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Background Early life adversity ( ELA) is a risk factor for development of gastrointestinal disorders later in life. The underlying mechanisms through which ELA and sex interact to influence disease susceptibility remains poorly understood. Methods Utilizing a porcine early weaning stress ( EWS) model to mimic ELA, we investigated the long-term effects of EWS on functional diarrhea, ileal permeability, mast cell activity and mast cell relationship with enteric ganglia. Key Results Juvenile and adult EWS pigs exhibited chronic, functional diarrhea ( EWS 43.6% vs late wean control( LWC) 4.8%, P<.0001), increased intestinal permeability (2 fold increase EWS vs LWC, P<.0001), and mast cell numbers (at 7 weeks and 20 weeks ~1.6 fold increase EWS vs LWC, P<.05). Compared with EWS male castrates (Male-C), females EWS pigs exhibited more frequent diarrhea (58.8% vs 29.9%, P=.0016), and increased intestinal permeability (1-2 fold higher in EWS females, P<.001). Increased mast cell numbers and their enhanced co-localization with neuronal ganglia were observed in both Male-C and female EWS pigs; however, female pigs exhibited greater release of mast cell tryptase upon activation with c48/80 (~1.5 fold increase, P<.05), compared with Male-C pigs. Conclusions and Inferences These data demonstrate that pigs exposed to ELA exhibit increased vulnerability to functional diarrhea, intestinal permeability and mast cell activity. Further, these studies also showed that EWS female and Male-C pigs exhibited dimorphic responses to EWS with female piglets exhibited greater susceptibility and severity of diarrhea, intestinal permeability and mast cell tryptase release. Together, these findings mimic some of the key pathophysiologic findings in human functional GI disorders functional gastrointestinal disorders ( FGIDs) suggesting that the EWS porcine model could be a valuable preclinical translational model for FGID research associated with ELA. [ABSTRACT FROM AUTHOR]

Background Early life adversity ( ELA) is a risk factor for the later-life onset of gastrointestinal ( GI) diseases such as irritable bowel syndrome ( IBS); however, the mechanisms are poorly understood. Here, we utilized a porcine model of ELA, early weaning stress ( EWS), to investigate the influence of ELA on the development and function of the enteric nervous system ( ENS). Methods Female and castrated male (Male-C) piglets were weaned from their sow either at 15 days of age ( EWS) or 28 days of age (late weaning control, LWC). At 60 and 170 days of age, ileal mucosa-submucosa preparations were mounted in Ussing chambers and veratridine- and corticotropin releasing factor (CRF)-releasing factor-evoked short circuit current ( Isc) responses were recorded as indices of secretomotor neuron function. Enteric neuron numbers and the expression of select neurotransmitters and their receptors were also measured. Key Results Compared with LWC pigs, female, but not Male-C EWS, pigs exhibited heightened veratridine-induced I sc responses at 60 and 170 days of age that were inhibited with tetrodotoxin and atropine. Ileum from EWS pigs had higher numbers of enteric neurons that were choline acetyltransferase positive. Markers of increased cholinergic signaling (increased acetylcholinesterase) and downregulated mucosal muscarinic receptor 3 gene expression were also observed in EWS pigs. Conclusions & Inferences This study demonstrated that EWS in pigs induces lasting and sex-specific hypersensitivity of secretomotor neuron function and upregulation of the cholinergic ENS. These findings may represent a mechanistic link between ELA and lifelong susceptibility to GI diseases such as IBS. [ABSTRACT FROM AUTHOR]

The present study examined whether a transient thyroid hormone (T4) deficit during infancy in male monkeys would compromise the arrest of luteinising hormone (LH) secretion during the infant–juvenile transition, and/or interfere with the pubertal resurgence of LH. Animals were orchidectomised and thyroidectomised (n = 3; Tx) or sham Tx (n = 3) within 5 days of birth. T4 replacement was initiated in two Tx monkeys at age 19 weeks to reestablish a euthyroid condition. Blood samples were drawn weekly for hormone assay. Body weight, crown–rump length, and bone age were assessed throughout the study. Within a week of Tx, plasma T4 declined to undetectable levels and, by 6–8 weeks of age, signs of hypothyroidism were evident. Transient hypothyroidism during infancy failed to prevent either arrest of LH secretion during the infant–juvenile transition or the pubertal resurgence of LH secretion, both of which occurred at similar ages to sham Tx animals. Although body weight exhibited complete catch-up with T4 replacement, crown–rump length and bone age did not. Thus, bone age at the time of the pubertal LH resurgence in Tx animals was less advanced than that in shams. Although Tx did not influence qualitatively the pattern of gonadotrophin secretion, LH levels during infancy and after pubertal LH resurgence were elevated in Tx monkeys. This was not associated with changes in LH pulse frequency and amplitude, but half-life (53 versus 65 min) of the slow second phase of LH clearance was greater in Tx animals. These results indicate that hypothalamic mechanisms dictating the pattern of gonadotrophin-releasing hormone release from birth to puberty are not dependent on T4 action during infancy, and fail to support the notion that onset of puberty is causally coupled to skeletal maturation. They also indicate that LH renal clearance mechanisms may be programmed in a T4 dependent manner during infancy. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the influence of thyroid status on the timing of the pubertal resurgence in gonadotrophin-releasing hormone pulse generator activity [tracked by circulating luteinising hormone (LH) levels] in male rhesus monkeys. Six juvenile monkeys were orchidectomised and then treated with the antithyroid drug, methimazole, from 15–19 months until 36 months of age, at which time thyroxine (T4) replacement was initiated. Four additional agonadal monkeys served as controls. Blood samples were drawn weekly for hormonal assessments. Body weight, crown–rump length and bone age were monitored at regular intervals. By 8 weeks of methimazole treatment, plasma T4 had fallen sharply, and the decline was associated with a plasma thyroid-stimulating hormone increase. In controls, plasma LH levels remained undetectable until the pubertal rise occurred at 29.3 ± 0.2 months of age. This developmental event occurred in only half of the methimazole-treated animals before 36 months of age when T4 replacement was initiated. The hypothyroid state was associated with a profound arrest of growth and bone maturation, but increased body mass indices and plasma leptin levels. T4 replacement in methimazole-treated monkeys was associated with the pubertal rise in LH in the remaining three animals and accelerated somatic development in all six animals. Although pubertal resurgence in LH secretion occurred at a later chronological age in methimazole-treated animals compared to controls, bone age, crown–rump length and body weight at that time did not differ between groups. There were no long-term differences in plasma prolactin between groups. We conclude that juvenile hypothyroidism in male primates causes a marked delay in the pubertal resurgence of LH secretion, probably occasioned at the hypothalamic level. Whether this effect is meditated by an action of thyroid hormone directly on the hypothalamus or indirectly as a result of the concomitant deficit in somatic development remains to be determined. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia is a risk factor for ischemic stroke. We investigated five functional polymorphisms involved in homocysteine metabolism in each 159 stroke patients and controls. The folate-sensitive polymorphism methylenetetrahydrofolate reductase (MTHFR) c. 677 C > T (A222V) referred a non-significant risk of ischemic stroke (odds ratio: 1.20) in all patients, and homozygosity for MTHFR c. 677 C > T was associated with an earlier onset of stroke selectively in patients younger than 60 years (38 ± 3 years vs. 45 ± 1 years; P = 0.043). This study suggests that the investigated polymorphisms are no major risk factors for stroke, although MTHFR c. 677 C > T could be a minor factor of vulnerability especially in young patients (TT genotype), which might be helpful for the clinical work-up of stroke cases and for preventive dietary strategies. [ABSTRACT FROM AUTHOR]

An enzyme-linked immunosorbent assay (ELISA) for human urinary beta follicle-stimulating hormone (FSH) subunit was validated for use in the laboratory macaque (Macaca mulatta and Macaca fasicularis ). This ELISA is based on the dissociation of the FSH heterodimer in urine and the subsequent measurement of the beta subunit as a representation of total urinary FSH. This assay was then used to describe the gonadotropin escape following ovarian senescence in post-menopausal macaques. In addition, the assay was used to observe the impact of an acute stressor on the pituitary-gonadal axis and how the impact of this stressor varies when experienced at different stages of the menstrual cycle. The study design involved the measurement of ovarian steroids and FSH in urine collected daily during a period of time when animals experienced a well-defined event on two occasions consisting of capture, restraint, and anesthesia. This unique study design was made possible by the ability to monitor both ovarian and pituitary function in the absence of confounding daily captures and restraint for blood collection. There was a high correlation between urinary FSH measured in macaques with the beta FSH subunit ELISA and serum FSH measured in paired blood samples by radioimmunoassay (n=39, r[sup 2] =0.878, P <0.001) and the composite urinary FSH profile obtained from normal, pre-menopausal macaques exhibited the expected dynamics with a transient rise of FSH during the luteal-follicular transition as well as an acute rise of FSH at mid-cycle. This pattern was lost in castrate and post-menopausal monkeys in which FSH levels were significantly increased (P <0.0001) above those of intact males and young females, respectively. In the stress study, we found that stressors occurring during the luteal-follicular transition not only resulted in acute perturbations of FSH but also led to abnormalities in the subsequent menstrual cycle in 50% of the cases. Am. J. Primatol. 48:135–151, 1999. © 1999 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Gender-related differences in spatial abilities favouring males are well established but have also generated a great deal of controversy. Cross-cultural research, meta-analyses and training studies could show the influence of socio-cultural and experiential factors on spatial-test performance. However, little is known about how experiences and gender-role stereotypes mediate performance differences in this area., Aim: The relationship between specific experiences (spatial activities, computer experience), achievement-related attitudes, and spatial abilities, i.e., mental-rotation ability was investigated with males and females in different academic subgroups., Sample: The sample comprised 112 female and 71 male undergraduates, majoring in arts, humanities and social sciences, sports, psychology and computational visualistics., Methods: A redrawn version of the Vandenberg and Kuse Mental Rotations Test (MRT) was administered and the participants completed a questionnaire about their spatial activities, computer experience, self-ratings regarding everyday spatial abilities, and attitudes towards mathematics and physics., Results: Mental Rotations Test performance was mainly affected by academic programme and gender, but the effect size of gender differences varied. It was largest with students majoring in arts, humanities and social sciences and smallest with those majoring in computational visualistics. Data analyses revealed statistically significant correlations with spatial activities and computer experience only for females. The relationship between test performance and scales of achievement-related self-concept also depended on gender., Conclusions: Compared to males, females' spatial abilities are extremely vulnerable to and thus modifiable through attitudinal and experiential factors. This has considerable consequences for intervention programmes that could help to overcome the gender gap in spatial abilities.

Objective: To evaluate the feasibility of flow determinations by contrast replenishment using harmonic power Doppler imaging (H-PDI)., Background: The application of indicator dilution principles on contrast echocardiography is limited by numerous methodical problems. Recently, a new method was introduced that relies on ultrasound-mediated microbubble destruction and evaluation of the contrast replenishment., Methods: Definity, a perfluorocarbon-derived contrast agent under development, was continuously infused into a steady flow phantom and H-PDI registrations were performed within a silicone tube (d = 8 mm). Replenishment interval between destruction and imaging frame was varied from 0.04-2 seconds. Nonlinear curve fitting was performed using an exponential mathematical model., Results: Strong linear correlation between contrast dose and maximum signal intensity as well as between flow and the slope variable beta of the replenishment curve was found for all settings (r > 0.96). Maximum signal intensity and contrast replenishment rate were found to be a function of emission power and were significantly influenced by depth and focus position., Conclusion: The feasibility of flow assessment using replenishment curves obtained by H-PDI was demonstrated. However, in experimental conditions, flow analysis was severely influenced by ultrasound system settings and imaging conditions such as emission power, sound field geometry, and investigation depth. For a clinical use of this promising approach, algorithms that take specific system settings and imaging conditions into account have to be found. Imaging modalities that enable a most homogeneous scan field are best suited for the assessment of contrast replenishment.

Hyperlipidaemia and hyperglycaemia are major risk factors for cardiovascular disease. In recent years, some evidence has been presented that periodontal disease is associated with an increased risk of cardiovascular disease. To further elucidate this association, we have studied standard blood chemistry variables known as risk markers for cardiovascular disease in periodontally diseased and healthy subjects. We have measured levels of plasma lipids and fasting blood glucose in 39 subjects with moderate periodontal disease (age 50-60 years) and compared the results with those obtained in 40 age- and sex-matched controls. Both groups were systemically healthy according to their medical history. Total cholesterol, low density lipoprotein cholesterol and triglycerides were significantly higher in periodontally diseased subjects by about 8% (p<0.03), 13% (p<0.003) and 39% (p<0.001), respectively, when compared to controls. Although subjects with diabetes were excluded from the study, we found significantly higher blood glucose levels in the patient than in the control group (85 +/- 25 versus 73 +/- 17 mg/dl; p<0.02). There was also a significantly higher frequency of pathological plasma lipid profiles in the patient than in the control group. The results indicate that hyperlipaemia and pre-diabetes may be associated with periodontal disease in systemically healthy subjects. These data do not allow us to decide, whether periodontal disease causes an increase in hyperlipaemia and in a prediabetic state or whether periodontal disease and cardiovascular disease share hyperlipidaemia and the prediabetic state as common risk factors.

Background: Harmonic power Doppler imaging (H-PDI) has been introduced into the field of contrast echocardiography as a contrast-specific imaging modality. However, there has been considerable skepticism as to whether H-PDI would be quantifiable, because it depends on the destruction of microbubbles and has more complex signal processing than gray scale imaging. The aim of the present study was to evaluate the relationship between the concentration of microbubbles and the resulting H-PDI signals even under conditions where bubble destruction is most likely. Furthermore, we evaluated whether microbubbles of Levovist freely pass the microcirculation, which is a prerequisite for the assessment of myocardial blood flow., Methods and Results: A strong positive correlation was found between the H-PDI signals and the amount of microbubbles up to the onset of acoustic shadowing (r = 0. 968, P<0.001). Time-intensity curves for H-PDI of air-filled microbubbles were compared with time-concentration curves of indocyanine green (ICG) in both a flow phantom and a working heart setup. The mean transit times (MTTs) through the myocardium of both agents were compared after a bolus injection into the left coronary artery. A close correlation was observed between 1/MTT and flow in both setups (r>0.98, P<0.0001). However, at high flow rates, the MTTs of the microbubbles were slightly, albeit not significantly, faster than those of indocyanine green., Conclusions: We conclude that microbubbles fulfill the prerequisites of free flowing tracers through the myocardium. Furthermore, H-PDI technology allows a reliable assessment of time-concentration curves of air-filled microbubbles up to the onset of acoustic shadowing.

Power pulse inversion (PPI) has been developed for echocontrast specific imaging in order to reduce destruction of microbubbles. The purpose of this study was to evaluate PPI for real-time contrast echocardiography. Therefore, in vitro studies in a physiological flow-phantom and clinical examinations in patients with coronary artery disease were performed. The in vitro rersults of this study indicate that PPI allows real-time imaging at low emission power and is almost nondestructive to contrast microbubbles of Definity. At this low emission power a strong linear relationship between the dosage of the contrast agent and the resulting PPI signal intensity was found (R = 0.998, p < 0.001). In the clinical examinations real-time imaging using low mechanical index PPI resulted in strong myocardial signals and a complete filling of the cavities indicating absence of bubble destruction. Most striking was the ability of PPI to display myocardial thickening and wall motion simultaneously with the assessment of myocardial contrast replenishment following ultrasound induced bubble destruction by high power frames. We conclude that PPI allows nondestructive contrast imaging both in experimental and clinical settings. Therefore, real-time imaging of myocardial perfusion and real-time assessment of contrast replenishment following ultrasound induced destruction of microbubbles is feasible. Moreover, PPI allows simultaneous assessment of perfusion and myocardial function.

BACKGROUND AND METHODS: For years, tissue has been assumed to be a linear medium in diagnostic ultrasound applications; thus, no backscattered signals in the second harmonic band are expected in harmonic imaging without the injection of a contrast agent. However, it has been shown that a useful tissue image is formed even without a contrast agent. The aim of this study was to evaluate whether this tissue harmonic image provided improved visualization of endocardial borders. Fifty-six adult patients with various heart diseases were investigated using conventional two-dimensional echocardiography and tissue harmonic imaging. In 30 of these patients, the left ventricular endocardial borders were well defined in the standard parasternal and apical views using conventional two-dimensional echocardiography. In the remaining 26 patients, delineation of endocardial borders was not possible in at least two segments. The equipment used was an ATL HDI-3000 diagnostic system equipped with harmonic imaging. RESULTS: In all 56 patients, the myocardium and valves could be imaged with tissue harmonic imaging. Harmonic recordings were sharper and contained fewer clutter artifacts than conventional recordings. Most striking was the enhancement of left ventricular endocardial borders. In the 26 patients with incomplete delineation of left ventricular endocardial borders, wall motion could be evaluated in 290 of 312 (93%) segments with tissue harmonic imaging compared with only 168 of 312 (54%) segments with conventional echocardiography (P < 0.001). CONCLUSIONS: Tissue harmonic imaging improves image quality and can be used to enhance the definition of left ventricular endocardial borders. These findings can be explained by the nonlinear propagation of ultrasound within the tissue, which results in distortion of the transmitted signal and, thus, harmonic generation.

The nonethanol congeners of bourbon have been found to possess estrogenic activity when tested using an in vivo oophorectomized rat bioassay, as well as an in vivo estrogen receptor assay system. The phytoestrogen, biochanin A, as well as the plant sterol, beta-sitosterol, were identified in the bourbon preparation using gas chromatography/mass spectrometry. These findings, using three methodological approaches, demonstrate that bourbon contains at least one biologically active phytoestrogen and suggest that the effects of alcoholic beverage use or abuse, particularly as they relate to endocrine systems, should not be viewed as resulting solely from exposure to ethanol.