulse frequency in women. Previous studies suggested that progesterone markedly increases LH pulse amplitude but does not slow LH pulse frequency within 10 h in estradiol‐pretreated women studied during the late follicular phase. However, this experimental paradigm may be a model of preovulatory physiology, and progesterone may have different effects at other times of the cycle. We studied regularly cycling, nonobese women without hyperandrogenism to assess the acute effect of progesterone during the midfollicular phase and in the absence of estradiol pretreatment. The study involved two admissions in separate cycles (cycle days 5–9). For each admission, either oral micronized progesterone (100 mg) or placebo was administered at 0900 h in a randomized, double‐blind fashion. Frequent blood sampling was performed between 0900 and 1900 h to define 10‐h LH pulsatility. Treatment crossover (placebo exchanged for progesterone and vice versa) occurred in a subsequent cycle. After an interim futility analysis, the study was halted after 7 women completed study. Mean progesterone concentrations after placebo and progesterone administration were 0.5 ± 0.1 (mean ± SD) and 6.7 ± 1.6 ng/mL, respectively. Compared to placebo, progesterone was not associated with a significant difference in 10‐h LH pulse frequency (0.79 ± 0.35 vs. 0.77 ± 0.28 pulses/h, P = 1.0) or amplitude (3.6 ± 2.8 vs. 4.3 ± 2.8 IU/L, P = 0.30). This study suggests that LH pulse frequency is not rapidly influenced by progesterone administration during the midfollicular phase.

Orthostatic intolerance is more common in women than men, and some studies have found that women in the early follicular (EF) phase of the menstrual cycle experience the greatest feelings of lightheadedness. Chemoreflex function while supine or upright was investigated to determine the potential contribution of ventilatory control to these phenomena. Men (n = 13) and women (n = 14) were tested while supine and 70° upright (head‐up tilt [HUT]) and given: (1) normoxia or (2) hypercapnia (5% CO2). Women were tested during the EF phase (days 2–5) and the midluteal phase (ML; days 18–24). During HUT, all groups reduced cerebrovascular resistance index (men: 1.45 ± 0.08 to 1.42 ± 0.07 mmHg/(cm·sec), EF: 1.38 ± 0.11 to 1.26 ± 0.10 mmHg/(cm·sec), ML: 1.25 ± 0.07 to 1.09 ± 0.07 mmHg/(cm·sec); P ≤ 0.019); however, only men increased ventilation (men: 11.99 ± 0.65 to 13.24 ± 0.83 L/min; P

To test the hypothesis that use of oral contraceptives (OC) changes diurnal variation in fluid balance mechanisms including blood pressure, secretion of vasopressin and oxytocin, and renal water and electrolyte excretion. Fifteen naturally cycling (NC) women in mid-follicular phase and 11 long-term OC users were included in a 24-h standardized inpatient study for measurements of vasopressin, oxytocin, sodium, and osmolality in plasma as well as urinary excretion of electrolytes, aquaporin-2, and prostaglandin E2. Blood pressure and heart rate were monitored noninvasively. Plasma vasopressin showed circadian rhythm (P = 0.02) and were similar in both groups (P = 0.18) including nighttime increases (P < 0.001). There was no circadian rhythm in plasma oxytocin within (P = 0.84) or between groups (P = 0.22). OC users had significantly lower plasma osmolality (Δosm: 3.05 ± 0.29 mosm/kg, P = 0.04) and lower plasma sodium (ΔNa+: 0.91 ± 0.09 mmol/l, P = 0.05). The two groups showed similar nighttime decreases in diuresis (1.08 ± 0.04 mL/(kg·h), P < 0.001) and increases in urine osmolality (109 ± 9 mosm/kg, P = 0.02), but similar rates of excretion of Aquaporin-2, prostaglandin E2 and sodium. Nighttime decreases in mean arterial pressure of approximately 13% were significant in both groups (P < 0.001), but 24-h average mean arterial pressure was significantly higher in OC users than in controls (+4.7 ± 0.4 mmHg, P = 0.02). Packed cell volumes were similar between groups (P = 0.54). OC does not change the diurnal patterns of renal fluid excretion, but resets the osmoreceptors for vasopressin release and leads to a significant increase in arterial blood pressure.

Central (aortic) blood pressure and aortic pulse wave characteristics are measures of cardiovascular health, predictive of cardiovascular mortality. Previous studies have compared aortic hemodynamics in women who do and do not take menopausal hormone therapy, but characteristics of these parameters following cessation of treatment have not been defined. Therefore, the purpose of this study was to define aortic pulse wave characteristics in postmenopausal women with and without a history of menopausal hormone therapy use. Pulse wave analysis was conducted on 67 women who had participated in the randomized, double‐blind, placebo‐controlled Kronos Early Estrogen Prevention Study (KEEPS), 3 years subsequent to the four‐year treatment period. Treatment was oral conjugated equine estrogen (0.45 mg/day; n = 18); transdermal 17 β ‐estradiol (50 μ g/day; n = 23) each with oral micronized progesterone (Prometrium 200 mg); and placebo pills and patch ( n = 26). At post‐treatment, median age (60 years) and body mass index (27 kg/m 2 ) did not differ across prior treatment assignment. Aortic blood pressures (median systolic 115 mm Hg and diastolic 76 mm Hg) and augmentation index (median 33%) did not differ among women across prior treatment assignment. These results suggest that these doses and formulations of menopausal hormone therapy had no long‐term effects on central vascular function 3 years after cessation of treatment.

Polycystic ovary syndrome (PCOS) is the most common endocrine and reproductive disorder in premenopausal women, characterized by hyperandrogenemia, metabolic syndrome, and inflammation. Women who had PCOS during their reproductive years remain hyperandrogenemic after menopause. The consequence of chronic hyperandrogenemia with advanced aging has not been studied to our knowledge. We have characterized a model of hyperandrogenemia in female rats and have aged them to 22–25 months to mimic advanced aging in hyperandrogenemic women, and tested the hypothesis that chronic exposure to hyperandrogenemia with aging has a deleterious effect on renal function. Female rats were chronically implanted with dihydrotestosterone pellets (DHT 7.5 mg/90 days) that were changed every 85 days or placebo pellets, and renal function was measured by clearance methods. Aging DHT‐treated females had a threefold higher level of DHT with significantly higher body weight, mean arterial pressure, left kidney weight, proteinuria, and kidney injury molecule‐1 (KIM‐1), than did age‐matched controls. In addition, DHT‐treated‐old females had a 60% reduction in glomerular filtration rate, 40% reduction in renal plasma flow, and significant reduction in urinary nitrate and nitrite excretion (UNOxV), an index of nitric oxide production. Morphological examination of kidneys showed that old DHT‐treated females had significant focal segmental glomerulosclerosis, global sclerosis, and interstitial fibrosis compared to controls. Thus chronic hyperandrogenemia that persists into old age in females is associated with renal injury. These data suggest that women with chronic hyperandrogenemia such as in PCOS may be at increased risk for development of chronic kidney disease with advanced age.

In the first case, the AA and glucose were infused through a perinatal port system into the umbilical vein at 30 weeks' gestation due to severe IUGR. The patient received daily hyperbaric oxygenation (HBO, 100% O2) with 1.4 atmospheres absolute for 50 min for 7 days. At 31+4 weeks' gestation, the patient gave birth spontaneously to a newborn weighing 1378 g, pH 7.33, APGAR score 4/6/intubation. In follow‐up examinations at 5 years of age, the boy was doing well without any neurological disturbance or developmental delay. In the second case, the patient presented at 25/5 weeks' gestation suffering from severe IUGR received HBO and maternal AA infusions. The cardiotocography was monitored continuously during HBO treatment. The short‐time variations improved during HBO from 2.9 to 9 msec. The patient developed pathologic CTG and uterine contractions 1 day later and gave birth to a hypotrophic newborn weighing 420 g. After initial adequate stabilization, the extremely preterm newborn unfortunately died 6 days later. Fetal nutrition combined with HBO is technically possible and may allow the prolongation of the pregnancy. Fetal‐specific amino‐acid composition would facilitate the treatment options of IUGR fetuses and extremely preterm newborn.

Current technology for penile hemodynamic evaluations in small animals is invasive and has limitations. We evaluated a novel laser speckle contrast imaging (LSCI) technique to determine age‐related changes in penile microvascular perfusion (PMP) and tested the role of cavernosal muscle (CC) fibrosis mediated by Wnt‐TGF β 1 signaling pathways in a mouse model. Ten young (2–3 months) and old (24–28 months) wild‐type C57BL6 male mice were subjected to PMP measured using a LSCI system. Penile blood flow (PBF, peak systolic velocity, PSV) was also measured using a color Doppler ultrasound for comparison. Measurements were made before and after injection of vasoactive drugs: prostaglandin E 1 (PGE 1 ) and acetylcholine (ACh). CC was processed for immunohistochemical studies for markers of endothelium and fibrosis. Protein levels were quantified by Western blot.PMP and PBF increased significantly from baseline after injection of vasoactive drugs. Peak PMP after PGE 1 and ACh was higher in young mice (225.0 ± 12.0 and 211.3 ± 12.1 AU) compared to old (155.9 ± 7.1 and 162.6 ± 5.1 AU, respectively). PSV after PGE 1 was higher in young than old mice (112.7 ± 8.5 vs. 78.2 ± 4.6 mm/sec). PSV after ACh was also higher in young (112.7 ± 5.6 mm/sec) than older mice (69.2 ± 7.1 mm/sec). PMP positively correlated with PSV ( r = 0.867, P = 0.001). Immunostaining and Western blot showed increased protein expression of all fibrosis markers with aging. LSCI is a viable technique for evaluating penile hemodynamics. Increased cavernosal fibrosis may cause impaired penile hemodynamics and increased incidence of erectile dysfunction in older men.

The importance of 1,5‐anhydroglucitol (1,5‐AG) as an intermediate biomarker for diabetic pregnancy is multi‐fold: (1) it serves as a reliable indicator of moderate‐level glycemic control, especially during early gestation; (2) it has been associated with increased risk of diabetes, independent of HbA1c and fasting glucose; and (3) it is an independent risk factor for the development of eclampsia during pregnancy. However, the clinical use of this biomarker during pregnancy has been underutilized due to physiological changes in glomerular filtration rate, plasma volume, and other hemodynamic parameters which have been hypothesized to bias gestational serum 1,5‐AG concentrations. Here, we develop an in‐silico model of gestational 1,5‐AG by combining pre‐existing physiological data in the literature with a two‐compartment mathematical model, building off of a previous kinetic model described by Stickle and Turk (1997) Am. J. Physiol., 273, E821. Our model quantitatively characterizes how renal and hemodynamic factors impact measured 1,5‐AG during normal pregnancy and during pregnancy with gestational diabetes and diabetes mellitus. During both normal and diabetic pregnancy, we find that a simple two‐compartment model of 1,5‐AG kinetics, with all parameters but reabsorption fraction adjusted for time in pregnancy, efficiently models 1,5‐AG kinetics throughout the first two trimesters. Allowing reabsorption fraction to decrease after 25 weeks permits parameters closer to expected physiological values during the last trimester. Our quantitative model of 1,5‐AG confirms the involvement of hypothesized renal and hemodynamic mechanisms during pregnancy, clarifying the expected trends in 1,5‐AG to aid clinical interpretation. Further research and data may elucidate biological changes during the third trimester that account for the drop in 1,5‐AG concentrations, and clarify physiological differences between diabetes subtypes during pregnancy.

Both the history of obesity and weight loss may change how menopause affects metabolic health. The purpose was to determine whether obesity and/or weight loss status alters energy balance (EB) and subsequent weight gain after the loss of ovarian function. Female lean and obese Wistar rats were randomized to 15% weight loss (WL) or ad libitum fed controls (CON). After the weight loss period, WL rats were kept in EB at the reduced weight for 8 weeks prior to ovariectomy (OVX). After OVX, all rats were allowed to eat ad libitum until weight plateaued. Energy intake (EI), spontaneous physical activity, and total energy expenditure (TEE) were measured with indirect calorimetry before OVX, immediately after OVX, and after weight plateau. Changes in energy intake (EI), TEE, and weight gain immediately after OVX were similar between lean and obese rats. However, obese rats gained more total weight and fat mass than lean rats over the full regain period. Post‐OVX, EI increased more (P ≤ 0.03) in WL rats (58.9 ± 3.5 kcal/d) than CON rats (8.5 ± 5.2 kcal/d), and EI partially normalized (change from preOVX: 20.5 ± 4.2 vs. 1.5 ± 4.9 kcal/day) by the end of the study. As a result, WL rats gained weight (week 1:44 ± 20 vs. 7 ± 25 g) more rapidly (mean = 44 ± 20 vs. 7 ± 25 g/week; P

Intrauterine growth restriction (IUGR) and maternal consumption of a high‐saturated‐fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. Many pregnant women eat a HFD, thus exposing the fetus to a HFD in utero. The cumulative effect of in utero exposure to IUGR and a HFD on offspring cholesterol levels remains unknown. Furthermore, little is known about the mechanism through which IUGR and maternal HFD consumption increase cholesterol. We hypothesize that IUGR combined with a maternal HFD would increase offspring serum and hepatic cholesterol accumulation via alteration in levels of key proteins involved in cholesterol metabolism. To test our hypothesis we used a rat model of surgically induced IUGR and fed the dams a regular diet or a HFD. HFD‐fed dams consumed the same kilocalories as regular diet‐fed dams, with no difference between surgical intervention groups. In the offspring, IUGR combined with a maternal HFD increased hepatic cholesterol levels, low‐density lipoprotein (LDL) receptor protein levels, and Ldlr activity in female rat offspring at birth and both sexes at postnatal day 14 relative to non‐IUGR offspring both from regular diet‐ and HFD‐fed dams. These findings suggest that IUGR combined with a maternal HFD increases hepatic cholesterol accumulation via increased LDL cholesterol uptake into the liver with resulting persistent increases in hepatic cholesterol accumulation.

Hypertension in postmenopausal women is less well controlled than in age‐matched men. The aging female SHR is a model of postmenopausal hypertension that is mediated in part by activation of the renin–angiotensin system (RAS) and by the renal sympathetic nervous system. In this study, the hypothesis was tested that renal denervation would lower the blood pressure in old female SHR and would attenuate the antihypertensive effects of AT1 receptor antagonism. Retired breeder female SHR were subjected to right uninephrectomy (UNX) and left renal denervation (RD) or UNX and sham, and 2 weeks later, baseline mean arterial pressure (MAP; radiotelemetry) was measured for 4 days, and then rats were treated with angiotensin (AT1) receptor antagonist, losartan (40 mg/kg/day po) for 6 days. Renal denervation reduced MAP in old females compared to sham (172 ± 6 vs. 193 ± 6 mm Hg; P

Mammalian target of rapamycin (mTOR) is a protein that regulates cell growth in response to altered nutrient and growth factor availability. Our objective was to assess activated mTOR and its intracellular intermediates p70, and 4EBP1 in placental and invasive trophoblast cells in a hypoxia‐induced model of intrauterine growth restriction (IUGR) in rats. Rats were treated with hypoxia (9%) for 4 days. Placental and fetal weights, as well as conceptus numbers were recorded at the time of necropsy. Immunohistochemistry was used to determine the level of trophoblast invasion and apoptosis. Western blots were used to determine the activation of mTOR, p70, and 4EBP1 in the placenta and the uterine mesometrial compartment. We observed (1) decreased placental (21%) and fetal (24%) weights (P

Allelic variants in vitamin D metabolism genes may increase the risk of preeclampsia, but few studies have systematically tested this hypothesis. Our objective was to evaluate the relationship between maternal allelic variants in three vitamin D metabolism genes and risk of preeclampsia. Samples were from two case‐control studies of pregnant women who delivered in Pittsburgh, PA from 1999 to 2010 and twelve recruiting sites across the United States from 1959 to 1965. Single‐nucleotide polymorphisms (SNPs) were genotyped 50 kilobases up‐ and down‐stream in three genes (VDR,GC, and CYP27B1) in the samples from both studies, for a total of 744 preeclampsia cases and 2411 controls. Using multivariable logistic regression, we estimated the associations between allelic variation in each locus and preeclampsia risk by maternal race and study. Meta‐analysis was used to estimate the association across race‐study groups for each SNP. Minor allele of a noncoding region of the VDR gene was significantly associated with preeclampsia risk, which was verified in the meta‐analysis [odds ratio (OR), 95% confidence intervals (CI)] after adjusting for multiple comparisons [rs12831006:1.5 (1.2, 2.0), P

Vascular endothelial function declines across the menopause transition in women. We tested the hypothesis that reduced availability of the endothelial nitric oxide synthase [eNOS] substrate L‐arginine is an underlying mechanism to vascular endothelial dysfunction across menopause stages. Endothelial function (brachial artery flow‐mediated dilation [FMD]) and plasma markers of L‐arginine metabolism (citrulline, NG‐mono‐methyl‐ւ‐arginine [L‐NMMA] asymmetric dimethylarginine [ADMA] and NG‐N′G‐dimethyl‐l‐arginine [SDMA]), were measured in 129 women: 36 premenopausal (33 ± 7 years), 16 early‐ (49 ± 3 years) or 21 late‐ (50 ± 4 years) perimenopausal, and 21 early‐ (55 ± 3 years) or 35 late‐ (61 ± 4 years) postmenopausal. FMD was progressively reduced across menopause stages (P

Estrogen deficiency that occurs during menopause is associated with wide‐ranging consequences, including effects on the gastrointestinal system. Although previous studies have implicated a role for estrogen in modulating colonic permeability and inflammatory gene expression, the kinetics of these changes following loss of estrogen and whether they are intestinal region specific are unknown. To test this, we performed sham or ovariectomy (OVX) surgery in BALB/c mice and examined permeability (in vivo and ex vivo) and gene expression changes in the duodenum, jejunum, ileum, and colon at 1, 4, and 8 weeks postsurgery. In vivo permeability, assessed by FITC‐dextran gavage and subsequent measures of serum levels, indicated that OVX significantly increased whole intestinal permeability 1 week postsurgery before returning to sham levels at 4 and 8 weeks. Permeability of individual intestinal sections, measured ex vivo by Ussing chambers, revealed specific regional and temporal responses to OVX, with the most dynamic changes exhibited by the ileum. Analysis of gene expression, by qPCR and by mathematical modeling, revealed an OVX‐specific effect with tight junction and inflammatory gene expression elevated and suppressed with both temporal and regional specificity. Furthermore, ileal and colonic expression of the tight junction protein occludin was found to be significantly correlated with expression of TNF α and IL‐1 β . Together, our studies reveal previously unappreciated effects of estrogen deficiency in specific intestinal segments and further demonstrate temporal links between estrogen deficiency, inflammatory genes, and intestinal permeability.

Intrauterine growth restriction (IUGR) may predispose offspring to an increased susceptibility of developing cardiovascular disease (CVD) in adult life. The window of opportunity to treat later life CVD programmed in fetal life is critical. The aim of this study was to identify the effect of resveratrol treatment of IUGR offspring at a time of known CV dysfunction. Sprague–Dawley male and female rat offspring who experienced normoxia (21% O2; control) or hypoxia (11% O2; IUGR) in utero were fed a high‐fat (HF) diet (3–21 weeks of age) or a HF diet (3–21 weeks of age) supplemented with resveratrol from 13 to 21 weeks of age. At 21 weeks of age, echocardiographic data showed that male IUGR offspring had mild in vivo diastolic dysfunction, whereas female IUGR offspring had early signs of cardiac diastolic dysfunction that was not altered by resveratrol treatment. Notably, male and female IUGR offspring demonstrated equal susceptibility to ex vivo cardiac dysfunction recovery after ischemia/reperfusion (I/R) injury and this was improved by resveratrol treatment, independent of sex. Resveratrol increased cardiac phospho‐adenosine monophosphate kinase (p‐AMPK) levels in only female IUGR offspring. IUGR or resveratrol did not alter cardiac superoxide levels. However, in male offspring, an overall effect of IUGR in reducing cardiac catalase levels was observed that was not altered by resveratrol. Interestingly, in only female IUGR offspring, resveratrol significantly increased cardiac superoxide dismutase (SOD) 2 levels. In conclusion, resveratrol treatment of adult IUGR offspring, at the time of known CV dysfunction, improved cardiac function recovery in both sexes and the mechanisms involved were partially sex‐specific.

In Southern Nigeria, the leaves of Emilia coccinea (Sims) G Dons are used traditionally for birth control. This study was therefore aimed at evaluating the activities of the methanolic leaf extract of Emilia coccinea (EM) on parameters that affect reproduction as well as the acute toxic effects of the plant using nonpregnant female mice models. Leaves of EM were extracted by maceration with 99.8% methanol. Oral acute toxicity profiles were examined. The effects of EM on female reproductive cycle were determined after oral treatment with EM at 1000 and 100 mg/kg/day daily for 6 days using stilbesterol (1 mg/kg/day) and normal saline as controls. The activities of EM (1000 mg/kg/day and 100 mg/kg/day p.o) on reproductive hormones and organs were also studied using estradiol valerat (100 mg/kg/day p.o), progesterone (10 mg/kg/day s.c.), and normal saline as controls. The extract did not induce any observable toxic effect after 24 h. At 1000 mg/kg, the extract significantly shortened the estrus cycle (P

Intrauterine growth restriction (IUGR) is interconnected with developmental programming of lifelong pathophysiology. IUGR is seen in human multifetal pregnancies, with stepwise rises in fetal numbers interfering with placental nutrient delivery. It remains unknown whether fetal blood analyses would reflect fetal nutrition, liver, and excretory function in the last trimester of human or ovine IUGR. In an ovine model, we hypothesized that fetal plasma biochemical values would reflect progressive placental, fetal liver, and fetal kidney dysfunction as the number of fetuses per gestation rose. To determine fetal plasma biochemical values in singleton, twin, triplet, and quadruplet/quintuplet ovine gestation, we investigated morphometric measures and comprehensive metabolic panels with nutritional measures, liver enzymes, and placental and fetal kidney excretory measures at gestational day (GD) 130 (90% gestation). As anticipated, placental dysfunction was supported by a stepwise fall in fetal weight, fetal plasma glucose, and triglyceride levels as fetal number per ewe rose. Fetal glucose and triglycerides were directly related to fetal weight. Plasma creatinine, reflecting fetal renal excretory function, and plasma cholesterol, reflecting placental excretory function, were inversely correlated with fetal weight. Progressive biochemical disturbances and growth restriction accompanied the rise in fetal number. Understanding the compensatory and adaptive responses of growth‐restricted fetuses at the biochemical level may help explain how metabolic pathways in growth restriction can be predetermined at birth. This physiological understanding is important for clinical care and generating interventional strategies to prevent altered developmental programming in multifetal gestation.

In polycystic ovary syndrome (PCOS), cardiovascular risk is increased. Peak O2 uptake (Embedded Image) predicts the cardiovascular risk. We were the first to examine the contribution of systemic O2 delivery and arteriovenous O2 difference to Embedded Image in overweight and obese women with PCOS. Fifteen overweight or obese PCOS women and 15 age‐, anthropometry‐, and physical activity‐matched control women performed a maximal incremental cycling exercise test. Alveolar gas exchange (volume turbine and mass spectrometry), arterial O2 saturation (pulse oximetry), and cardiac output (CO) (impedance cardiography) were monitored. Hb concentration was determined. Arterial O2 content and arteriovenous O2 difference (C(a‐v)O2) (Fick equation) were calculated. Insulin resistance was evaluated by homeostasis model assessment (HOMA‐IR). PCOS women had lower Embedded Image than controls (40 ± 6 vs. 46 ± 5 mL/min/kg fat‐free mass [FFM], P = 0.011). Arterial O2 content was similarly maintained in the groups throughout the exercise test (P > 0.05). Linear regression analysis revealed a pronounced response of CO to increasing Embedded Image in PCOS women during the exercise test: A ∆CO/∆Embedded Image slope was steeper in PCOS women than in controls (β = 5.84 vs. β = 5.21, P = 0.004). Eventually, the groups attained similar peak CO and peak CO scaled to FFM (P > 0.05). Instead, C(a‐v)O2 at peak exercise was lower in PCOS women than in controls (13.2 ± 1.6 vs. 14.8 ± 2.4 mL O2/100 mL blood, P = 0.044). HOMA‐IR was similar in the groups (P > 0.05). The altered cardiorespiratory responses to exercise in overweight and obese PCOS women indicate that PCOS per se is associated with alterations in peripheral adjustments to exercise rather than with limitations of systemic O2 delivery., published version, peerReviewed

Sudden infant death syndrome (SIDS) is one of the most common causes of postneonatal infant mortality in the developed world. An insufficient cardiorespiratory response to multiple environmental stressors (such as prone sleeping positioning, overwrapping, and infection), during a critical period of development in a vulnerable infant, may result in SIDS. However, the effect of multiple risk factors on cardiorespiratory responses has rarely been tested experimentally. Therefore, this study aimed to quantify the independent and possible interactive effects of infection, hyperthermia, and hypoxia on cardiorespiratory control in rats during the neonatal period. We hypothesized that lipopolysaccharide (LPS) administration will negatively impact cardiorespiratory responses to increased ambient temperature and hypoxia in neonatal rats. Sprague–Dawley neonatal rat pups were studied at postnatal day 6–8. Rats were examined at an ambient temperature of 33°C or 38°C. Within each group, rats were allocated to control, saline, or LPS (200 μg/kg) treatments. Cardiorespiratory and thermal responses were recorded and analyzed before, during, and after a hypoxic exposure (10% O2). Serum samples were taken at the end of each experiment to measure cytokine concentrations. LPS significantly increased cytokine concentrations (such as TNF α, IL‐1β, MCP‐1, and IL‐10) compared to control. Our results do not support a three‐way interaction between experimental factors on cardiorespiratory control. However, independently, heat stress decreased minute ventilation during normoxia and increased the hypoxic ventilatory response. Furthermore, LPS decreased hypoxia‐induced tachycardia. Herein, we provide an extensive serum cytokine profile under various experimental conditions and new evidence that neonatal cardiorespiratory responses are adversely affected by dual interactions of environmental stress factors.