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Aim of the present study was to explore the evaluative effectiveness of age, ovarian volume (OV), antral follicle count (AFC), serum follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), AFC/Age ratio, AMH/Age ratio, FSH/luteinizing hormone (LH) ratio, and ovarian response prediction index (ORPI) to determine which could more advantageously assess ovarian reserve and response.This research enrolled 319 consecutive infertile women who had undergone in vitro fertilization-ET/intracytoplasmic sperm injection (IVF-ET/ICSI) treatments. Abovementioned variables were measured and calculated. Receiver operating characteristic (ROC) curve analysis was used to analyze the predictive accuracy of variables and to calculate cut-off values and corresponding sensitivity and specificity.Our study revealed that the significant variables for evaluating a decline in ovarian reserve include age, OV, FSH, AFC/Age ratio, AMH/Age ratio, and ORPI. Moreover, the area under the curve (AUC) of AFC/Age ratio was higher than other 5 variables (AUC = 1.000), and the cut-off value of AFC/Age ratio was 0.111 (sensitivity 100.00%, specificity 100.00%). The significant variables forecasting excessive ovarian response were age, AFC, AMH, FSH, AFC/Age ratio, AMH/Age ratio, FSH/LH ratio, and ORPI, and the significant variables forecasting poor ovarian response were AMH, LH, OV, AFC/Age ratio, AMH/Age ratio, and FSH/LH ratio. When ORPI was used to predict excessive response, the cut-off value of ORPI was 0.880 (sensitivity 84.72%, specificity 67.32%) and ORPI presented better effectiveness. When used to predict poor response, the evaluative effectiveness of 6 variables was almost similar, although the AUC of AFC/Age ratio presented the largest value.Regarding the infertile women, AFC/Age ratio performed better than did the other variables in evaluating ovarian reserve, and it offered excellent effectiveness in predicting poor ovarian response, however, ORPI presented better effectiveness in predicting excessive ovarian response.

Objective: To investigate sex differences in late-onset Alzheimer disease (AD) risks by means of multimodality brain biomarkers (β-amyloid load via 11 C-Pittsburgh compound B [PiB] PET, neurodegeneration via 18 F-fluorodeoxyglucose [FDG] PET and structural MRI)., Methods: We examined 121 cognitively normal participants (85 women and 36 men) 40 to 65 years of age with clinical, laboratory, neuropsychological, lifestyle, MRI, FDG- and PiB-PET examinations. Several clinical (e.g., age, education, APOE status, family history), medical (e.g., depression, diabetes mellitus, hyperlipidemia), hormonal (e.g., thyroid disease, menopause), and lifestyle AD risk factors (e.g., smoking, diet, exercise, intellectual activity) were assessed. Statistical parametric mapping and least absolute shrinkage and selection operator regressions were used to compare AD biomarkers between men and women and to identify the risk factors associated with sex-related differences., Results: Groups were comparable on clinical and cognitive measures. After adjustment for each modality-specific confounders, the female group showed higher PiB β-amyloid deposition, lower FDG glucose metabolism, and lower MRI gray and white matter volumes compared to the male group ( p < 0.05, family-wise error corrected for multiple comparisons). The male group did not show biomarker abnormalities compared to the female group. Results were independent of age and remained significant with the use of age-matched groups. Second to female sex, menopausal status was the predictor most consistently and strongly associated with the observed brain biomarker differences, followed by hormone therapy, hysterectomy status, and thyroid disease., Conclusion: Hormonal risk factors, in particular menopause, predict AD endophenotype in middle-aged women. These findings suggest that the window of opportunity for AD preventive interventions in women is early in the endocrine aging process., (© 2020 American Academy of Neurology.)

Background: This pilot study investigated the effect of sufentanil titration by 3 different analgesia monitoring devices or clinical signs during general anesthesia., Methods: Forty-eight patients undergoing radical retropubic prostatectomy with sevoflurane/sufentanil anesthesia were randomly assigned into 4 groups and received sufentanil guided either by 1 of 3 analgesia monitoring devices (Surgical Pleth Index [SPI], Pupillary Pain Index [PPI], Nociception Level [NoL]) or by clinical judgment (control). The primary end point was intraoperative sufentanil consumption. Adrenocorticotropic hormone (ACTH) and cortisol were measured at 4 time points during the day of surgery. Data were analyzed by Kruskal-Wallis and Mann-Whitney U tests and by mixed model and area under the curve (AUC) analyses for group comparisons and time effects of stress hormones., Results: The total amount of sufentanil administration (μg·kg·minute·10) differed between the groups (median [quartiles]: control = 5.6 [4.4-6.4], SPI = 7.2 [4.8-8.4], PPI = 2.0 [1.8-2.9], NoL = 3.8 [3.3-5.1]; PPI versus SPI, -5.1 [-6.6 to -1.3], P < .001; NoL versus SPI, -3.0 [-5.2 to 0.2], P = .024; control versus SPI, -1.6 [-3.7 to 1.7], P = .128; NoL versus PPI, 1.7 [0.6-3.4], P < .001; control versus PPI, 3.4 [2.0-4.6], P < .001; control versus NoL, 1.6 [-0.2 to 3.3], P = .017) (Hodges-Lehmann estimator [99% confidence interval {CI}], P values). The AUC analysis indicated differences among groups in cumulative ACTH levels (ng·liter·minute, natural logarithm (ln)-transformed data) of NoL versus PPI (-1.079 [-1.950 to -0.208], P = .001) and PPI versus SPI (1.192 [0.317-2.068], P= .001), as well as differences in cortisol levels (µg·liter·minute) for PPI versus SPI (46,710 [21,145-72,274], P < .001), NoL versus SPI (27,645 [3163-52,126], P = .003), and control versus SPI (31,824 [6974-56,675], P = .001) (differences in means [99% CI], P value). Secondary end points (postoperative recovery, pain level, and analgesia medication) showed no differences., Conclusions: The type of analgesia nociception monitoring affected the total amount of sufentanil administered. Lower sufentanil doses in the PPI group were associated with an increased endocrine stress response. Titration by SPI caused no opioid reduction compared to the control but was associated with a reduced endocrine stress response.

Background: Minimally invasive fingerstick sampling allows testing of reproductive hormone levels at home, providing women with increased access to tests that can screen for conditions such as polycystic ovarian syndrome, primary ovarian insufficiency, and pituitary and thyroid dysfunction., Method: We present a measurement procedure comparison study of matched venipuncture and fingerstick samples from 130 women aged 18-40 years, tested on menstrual cycle day 3. Samples were measured for anti-müllerian hormone, estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), testosterone, thyroid-stimulating hormone (TSH), and free thyroxine (T4) levels. Samples were tested using U.S. Food and Drug Administration-cleared immunoassays, with a modified reconstitution step for fingerstick samples., Experience: Venipuncture and fingerstick hormone values were concordant and linear across all assay ranges. There was no evidence of systematic bias across the assay ranges, and bias measures were below recommended guidelines. The correlation between venipuncture and fingerstick was between 0.99 and 1.0 for each hormone. Each assay displayed a high degree of precision (less than 13% coefficient of variation) and a high level of accuracy (average recovery equaled 95.5-102.3%)., Conclusion: Venipuncture and fingerstick samples can be used interchangeably to measure anti-müllerian hormone, E2, FSH, LH, PRL, testosterone, TSH, and free T4 levels. Fingerstick sampling provides doctors and women more convenient testing options., Funding Source: The study was sponsored by Modern Fertility.

Background: Exposure to ambient particulate matter (PM) is associated with a number of adverse health outcomes, but potential mechanisms are largely unknown. Metabolomics represents a powerful approach to study global metabolic changes in response to environmental exposures. We therefore conducted this study to investigate changes in serum metabolites in response to the reduction of PM exposure among healthy college students., Methods: We conducted a randomized, double-blind crossover trial in 55 healthy college students in Shanghai, China. Real and sham air purifiers were placed in participants' dormitories in random order for 9 days with a 12-day washout period. Serum metabolites were quantified by using gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-mass spectrometry. Between-treatment differences in metabolites were examined using orthogonal partial least square-discriminant analysis and mixed-effect models. Secondary outcomes include blood pressure, corticotropin-releasing hormone, adrenocorticotropic hormone, insulin resistance, and biomarkers of oxidative stress and inflammation., Results: The average personal exposure to PMs with aerodynamic diameters ≤2.5 μm was 24.3 μg/m 3 during the real purification and 53.1 μg/m 3 during the sham purification. Metabolomics analysis showed that higher exposure to PMs with aerodynamic diameters ≤2.5 μm led to significant increases in cortisol, cortisone, epinephrine, and norepinephrine. Between-treatment differences were also observed for glucose, amino acids, fatty acids, and lipids. We found significantly higher blood pressure, hormones, insulin resistance, and biomarkers of oxidative stress and inflammation among individuals exposed to higher PMs with aerodynamic diameters ≤2.5 μm., Conclusions: This study suggests that higher PM may induce metabolic alterations that are consistent with activations of the hypothalamus-pituitary-adrenal and sympathetic-adrenal-medullary axes, adding potential mechanistic insights into the adverse health outcomes associated with PM. Furthermore, our study demonstrated short-term reductions in stress hormone following indoor air purification., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02712333., (© 2017 American Heart Association, Inc.)

Steroid profiling was introduced to determine the endogenous steroid misuse in sports. Thus, screening for the exogenous use of these prohibited substances can be established by monitoring a range of endogenous steroids, which constitute the steroid profile and evaluate their concentrations and ratios against reference values. The steroid profiling is currently based on population statistics. As large interindividual variations exist, athlete biological passport (ABP) analysis is ongoing. This study aimed to identify new biomarker(s) for aromatase inhibitor detection in sports using statistical analysis and adapt the model into ABP analysis.Forty-one Chinese nonathlete volunteers (21 males and 20 females) were administered 3 nonsteroidal aromatase inhibitors (aminoglutethimide, letrozole, and anastrozole) independently. Statistical analysis was performed on 16 steroid profile parameters.After administration, the concentrations of endogenous androgen biomarkers including testosterone (T), epitestosterone, androsterone (AN), etiocholanolone (ETIO), 5α-diol, 5β-diol, and dehydroepiandrosterone were increased, while the level of estrogen was decreased. These biomarkers returned to the baselines levels within 1 month. In females, the concentrations of endogenous biomarkers were affected by nonsteroidal aromatase inhibitors, without a common trend. Three new endogenous biomarkers (AN/estrone, ETIO/estrone, and T/estrone) elevated significantly after treatment. The 3 new models were more sensitive than the World Anti-Doping Agency ratio biomarkers. They were also effective in exponentially weighted moving average chart analysis.Verification experiment demonstrated that the biomarker T/estrone was valid in judging the steroidal aromatase inhibitor abuse. The screening of these new endogenous biomarkers can provide additional parameters to support ABP monitoring and specific information regarding the administered steroids.

Purpose: Investigate development of specific performance adaptions and hormonal responses every fourth week during a 12-wk high-intensity training (HIT) period in groups with different interval-training prescriptions., Methods: Sixty-three well-trained cyclists performing a 12-wk intervention consisting of two to three HIT sessions per week in addition to ad libitum low-intensity training. Groups were matched for total training load, but increasing HIT (INC) group (n = 23) performed interval-sessions as 4 × 16 min in weeks 1-4, 4 × 8 min in weeks 5-8, and 4 × 4 min in weeks 9-12. Decreasing HIT (DEC) group (n = 20) performed interval sessions in the opposite order as INC, and mixed HIT (MIX) group (n = 20) performed all interval-sessions in a mixed distribution during 12 wk. Cycling-tests and measures of resting blood hormones were conducted pre, weeks 4, 8, and 12., Results: INC and MIX achieved >70% of total change in workload eliciting 4 mmol·L [la] (Power4mM) and V˙O2peak during weeks 1-4, versus only 34%-38% in DEC. INC induced larger improvement versus DEC during weeks 1-4 in Power4mM (effect size, 0.7) and V˙O2peak (effect size, 0.8). All groups increased similarly in peak power output during weeks 1-4 (64%-89% of total change). All groups' pooled, total and free testosterone and free testosterone/cortisol ratio decreased by 22% ± 15%, 13% ± 23%, and 14% ± 31% (all P < 0.05), and insulin-like growth factor-1 increased by 10% ± 14% (P < 0.05) during weeks 1-4., Conclusions: Most of progression in Power4mM, V˙O2peak and peak power output was achieved during weeks 1-4 in INC and MIX, and accompanied by changes in resting blood hormones consistent with increased but compensable stress load. In these well-trained subjects, accumulating 2-3 h·wk performing 4 × 16 min work bouts at best effort induces greater adaptions in Power4mM and V˙O2peak than accumulating ~1 h·wk performing best effort intervals as 4 × 4 min.

Peripartum cardiomyopathy is a potentially life-threatening pregnancy-associated disease that typically arises in the peripartum period and is marked by left ventricular dysfunction and heart failure. The disease is relatively uncommon, but its incidence is rising. Women often recover cardiac function, but long-lasting morbidity and mortality are not infrequent. Management of peripartum cardiomyopathy is largely limited to the same neurohormonal antagonists used in other forms of cardiomyopathy, and no proven disease-specific therapies exist yet. Research in the past decade has suggested that peripartum cardiomyopathy is caused by vascular dysfunction, triggered by late-gestational maternal hormones. Most recently, information has also indicated that many cases of peripartum cardiomyopathy have genetic underpinnings. We review here the known epidemiology, clinical presentation, and management of peripartum cardiomyopathy, as well as the current knowledge of the pathophysiology of the disease., (© 2016 American Heart Association, Inc.)

Gastrectomy induces severe osteoporosis in humans but its quantitative scale within trabecular and cortical compartments was not estimated. The aim of the study was to determine changes of volumetric bone mineral density (vBMD) in lumbar vertebrae (L1-L4) and biochemical bone metabolism markers in serum of patients 1 year after total gastrectomy. The control group consisted of patients (N = 8) subjected to abdominal surgery due to cardiospasmus. Total gastrectomy was performed in the experimental group (N = 6). Volumetric bone mineral density of trabecular and cortical bone of lumbar spine was measured before (baseline) and 1 year after the gastric surgery using the quantitative computed tomography method. Serum concentrations of insulin, insulin-like growth factor-1, tyroxine, interleukin-6, C-terminal telopeptides of type II collagen and bone formation, and resorption markers were determined at baseline and 1 year later, using ELISA, EIA, and IEMA methods. Total gastrectomy induced significant decrease of vBMD values, up to 16.8% and 10.0%, within the trabecular and cortical bone compartments of lumbar spine (P < 0.05). These negative changes of vBMD were associated with significantly increased serum concentration of bone resorption markers such as deoxypyridinoline, pyridinoline, and C-terminal telopeptides of type I collagen, by 13.5%, 32.2%, and 121.5%, respectively (P < 0.05). Neither vBMD nor biochemical bone turnover markers and hormone concentrations were influenced in the control patients. Dramatic bone loss during the first year in gastrectomized patients has proven dynamic osteoporosis progress indicating an importance of treatment interventions in these patients with emphasis on inhibition of intensive bone resorption processes., Competing Interests: The authors have no conflicts of interest to disclose.

Objective: To contrast the relationships of hormonal eating peptides and hypothalamic volumes to eating behavior and metabolic changes (body mass index [BMI]) in behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA)., Methods: Seventy-five patients with dementia (19 bvFTD, 26 svPPA, and 30 Alzheimer disease dementia) and 23 controls underwent fasting blood analyses of leptin, ghrelin, cholecystokinin, peptide tyrosine tyrosine (PYY), and agouti-related peptide (AgRP) levels. On brain MRI anterior, posterior, and total hypothalamic volumes were measured. Relationships between endocrine measures, hypothalamic volumes, eating behaviors, and BMI were investigated., Results: Levels of AgRP were higher in patients with bvFTD (69 ± 89 pg/mL) and svPPA (62 ± 81 pg/mL) compared with controls (23 ± 19 pg/mL, p < 0.01). No differences were found for leptin, oxytocin, cholecystokinin, ghrelin, and PYY levels. Patients with bvFTD and svPPA had higher scores on questionnaires measuring eating behaviors. Atrophy of the posterior and total hypothalamus was observed in the bvFTD group only. Linear regression modeling revealed that leptin and AgRP levels predicted BMI., Conclusion: Eating abnormalities are multifactorial in FTD. In bvFTD, they are in part related to hypothalamic degeneration, with potential disintegration of the network connections between the hypothalamus and orbitofrontal cortex/reward pathways. In svPPA, although hypothalamic volumes are preserved, this group experiences elevated AgRP levels similar to bvFTD, which predicts BMI in both groups. This finding highlights the potential key role of AgRP in eating and metabolic changes and provides a potential target for treatment to modify disease progression., (© 2015 American Academy of Neurology.)

Purpose of Review: The primary focus of this review is threefold: first, to summarize available knowledge on exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus (T1DM); second, to elucidate physiological mechanisms predisposing to glycemic variations in patients in T1DM; and third, to describe novel approaches derived from physiological perceptions applicable to stabilize exercise-related glycemia in individuals with T1DM., Recent Findings: Recent studies corroborate the concept that despite partial differences in counter-regulatory mechanisms individuals with T1DM do not fundamentally differ in their glucose response to exercise when compared with healthy individuals if studies are performed under standardized conditions with insulin and glucose levels held close to physiological ranges. Novel approaches derived from a better understanding of exercise-associated glucose metabolism (e.g., the concept of intermittent high-intensity exercise) may provide alternative ways to master the challenges imposed by exercise to individuals with T1DM., Summary: Exercise still imposes high demands on patients with T1DM and increases risks for hypoglycemia and hyperglycemia. Deeper insight into the associated metabolic pathways has revealed novel options to stabilize exercise-associated glucose levels in these patients.

Objectives: To determine the population pharmacokinetics of unbound hydrocortisone in critically ill neonates and infants receiving IV hydrocortisone for treatment of vasopressor-resistant hypotension and to identify patient-specific sources of pharmacokinetic variability., Design: Prospective observational cohort study., Setting: Level 3 neonatal ICU., Patients: Sixty-two critically ill neonates and infants receiving IV hydrocortisone as part of standard of care for the treatment of vasopressor-resistant hypotension: median gestational age 28 weeks (range, 23-41), median weight 1.2 kg (range, 0.5-4.4), and 29 females., Interventions: None., Measurements and Main Results: Unbound baseline cortisol and postdose hydrocortisone concentrations measured from blood samples being drawn for routine laboratory tests. A one-compartment model best described the data. Allometric weight and postmenstrual age were significant covariates on unbound hydrocortisone clearance and volume of distribution. Final population estimates for clearance, volume of distribution, and baseline cortisol concentration were 20.2 L/hr, 244 L, and 1.37 ng/mL, respectively. Using the median weight and postmenstrual age of our subjects (i.e., 1.2 kg and 28 wk) in the final model, the typical unbound hydrocortisone clearance and volume of distribution were 1.0 L/hr and 4.2 L, respectively. The typical half-life for unbound hydrocortisone was 2.9 hours. A sharp and continuous increase in unbound hydrocortisone clearance was observed at 35 weeks postmenstrual age., Conclusions: We report the first pharmacokinetic data for unbound hydrocortisone, the pharmacologically active moiety, in critically ill neonates and infants with vasopressor-resistant hypotension. Unbound hydrocortisone clearance increased with body weight and was faster in children with an older postmenstrual age. Unbound hydrocortisone clearance increased sharply at 35 weeks postmenstrual age and continued to mature thereafter. This study lays the groundwork for evaluating unbound hydrocortisone exposure-response relationships and drawing definitive conclusions about the dosing of IV hydrocortisone in critically ill neonates and infants with vasopressor-resistant hypotension.

Objective: To evaluate whether a panel of common biomedical markers can be utilized as trajectories to determine survival in pediatric burn patients., Background: Despite major advances in clinical care, of the more than 1 million people burned in the United States each year, more than 4500 die as a result of their burn injuries. The ability to predict patient outcome or anticipate clinical trajectories using plasma protein expression would allow personalization of clinical care to optimize the potential for patient survival., Methods: A total of 230 severely burned children with burns exceeding 30% of the total body surface, requiring at least 1 surgical procedure were enrolled in this prospective cohort study. Demographics, clinical outcomes, and inflammatory and acute-phase responses (serum cytokines, hormones, and proteins) were determined at admission and at 11 time points for up to 180 days postburn. Statistical analysis was performed using a 1-way analysis of variance, the Student t test, χ test, and Mann-Whitney test where appropriate., Results: Survivors and nonsurvivors exhibited profound differences in critical markers of inflammation and metabolism at each time point. Nonsurvivors had significantly higher serum levels of interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, C-reactive protein, glucose, insulin, blood urea nitrogen, creatinine, and bilirubin (P < 0.05). Furthermore, nonsurvivors exhibited a vastly increased hypermetabolic response that was associated with increases in organ dysfunction and sepsis when compared with survivors (P < 0.05)., Conclusions: Nonsurvivors have different trajectories in inflammatory, metabolic, and acute phase responses allowing differentiation of nonsurvivors from survivors and now possibly allowing novel predictive models to improve and personalize burn outcomes.

Background and Purpose: Stroke-induced immune alterations predispose patients to infections. Although the relationship between stroke and the adaptive immune system has been investigated in detail, to date it is unknown whether the innate immune system, which forms the first line of antibacterial defense, is also impaired in patients with stroke. Therefore, we investigated whether chemotaxis, phagocytosis, oxidative burst, degranulation of defensins, and NETosis in monocytes and in neutrophil granulocytes are altered in patients with stroke compared with controls., Methods: Sixty-three patients having acute ischemic stroke were recruited within 12 hours of symptom onset; blood was sampled on admission and on days 1, 3, 5, and 7. Thirty-seven age-matched controls were also recruited. Cell migration, phagocytosis, and oxidative burst of phagocytes were determined in vitro. Human neutrophil peptides 1 to 3 and serum metanephrine levels were measured by enzyme-linked immunosorbent assay, and NETosis was quantified by immunohistochemistry., Results: The key mechanisms required for bacterial killing, oxidative burst, and NETosis were significantly reduced in samples taken from patients with stroke compared with controls, whereas migration, phagocytic function, and defensin production remained unimpaired in monocytes and granulocytes from patients with stroke., Conclusions: Stroke-induced immune alterations include impairment of the first-line defense performed by specialized phagocytes against bacteria. The hypothesis that these changes enhance susceptibility to acquired infections is supported by our observation that on admission oxidative burst in monocytes was more impaired in patients with stroke with subsequent stroke-associated infections.

Leptin, a hormone produced by body fat tissue, acts on hypothalamic receptors in the brain to regulate appetite and energy expenditure, and on neurons in the arcuate nucleus to signal that an individual has had enough to eat. Leptin enters the central nervous system at levels that depend on an individual's body fat. Obese people, on average, show greater brain atrophy in old age, so it is valuable to know whether brain atrophy relates to leptin levels, which can be targeted by interventions. We therefore determined how plasma leptin levels, and BMI, relate to brain structure, and whether leptin levels might account for BMI's effect on the brain. We measured regional brain volumes using tensor-based morphometry, in MRI scans of 517 elderly individuals with plasma leptin measured (mean: 13.3±0.6 ng/ml; mean age: 75.2±7.3 years; 321 men/196 women). We related plasma leptin levels to brain volumes at every location in the brain after adjusting for age, sex, and diagnosis and, later, also BMI. Plasma leptin levels were significantly higher (a) in women than men, and (b) in obese versus overweight, normal or underweight individuals. People with higher leptin levels showed deficits in frontal, parietal, temporal and occipital lobes, brainstem, and the cerebellum, irrespective of age, sex, or diagnosis. These associations persisted after controlling for BMI. Greater brain atrophy may occur in people with central leptin insufficiency, a marker of obesity. Therapeutic manipulation of leptin may be a promising direction for slowing brain decline.

Background: The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure (HF). The effects of (P)RR blockade in HF have not been previously investigated., Methods and Results: Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administration produced a dose-dependent decrease in plasma renin activity (P=0.004), with similar trends observed for plasma angiotensin II and aldosterone (P=0.093 and P=0.088, respectively). Circulating natriuretic peptides, endothelin-1, and catecholamine levels were unchanged. HRP also induced a reduction in plasma sodium concentrations relative to control (P=0.024), a natriuresis (P=0.046), and a tendency for creatinine excretion and clearance to improve., Conclusions: (P)RR antagonism in experimental HF resulted in cardiovascular and renal benefits in association with inhibition of the renin-angiotensin-aldosterone system. These findings suggest that (P)RR contributes to pressure/volume regulation in HF and identifies the receptor as a potential therapeutic target in this disease.

Background: Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury., Methods and Results: In 3127 stroke-free Framingham offspring (age, 59±10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995-1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999-2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume (P<0.05 for both) but not with covert brain infarcts or white-matter hyperintensity volume (P>0.05). In backward elimination analyses, higher log-B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P=0.002) and log-urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P=0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the <5%, 5% to 15%, or >15% 10-year risk category was used, the net reclassification index was 0.109 (P=0.037). Higher C-reactive protein (β=-0.21 per 1-SD increment; P=0.008), D-dimer (β=-0.18 per 1-SD increment; P=0.041), total homocysteine (β=-0.21 per 1-SD increment; P=0.005), and urinary albumin/creatinine ratio (β=-0.15 per 1-SD increment; P=0.042) were associated with lower total cerebral brain volume., Conclusion: In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.

Over the past several decades, social and demographic trends have led to an increased tendency for women to delay childbearing. Owing primarily to abnormalities in the oocyte and resulting embryonic aneuploidy, implantation, clinical pregnancy, and live birth rates decline sharply by the end of the fourth decade. As a result, the incidence of age-related infertility has increased. Improved awareness of the effects of aging on fertility combined with ovarian reserve assessment, patient education, and early infertility evaluation and intervention are important elements in appropriate family planning and prevention of age-related infertility.

A practical approach to semen analysis (SA) interpretation and the initial management of subfertile men is presented. Each parameter of the SA is described and management recommendations based upon SA findings are provided. The indications for and interpretation of adjunctive diagnostic testing for male factor subfertility are also discussed.

Patients with chronic pain conditions demonstrate altered central processing of experimental noxious stimuli, dysfunction of the hypothalamic-pituitary-adrenal axis, and reduced quality of life. Dysmenorrhoea is not considered a chronic pain condition, but is associated with enhanced behavioural responses to experimental noxious stimuli. We used behavioural measures, functional magnetic resonance imaging, and serum steroid hormone levels to investigate the response to experimental thermal stimuli in otherwise healthy women, with and without dysmenorrhoea. Women with dysmenorrhoea reported increased pain to noxious stimulation of the arm and abdomen throughout the menstrual cycle; no menstrual cycle effect was observed in either group. During menstruation, deactivation of brain regions in response to noxious stimulation was observed in control women but not in women with dysmenorrhoea. Without background pain (ie, in nonmenstrual phases), activity in the entorhinal cortex appeared to mediate the increased responses in women with dysmenorrhoea. Mean cortisol was significantly lower in women with dysmenorrhoea and was negatively correlated with the duration of the symptom. Additionally, women with dysmenorrhoea reported significantly lower physical but not mental quality of life. Thus, many features of chronic pain conditions are also seen in women with dysmenorrhoea: specifically a reduction in quality of life, suppression of the hypothalamic-pituitary-adrenal axis, and alterations in the central processing of experimental noxious stimuli. These alterations persist when there is no background pain and occur in response to stimuli at a site distant from that of the clinical pain. These findings indicate the potential importance of early and adequate treatment of dysmenorrhoea., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objectives: The objective of the study was to investigate whether sex differences in oxidative stress-associated insulin resistance previously reported in rats could be attributed to a possible sex dimorphism in pancreas redox status., Methods: Fifteen-month-old male and female Wistar rats were fed a control diet or a high-fat diet for 14 weeks. Serum glucose, lipids, and hormone levels were measured. Insulin immunohistochemistry and morphometric analysis of islets were performed. Pancreas triglyceride content, oxidative damage, and antioxidant enzymatic activities were determined. Lipoprotein lipase, hormone-sensitive lipase, and uncoupling protein 2 (UCP2) levels were also measured., Results: Male rats showed a more marked insulin resistance profile than females. In control female rats, pancreas Mn-superoxide dismutase activity and UCP2 levels were higher, and oxidative damage was lower compared with males. High-fat-diet feeding decreased pancreas triglyceride content in female rats and UCP2 levels in male rats. High-fat-diet female rats showed larger islets than both their control and sex counterparts., Conclusions: These results confirm the existence of a sex dimorphism in pancreas oxidative status in both control and high-fat-diet feeding situations, with female rats showing higher protection against oxidative stress, thus maintaining pancreatic function and contributing to a lower risk of insulin resistance.

Introduction: Homozygous beta-thalassemia major (hbeta-TM) is an autosomal recessive hemoglobinopathy with prominent endocrine complications. Our aims were to evaluate reproductive hormones, hypothalamic-pituitary-ovarian axis, and fertility in female patients with hbeta-TM., Patients and Methods: One hundred forty-four female patients with hbeta-TM, aged 18 years or above were enrolled in the study. Seventy-four age-matched healthy female volunteers served as controls. Two blood samples were drawn from each subject at 20-minute intervals for the determination of the resting levels of the following hormones: luteinizing hormone, follicle-stimulating hormone, estradiol, insulin-like growth factor-1, and insulin-like growth factor binding protein-3. The hypothalamic-pituitary-ovarian axis was also assessed using the gonadotropin-releasing hormone test. Menstruation status and growth rate were also noted. Puberty was assessed in both groups by Tanner classification., Results: The mean age of puberty in the control group and hbeta-TM patients was 10.8+/-1.2 and 16.4+/-2.2 years, respectively (P=0.01). The mean age of menarche was 11.4+/-1.3 and 16.8+/-2.1 years in control subjects and patients with thalassemia, respectively (P=0.01). Of studied subjects with hbeta-TM, 61 (42.4%) were short in stature (height below the third percentile and below -2 SD scores). The baseline and peak levels of luteinizing hormone, follicle-stimulating hormone, and estradiol after gonadotropin-releasing hormone test in thalassemic group were significantly lower than in the control group., Conclusions: Further interventional studies are warranted to better clarify the treatment options to attain normal puberty and sexual maturation in patients with thalassemia.

Anorexia nervosa (AN) has serious negative effects on multiple organs and systems of the human body. As patients often do not make their eating disorder the subject of discussion, the physician is forced to rely on the physical examination and laboratory parameters as diagnostic hints. Obvious signs of AN are a body mass index (BMI) below 17.5 kg/m, dry and scaly skin, lanugo, edema, acrocyanosis, petechias, dental problems, and low blood pressure. However, because the often complex laboratory alterations can be difficult for the general psychiatrist to interpret, this article presents some useful guidelines. The plasma of patients with AN often shows alterations in laboratory parameters and appetite regulators, including electrolytes, liver enzymes, leukocyte count, hemoglobin (Hb), leptin, neuropeptide Y (NPY), triiodothyronine (T3), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, ghrelin, pancreatic polypeptide (PP), tumor necrosis factor-alpha (TNF-alpha), and cortisol. Medical problems secondary to AN or due to the treatment itself may lead to further laboratory abnormalities. To date, despite these associated laboratory alterations, the diagnosis of anorexia is a clinical one, based on weight and specific psychopathology.

Medical disease and the methods used to treat disease that can result in sexual problems. The prevalence and pathophysiology of sexual dysfunction have been prominent questions in medicine for more than a decade. Pertinent information related to sexual dysfunction and medical illness, with special emphasis on cardiovascular health, endocrine-related disorders, and malignancy are presented.

Background: Hyponatremia is often associated with, and worsens, the prognosis of severe aneurysmal subarachnoid hemorrhage (SAH). Several possible endocrine perturbations of variable severity and variable sodium and water intake have been described in SAH. However, a comprehensive study of the different hormonal systems involved in sodium and water homeostasis and circulating blood volume modifications is still needed. Our aim was to assess water and sodium regulation after severe SAH by investigating blood volume and several hormonal regulatory systems in the context of hyponatremia prevention by controlled sodium intake., Methods: Nineteen mechanically ventilated patients with severe SAH, were prospectively studied. Replacement of sodium was at least 4.5 mmol x kg(-1) x d(-1) and adjusted on natriuresis. Hormones involved in electrolyte and water homeostasis: vasopressin, renin, angiotensin, aldosterone, and natriuretic peptides were assessed every 3 days for 12 days. Red blood cell volume was measured by the isotopic method (technetium-labeled red blood cells), in the first 48 h after admission and at day 7. Cardiac function was assessed using electrocardiogram, transthoracic echocardiography, and troponin Ic (cTnI). Outcome was assessed at 3 mo., Results: After SAH onset, hyponatremia, but not decreased circulating blood volume, was prevented by high sodium and water infusion adapted to renal excretion. The hormonal profiles were characterized by an increase in renin, angiotensin II, natriuretic peptide concentrations associated with increased troponin Ic, stable low levels of vasopressin, and the absence of increased aldosterone concentrations. There were no correlations between hormone concentrations and natriuresis., Conclusion: After severe SAH, in the context of multiple clinical interventions, increased natriuresis and low blood volume are consistent with cerebral salt wasting syndrome, probably related to the sequence of severe SAH, highly increased sympathetic tone, hyperreninemic hypoaldosteronism syndrome, and increased natriuretic peptides release.

Objective: To investigate the effect of laughter and mental stress on arterial stiffness and central hemodynamics. Arterial stiffness and wave reflections are independent predictors of cardiovascular risk. Chronic psychological stress is an independent risk factor for cardiovascular events, whereas acute stress deteriorates vascular function., Methods: Eighteen healthy individuals were studied on three occasions, according to a randomized, single-blind, crossover, sham procedure-controlled design. The effects of viewing a 30-minute segment of two films inducing laughter or stress were assessed. Carotid-femoral pulse wave velocity was used as an index of arterial stiffness; augmentation index was used as a measure of wave reflections., Results: Laughter decreased pulse wave velocity (by 0.30 m/sec, p = .01), and augmentation index (by 2.72%, p = .05). Conversely, stress increased pulse wave velocity (by 0.29 m/sec, p = .05) and augmentation index (by 5.1%, p = .005). Laughter decreased cortisol levels by 1.67 microg/dl (p = .02), soluble P-selectin by 26 ng/ml (p = .02) and marginally von Willebrand factor (by 2.4%, p = .07) and increased total oxidative status (by 61 micromol/L, p < .001). Stress decreased interleukin-6 (by 0.11 pg/ml, p = .04) and increased total oxidative status (by 44 micromol/L, p = .007). Soluble CD40 ligand and fibrinogen remained unchanged., Conclusions: Positive (laughter) and negative (stress) behavioral interventions have divergent acute effects on arterial stiffness and wave reflections. These findings have important clinical implications extending the spectrum of lifestyle modifications that can ameliorate arterial function.

Reduced sensitivity to naturally occurring and laboratory pain stimuli has been observed in individuals with hypertension, high-normal blood pressure, and a family history of hypertension. The present study sought to extend these findings by examining the relationship between familial history of hypertension and pain responsivity in neonates. Eighty infants had intramuscular (IM) injections of vitamin K performed in the delivery room within 1h of birth as per institutional practice. Video recordings of the injection procedure were used by trained observers to code infant pain responses using facial grimacing and cry duration. Prior to the birth of the child, the infants' parents each completed a family blood pressure history survey and these responses were used to identify infants with and without a maternal and paternal family history of hypertension. As compared to infants without a maternal family history of hypertension, infants with a maternal family history of hypertension had significantly shorter crying times, F(1,74)=6.96, p=.01, eta(2)=.086, and marginally lower facial grimacing scores, F(1,74)=2.68, p=.10, eta(2)=.035, during vitamin K injection. The presence of attenuated responses to the IM injection in neonates with a maternal family history of hypertension provides important and novel evidence that reduced pain responding in individuals at risk for hypertension is not a learned response style, but rather may arise from prenatal or genetic influences.

Objective: To describe a case of a rare adult-onset craniopharyngioma presenting as rapidly progressive catatonia that was reversed after surgical resection of the tumor., Background: Profoundly depressed states of awareness classified as either catatonia or akinetic mutism have been reported in patients with hypothalamic neoplasms, but reports of improvement in consciousness level after surgical resection are rare and limited to very large tumors., Method: Medical, neurologic, and psychiatric histories, physical examination findings, laboratory workup results, pathologic and imaging studies, and response to surgical treatment were documented., Result: The patient showed progressive improvement in mental status and overall neurologic function after surgical treatment., Conclusions: The search for an etiology of a profound catatonic state should include the probability of a suprasellar/hypothalamic lesion, which in this case was owing to the rare finding of an imaging-documented adult-onset craniopharyngioma.

Objectives: To determine whether patients with unexplained nonunions, patients with a history of multiple low-energy fractures with at least one progressing to a nonunion, and patients with a nonunion of a nondisplaced pubic rami or sacral ala fracture would have an underlying metabolic or endocrine abnormality that had not been previously diagnosed., Design: Case series., Setting: Tertiary referral center., Patients and Intervention: From a larger series of 683 consecutive patients with nonunion seen by us between January 1998 and December 2005, 37 patients were referred to 1 of 2 clinically practicing endocrinologists to undergo an evaluation for metabolic and endocrine abnormalities. The screening criteria were: 1) an unexplained nonunion that occurred despite adequate reduction and stabilization (and debridement in initially infected cases) without obvious technical error and without any other obvious etiology; 2) a history of multiple low-energy fractures with at least one progressing to a nonunion; or 3) a nonunion of a nondisplaced pubic rami or sacral ala fracture., Results: In all, 31 of the 37 patients (83.8%, 95% CI: 71.3% to 93.8%) who met our screening criteria had one or more new diagnoses of metabolic or endocrine abnormalities. The most common newly diagnosed abnormality was vitamin D deficiency (25 of 37 patients; 68%). Other newly diagnosed abnormalities included calcium imbalances, central hypogonadism, thyroid disorders, and parathyroid hormone disorders. All newly diagnosed abnormalities were treated medically. Eight patients who underwent no operative intervention following the diagnosis and treatment of a new metabolic or endocrine abnormality achieved bony union in an average of 7.6 months (range, 3 to 12 months) following their first visit to the endocrinologist., Conclusions: Although our study does not prove a causal link between metabolic and endocrine abnormalities and either the development or healing of nonunions, 84% of the patients who met our screening criteria were found to have metabolic or endocrine abnormalities, and eight of our patients achieved bony union following medical treatment alone. All patients with nonunion who meet our screening criteria should be referred to an endocrinologist for evaluation because they are likely to have undiagnosed metabolic or endocrine abnormalities that may be interfering with bone healing.

Background: In previous work, extravascular expansion was observed to be enhanced by isoflurane anesthesia in sheep when a crystalloid bolus was administered. The aim of the current study was to further elaborate these investigations to humans and to explore the use of population kinetics in the analysis of fluid shifts., Methods: Eleven healthy volunteers participated in two experiments each, either awake or isoflurane anesthetized, during which they received 25 ml/kg saline, 0.9%, intravenously over 20 min. Plasma dilution data were derived from repeated sampling of hemoglobin concentration, and population pharmacokinetic analysis was conducted using the WinNonMix 2.0.1 software (Pharsight Corporation, Mountain View, CA). Plasma hormones were measured, and hemodynamic values were monitored., Results: Fluid infusion during isoflurane anesthesia was followed by a higher cardiac output, lower arterial pressure, and lower urinary excretion as compared with the awake protocol (P < 0.05). Albumin dilution was greater than hemoglobin concentration-derived plasma dilution, which indicates a transcapillary leak of albumin. A two-compartment model with an isoflurane-depressed, intercompartmental distribution parameter predicted that more than 50% of the infused volume was retained in the peripheral compartment at 180 min in both protocols. Isoflurane markedly increased the plasma levels of renin and aldosterone, whereas vasopressin was mostly unchanged., Conclusion: Fluid retention after rapid infusion of 0.9% saline was prominent in both awake and isoflurane-anesthetized subjects. Altered kinetics of infused 0.9% saline during isoflurane anesthesia was expressed as reduced clearance and a slower distribution, resulting in a small but significant increase in fluid accumulation in the body fluid compartments. These changes may be due to the associated decreasing of mean arterial pressure and increased release of renin and aldosterone.

Purpose: To examine the effect of progressive resistance training on muscle function, functional performance, balance, body composition, and muscle thickness in men receiving androgen deprivation for prostate cancer., Methods: Ten men aged 59-82 yr on androgen deprivation for localized prostate cancer undertook progressive resistance training for 20 wk at 6- to 12-repetition maximum (RM) for 12 upper- and lower-body exercises in a university exercise rehabilitation clinic. Outcome measures included muscle strength and muscle endurance for the upper and lower body, functional performance (repeated chair rise, usual and fast 6-m walk, 6-m backwards walk, stair climb, and 400-m walk time), and balance by sensory organization test. Body composition was measured by dual-energy x-ray absorptiometry and muscle thickness at four anatomical sites by B-mode ultrasound. Blood samples were assessed for prostate specific antigen (PSA), testosterone, growth hormone (GH), cortisol, and hemoglobin., Results: Muscle strength (chest press, 40.5%; seated row, 41.9%; leg press, 96.3%; P < 0.001) and muscle endurance (chest press, 114.9%; leg press, 167.1%; P < 0.001) increased significantly after training. Significant improvement (P < 0.05) occurred in the 6-m usual walk (14.1%), 6-m backwards walk (22.3%), chair rise (26.8%), stair climbing (10.4%), 400-m walk (7.4%), and balance (7.8%). Muscle thickness increased (P < 0.05) by 15.7% at the quadriceps site. Whole-body lean mass was preserved with no change in fat mass. There were no significant changes in PSA, testosterone, GH, cortisol, or hemoglobin., Conclusions: Progressive resistance exercise has beneficial effects on muscle strength, functional performance and balance in older men receiving androgen deprivation for prostate cancer and should be considered to preserve body composition and reduce treatment side effects.

Background: Net loss of body protein is a prominent feature of the catabolic response to surgical tissue trauma. Epidural analgesia with hypocaloric dextrose has been demonstrated to attenuate leucine oxidation but was unable to make protein balance positive. The current study was set to determine whether an infusion of amino acids on the second day after colon surgery would revert the catabolic state and promote protein synthesis while maintaining glucose homeostasis in patients receiving epidural analgesia as compared with patient-controlled analgesia with morphine (PCA)., Methods: Sixteen patients undergoing colorectal surgery were randomly assigned to receive epidural blockade or PCA as analgesic techniques and underwent a 6-h stable isotope infusion study (3 h fasted, 3 h fed) on the second postoperative day. Whole body glucose kinetics and protein turnover were measured using [6,6-2H2]glucose and l-[1-13C]leucine as tracer., Results: The infusion of amino acids caused a decrease in endogenous glucose rate of appearance in both groups (P < 0.05), with greater changes in the PCA group (P < 0.05). Administration of amino acids suppressed the appearance of leucine from protein breakdown in both groups (P < 0.05), although the decrease was greater in the PCA group (P < 0.05). Leucine oxidation increased in both groups (P < 0.05), with greater change in the epidural group (P < 0.05). Protein synthesis increased to the same extent in both groups (P < 0.05). Protein balance became positive after the infusion of amino acids, and the effect was greater in the PCA group (P < 0.05)., Conclusions: Infusion of amino acids decreased the endogenous glucose production and induced a positive protein balance independent of the type of anesthesia provided, although such effects were greater in the PCA group.

Background: Major trauma and burns are associated with whole body catabolism which can persist for 1 or more years after injury. This study investigates body composition in massively burned children for up to 2 years., Methods: Twenty-five pediatric patients with greater than 40% total body surface area burns were studied. At discharge, 6, 12, 18, and 24 months after burn height, weight, body composition, resting energy expenditure (REE), serum growth hormone, insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), insulin, cortisol, parathyroid hormone, and thyroid hormones were measured. Tukey's test was used for analysis. Significance was accepted at p < 0.05., Results: Lean body mass, fat mass, bone mineral content, height, and weight increased significantly during the second year after burn. Percent predicted REE decreased significantly, whereas IGFBP-3 and parathyroid hormone levels increased significantly over time. Insulin and T3 uptake were significantly higher at discharge., Conclusions: Body composition of severely burned children significantly improved in the second year compared with the first year after injury. This demonstrates a need for long-term rehabilitation in these burn patients.

Dehydroepiandrosterone (DHEA) is an important neurosteroid and has demonstrated efficacy in the improvement of mood and energy. The authors previously reported the efficacy of DHEA augmentation in the management of negative, depressive, and anxiety symptoms of schizophrenia. To characterize further the effects of DHEA administration and to describe any hormonal effects following DHEA augmentation of antipsychotic medication, several hormones were measured (TSH, prolactin, testosterone, insulin, and estradiol) in 27 chronic schizophrenic inpatients receiving DHEA or placebo augmentation for 6 weeks. No significant changes in hormonal blood measures were noted. At the study end point, an association was noted between DHEA-S and TSH levels (P < 0.05) as well as a change in DHEA-S and insulin levels (P < 0.001). A modest nonsignificant decrease in plasma testosterone was observed following DHEA treatment. In subjects receiving DHEA, change in testosterone levels was associated with improvement in anxiety (P < 0.05) and illness severity (P < 0.05). Findings in this preliminary study demonstrate minimal effects on hormonal profiles despite the theoretic possibility that DHEA may elevate various hormones (eg, testosterone) with potential long-term adverse effects. DHEA's clinical efficacy appears to be mediated by other mechanisms, including direct effects on membrane channel-coupled receptors.

Macrophage migration inhibitory factor (MIF) is a cytokine produced by neuroendocrine and immune tissues that possesses several characteristics of a neuroendocrine mediator. Chronic pain is known to affect and to be affected by neuroendocrine and immune mechanisms. In the present study, the plasma levels of MIF and several hormones (cortisol, estradiol, testosterone) were determined to evaluate their mutual behaviour in controls and in chronic pain patients. Blood samples were collected from males and females divided into groups depending on their age (younger or older than 55) and health condition: (1) pain-free control subjects; (2) chronic non-malignant pain subjects. Moreover, two additional groups were added to evaluate the effects of short- and long-term opioid administration: (3) short-term opioid-treated chronic pain patients and (4) long-term opioid-treated chronic pain patients (longer than 6 months). MIF in control/younger men was higher than in all the other control and chronic pain groups. MIF was lower in pain patients than in controls of both sexes. MIF was not changed by morphine administration; its levels remained lower in opioid-treated subjects than in controls after both short- and long-lasting administration. Chronic pain changed hormone plasma levels differently in male and female patients. MIF was positively correlated with testosterone and negatively with estradiol. These results demonstrate sex differences in the younger men and women and a strong pain-induced decrease of MIF availability. These findings suggest the involvement of this cytokine in the sex differences observed in chronic pain conditions.

Dopamine of renal origin has natriuretic/diuretic actions by activating D1-like receptors of the nephron. Saline load increases renal dopamine production and natriuresis in healthy subjects, and, under these conditions, the activation of D2-like receptors also produces natriuresis/diuresis. Metoclopramide is a D2-like receptor antagonist. Patients with heart failure (HF) have an increased renal dopamine-synthesizing efficiency. However, the effect of salt loading was not explored in HF. We hypothesized that HF patients respond to salt loading with increased production of renal dopamine and that metoclopramide antagonizes this response. This was a randomized, controlled, crossover study exploring the effect of NaCl and metoclopramide on renal dopaminergic, sympathetic, renin-angiotensin-aldosterone, and arginine-vasopressin (AVP) systems activity on sodium handling in 9 HF patients and 9 controls. NaCl markedly increased renal dopamine production and natriuresis in both groups. Metoclopramide blunted these responses in HF patients but not in controls. NaCl decreased renin and aldosterone plasma levels in controls but not in HF patients. In these patients B-type natriuretic peptide (BNP) levels increased, but AVP was not affected. HF patients respond to salt loading with increased natriuresis. However, the mechanisms for this response are different from those found in healthy subjects. Metoclopramide has antinatriuretic effects only in HF patients.

We studied the effect of large-dose intrathecal sufentanil (ITS) for major abdominal surgery on the hormonal stress response. Forty patients were randomly allocated to receive either IV sufentanil (IVS) or 150 microg of ITS as part of general anesthesia. In the IVS group, adrenocorticotropic hormone (ACTH) and cortisol concentrations were larger than baseline and the ITS group, 60 min after incision and at skin closure. Plasma concentrations of cortisol and ACTH were not different from baseline in the ITS group during surgery. Six hours after skin closure, cortisol concentrations were larger than baseline in both groups. Twenty-four and 48 h after skin closure, ACTH and cortisol values were similar between groups. Norepinephrine concentrations increased after surgery in both groups. Blood glucose levels increased in both groups during and after surgery. Pain scores and morphine consumption during the first 48 h after surgery were lower in the ITS group. The data show that large-dose ITS prevents the intraoperative hormonal stress response in comparison with balanced anesthesia. We speculate that this is due to the highly specific binding of sufentanil to spinal and supraspinal receptors. This technique improves postoperative analgesia when compared with balanced anesthesia.

Objective: Although oral estrogen replacement therapy (ERT) in postmenopausal women improves endothelial function, it also increases plasma C-reactive protein (CRP) and interleukin-6 (IL-6) concentration. The proinflammatory effect of oral ERT may explain the increased risk of coronary heart disease (CHD) associated with this treatment. Recent observational studies have demonstrated that a lower dose of oral estrogen reduces the risk for CHD. The purpose of the present study was to investigate the effects of low-dose oral estrogen on vascular inflammatory markers and endothelium-dependent vasodilation in postmenopausal women., Methods and Results: Postmenopausal women were randomized into 3 groups to receive no treatment (n=14) or oral conjugated equine estrogen (CEE) at a dosage of 0.625 mg (n=15) or 0.3125 mg (n=15) daily for 3 months. CEE at a dosage of 0.625 mg resulted in significant increases in plasma concentrations of CRP from 690.9+/-749.5 to 1541.9+/-1608.0 ng/mL, serum amyloid A from 6.12+/-4.15 to 8.25+/-4.40 microg/mL, and IL-6 from 1.45+/-0.73 to 2.35+/-1.16 pg/mL. In contrast, CEE at a dosage of 0.3125 mg had no effect on these inflammatory markers. Both dosages of estrogen significantly decreased E-selectin concentration, whereas the concentrations of intercellular and vascular cell adhesion molecules remained unchanged. In both CEE groups, flow-mediated vasodilation in the brachial artery was increased significantly, whereas nitroglycerine-induced vasodilation was unaltered., Conclusions: Oral CEE at a low dose of 0.3125 mg in postmenopausal women eliminated the adverse effects of high-dosage oral CEE on vascular inflammatory markers in addition to preserving the favorable effects of estrogen on cell adhesion molecules and endothelial function.

The first hours of extracorporeal life support (ECLS) are commonly marked by new hemodynamic instability without a known etiology. We measured hormone and catecholamine concentrations in six ECLS primed circuits immediately before joining the patient's circulation to assess a potential role of these agents in this condition. The following hormones were significantly below the lower end of the normal range for the first week of life (data are presented as mean +/- SEM): cortisol 1.95 +/- 0.15 microg/dl (p < 0.001), aldosterone 3.73 +/- 0.74 ng/dl (p < 0.05), free thyroxine 1.2 +/- 0.1 ng/dl (p < 0.05), free triiodothyronine 0.53 +/- 0.03 pg/ml (p < 0.001), thyroid stimulating hormone 0.31 +/- 0.05 microU/ml (p < 0.001), growth hormone (GH) 0.09 +/- 0.01 ng/ml (p < 0.001), estradiol 38.3 +/- 3.72 pg/ml (p < 0.001), IGF-BP1 0.95 +/- 0.1 ng/ml (p < 0.001), glucagon 26 +/- 1.2 pg/ml (p < 0.001), epinephrine 17.3 +/- 3.7 pg/ml (p < 0.001), and norepinephrine 127 +/- 27 pg/ml (p < 0.05). No dopamine was detected. Normal hormone concentrations included IGF-I, IGF-BP3, insulin, parathyroid hormone, leptin, and testosterone. Critically low concentrations of cortisol, thyroid hormones, GH, IGF-BP1, glucagon and catecholamines were measured in the ECLS circuit even though it was primed with fresh frozen plasma. These concentrations may cause significant and precipitous dilutional reductions in the patient's circulating levels immediately after connection to the ECLS circuit and hence contribute to hemodynamic instability.

In patients with multiple endocrine neoplasia type 1 (MEN1), the most common functional pancreatic endocrine tumor (PET) syndrome is Zollinger-Ellison syndrome (ZES). ZES has been well studied in its sporadic form (that is, without MEN1); however, there are limited data on patients with MEN1 and ZES (MEN1/ZES), and the long-term natural history is largely unknown. To address this issue we report the results of a prospective long-term National Institutes of Health (NIH) study of 107 MEN1/ZES patients and compare our results with those of 1009 MEN1/ZES patients in 278 case reports and small series in the literature. Patients were clinically, radiologically, and biochemically evaluated yearly for all MEN1 manifestations (mean follow-up, 10 yr; range, 0.1-31 yr). Compared with patients from the literature, the NIH MEN1/ZES patients more frequently had pituitary (60%) and adrenal (45%) disease and carcinoid tumors (30%), but had equal frequency of hyperparathyroidism (94%), thyroid disease (6%), or lipomas (5%). Twenty-five percent of both the NIH and the literature patients lacked a family history of MEN1; ZES was the initial clinical manifestation of MEN1 in 40%. ZES onset preceded the diagnosis of hyperparathyroidism in 45%. However, ZES was rarely (8%) the only initial manifestation of MEN1 if careful testing was done. ZES occurred before age 40 years in 50%-60% of the current patients, in contrast to older studies. The diagnosis of ZES is delayed 3-5 years from its onset and is delayed as long as in sporadic ZES cases. Pituitary disease and carcinoid tumors (gastric > bronchial, thymic) are more frequent than generally reported, whereas a second functional PET is uncommon. In patients with MEN1/ZES without a family history of MEN1, the MEN1 manifestations are not as severe. This study shows that MEN1/ZES patients differ in many aspects from those commonly reported in older studies involving few MEN1/ZES patients. In this study we have identified a number of important clinical and laboratory features of MEN1/ZES that were not previously appreciated, which should contribute to earlier diagnosis and improve both short- and long-term management.

The authors investigated whether hypoglycemia develops during 23 hours of fasting in patients with Duchenne dystrophy (7 patients), spinal muscular atrophy (4 patients), and congenital myopathy (2 patients), all with residual muscle mass <10% of body weight. All patients with spinal muscular atrophy and congenital myopathy and one patient with Duchenne dystrophy, but none of six healthy subjects, developed hypoglycemia. Skeletal muscle is an important source of gluconeogenic substrates during fasting. Hypoglycemia must be considered in patients with low muscle mass, especially during surgery and febrile episodes.

Purpose: Epidemiological evidence suggests that physical activity protects against colon cancer. We previously used a mouse predisposed to intestinal polyps (APCMin) to evaluate this association and found the suggestion of fewer polyps in exercised males but not females. The present study was designed to further explore the potential exercise x sex interaction on polyp development and to begin to look at potential mechanisms., Methods: Six-week-old APCMin mice (N = 60 males; 60 females) were randomly assigned to one of two groups by sex: treadmill running at 20 m.min-1, 5% grade, 45 min.d-1, 5 d.wk-1 (EX) or nonrunning controls (CON) (N = 30 per group). EX mice ran in running wheels while in quarantine (weeks 0-3), followed by treadmill running weeks 3-8. Body weights were measured weekly. Urine was collected at 5 wk and fasting blood at 7.5 wk. Body composition was measured, serum was frozen, and polyp number and size were measured at sacrifice., Results: EX resulted in lower body weights (P < 0.01) and reduced fat mass (P < 0.01). Fasting glucose was lower in EX (P < 0.01), and leptin was lower in EX (P = 0.05) compared with CON. EX did not affect serum insulin-like growth factor-1 or urinary corticosterone. Total polyp number and size were not statistically different between groups; however, there were fewer jejunal polyps in EX (3.6 +/- 0.7, mean +/- SE) versus CON males (5.2 +/- 0.8; P = 0.04) and an even larger difference when only the consistent runners were kept in the analysis (2.7 +/- 0.5 in EX; P = 0.01)., Conclusion: Despite favorable changes in body composition, blood glucose, and leptin, 8 wk of running resulted in only minor changes related to polyp development in male but not female APCMin mice.

Unlabelled: Application of four loose ligatures to the sciatic nerve of a rat (chronic constriction injury [CCI]) induces clear hypersensitivity to non-noxious stimulation and chemical irritants. However, in this study, an injection of formalin in the hind paw of a rat with CCI-induced mononeuropathy resulted in an ipsilateral decreased flinching and licking or biting behavior in both phases of the formalin testing. The effect was independent of the formalin concentration used. This altered behavior was accompanied with smaller plasma levels of adrenocorticotrope hormone and corticosterone compared with sham and non-operated animals. Formalin injection in the contralateral nonligated hind paw of CCI rats also reduced the licking or biting behavior as compared with sham-operated and non-operated control animals only in the second phase of the formalin test. Thus, CCI reduces the pain reactivity and hypothalamic-pituitary-adrenal-axis activation to ipsilateral and contralateral formalin injection. Further research should investigate whether the decreased pain reactivity by CCI is situated at the peripheral, spinal, or supraspinal level or is result of changes in the stress reactivity and coping strategies., Implications: We evaluated the changes in the behavioral reactions and the hormonal effects of a noxious chemical stimulus, i.e., formalin injection in animals with previously induced chronic constriction injury to the sciatic nerve. The effect in animals injected at the ipsilateral and contralateral site, sham-operated and controls, were compared.

We tested the hypothesis that a decrease in the blood-to-tissue movement of albumin contributes to the recovery of plasma albumin and plasma volume after acute plasma protein depletion (plasmapheresis). Awake and unrestrained male Sprague-Dawley rats (220-320 g) fitted with jugular catheters were plasmapheresed, and plasma volume, plasma albumin, and total plasma protein content were measured at 1, 5, 24, and 48 h postplasmapheresis. Plasma volume recovered to baseline within 1 h (4.6 +/- 0.42 vs. 4.7 +/- 0.46 mL/100 g body weight (bw), remained at baseline from 5 h to 24 h but increased to 5.5 + 0.57 mL/100 g bw at 48 h (P < 0.05). Plasma albumin and total protein content recovered rapidly but remained below baseline levels at 1 h (10.05 +/- 0.98 vs. 12.33 +/- 1.29 and 19.75 +/- 1.75 vs. 24.73 +/- 2.56 mg/100 g bw, respectively). Plasma protein content retumed to baseline by 5 h of recovery. Tissue uptake of I125-labeled albumin decreased in the heart, skin, skeletal muscle, and small Intestines of plasmapheresed rats (P < 0.05). These data support the hypothesis that a reduction in albumin efflux from the vascular space contrlbutes to the recovery of plasma albumin and total protein content during plasma volume recovery and eventual expansion after plasmapheresis.

Background and Purpose: Maintenance of an adequate intravascular volume is important in the management of patients with subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the circulating blood volume (CBV) after SAH with the use of indocyanine green pulse spectrophotometry., Methods: CBV and plasma hormones related to stress and fluid regulation were measured 4 times: day 2 to 3, day 4 to 5, day 7 to 8, and day 14 in 50 consecutive patients with SAH surgically treated within 48 hours., Results: The mean value of CBV was 64 mL/kg on day 2 to 3, which gradually increased to 69 mL/kg on day 4 to 5, 71 mL/kg on day 7 to 8, and 70 mL/kg on day 14 (P=0.005) (control, 72 mL/kg). The clinical grades and plasma corticotropin levels were higher in patients with <60 mL/kg of CBV on day 2 to 3 (P<0.05 for both). There were no significant differences in other physiological and laboratory parameters such as time for surgery, estimated blood loss, levels of plasma noradrenaline, brain natriuretic peptide, serum sodium, and hematocrit. When CBV was decreased >10% of the former level, there were decreases in hematocrit (P<0.05), serum sodium (P<0.01), and serum albumin (P<0.05) and an increase in urinary sodium (P<0.05)., Conclusions: A significant reduction of CBV, especially in patients with poor clinical grades, was noted after SAH and early surgery, which could not be detected by routine examinations. Anemia, central salt wasting, and hypoalbuminemia may be related to a decrease in CBV from the former level. Indocyanine green pulse spectrophotometry may be a powerful tool for the management of patients with SAH.

Aims: To quantitatively determine the influence of estradiol on acinar cell apoptosis and chronic pancreatitis; assess its effects on infiltration of CD4 and CD8 T cells in the pancreas; investigate the role of testosterone on chronic pancreatitis in 20-week-old male WBN/Kob rats; and determine the impact of estradiol on proliferation of splenocytes derived from these animals in vitro., Methodology and Findings: Treatment with high (0.4 mg x kg x week) but not low (0.1 mg x kg x week) doses of estradiol for 10 weeks significantly decreased the number of apoptotic acinar cells stained with an anti-single strand DNA antibody, histologic scores, and pancreatic myeloperoxidase activity in 20-week-old WBN/Kob rats, in comparison with control values. The high doses also significantly attenuated the increase in pancreatic hydroxyproline content, an indicator of collagen deposition, at 20 weeks. They caused significant decreases in the numbers of CD4 and CD8 T cells infiltrating the pancreas. Both doses suppressed levels of testosterone but without any influence on the serum corticosterone concentrations. Androgen receptors could not be immunohistochemically identified in the pancreas at 20 weeks, and dietary treatment with flutamide, an androgen receptor antagonist, did not influence the chronic pancreatitis. Estradiol significantly reduced 1% phytohemagglutinin-induced incorporation of bromodeoxyuridine into the splenocytes in vitro., Conclusions: We conclude that estradiol dose-dependently attenuates acinar cell apoptosis and development of chronic pancreatitis, independent of any change in endogenous corticosterone and testosterone, by suppressing infiltration and function of T cells.

Objective: To evaluate peripheral joint laxity during pregnancy and to correlate changes with serum cortisol, estradiol, progesterone, and relaxin., Methods: Forty-six women with first-trimester singleton gestations consented to participate in this longitudinal observational study. Bilateral wrist laxity measurements (flexion-extension and medial-lateral deviation) were made using a clinical goniometer, and serum levels of cortisol, estradiol, progesterone, and relaxin were determined during each trimester of pregnancy and postpartum. Patients were also screened for subjective joint complaints. Statistical analysis included Student t test, analysis of variance, and linear regression analysis., Results: Eleven women (24%) were excluded from the study after spontaneous first-trimester pregnancy loss. Fifty-four percent (19 of 35) demonstrated increased laxity (10% or higher) in either wrist from the first to the third trimester. Although serum levels of cortisol, estradiol, progesterone, and relaxin were significantly elevated during pregnancy, no significant differences in these levels were noted between those who became lax during gestation and those who did not. Linear regression analysis of wrist joint laxity and level of serum estradiol, progesterone, and relaxin demonstrated no significant correlation. Wrist flexion-extension laxity, however, did significantly correlate with level of maternal cortisol (r = 0.18, P =.03). Fifty-seven percent of women developed subjective joint pain during pregnancy, which was not associated with increased joint laxity, but was associated with significantly increased levels of estradiol and progesterone., Conclusion: Peripheral joint laxity increases during pregnancy; however, these changes do not correlate well with maternal estradiol, progesterone, or relaxin levels.

Although the nitrogen-sparing properties of epidural block and i.v. glucose on the days after surgical trauma have been well established, their metabolic effects during the acute phase of the stress response remain unclear. Therefore, in this study we investigated the effect of epidural block on glucose and protein kinetics during and immediately after surgery in patients receiving i.v. glucose at 2 mg x kg(-1) x min(-1). Sixteen patients undergoing colorectal surgery received either general anesthesia with epidural block with bupivacaine (EDA; n = 8) or general anesthesia alone (control; n = 8). Glucose and protein kinetics were determined during and 2 h after the operation by stable isotope tracers [6,6-(2)H(2)]glucose and L-[1-(13)C]leucine. Plasma concentrations of glucose, insulin, cortisol, and glucagon were also determined. Epidural block attenuated the perioperative increase in plasma glucose concentration (P < 0.05). The rate of appearance of glucose (R(a) glucose) and endogenous glucose production (EGP) were slower in the EDA group than in control subjects during (R(a) glucose, EDA 13.2 +/- 1.0 versus control 15.3 +/- 1.8 micromol x kg(-1) x min(-1); P < 0.05; EGP, EDA 1.2 +/- 1.2 versus control 3.8 +/- 1.7 micromol x kg(-1) x min(-1); P < 0.05) and after the operation (P > 0.05). Whereas protein breakdown and amino acid oxidation decreased in both groups (P < 0.05), whole-body protein synthesis remained unchanged. Insulin levels increased with both anesthetic techniques (P < 0.05). Intraoperative plasma concentrations of cortisol and glucagon were smaller in the EDA group (P < 0.05). The intraoperative suppression of EGP by exogenous glucose was more pronounced in the presence of epidural block. However, epidural block failed to exert a protein-sparing effect during the acute phase of the stress response in patients receiving i.v. glucose.

Implications: This report concerns a case for which the intraoperative use of magnesium sulfate as an adjunct to the conventional use of nicardipine was effective for managing a pediatric patient with pheochromocytoma who was undergoing a laparoscopic operation.